List of Nobel laureates in Physiology or Medicine
1901: Emil von Behring
1902: Ronald Ross
1903: Niels Ryberg Finsen
1904: Ivan Pavlov
1905: Robert Koch
1906: Camillo Golgi / Santiago Ramón y Cajal
1907: Alphonse Laveran
1908: Ilya Mechnikov / Paul Ehrlich
1909: Theodor Kocher
1910: Albrecht Kossel
1911: Allvar Gullstrand
1912: Alexis Carrel
1913: Robert Bárány
1914: no award
1915: no award
1916: no award
1917: no award
1918: no award
1919: Jules Bordet
1920: August Krogh
1921: no award
1922: Archibald Vivian Hill / Otto Meyerhof
1923: Frederick G. Banting / John James Richard Macleod
1924: Willem Einthoven
1925: no award
1926: Johannes Fibiger
1927: Julius Wagner-Jauregg
1928: Charles Nicolle
1929: Christiaan Eijkman / Sir Frederick Hopkins
1930: Karl Landsteiner
1931: Otto Heinrich Warburg
1932: Sir Charles Sherrington / Edgar Adrian
1933: Thomas H. Morgan
1934: George H. Whipple / George R. Minot / William P. Murphy
1935: Hans Spemann
1936: Sir Henry Dale / Otto Loewi
1937: Albert Szent-Györgyi
1938: Corneille Heymans
1939: Gerhard Domagk
1940: no award
1941: no award
1942: no award
1943: Henrik Dam / Edward A. Doisy
1944: Joseph Erlanger / Herbert S. Gasser
1945: Sir Alexander Fleming / Ernst B. Chain / Sir Howard Florey
1946: Hermann J. Muller
1947: Carl Cori / Gerty Cori / Bernardo Houssay
1948: Paul Müller
1949: Walter Hess / Egas Moniz
1950: Edward C. Kendall / Tadeus Reichstein / Philip S. Hench
1951: Max Theiler
1952: Selman A. Waksman
1953: Hans Krebs / Fritz Lipmann
1954: John Franklin Enders / Thomas Huckle Weller / Frederick Chapman Robbins
1955: Hugo Theorell
1956: André F. Cournand / Werner Forssmann / Dickinson W. Richards
1957: Daniel Bovet
1958: George Beadle / Edward Tatum / Joshua Lederberg
1959: Severo Ochoa / Arthur Kornberg
1960: Frank Macfarlane Burnet / Peter Medawar
1961: Georg von Békésy
1962: Francis Crick / James D. Watson / Maurice Wilkins
1963: Sir John Eccles / Alan L. Hodgkin / Andrew Huxley
1964: Konrad Bloch / Feodor Lynen
1965: François Jacob / André Lwoff / Jacques Monod
1966: Peyton Rous / Charles B. Huggins
1967: Ragnar Granit / Haldan K. Hartline / George Wald
1968: Robert W. Holley / H. Gobind Khorana / Marshall W. Nirenberg
1969: Max Delbrück / Alfred D. Hershey / Salvador E. Luria
1970: Sir Bernard Katz / Ulf von Euler / Julius Axelrod
1971: Earl W. Sutherland, Jr.
1972: Gerald M. Edelman / Rodney R. Porter
1973: Karl von Frisch / Konrad Lorenz / Nikolaas Tinbergen
1974: Albert Claude / Christian de Duve / George E. Palade
1975: David Baltimore / Renato Dulbecco / Howard M. Temin
1976: Baruch S. Blumberg / D. Carleton Gajdusek
1977: Roger Guillemin / Andrew V. Schally / Rosalyn Yalow
1978: Werner Arber / Daniel Nathans / Hamilton O. Smith
1979: Allan M. Cormack / Godfrey N. Hounsfield
1980: Baruj Benacerraf / Jean Dausset / George D. Snell
1981: Roger W. Sperry / David H. Hubel / Torsten N. Wiesel
1982: Sune K. Bergström / Bengt I. Samuelsson / John R. Vane
1983: Barbara McClintock
1984: Niels K. Jerne / Georges J.F. Köhler / César Milstein
1985: Michael S. Brown / Joseph L. Goldstein
1986: Stanley Cohen / Rita Levi-Montalcini
1987: Susumu Tonegawa
1988: James W. Black / Gertrude B. Elion / George H. Hitchings
1989: J. Michael Bishop / Harold E. Varmus
1990: Joseph E. Murray / E. Donnall Thomas
1991: Erwin Neher / Bert Sakmann
1992: Edmond H. Fischer / Edwin G. Krebs
1993: Richard J. Roberts / Phillip A. Sharp
1994: Alfred G. Gilman / Martin Rodbell
1995: Edward B. Lewis / Christiane Nüsslein-Volhard / Eric F. Wieschaus
1996: Peter C. Doherty / Rolf M. Zinkernagel
1997: Stanley B. Prusiner
1998: Robert F. Furchgott / Louis J. Ignarro / Ferid Murad
1999: Günter Blobel
2000: Arvid Carlsson / Paul Greengard / Eric R. Kandel
2001: Leland H. Hartwell / Tim Hunt / Sir Paul Nurse
2002: Sydney Brenner / H. Robert Horvitz / John E. Sulston
2003: Paul C. Lauterbur / Peter Mansfield
2004: Richard Axel / Linda B. Buck
2005: Barry J. Marshall / J. Robin Warren
2006: Andrew Z. Fire / Craig C. Mello
2007: Mario Capecchi / Martin Evans / Oliver Smithies
2008: Harald zur Hausen / Françoise Barré-Sinoussi / Luc Montagnier
Physics
1901: Wilhelm Conrad Röntgen
1902: Hendrik A. Lorentz / Pieter Zeeman
1903: Henri Becquerel / Pierre Curie / Marie Sklodowska-Curie
1904: Lord Rayleigh
1905: Philipp Lenard
1906: J.J. Thomson
1907: Albert A. Michelson
1908: Gabriel Lippmann
1909: Guglielmo Marconi / Ferdinand Braun
1910: Johannes Diderik van der Waals
1911: Wilhelm Wien
1912: Gustaf Dalén
1913: Heike Kamerlingh Onnes
1914: Max von Laue
1915: William Henry Bragg / William Lawrence Bragg
1916: no award
1917: Charles Glover Barkla
1918: Max Planck
1919: Johannes Stark
1920: Charles Edouard Guillaume
1921: Albert Einstein
1922: Niels Bohr
1923: Robert A. Millikan
1924: Manne Siegbahn
1925: James Franck / Gustav Hertz
1926: Jean Baptiste Perrin
1927: Arthur H. Compton / C.T.R. Wilson
1928: Owen Willans Richardson
1929: Louis de Broglie
1930: Venkata Raman
1931: no award
1932: Werner Heisenberg
1933: Erwin Schrödinger / Paul A.M. Dirac
1934: no award
1935: James Chadwick
1936: Victor F. Hess / Carl D. Anderson
1937: Clinton Davisson / George Paget Thomson
1938: Enrico Fermi
1939: Ernest Lawrence
1940: no award
1941: no award
1942: no award
1943: Otto Stern
1944: Isidor Isaac Rabi
1945: Wolfgang Pauli
1946: Percy W. Bridgman
1947: Edward V. Appleton
1948: Patrick M.S. Blackett
1949: Hideki Yukawa
1950: Cecil Powell
1951: John Cockcroft / Ernest T.S. Walton
1952: Felix Bloch / E. M. Purcell
1953: Frits Zernike
1954: Max Born / Walther Bothe
1955: Willis E. Lamb / Polykarp Kusch
1956: William B. Shockley / John Bardeen / Walter H. Brattain
1957: Chen Ning Yang / Tsung-Dao Lee
1958: Pavel A. Cherenkov / Il´ja M. Frank / Igor Y. Tamm
1959: Emilio Segrè / Owen Chamberlain
1960: Donald A. Glaser
1961: Robert Hofstadter / Rudolf Mössbauer
1962: Lev Landau
1963: Eugene Wigner / Maria Goeppert-Mayer / J. Hans D. Jensen
1964: Charles H. Townes / Nicolay G. Basov / Aleksandr M. Prokhorov
1965: Sin-Itiro Tomonaga / Julian Schwinger / Richard P. Feynman
1966: Alfred Kastler
1967: Hans Bethe
1968: Luis Alvarez
1969: Murray Gell-Mann
1970: Hannes Alfvén / Louis Néel
1971: Dennis Gabor
1972: John Bardeen / Leon Neil Cooper / Robert Schrieffer
1973: Leo Esaki / Ivar Giaever / Brian D. Josephson
1974: Martin Ryle / Antony Hewish
1975: Aage N. Bohr / Ben R. Mottelson / James Rainwater
1976: Burton Richter / Samuel C.C. Ting
1977: Philip W. Anderson / Sir Nevill F. Mott / John H. van Vleck
1978: Pyotr Kapitsa / Arno Penzias / Robert Woodrow Wilson
1979: Sheldon Glashow / Abdus Salam / Steven Weinberg
1980: James Cronin / Val Fitch
1981: Nicolaas Bloembergen / Arthur L. Schawlow / Kai M. Siegbahn
1982: Kenneth G. Wilson
1983: Subramanyan Chandrasekhar / William A. Fowler
1984: Carlo Rubbia / Simon van der Meer
1985: Klaus von Klitzing
1986: Ernst Ruska / Gerd Binnig / Heinrich Rohrer
1987: J. Georg Bednorz / K. Alex Müller
1988: Leon M. Lederman / Melvin Schwartz / Jack Steinberger
1989: Norman F. Ramsey / Hans G. Dehmelt / Wolfgang Paul
1990: Jerome I. Friedman / Henry W. Kendall / Richard E. Taylor
1991: Pierre-Gilles de Gennes
1992: Georges Charpak
1993: Russell A. Hulse / Joseph H. Taylor, Jr.
1994: Bertram N. Brockhouse / Clifford G. Shull
1995: Martin L. Perl / Frederick Reines
1996: David M. Lee / Douglas D. Osheroff / Robert Coleman Richardson
1997: Steven Chu / Claude Cohen-Tannoudji / William D. Phillips
1998: Robert B. Laughlin / Horst L. Störmer / Daniel C. Tsui
1999: Gerardus 't Hooft / Martinus J.G. Veltman
2000: Zhores I. Alferov / Herbert Kroemer / Jack S. Kilby
2001: Eric A. Cornell / Wolfgang Ketterle / Carl E. Wieman
2002: Raymond Davis, Jr. / Masatoshi Koshiba / Riccardo Giacconi
2003: Alexei A. Abrikosov / Vitaly L. Ginzburg / Anthony J. Leggett
2004: David J. Gross / H. David Politzer / Frank Wilczek /
2005: Roy J. Glauber / John L. Hall / Theodor W. Hänsch
2006: John C. Mather / George F. Smoot
2007: Albert Fert / Peter Grünberg
2008: Yoichiro Nambu / Makoto Kobayashi / Toshihide Maskawa
Chemistry.
1901: Jacobus H. van 't Hoff
1902: Emil Fischer
1903: Svante Arrhenius
1904: Sir William Ramsay
1905: Adolf von Baeyer
1906: Henri Moissan
1907: Eduard Buchner
1908: Ernest Rutherford
1909: Wilhelm Ostwald
1910: Otto Wallach
1911: Marie Skłodowska-Curie
1912: Victor Grignard / Paul Sabatier
1913: Alfred Werner
1914: Theodore William Richards
1915: Richard Willstätter
1916: no award
1917: no award
1918: Fritz Haber
1919: no award
1920: Walther Nernst
1921: Frederick Soddy
1922: Francis W. Aston
1923: Fritz Pregl
1924: no award
1925: Richard Zsigmondy
1926: The Svedberg
1927: Heinrich Wieland
1928: Adolf Windaus
1929: Arthur Harden / Hans von Euler-Chelpin
1930: Hans Fischer
1931: Carl Bosch / Friedrich Bergius
1932: Irving Langmuir
1933: no award
1934: Harold C. Urey
1935: Frédéric Joliot-Curie / Irène Joliot-Curie
1936: Peter Debye
1937: Norman Haworth / Paul Karrer
1938: Richard Kuhn
1939: Adolf Butenandt / Leopold Ruzicka
1940: no award
1941: no award
1942: no award
1943: George de Hevesy
1944: Otto Hahn
1945: Artturi Virtanen
1946: James B. Sumner / John H. Northrop / Wendell M. Stanley
1947: Sir Robert Robinson
1948: Arne Wilhelm Kaurin Tiselius
1949: William F. Giauque
1950: Otto Diels / Kurt Alder
1951: Edwin M. McMillan / Glenn T. Seaborg
1952: Archer J.P. Martin / Richard L.M. Synge
1953: Hermann Staudinger
1954: Linus Pauling
1955: Vincent du Vigneaud
1956: Sir Cyril Hinshelwood / Nikolay Semenov
1957: Lord Todd
1958: Frederick Sanger
1959: Jaroslav Heyrovský
1960: Willard F. Libby
1961: Melvin Calvin
1962: Max F. Perutz / John C. Kendrew
1963: Karl Ziegler / Giulio Natta
1964: Dorothy Crowfoot Hodgkin
1965: Robert Burns Woodward
1966: Robert S. Mulliken
1967: Manfred Eigen / Ronald G.W. Norrish / George Porter
1968: Lars Onsager
1969: Derek Barton / Odd Hassel
1970: Luis Leloir
1971: Gerhard Herzberg
1972: Christian Anfinsen / Stanford Moore / William H. Stein
1973: Ernst Otto Fischer / Geoffrey Wilkinson
1974: Paul J. Flory
1975: John Cornforth / Vladimir Prelog
1976: William Lipscomb
1977: Ilya Prigogine
1978: Peter Mitchell
1979: Herbert C. Brown / Georg Wittig
1980: Paul Berg / Walter Gilbert / Frederick Sanger
1981: Kenichi Fukui / Roald Hoffmann
1982: Aaron Klug
1983: Henry Taube
1984: Bruce Merrifield
1985: Herbert A. Hauptman / Jerome Karle
1986: Dudley R. Herschbach / Yuan T. Lee / John C. Polanyi
1987: Donald J. Cram / Jean-Marie Lehn / Charles J. Pedersen
1988: Johann Deisenhofer / Robert Huber / Hartmut Michel
1989: Sidney Altman / Thomas R. Cech
1990: Elias James Corey
1991: Richard R. Ernst
1992: Rudolph A. Marcus
1993: Kary B. Mullis / Michael Smith
1994: George A. Olah
1995: Paul J. Crutzen / Mario J. Molina / F. Sherwood Rowland
1996: Robert F. Curl, Jr. / Sir Harold Kroto / Richard E. Smalley
1997: Paul D. Boyer / John E. Walker / Jens C. Skou
1998: Walter Kohn / John Pople
1999: Ahmed Zewail
2000: Alan Heeger / Alan G. MacDiarmid / Hideki Shirakawa
2001: William S. Knowles / Ryoji Noyori / K. Barry Sharpless
2002: John B. Fenn / Koichi Tanaka / Kurt Wüthrich
2003: Peter Agre / Roderick MacKinnon
2004: Aaron Ciechanover / Avram Hershko / Irwin Rose
2005: Robert Grubbs / Richard Schrock / Yves Chauvin
2006: Roger D. Kornberg
2007: Gerhard Ertl
2008: Osamu Shimomura / Martin Chalfie / Roger Y. Tsien
Courtesy : wikipedia
Friday, November 7, 2008
The Nobel Prize in Physiology or Medicine 2008
The Nobel Prize in Physiology or Medicine 2008
1)Harald zur Hausen , "for his discovery of human papilloma viruses causing cervical cancer"
Françoise Barré-Sinoussi & Luc Montagnier , for their discovery of human immunodeficiency virus"
1)Harald zur Hausen , "for his discovery of human papilloma viruses causing cervical cancer"
Françoise Barré-Sinoussi & Luc Montagnier , for their discovery of human immunodeficiency virus"
Endocrine glands
Endocrine glands
Endocrine glands are glands that secrete their product (hormones) directly into the blood rather than through a duct. This group contains the glands of the Endocrine system.
Chemistry
1. Most hormones are steroids or amino acid based.
2. Hormones alter cell activity by stimulating or inhibiting characteristic cellular processes of their target cells.
3. Cell responses to hormone stimulation may involve changes in membrane permeability; enzyme synthesis, activation, or inhibition; secretory activity; gene activation; and mitosis.
4. Second-messenger mechanisms employing intracellular messengers and transduced by G proteins are a common means by which amino acid–based hormones interact with their target cells. In the cyclic AMP system, the hormone binds to a plasma membrane receptor that couples to a G protein. When the G protein is activated it, in turn, couples to adenylate cyclase, which catalyzes the synthesis of cyclic AMP from ATP. Cyclic AMP initiates reactions that activate protein kinases and other enzymes, leading to cellular response. The PIP-calcium signal mechanism, involving phosphatidyl inositol, is another important second-messenger system. Other second messengers are cyclic GMP and calcium.
5. Steroid hormones (and thyroid hormone) enter their target cells and effect responses by activating DNA, which initiates messenger RNA formation leading to protein synthesis. Target Cell Specificity
6. The ability of a target cell to respond to a hormone depends on the presence of receptors, within the cell or on its plasma membrane, to which the hormone can bind.
7. Hormone receptors are dynamic structures. Changes in number and sensitivity of hormone receptors may occur in response to high or low levels of stimulating hormones.
8. Blood levels of hormones reflect a balance between secretion and degradation/excretion. The liver and kidneys are the major organs that degrade hormones; breakdown products are excreted in urine and feces.
9. Hormone half-life and duration of activity are limited and vary from hormone to hormone.
Interaction of Hormones at Target Cells
10. Permissiveness is the situation in which a hormone cannot exert its full effects without the presence of another hormone.
11. Synergism occurs when two or more hormones produce the same effects in a target cell and their results are amplified.
12. Antagonism occurs when a hormone opposes or reverses the effect of another hormone.
Control of Hormone Release
13. Endocrine organs are activated to release their hormones by humoral, neural, or hormonal stimuli. Negative feedback is important in regulating hormone levels in the blood.
14. The nervous system, acting through hypothalamic controls, can in certain cases override or modulate hormonal effects.
Table of endocrine glands and secreted hormones
Hypothalamus
Secreted hormone
Abbreviation
From cells
Effect
Thyrotropin-releasing hormone
TRH
Parvocellular neurosecretory neurons
Release thyroid-stimulating hormone from anterior pituitary (primarily)Stimulate prolactin release from anterior pituitary.
Gonadotropin-releasing hormone
GnRH
Neuroendocine cells of the Preoptic area
Release of FSH and LH from anterior pituitary.
Growth hormone-releasing hormone
GHRH
Neuroendocrine neurons of the Arcuate nucleus
Release GH from anterior pituitary
Corticotropin-releasing hormone
CRH
Parvocellular neurosecretory neurons
Release ACTH from anterior pituitary
Vasopressin
Parvocellular neurosecretory neurons
Increases permeability of distal convoluted tubule and collecting duct to water in the nephrons of the kidney, thus increasing water reabsorbiton.
Somatostatin, also growth hormone-inhibiting hormone
SS or GHIH
Neuroendocrince cells of the Periventricular nucleus
Inhibit release of GH and TSH from anterior pituitary
Prolactin inhibiting hormone or Dopamine
PIH or DA
Dopamine neurons of the arcuate nucleus
Inhibit release of prolactin and TSH from anterior pituitary
Prolactin-releasing hormone
PRH
Release prolactin from anterior pituitary
Pineal body
Secreted hormone
From cells
Effect
Melatonin (Primarily)
Pinealocytes
antioxidant and causes drowsiness
Pituitary gland (hypophysis)
Anterior pituitary lobe (adenohypophysis)
Secreted hormone
From cells
Effect
Growth hormone
Somatotropes
stimulates growth and cell reproduction
Release Insulin-like growth factor 1 from liver
Prolactin
Lactotropes
milk production in mammary glandssexual gratification after sexual acts
Adrenocorticotropic hormone or corticotropin
Corticotropes
synthesis of corticosteroids (glucocorticoids and androgens) in adrenocortical cells
Lipotropin
Corticotropes
lipolysis and steroidogenesis,stimulates melanocytes to produce melanin
Thyroid-stimulating hormone or thyrotropin
Thyrotropes
stimulates thyroid gland to secrete thyroxine (T4) and triiodothyronine (T3)
Follicle-stimulating hormone
Gonadotropes
In female: stimulates maturation of Graafian follicles in ovary.
In male: spermatogenesis, enhances production of androgen-binding protein by the Sertoli cells of the testes
Luteinizing hormone
Gonadotropes
In female: ovulation
In male: stimulates Leydig cell production of testosterone
Posterior pituitary lobe (neurohypophysis)
Secreted hormone
From cells
Effect
Oxytocin
Magnocellular neurosecretory cells
Contraction of cervix and vagina
Involved in orgasm, trust between people.and circadian homeostasis (body temperature, activity level, wakefulness) release breast milk
Vasopressin or antidiuretic hormone
Magnocellular neurosecretory cells
retention of water in kidneys
moderate vasoconstriction
Oxytocin and Anti-Diuretic Hormone are not secreted in the posterior lobe, merely stored.
Intermediate pituitary lobe (pars intermedia)
Secreted hormone
From cells
Effect
Melanocyte-stimulating hormone
Melanotroph
melanogenesis by melanocytes in skin and hair.
Thyroid
Secreted hormone
From cells
Effect
Triiodothyronine
Thyroid epithelial cell
potent form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines,
affect protein synthesis
Thyroxine or tetraiodothyronine
Thyroid epithelial cells
less active form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines,
affect protein synthesis, often functions as a prohormone
Calcitonin
Parafollicular cells
Construct bone
reduce blood Ca2+
Parathyroid
Secreted hormone
From cells
Effect
Parathyroid hormone
Parathyroid chief cell
increase blood Ca2+: *indirectly stimulate osteoclasts
Ca2+ reabsorption in kidney
activate vitamin D
(Slightly) decrease blood phosphate:
(decreased reuptake in kidney but increased uptake from bones
activate vitamin D)
Heart
Secreted hormone
From cells
Effect
Atrial-natriuretic peptide
Cardiac myocytes
Reduce blood pressure by:
reducing systemic vascular resistance, reducing blood water, sodium and fats
Brain natriuretic peptide
Cardiac myocytes
(To a minor degree than ANP) reduce blood pressure by:
reducing systemic vascular resistance, reducing blood water, sodium and fats
Striated muscle
Secreted hormone
From cells
Effect
Thrombopoietin
Myocytes
stimulates megakaryocytes to produce platelets
Skin
Secreted hormone
Effect
Calcidiol (25-hydroxyvitamin D3)
Inactive form of Vitamin D3
Adipose tissue
Secreted hormone
From cells
Effect
Leptin (Primarily)
Adipocytes
decrease of appetite and increase of metabolism.
Estrogens(mainly Estrone)
Adipocytes
Stomach
Secreted hormone
From cells
Effect
Gastrin(Primarily)
G cells
Secretion of gastric acid by parietal cells
Ghrelin
P/D1 cells
Stimulate appetite,
secretion of growth hormone from anterior pituitary gland
Neuropeptide Y
increased food intake and decreased physical activity
Secretin
S cells
Secretion of bicarbonate from liver, pancreas and duodenal Brunner's glands
Enhances effects of cholecystokinin Stops production of gastric juice
Somatostatin
D cells
Suppress release of gastrin, cholecystokinin (CCK), secretin, motilin, vasoactive intestinal peptide(VIP), gastric inhibitory polypeptide(GIP), enteroglucagon
Lowers rate of gastric emptying Reduces smooth muscle contractions and blood flow within the intestine
Histamine
ECL cells
stimulate gastric acid secretion
Endothelin
X cells
Smooth muscle contraction of stomach
Duodenum
Secreted hormone
From cells
Effect
Cholecystokinin
I cells
Release of digestive enzymes from pancreas
Release of bile from gallbladder, hunger suppressant
Liver
Secreted hormone
From cells
Effect
Insulin-like growth factor (or somatomedin) (Primarily)
Hepatocytes
insulin-like effects
regulate cell growth and development
Angiotensinogen and angiotensin
Hepatocytes
vasoconstriction
release of aldosterone from adrenal cortex dipsogen.
Thrombopoietin
Hepatocytes
stimulates megakaryocytes to produce platelets
Pancreas
Secreted hormone
From cells
Effect
Insulin (Primarily)
ß Islet cells
Intake of glucose, glycogenesis and glycolysis in liver and muscle from blood
intake of lipids and synthesis of triglycerides in adipocytes Other anabolic effects
Glucagon (Also Primarily)
a Islet cells
glycogenolysis and gluconeogenesis in liver
increases blood glucose level
Somatostatin
d Islet cells
Inhibit release of insulin
Inhibit release of glucagon Suppress the exocrine secretory action of pancreas.
Pancreatic polypeptide
PP cells
Unknown
Kidney
Secreted hormone
From cells
Effect
Renin (Primarily)
Juxtaglomerular cells
Activates the renin-angiotensin system by producing angiotensin I of angiotensinogen
Erythropoietin (EPO)
Extraglomerular mesangial cells
Stimulate erythrocyte production
Calcitriol (1,25-dihydroxyvitamin D3)
Active form of vitamin D3
Increase absorption of calcium and phosphate from gastrointestinal tract and kidneys inhibit release of PTH
Thrombopoietin
stimulates megakaryocytes to produce platelets
Adrenal glands
Adrenal cortex
Secreted hormone
From cells
Effect
Glucocorticoids (chiefly cortisol)
zona fasciculata and zona reticularis cells
Stimulation of gluconeogenesis
Inhibition of glucose uptake in muscle and adipose tissue Mobilization of amino acids from extrahepatic tissues Stimulation of fat breakdown in adipose tissue anti-inflammatory and immunosuppressive
Mineralocorticoids (chiefly aldosterone)
Zona glomerulosa cells
Increase blood volume by reabsorption of sodium in kidneys (primarily)
Potassium and H+ secretion in kidney.
Androgens (including DHEA and testosterone)
Zona fasciculata and Zona reticularis cells
Virilization, anabolic
Adrenal medulla
Secreted hormone
From cells
Effect
Adrenaline (epinephrine) (Primarily)
Chromaffin cells
Fight-or-flight response:
Boost the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasodilation, increasing catalysis of glycogen in liver, breakdown of lipids in fat cells)
Dilate the pupils
Suppress non-emergency bodily processes (e.g., digestion)
Suppress immune system
Noradrenaline (norepinephrine)
Chromaffin cells
Fight-or-flight response:
Boost the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasoconstriction and increased blood pressure, breakdown of lipids in fat cells)
Increase skeletal muscle readiness.
Dopamine
Chromaffin cells
Increase heart rate and blood pressure
Enkephalin
Chromaffin cells
Regulate pain
Testis
Secreted hormone
From cells
Effect
Androgens (chiefly testosterone)
Leydig cells
Anabolic: growth of muscle mass and strength, increased bone density, growth and strength,
Virilizing: maturation of sex organs, formation of scrotum, deepening of voice, growth of beard and axillary hair.
Estradiol
Sertoli cells
Prevent apoptosis of germ cells
Inhibin
Sertoli cells Inhibit production of FSH
Ovary
These originate either from the ovarian follicle or the corpus luteum.
Secreted hormone
From cells
Effect
Progesterone
Granulosa cells, theca cells
Support pregnancy:
Convert endometrium to secretory stage
Make cervical mucus permeable to sperm.
Inhibit immune response, e.g., towards the human embryo
Decrease uterine smooth muscle contractility
Inhibit lactation
Inhibit onset of labor
Other:
Raise epidermal growth factor-1 levels
Increase core temperature during ovulation
Reduce spasm and relax smooth muscle
(widen bronchi and regulate mucus)
Anti-inflammatory
Reduce gall-bladder activity
Normalize blood clotting and vascular tone, zinc
and copper levels,
cell oxygen levels, and use of fat stores for energy
Assist in thyroid function and bone growth by osteoblasts
Increase resilience in bone, teeth, gums, joint, tendon,
ligament, and skin
Promote healing by regulating collagen
Provide nerve function and healing by regulating myelin
Prevent endometrial cancer by regulating effects of estrogen
Androstenedione
Theca cells
Substrate for estrogen
Estrogens (mainly estradiol)
Granulosa cells
Structural:
Promote formation of female secondary sex characteristics
Accelerate height growth
Accelerate metabolism (burn fat)
Reduce muscle mass
Stimulate endometrial growth
Increase uterine growth
Maintain blood vessels and skin
Reduce bone resorption, increase bone formation
Protein synthesis:
Increase hepatic production of binding proteins
Coagulation:
Increase circulating level of factors 2, 7, 9, 10, antithrombin III, plasminogen
Increase platelet adhesiveness
Increase HDL, triglyceride, height growth
Decrease LDL, fat deposition
Fluid balance:
Regulate salt (sodium) and water retention
Increase growth hormone
Increase cortisol, SHBG
Gastrointestinal tract:
Reduce bowel motility
Increase cholesterol in bile
Melanin:
Increase pheomelanin, reduce eumelanin
Cancer:
Support hormone-sensitive breast cancers (Suppression of production in the body of estrogen is a treatment for these cancers.)
Lung function:
Promote lung function by supporting alveoli
Inhibin
Granulosa cells
Inhibit production of FSH from anterior pituitary
Placenta (when pregnant)
Secreted hormone
From cells
Effect
Progesterone (Primarily)
Support pregnancy
Inhibit immune response, towards the fetus.
Decrease uterine smooth muscle contractility
Inhibit lactation
Inhibit onset of labor.
Support fetal production of adrenal mineralo-
and glucosteroids.
Other effects on mother similar to ovarian
follicle-progesterone
Estrogens (mainly Estriol) (Also Primarily)
Effects on mother similar to ovarian follicle estrogen
Human chorionic gonadotropin
Syncytiotrophoblast
promote maintenance of corpus luteum during
beginning of pregnancy
Inhibit immune response, towards the human embryo.
Human placental lactogen
Syncytiotrophoblast
increase production of insulin and IGF-1
increase insulin resistance and carbohydrate intolerance
Inhibin
Fetal Trophoblasts
suppress FSH
Uterus (when pregnant)
Secreted hormone
From cells
Effect
Prolactin
Decidual cells
milk production in mammary glands
Relaxin
Decidual cells
Unclear in humans
Estradiol
Estradiol (17β-estradiol) (also oestradiol) is a sex hormone. Mislabelled the "female" hormone, it is also present in males; it represents the major estrogen in humans. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs including bone structure.
Estradiol, like other steroids, is derived from cholesterol. After side chain cleavage and utilizing the delta-5 pathway or the delta-4 pathway androstenedione is the key intermediary. A fraction of the androstenedione is converted to testosterone, which in turn undergoes conversion to estradiol by an enzyme called aromatase. Alternatively, androstenedione is "aromatized" to estrone, which is subsequently converted to estradiol.
Production
During the reproductive years, most estradiol in women is produced by the granulosa cells of the ovaries by the aromatization of androstenedione (produced in the theca folliculi cells) to estrone, followed by conversion of estrone to estradiol by 17β-hydroxysteroid reductase. Smaller amounts of estradiol are also produced by the adrenal cortex, and (in men), by the testes.
Estradiol is not only produced in the gonads: in both sexes, precursor hormones, specifically testosterone, are converted by aromatization to estradiol. In particular, fat cells are active to convert precursors to estradiol, and will continue to do so even after menopause. Estradiol is also produced in the brain and in arterial walls.
Mechanism of action
Estradiol enters cells freely and interacts with a cytoplasmic target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell.
Estradiol binds well to both estrogen receptors, ERα and ERβ, in contrast to certain other estrogens, notably medications that preferentially act on one of these receptors. These medications are called selective estrogen receptor modulators, or SERMs.
Estradiol is the most potent naturally-occurring estrogen.
Recently there has been speculation about a membrane estrogen receptor, ERX.
Metabolism
In plasma, estradiol is largely bound to sex hormone binding globulin, also to albumin, -only a fraction is free and biologically active. Deactivation includes conversion to less active estrogens such as estrone and estriol. Estriol is the major urinary metabolite. Estradiol is conjugated in the liver by sulfate and glucuronide formation and as such excreted via the kidneys. Some of the watersoluble conjugates are excreted via the bile duct, and partly reabsorbed after hydrolysis from the intestinal tract. This enterohepatic circulation contributes to maintaining estradiol levels.
Measurement
Serum estradiol measurement in women reflects primarily the activity of the ovaries. As such they are useful in the detection of baseline estrogen in women with amenorrhea or menstrual dysfunction and to detect the state of hypoestrogenicity and menopause. Furthermore, estrogen monitoring during fertility therapy assesses follicular growth and is useful in monitoring the treatment. Estrogen-producing tumors will demonstrate persistent high levels of estradiol and other estrogens. In precocious puberty estradiol levels are inappropriately increased.
Estradiol levels (blue line) during the menstrual cycle
In the normal menstrual cycle estradiol levels measure typically <50 ng/ml at menstruation, rise with follicular development, drop briefly at ovulation, and rise again during the luteal phase for a second peak. At the end of the luteal phase estradiol levels drop to their menstrual levels unless there is a pregnancy.
During pregnancy estrogen levels including estradiol rise steadily towards term. The source of these estrogens is the placenta that aromatizes prohormones produced in the fetal adrenal gland.
Effects on Female reproduction
In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of the vagina, the cervical glands, the endometrium and the lining of the fallopian tubes. It enhances growth of the myometrium. Estradiol appears necessary to maintain oocytes in the ovary. During the menstrual cycle, estradiol that is produced by the growing follicle triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to the luteinizing hormone surge, inducing ovulation. In the luteal phase estradiol, in conjunction with progesterone, prepares the endometrium for implantation. During pregnancy estradiol increases due to placental production. In baboons, blocking of estrogen production leads to pregnancy loss suggesting that estradiol has a role in the maintenance of pregnancy. Research is investigating the role of estrogens in the process of initiation of labor.
Sexual development
The development of secondary sex characteristics in women is driven by estrogens, specifically estradiol. These changes are initiated at the time of puberty, most enhanced during the reproductive years, and become less pronounced with declining estradiol support after the menopause. Thus, estradiol enhances breast development, and is responsible for changes in the body shape affecting bones, joints, fat deposition. Fat structure and skin composition are modified by estradiol.
Effects on Male reproduction
The effect of estradiol (and estrogens) upon male reproduction is complex. Estradiol is produced in the Sertoli cells of the testes. There is evidence that estradiol is to prevent apoptosis of male germ cells.
Several studies have noted that sperm counts have been declining in many parts of the world and it has been postulated that this may be related to estrogen exposure in the environment.Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.
Males with sex chromosome genetic conditions such as Klinefelters Syndrome will have a higher level of estradiol.
Bone
There is ample evidence that estradiol has a profound effect on bone. Individuals without estradiol (or other estrogens) will become tall and eunuchoid as epiphysieal closure is delayed or may not take place. Bone structure is affected resulting in early osteopenia and osteoporosis.Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
Liver
Estradiol has complex effects on the liver. It can lead to cholestasis. It affects the production of multiple proteins including lipoproteins, binding proteins, and proteins responsible for blood clotting.
Brain
Estrogens can be produced in the brain from steroid precursors. As antioxidants, they have been found to have neuroprotective function.
The positive and negative feedback loop of the menstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropins.
Estrogen is considered to play a significant role in women’s mental health. A conceptual model of how estrogen affects mood was suggested by Douma et al 2005 based on their extensive literature review relating activity of endogenous, bio-identical and synthetic estrogen with mood and well-being. They concluded that the sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlated with significant mood lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized and/or restored.
Blood vessels
Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in coronary arteries.
Oncogene
Estrogen is suspected to activate certain oncogenes, as it supports certain cancers, notably breast cancer and cancer of the uterine lining. In addition there are several benign gynecologic conditions that are dependent on estrogen such as endometriosis, leiomyomata uteri, and uterine bleeding.
Pregnancy
The effect of estradiol, together with estrone and estriol, in pregnancy is less clear. They may promote uterine blood flow, myometrial growth, sitmulate breast growth and at term, promote cervical softening and expression of myometrial oxytocin receptors.
Hormone replacement therapy
If severe side effects of low levels of estradiol in a woman's blood are experienced (commonly at the beginning of menopause or after oophorectomy), hormone replacement therapy may be prescribed. Often such therapy is combined with a progestin.
Estrogen therapy may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucus or an appropriate uterine lining.
Estrogen therapy is also used to maintain female hormone levels in male-to-female transsexuals.
if (window.runOnloadHook) runOnloadHook();
Follicle-stimulating hormone
Follicle-stimulating hormone (FSH) is a hormone synthesized and secreted by gonadotropes in the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the human body. FSH and Luteinizing hormone (LH) act synergistically in reproduction:
•In females, in the ovary FSH stimulates the growth of immature Graafian follicles to maturation. Graafian follicles are the mature follicle. Primary follicles mature to Graafian follicles. As the follicle grows, it releases inhibin, which shuts off the FSH production.
•In males, FSH enhances the production of androgen-binding protein by the Sertoli cells of the testes, and is critical for spermatogenesis.
Structure
FSH is a glycoprotein. Each monomeric unit is a protein molecule with a sugar attached to it; two of these make the full, functional protein. Its structure is similar to those of LH, TSH, and hCG. The protein dimer contains 2 polypeptide units, labeled alpha and beta subunits. The alpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92 amino acids. The beta subunits vary. FSH has a beta subunit of 118 amino acids (FSHB), which confers its specific biologic action and is responsible for interaction with the FSH-receptor. The sugar part of the hormone is composed of fucose, galactose, mannose, galactosamine, glucosamine, and sialic acid, the latter being critical for its biologic half-life. The half-life of FSH is 3-4 hours. Its molecular wt is 30000.
Activity
FSH regulates the development, growth, pubertal maturation, and reproductive processes of the human body.
• In both males and females, FSH stimulates the maturation of germ cells.
• In males, FSH induces sertoli cells to secrete inhibin and stimulates the formation of sertoli-sertoli tight junctions (zonula occludens).
• In females, FSH initiates follicular growth, specifically affecting granulosa cells. With the concomitant rise in inhibin B, FSH levels then decline in the late follicular phase. This seems to be critical in selecting only the most advanced follicle to proceed to ovulation. At the end of the luteal phase, there is a slight rise in FSH that seems to be of importance to start the next ovulatory cycle.
Like its partner, LH, FSH release at the pituitary gland is controlled by pulses of gonadotropin-releasing hormone (GnRH). Those pulses, in turn, are subject to the oestrogen feed-back from the gonads.
High FSH levels
High levels of Follicle-Stimulating Hormone are indicative of situations where the normal restricting feedback from the gonad is absent, leading to an unrestricted pituitary FSH production. Whereas this is normal in females leading up to and during postmenopause, it is abnormal during the reproductive years.
If the FSH level is high during the reproductive years, this may be a sign of:
1. Premature menopause also known as Premature Ovarian Failure
2. Gonadal dysgenesis, Turner syndrome
3. Castration
4. Swyer syndrome
5. Certain forms of CAH
6. Testicular failure.
Low FSH levels
Diminished secretion of FSH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. In females, cessation of reproductive cycles is commonly observed. Conditions with very low FSH secretions are:
1.Kallmann syndrome
2.Hypothalamic suppression
3.Hypopituitarism
4.Hyperprolactinemia
5.Gonadotropin deficiency
6.Gonadal suppression therapy
1.GnRH antagonist
2.GnRH agonist (downregulation).
Luteinizing hormone
LH surges at ovulation
Luteinizing hormone (LH, also known as lutropin) is a hormone produced by the anterior pituitary gland.
•In the female, an acute rise of LH – the LH surge – triggers ovulation.
•In the male, where LH had also been called Interstitial Cell Stimulating Hormone (ICSH),it stimulates Leydig cell production of testosterone.
Structure
LH is a glycoprotein. Each monomeric unit is a sugar-like protein molecule; two of these make the full, functional protein.
Its structure is similar to the other glycoproteins, follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG). The protein dimer contains 2 polypeptide units, labeled alpha and beta subunits that are connected by two disulfide bridges:
• The alpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92 amino acids.
• The beta subunits vary. LH has a beta subunit of 121 amino acids (LHB) that confers its specific biologic action and is responsible for interaction with the LH receptor. This beta subunit contains the same amino acids in sequence as the beta sub unit of hCG and both stimulate the same receptor, however, the hCG beta subunit contains an additional 24 amino acids, and both hormones differ in the composition of their sugar moieties.
The different composition of these oligosaccharides affects bioactivity and speed of degradation. The biologic half-life of LH is 20 minutes, shorter than that of FSH (3-4 hours) or hCG (24 hours).
Activity
In both males and females, LH is essential for reproduction.
• In females, at the time of menstruation, FSH initiates follicular growth, specifically affecting granulosa cells.[5] With the rise in estrogens, LH receptors are also expressed on the maturing follicle that produces an increasing amount of estradiol. Eventually at the time of the maturation of the follicle, the estrogen rise leads via the hypothalamic interface to the “positive feed-back” effect, a release of LH over a 24-48 hour period. This 'LH surge' triggers ovulation hereby not only releasing the egg, but also initiating the conversion of the residual follicle into a corpus luteum that, in turn, produces progesterone to prepare the endometrium for a possible implantation. LH is necessary to maintain luteal function for the first two weeks. In case of a pregnancy luteal function will be further maintained by the action of hCG (a hormone very similar to LH) from the newly established pregnancy. LH supports thecal cells in the ovary that provide androgens and hormonal precursors for estradiol production.
• In the male, LH acts upon the Leydig cells of the testis and is responsible for the production of testosterone, an androgen that exerts both endocrine activity and intratesticular activity such as spermatogenesis.
The release of LH at the pituitary gland is controlled by pulses of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Those pulses, in turn, are subject to the estrogen feedback from the gonads.
Normal levels
LH levels are normally low during childhood and, in women, high after menopause.
During the reproductive years typical levels are between 5-20 mIU/ml.
Physiologic high LH levels are seen during the LH surge (v.s.); typically they last 48 hours.
Disease states
Relative elevations
In children with precocious puberty of pituitary or central origin, LH and FSH levels may be in the reproductive range instead of the low levels typical for their age.
During the reproductive years, relatively elevated LH is frequently seen in patients with the polycystic ovary syndrome; however it would be unusual for them to have LH levels outside of the normal reproductive range.
High LH levels
Persistently high LH levels are indicative of situations where the normal restricting feedback from the gonad is absent, leading to a pituitary production of both LH and FSH. While this is typical in the menopause, it is abnormal in the reproductive years. There it may be a sign of:
1. Premature menopause
2. Gonadal dysgenesis, Turner syndrome
3. Castration
4. Swyer syndrome
5. Polycystic Ovary Syndrome
6. Certain forms of CAH
7. Testicular failure
Deficient LH activity
Diminished secretion of LH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. In females, amenorrhea is commonly observed. Conditions with very low LH secretions are:
1. Kallmann syndrome
2. Hypothalamic suppression
3. Hypopituitarism
4. Eating disorder
5. Hyperprolactinemia
6. Gonadotropin deficiency
7. Gonadal suppression therapy
1.GnRH antagonist
2.GnRH agonist (downregulation)
Thyroid hormone
The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are tyrosine-based hormones produced by the thyroid gland. An important component in the synthesis is iodine. The major form of thyroid hormone in the blood is thyroxine (T4). The ratio of T4 to T3 released in the blood is roughly 20 to 1. Thyroxine is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5'-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a).
Circulation
Most of the thyroid hormone circulating in the blood is bound to transport proteins. Only a very small fraction of the circulating hormone is free (unbound) and biologically active, hence measuring concentrations of free thyroid hormones is of great diagnostic value.
When thyroid hormone is bound, it is not active, so the amount of free T3/T4 is what is important. For this reason, measuring total thyroxine in the blood can be misleading.
Type
Percent
bound to thyroxine-binding globulin (TBG)
70%
bound to transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA)
10-15%
paraalbumin
15-20%
unbound T4 (fT4)
0.03%
unbound T3 (fT3)
0.3%
T3 and T4 cross the cell membrane, probably via amino acid importins, and function via a well-studied set of nuclear receptors in the nucleus of the cell, the thyroid hormone receptors.
T1a and T0a are positively charged and do not cross the membrane; they are believed to function via the trace amine-associated receptor TAAR1 (TAR1, TA1), a G-protein-coupled receptor located in the cell membrane.
Another critical diagnostic tool is measurement of the amount of thyroid-stimulating hormone (TSH) that is present.
Function
The thyronines act on the body to increase the basal metabolic rate, affect protein synthesis and increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness. The thyroid hormones are essential to proper development and differentiation of all cells of the human body. These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds. They also stimulate vitamin metabolism. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.
Thyroid hormone leads to heat generation in humans. However, the thyronamines function via some unknown mechanism to inhibit neuronal activity; this plays an important role in the hibernation cycles of mammals and the moulting behaviour of birds. One effect of administering the thyronamines is a severe drop in body temperature.
Related diseases
Both excess and deficiency of thyroxine can cause disorders.
•Thyrotoxicosis or hyperthyroidism (an example is Graves Disease) is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men.
•Hypothyroidism (an example is Hashimoto's thyroiditis) is the case where there is a deficiency of thyroxine, triiodiothyronine, or both.
•Clinical depression can sometimes be caused by hypothyroidism.Some research has shown that T3 is found in the junctions of synapses, and regulates the amounts and activity of serotonin, norepinephrine, and Gamma-aminobutyric acid (GABA) in the brain.
Medical use of thyroid hormones
Both T3 and T4 are used to treat thyroid hormone deficiency (hypothyroidism). They are both absorbed well by the gut, so can be given orally. Levothyroxine, the most commonly used synthetic thyroxine form, is a stereoisomer of physiological thyroxine, which is metabolised more slowly and hence usually only needs once-daily administration. Natural desiccated thyroid hormones, also under the commercial name Armour Thyroid, is derived from pig thyroid glands, it is a "natural" hypothyroid treatment containing 20% T3 and traces of T2, T1 and calcitonin. Also available are synthetic combinations of T3/T4 in different ratios (such as Thyrolar) and pure-T3 medications (Cytomel).
Thyronamines have no medical usages yet, though their use has been proposed for controlled induction of hypothermia which causes the brain to enter a protective cycle, useful in preventing damage during ischemic shock.
Synthetic thyroxine was first successfully produced by Charles Robert Harington and George Barger in 1926.
Production of the thyroid hormones
Thyroxine (3,5,3',5'-tetra¬iodothyronine) is produced by follicular cells of the thyroid gland. It is produced as the precursor thyroglobulin (this is not the same as TBG), which is cleaved by enzymes to produce active T4.
Thyroxine is produced by attaching iodine atoms to the ring structures of tyrosine molecules. Thyroxine (T4) contains four iodine atoms. Triiodothyronine (T3) is identical to T4, but it has one less iodine atom per molecule.
Iodide is actively absorbed from the bloodstream by a process called 'iodine trapping' and concentrated in the thyroid follicles. (If there is a deficiency of dietary iodine, the thyroid enlarges in an attempt to trap more iodine, resulting in goitre.) Via a reaction with the enzyme thyroperoxidase, iodine is covalently bound to tyrosine residues in the thyroglobulin molecules, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). Linking two moieties of DIT produces thyroxine. Combining one particle of MIT and one particle of DIT produces triiodothyronine.
• DIT + MIT → r-T3 (biologically inactive)
• MIT + DIT → triiodothyronine (usually referred to as T3)
• DIT + DIT → thyroxine (referred to as T4)
Proteases digest iodinated thyroglobulin, releasing the hormones T4 and T3, the biologically active agents central to metabolic regulation. Thyroxine is supposedly a prohormone and a reservoir for the most active and main thyroid hormone T3. T4 is converted as required in the tissues by deiodinases. Deficiency of deiodinase can mimic an iodine deficiency. T3 is more active than T4 and is the final form of the hormone, though it is present in less quantity than T4.
Anti-thyroid drugs
Iodine uptake against a concentration gradient is mediated by a sodium iodine symporter. Perchlorate and thiocyanate are drugs that can compete with iodine at this point.
Effects of thyroxine
• Increases cardiac output
• Increases heart rate
• Increases ventilation rate
• Increases basal metabolic rate
• Potentiates the effects of catecholamines (i.e increases sympathetic activity)
• Potentiates brain development
• Thickens endometrium in females
Thyroid-stimulating hormone
Thyroid-stimulating hormone (also known as TSH or thyrotropin) is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland which regulates the endocrine function of the thyroid gland.
TSH stimulates the thyroid gland to secrete the hormones thyroxine (T4) and triiodothyronine (T3).TSH production is controlled by a Thyrotrophin Releasing Hormone, (TRH), which is manufactured in the hypothalamus and transported to the anterior pituitary gland via the superior hypophyseal artery, where it increases TSH production and release. Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release.
The level of thyroid hormones (T3 and T4) in the blood have an additional effect on the pituitary release of TSH; When the levels of T3 and T4 are low, the production of TSH is increased, and conversely, when levels of T3 and T4 are high, then TSH production is decreased. This effect creates a regulatory negative feedback loop.
Subunits of TSH
TSH is a glycoprotein and consists of two subunits, the alpha and the beta subunit.
•The α (alpha) subunit (i.e., chorionic gonadotropin alpha) is identical to that of human chorionic gonadotropin (HCG), luteinizing hormone (LH), follicle-stimulating hormone (FSH).
•The β (beta) subunit is unique to TSH, and therefore determines its function.
The TSH receptor
The TSH receptor is found mainly on thyroid follicular cells.Stimulation of the receptor increases T3 and T4 production and secretion.
Stimulating antibodies to this receptor mimic TSH action and are found in Graves' disease.
Diagnostic use
TSH levels are tested in the blood of patients suspected of suffering from excess (hyperthyroidism), or deficiency (hypothyroidism) of thyroid hormone. Generally, a normal range for TSH for adults is between 0.4 and 5.0 uIU/mL
Source of pathology
TSH level
thyroid hormone level
Disease causing conditions
hypothalamus/pituitary
high
high
benign tumor of the pituitary (adenoma) or thyroid hormone resistance
hypothalamus/pituitary
low
low
hypopituitarism
thyroid
low
high
hyperthyroidism or Grave's disease
thyroid
high
low
congenital hypothyroidism (cretinism), hypothyroidism
Clearly, both TSH and T3 and T4 should be measured to ascertain where a specific thyroid dysfunction is caused by primary pituitary or by a primary thyroid disease. If both are up (or down) then the problem is probably in the pituitary. If the one component (TSH) is up, and the other (T3 and T4) is down, then the disease is probably in the thyroid itself. The same holds for a low TSH, high T3 and T4 finding.
A TSH assay is now also the recommended screening tool for thyroid disease. Recent advances in increasing the sensitivity of the TSH assay make it a better screening tool than free T4
Progesterone
Progesterone is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.Progesterone should not be confused with progestins, which are synthetically produced progestogens.
Synthesis
Progesterone, * like all other steroid hormones, is synthesized from pregnenolone, a derivative of cholesterol. This conversion takes place in two steps. The 3-hydroxyl group is converted to a keto group and the double bond is moved to C-4, from C-5.
Conversion of Pregnenolone to Progesterone
Progesterone is the precursor of the mineralocorticoid aldosterone, and after conversion to 17-hydroxyprogesterone (another natural progestogen) of cortisol and androstenedione. Androstenedione can be converted to testosterone, estrone and estradiol.
Progesterone is important for aldosterone (mineralocorticoid) synthesis, as 17-hydroxyprogesterone is for cortisol (glucocorticoid), and androstenedione for sex steroids.
Sources
Progesterone is produced in the ovaries, the gonads (specifically after ovulation in the corpus luteum), the brain, and, during pregnancy, in the placenta.
In humans, increasing amounts of progesterone are produced during pregnancy:
•Initially, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropins (hCG) from the conceptus.
•However, after the 8th week production of progesterone shifts to the placenta. The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term the placenta produces about 250 mg progesterone per day.
•An additional source of progesterone is milk products. They contain much progesterone because on dairy farms cows are milked during pregnancy, when the progesterone content of the milk is high. After consumption of milk products the level of bioavailable progesterone goes up.This observation has resulted in concern that diets high in dairy products might induce pet and human diseases.
Progesterone levels during the menstrual cycle
In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. Progesterone levels tend to be <> 5 ng/ml after ovulation. If pregnancy occurs, progesterone levels are initially maintained at luteal levels. With the onset of the luteal-placental shift in progesterone support of the pregnancy, levels start to rise further and may reach 100-200 ng/ml at term. Whether a decrease in progesterone levels is critical for the initiation of labor has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.
Progesterone levels are relatively low in children and postmenopausal women.[8] Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.
Effects
Progesterone exerts its action primarily through the intracellular progesterone receptor although a distinct, membrane bound progesterone receptor has also been postulated.Progesterone has a number of physiological effects which are amplified in the presence of estrogen. Estrogen through estrogen receptors upregulates the expression of progesterone receptors.
Reproductive system
Progesterone is sometimes called the "hormone of pregnancy",and it has many roles relating to the development of the fetus:
•Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus, making the mucus thick and impermeable to sperm. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. Normal menstrual bleeding is progesterone withdrawal bleeding.
•During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.
•Progesterone decreases contractility of the uterine smooth muscle.
•In addition progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.
•A drop in progesterone levels is possibly one step that facilitates the onset of labor.
The fetus metabolizes placental progesterone in the production of adrenal mineralo- and glucosteroids.
Nervous system
Progesterone, like pregnenolone and dehydroepiandrosterone, belongs to the group of neurosteroids that are found in high concentrations in certain areas in the brain and are synthesized there.
Neurosteroids affect synaptic functioning, are neuroprotective, and affect myelination.They are investigated for their potential to improve memory and cognitive ability.
Progesterone as neuroprotectant affects regulation of apoptotic genes.
Its effect as a neurosteroid works predominantly through the GSK-3 beta pathway, as an inhibitor. (Other GSK-3 beta inhibitors include bipolar mood stabilizers, lithium and valproic acid.)
Other systems
•It raises epidermal growth factor-1 levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.
•It increases core temperature (thermogenic function) during ovulation.
•It reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated. (Progesterone receptors are widely present in submucosal tissue.)
•It acts as an antiinflammatory agent and regulates the immune response.
•It reduces gall-bladder activity.
•It normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy.
•It assists in thyroid function, in bone building by osteoblasts, in bone, teeth, gums, joint, tendon, ligament and skin resilience and in some cases healing by regulating various types of collagen, and in nerve function and healing by regulating myelin.
•It appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen.
Specific uses
•Progesterone is used to support pregnancy in Assisted Reproductive Technology (ART) cycles such as In-vitro Fertilization (IVF). While daily intramuscular injections of progesterone have been the standard route of administration, a recent meta-analysis showed that the intravaginal route with an appropriate dose and dosing frequency is equivalent to daily intramuscular injections.
•Progesterone is used to control anovulatory bleeding. It is also used to prepare uterine lining in infertility therapy and to support early pregnancy. Patients with recurrent pregnancy loss due to inadequate progesterone production may receive progesterone.
•Progesterone is being investigated as potentially beneficial in treating multiple sclerosis, since the characteristic deterioration of nerve myelin insulation halts during pregnancy, when progesterone levels are raised; deterioration commences again when the levels drop.
•Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. The initial study by Fonseca suggested that vaginal progesterone could prevent preterm birth in women with a history of preterm birth.
A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth,but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care.In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline.An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.
•Progesterone is used in hormone replacement therapy for transwomen, and some women with intersex conditions - especially when synthetic progestins have been ineffective or caused side-effects - since normal breast tissue cannot develop except in the presence of both progestogen and estrogen. Mammary glandular tissue is otherwise fibrotic, the breast shape conical and the areola immature. Progesterone can correct those even after years of inadequate hormonal treatment. Research usually cited against such value was conducted using Provera, a synthetic progestin. Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually-dimorphic proportions of those.
•Progesterone receptor antagonists, or selective progesterone receptor modulators (SPRM)s, such as RU-486 (Mifepristone), can be used to prevent conception or induce medical abortions.
Note that methods of hormonal contraception do not contain progesterone but a progestin.
Progesterone may affect male behavior.
Aging
Since most progesterone in males is created during testicular production of testosterone, and most in females by the ovaries, the shutting down (whether by natural or chemical means), or removal, of those inevitably causes a considerable reduction in progesterone levels. Previous concentration upon the role of progestagens (progesterone and molecules with similar effects) in female reproduction, when progesterone was simply considered a "female hormone", obscured the significance of progesterone elsewhere in both sexes.
The tendency for progesterone to have a regulatory effect, the presence of progesterone receptors in many types of body tissue, and the pattern of deterioration (or tumor formation) in many of those increasing in later years when progesterone levels have dropped, is prompting widespread research into the potential value of maintaining progesterone levels in both males and females.
Brain damage
It has been observed in animal models that females have reduced susceptibility to traumatic brain injury and this protective effect has been hypothesized to be caused by increased circulating levels of estrogen and progesterone in females.[26] A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury.Encouraging results have also been reported in human clinical trials.
The mechanism of progesterone protective effects may be the reduction of inflammation which follows brain trauma.
Prolactin
Prolactin (PRL) or Luteotropic hormone (LTH) is a peptide hormone primarily associated with lactation. In breastfeeding, the act of an infant suckling the nipple stimulates the production of prolactin, which fills the breast with milk via a process called lactogenesis, in preparation for the next feed. Oxytocin, another hormone, is also released, which triggers milk let-down.
Production and regulation
Prolactin or luteotropic hormone is synthesised and secreted by lactotrope cells in the adenohypophysis (anterior pituitary gland). It is also produced in other tissues including the breast, the decidua, parts of the central nervous system and the immune system.The gene encoding prolactin in humans is located on chromosome 6.
Pituitary prolactin secretion is regulated by neuroendocrine neurons in the hypothalamus, the most important ones being the neurosecretory tuberoinfundibulum (TIDA) neurons of the arcuate nucleus, which secrete dopamine to act on the dopamine-2 receptors (D2-R) of lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing factor has a stimulatory effect on prolactin release.
Vasoactive intestinal peptide and peptide histidine isoleucine help to regulate prolactin secretion in humans, but the functions of these hormones in birds can be quite different.
Effects
Prolactin has many effects including regulating lactation, orgasms, and stimulating proliferation of oligodendrocyte precursor cells.
It stimulates the mammary glands to produce milk (lactation): Increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands of the breasts and increases the production of milk. However, the high levels of progesterone during pregnancy act directly on the breasts to stop ejection of milk. It is only when the levels of this hormone fall after childbirth that milk ejection is possible. Sometimes, newborn babies (males as well as females) secrete a milky substance from their nipples. This substance is commonly known as Witch's milk. This is caused by the fetus being affected by prolactin circulating in the mother just before birth, and usually stops soon after birth.
Prolactin provides the body with sexual gratification after sexual acts: The hormone counteracts the effect of dopamine, which is responsible for sexual arousal. This is thought to cause the sexual refractory period.The amount of prolactin can be an indicator for the amount of sexual satisfaction and relaxation. Unusually high amounts are suspected to be responsible for impotence and loss of libido (see hyperprolactinemia Symptoms). Prolactin also stimulates proliferation of oligodendrocyte precursor cells. These cells differentiate into oligodendrocytes, the cells responsible for the formation of myelin coatings on axons in the central nervous system.
Prolactin also has a number of other effects including contributing to surfactant synthesis of the fetal lungs at the end of the pregnancy and immune tolerance of the fetus by the maternal organism during pregnancy;it also decreases normal levels of sex hormones — estrogen in women and testosterone in men."Prolactin delays hair regrowth in mice.
Variance in levels
There is a diurnal as well as an ovulatory cycle in prolactin secretion.
During pregnancy, high circulating concentrations of estrogen promote prolactin production. The resulting high levels of prolactin secretion cause further maturation of the mammary glands, preparing them for lactation.
After childbirth, prolactin levels fall as the internal stimulus for them is removed. Sucking by the baby on the nipple then promotes further prolactin release, maintaining the ability to lactate. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland cause increased prolactin secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk let-down: Prolactin controls milk production (lactogenesis) but not the milk-ejection reflex; the rise in prolactin fills the breast with milk in preparation for the next feed.
In usual circumstances, in the absence of galactorrhea, lactation will cease within one or two weeks of the end of demand breastfeeding.
High prolactin levels also tend to suppress the ovulatory cycle by inhibiting the secretion of both follicle-stimulating hormone (FSH) and gonadotropic-releasing hormone (GnRH).
Prolactin levels peak during REM sleep, and in the early morning. Levels can rise after exercise, meals, sexual intercourse, or minor surgical procedures.
Diagnostic use
Prolactin levels may be checked as part of a sex hormone workup, as elevated prolactin secretion can suppress the secretion of FSH and GnRH, leading to hypogonadism, and sometimes causing erectile dysfunction in men.
Prolactin levels may be of some use in distinguishing epileptic seizures from psychogenic non-epileptic seizures. The serum prolactin level usually rises following an epileptic seizure.
Conditions causing elevated prolactin secretion
Hyperprolactinaemia is the term given to having too-high levels of prolactin in the blood.
• Prolactinoma
• Excess thyrotropin-releasing hormone (TRH), usually in primary hypothyroidism
• Many anti-psychotic medications
• Emotional stress
• Pregnancy and Lactation.
Conditions causing decreased prolactin
• Bulimia
• Excess dopamine
Cortisol
Cortisol is a corticosteroid hormone or glucocorticoid produced by the adrenal gland (in the Zona fasciculata and the Zona Reticularis of the adrenal cortex). It is often referred to as the "stress hormone" as it is involved in response to stress. It increases blood pressure and blood sugar, and reduces immune responses. In pharmacology, the synthetic form of cortisol is referred to as hydrocortisone, and is used to treat allergies and inflammation, and to supplement natural cortisol when its production is too low.
When first introduced as a treatment for rheumatoid arthritis, it was referred to as Compound E.
Physiology
The amount of cortisol present in the blood undergoes diurnal variation, with the highest levels present in the early morning, and the lowest levels present around midnight, 3-5 hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. The pattern is not present at birth (estimates of when it starts vary from two weeks to 9 months).
Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of temperature.There is also significant individual variation, although a given person tends to have consistent rhythms.
Effects
In normal release, cortisol (like other glucocorticoid agents) has widespread actions which help restore homeostasis after stress. (These normal endogenous functions are the basis for the physiological consequences of chronic stress - prolonged cortisol secretion.). It has been proposed that its primary function is to inversely mobilize the immune system to fight potassium-depleting diarrhea diseases.Its odd attributes all support this.
Insulin
Cortisol counteracts insulin by increasing gluconeogenesis and promotes breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood) by increasing gluconeogenesis. There is an increased glycogen breakdown in the liver.Prolonged cortisol secretion causes hyperglycemia. Cortisol has no effect on insulin.The reason why in vivo experiments seem to deny this is that cortisone (a cortisol metabolite) greatly inhibits insulin. So the cortisone-cortisol equilibrium may explain why in vivo experiments contradict the cortisol effect.Cortisol does cause serum glucose to rise, but this is probably an indirect effect caused by stimulation of amino acid degradation, especially that derived from collagen in the skin. Loss of collagen from skin by cortisol is ten times greater than from all other tissue in the rat.
Amino acids
Cortisol raises the free amino acids in the serum. It does this by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis. Cortisol (as opticortinol) probably inversely inhibits IgA precursor cells in the intestines of calves.[8] Cortisol also inhibits IgA in serum, as it does IgM, but not IgE.
Gastric secretion
Cortisol stimulates gastric acid secretion.Gastric acid secretion would increase loss of potassium into the stomach during diarrhea as well as acid loss. Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to stimulate excretion of ammonium ion by inactivation of renal glutaminase enzyme.Net chloride secretion in the intestines is inversely decreased by cortisol in vitro (methylprednisolone).
Sodium
Cortisol inhibits loss of sodium from small intestines of mammals.However, sodium depletion does not affect cortisol,so cortisol is not used to regulate serum sodium. Cortisol's purpose may originally have been centered around moving sodium because cortisol is used to stimulate sodium inward for fresh water fish and outward for salt-water fish.
Potassium
Sodium load augments the intense potassium excretion by cortisol, and corticosterone is comparable to cortisol in this case.In order for potassium to move out of the cell, cortisol moves in an equal number of sodium ions.It can be seen that this should make pH regulation much easier, unlike the normal potassium deficiency situation in which about 2 sodium ions move in for each 3 potassium ions that move out, which is closer to the deoxycorticosterone effect. Nevertheless, cortisol consistently causes alkalosis of the serum, while in a deficiency pH does not change. Perhaps this may be for the purpose of bringing serum pH to a value most optimum for some of the immune enzymes during infection in those times when cortisol declines. Potassium is also blocked from loss in the kidneys directly somewhat by decline of cortisol (9 alpha fluorohydrocortisone).
Water
Cortisol also acts as a water diuretic hormone. Half the intestinal diuresis is so controlled.Kidney diuresis is also controlled by cortisol in dogs. The decline in water excretion upon decline of cortisol (dexamethasone) in dogs is probably due to inverse stimulation of antidiuretic hormone (ADH or arginine vasopressin), the inverse stimulation of which is not overridden by water loading.Humans also use this mechanism and other different animal mechanisms operate in the same direction.
Copper
It is probable that increasing copper availability for immune purposes is the reason why many copper enzymes are stimulated to an extent which is often 50% of their total potential by cortisol.This includes lysyl oxidase, an enzyme which is used to cross link collagen and elastin.Particularly valuable for immunity is the stimulation of superoxide dismutase by cortisol since this copper enzyme is almost certainly used by the body to permit superoxide to poison bacteria. Cortisol causes an inverse four- or fivefold decrease of metallothionein, a copper storage protein, in mice(however rodents do not synthesize cortisol themselves). This may be to furnish more copper for ceruloplasmin synthesis or release of free copper. Cortisol has an opposite effect on alpha aminoisobuteric acid than on the other amino acids.If alpha aminoisobuteric acid is used to transport copper through the cell wall, this anomaly would possibly be explained.
Immune system
Cortisol can weaken the activity of the immune system. Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1(IL-1), and unable to produce the T-cell growth factor.Cortisol has a negative feedback effect on interleukin-1which must be especially useful in combating diseases, such as the endotoxin bacteria, that gain an advantage by forcing the hypothalamus to secrete a hormone called CRH. The suppressor cells are not affected by GRMF,[29] so that the effective set point for the immune cells may be even higher than the set point for physiological processes. It reflects leukocyte redistribution to lymph nodes, bone marrow, and skin. Acute administration of corticosterone (the endogenous Type I and Type II receptor agonist), or RU28362 (a specific Type II receptor agonist), to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are not affected by cortisol.
Bone metabolism
It lowers bone formation thus favoring development of osteoporosis in the long term. Cortisol moves potassium out of cells in exchange for an equal number of sodium ions as mentioned above.This can cause a major problem with the hyperkalemia of metabolic shock from surgery.
Memory
It cooperates with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future. However, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning. The desirability of inhibiting activity during infection is no doubt the reason why cortisol is responsible for creating euphoria.The desirability of not disturbing tissues weakened by infection or of not cutting off their blood supply could explain the inhibition of pain widely observed for cortisol.
Additional effects
•It increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine. In the absence of cortisol, widespread vasodilation occurs.
•It inhibits the secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH (Adrenocorticotropic hormone or corticotropin) secretion. Some researchers believe that this normal feedback system may become dysregulated when animals are exposed to chronic stress.
•It increases the effectiveness of catecholamines.
•It allows for the kidneys to produce hypotonic urine.
•It has anti-inflammatory effects by reducing histamine secretion and stabilizing lysosomal membranes. The stabilization of lysosomal membranes prevents their rupture, thereby preventing damage to healthy tissues.
•It stimulates hepatic detoxification by inducing tryptophan oxygenase (to reduce serotonin levels in the brain), glutamine synthase (reduce glutamate and ammonia levels in the brain), cytochrome P-450 hemoprotein (mobilizes arachidonic acid), and metallothionein (reduces heavy metals in the body).
•In addition to the effects caused by cortisol binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone, it also binds to the mineralocorticoid receptor. Aldosterone and cortisol have similar affinity for the mineralocorticoid receptor however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids and allow selective mineralocorticoid action. This enzyme, 11-beta hydroxysteroid dehydrogenase type II (Protein:HSD11B2), catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites.
Regulation
The primary control of cortisol is the pituitary gland peptide, adrenocorticotropic hormone (ACTH). ACTH probably controls cortisol by controlling movement of calcium into the cortisol secreting target cells. ACTH is in turn controlled by the hypothalamic peptide, corticotropin releasing hormone (CRH), which is under nervous control. CRH acts synergistically with arginine vasopressin, angiotensin II, and epinephrine. When activated macrophages start to secrete interleukin-1 (IL-1), which synergistically with CRH increases ACTH,T-cells also secrete glucosteroid response modifying factor (GRMF or GAF) as well as IL-1, both of which increase the amount of cortisol required to inhibit almost all the immune cells. Thus immune cells take over their own regulation, but at a higher cortisol set point. Even so, the rise of cortisol in diarrheic calves is minimal over healthy calves and drops below with time. The cells do not lose all of the fight or flight override because of interleukin-1's synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1 which must be especially useful against those diseases which gain an advantage by forcing the hypothalamus to secrete too much CRH, such as the endotoxin bacteria..The suppressor immune cells are not affected by GRMF, [39] so that the effective set point for the immune cells may be even higher than the set point for physiological processes. GRMF (called GAF in this reference) primarily affects the liver rather than the kidneys for some physiological processes.
A high potassium media, which stimulates aldosterone secretion in vitro, also stimulates cortisol secretion from the fasciculata zone of dog adrenals unlike corticosterone, upon which potassium has no effect. Potassium loading increases ACTH and cortisol in people also. This is no doubt the reason why a potassium deficiency causes cortisol to decline (as just mentioned) and why a potassium deficiency causes a decrease in conversion of 11deoxycortisol to cortisol . This probably contributes to the pain in rheumatoid arthritis since cell potassium is always low in that disease.
Diseases and disorders
Hypercortisolism: Excessive levels of cortisol in the blood result in Cushing's syndrome.
Hypocortisolism, or adrenal insufficiency: If on the other hand the adrenal glands do not produce sufficient amounts of cortisol, Addison's disease is the consequence.
The relationship between cortisol and ACTH is as follows:
THE DISORDERS OF CORTISOL SECRETION
Plasma Cortisol
Plasma ACTH
Primary Hypercortisolism (Cushing's syndrome)
↑
↓
Secondary Hypercortisolism (pituitary or ectopic tumor, Cushing's disease)
↑
↑
Primary Hypocortisolism (Addison's disease)
↓
↑
Secondary Hypocortisolism (pituitary tumor)
↓
↓
Biosynthesis
Cortisol is synthesized from cholesterol. The synthesis takes place in the zona fasciculata of the cortex of the adrenal glands.While the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion. The medulla of the adrenal gland lies under the cortex and mainly secretes the catecholamines, adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation (more epinephrine is produced than norepinephrine, in a ratio 4:1).
The synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with adrenocorticotropic hormone (ACTH); production of ACTH is in turn stimulated by corticotropin-releasing hormone (CRH), released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane (via regulation of STAR (steroidogenic acute regulatory) protein). The cholesterol is converted to pregnenolone, catalysed by Cytochrome P450SCC (side chain cleavage).
Metabolism
Cortisol is metabolized by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2.
•11-beta HSD1 utilizes the cofactor NADPH to convert biologically inert cortisone to biologically active cortisol.
•11-beta HSD2 utilizes the cofactor NAD+ to convert cortisol to cortisone.
Overall the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically active cortisol in a given tissue, while 11-beta HSD2 serves to decrease the local concentrations of biologically active cortisol.
Cortisol is also metabolized by 5-alpha reductase and 5-beta reductase into 5-alpha tetrahydrocortisol (5-alpha THF) and 5-beta tetrahydrocortisol (5-beta THF), respectively. 5-beta reductase is also responsible for converting cortisone to tetrahydrocortisone (THE).
The CA3 area of hippocampus (memory) is affected by cortisol.
An alteration in 11-beta HSD1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance, sometimes referred to the metabolic syndrome.
An alteration in 11-beta HSD2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (SAME).
Laboratory tests
Blood and urine tests for cortisol are used to help diagnose Cushing's syndrome and Addison's disease, two serious adrenal disorders. Some physicians are using salivary cortisol to diagnose Cushing's syndrome as well as to evaluate possible stress-related disorders, although these uses are not widespread.Both the urine and saliva tests are most frequently used to evaluate excess cortisol production.
Once an abnormal cortisol concentration has been detected, the doctor will do additional testing to help confirm the excess or deficiency and to help determine its cause.
Dexamethasone Suppression
If there is excess cortisol production, the doctor may perform a dexamethasone suppression test to help determine whether the cause of the cortisol is related to excess ACTH production by the pituitary. This test involves giving the patient oral dexamethasone (a synthetic glucocorticoid) and then measuring their blood and urine cortisol levels. Dexamethasone suppresses ACTH production and should decrease cortisol production if the source of the excess is pituitary related. There are a variety of dosing schedules, but the medication is usually given every 6 hours for either 2 or 4 days prior to blood or urine collection. Separate 24-hour urine samples are collected prior to and throughout the testing period and then the blood and urine samples are measured for cortisol and evaluated.
ACTH Stimulation
If the findings of the initial blood and/or urine tests indicate insufficient cortisol production, the doctor may order an ACTH stimulation test. This test involves measuring the concentration of cortisol in a patient’s blood before and after an injection of synthetic ACTH. If the adrenal glands are functioning normally, then cortisol levels will rise with the ACTH stimulation. If they are damaged, then the response will be limited. A longer version of this test (1-3 days) may be performed to help distinguish between adrenal and pituitary insufficiency.
What does the test result mean?
NOTE: A standard reference range is not available for this test. Because reference values are dependent on many factors, including patient age, gender, sample population, and test method, numeric test results have different meanings in different labs. Your lab report should include the specific reference range for your test. Lab Tests Online strongly recommends that you discuss your test results with your doctor. For more information on reference ranges, please read Reference Ranges and What They Mean.
In normal people, cortisol levels are very low at bedtime and at their highest just after waking. This pattern will change if a person works irregular shifts (such as the night shift) and sleeps at different times of the day. With Cushing’s syndrome, this pattern is typically lost.
Increased or normal cortisol concentrations in the morning along with levels that do not drop in the afternoon and evening suggest an overproduction of cortisol. If this excess cortisol is suppressed during a dexamethasone suppression test, it suggests that the excess cortisol is due to increased pituitary ACTH production. If it is not suppressed, then the increased cortisol could be due to an ACTH-producing tumor outside of the pituitary, due to a problem with the adrenal gland, or due to a medication that the patient is taking.
If the adrenal glands are overactive, then a patient may have Cushing’s syndrome, with symptoms and signs caused by prolonged exposure to the effects of too much cortisol. This may be due to excess production of cortisol by the adrenal glands (which is frequently due to a benign adrenal tumor) or excess ACTH stimulation (due to a pituitary or other ACTH-producing tumor). It can also be seen in patients who must take corticosteroid medications, such as those used to treat asthma. If insufficient cortisol is present and the patient responds to an ACTH stimulation test, then the problem is likely due to insufficient ACTH production by the pituitary. If cortisol levels do not respond to the ACTH stimulation test, then it is more likely that the problem is based in the adrenal glands. If the adrenal glands are underactive, due to adrenal damage or insufficient ACTH production, then the patient is said to have adrenal insufficiency. If decreased cortisol production is due to adrenal damage, then the patient is said to have Addison’s disease.
Once an abnormality has been identified and associated with the pituitary gland, adrenal glands, or other cause, then the doctor may use other testing such as CT (computerized tomography) or MRI (magnetic resonance imaging) scans to locate the source of the excess (such as a pituitary, adrenal, or other tumor) and to evaluate the extent of any damage to the glands.
Pregnancy, physical and emotional stress, and illness can increase cortisol levels. Cortisol levels may also increase as a result of hyperthyroidism or obesity. A number of drugs can also increase levels, particularly oral contraceptives (birth control pills), hydrocortisone (the synthetic form of cortisol), and spironolactone. Adults have slightly higher cortisol levels than children do.
Hypothyroidism may decrease cortisol levels. Drugs that may decrease levels include some steroid hormones.
Salivary cortisol testing is being used more frequently to help diagnose Cushing's syndrome and stress-related disorders but still requires specialized expertise to perform.
Insulin
Insulin is a hormone with intensive effects on both metabolism and several other body systems (eg, vascular compliance). Insulin causes most of the body's cells to take up glucose from the blood (including liver, muscle, and fat tissue cells), storing it as glycogen in the liver and muscle, and stops use of fat as an energy source. When insulin is absent (or low), glucose is not taken up by most body cells and the body begins to use fat as an energy source (ie, transfer of lipids from adipose tissue to the liver for mobilization as an energy source). As its level is a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as amino acid uptake by body cells). It has several other anabolic effects throughout the body. When control of insulin levels fails, diabetes mellitus results.
Insulin is used medically to treat some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. Patients with Type 2 diabetes mellitus are insulin resistant, have relatively low insulin production, or both; some patients with Type 2 diabetes may eventually require insulin when other medications fail to control blood glucose levels adequately.
Insulin is a peptide hormone composed of 51 amino acid residues and has a molecular weight of 5808 Da. It is produced in the islets of Langerhans in the pancreas. The name comes from the Latin insula for "island".
Release
Beta cells in the islets of Langerhans release insulin mostly in response to increased blood glucose levels through the following mechanism
•Glucose enters the beta cells through the glucose transporter GLUT2
•Glucose goes into the glycolysis and the respiratory cycle where multiple high-energy ATP molecules are produced by oxidation
•Dependent on ATP levels, and hence blood glucose levels, the ATP-controlled potassium channels (K+) close and the cell membrane depolarizes
•On depolarization, voltage controlled calcium channels (Ca2+) open and calcium flows into the cells
•An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol.
•Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER). This allows the release of Ca2+ from the ER via IP3 gated channels, and further raises the cell concentration of calcium.
•Significantly increased amounts of calcium in the cells causes release of previously synthesised insulin, which has been stored in secretory vesicles
This is the main mechanism for release of insulin and regulation of insulin synthesis. In addition some insulin synthesis and release takes place generally at food intake, not just glucose or carbohydrate intake, and the beta cells are also somewhat influenced by the autonomic nervous system. The signalling mechanisms controlling these linkages are not fully understood.Other substances known to stimulate insulin release include amino acids from ingested proteins, acetylcholine, released from vagus nerve endings (parasympathetic nervous system), cholecystokinin,released by enteroendocrine cells of intestinal mucosa and glucose-dependent insulinotropic peptide (GIP). Three amino acids (alanine, glycine and arginine) act similarly to glucose by altering the beta cell's membrane potential. Acetylcholine triggers insulin release through phospholipase C, while the last acts through the mechanism of adenylate cyclase.
The sympathetic nervous system (via Alpha2-adrenergic stimulation)inhibit the release of insulin. However, it is worth noting that circulating adrenaline will activate Beta2-Receptors on the Beta cells in the pancreatic Islets to promote insulin release. This is important since muscle cannot benefit from the raised blood sugar resulting from adrenergic stimulation (increased gluconeogenesis and glycogenolysis from the low blood insulin: glucagon state) unless insulin is present to allow for GLUT-4 translocation in the tissue. Therefore, beginning with direct innervation, norepinephrine inhibits insulin release via alpha2-receptors, then subsequently, circulating adrenaline from the adrenal medulla will stimulate beta2-receptors thereby promoting insulin release.When the glucose level comes down to the usual physiologic value, insulin release from the beta cells slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently glucagon from Islet of Langerhans' alpha cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of glycogen. By increasing blood glucose, the hyperglycemic hormones correct life-threatening hypoglycemia. Release of insulin is strongly inhibited by the stress hormone norepinephrine (noradrenaline), which leads to increased blood glucose levels during stress.
Oscillations
Insulin release from pancreas oscillates with a period of 3–6 minutes.
Even during digestion, generally one or two hours following a meal, insulin release from pancreas is not continuous, but oscillates with a period of 3–6 minutes, changing from generating a blood insulin concentration more than ~800 pmol/l to less than 100 pmol/l.This is thought to avoid downregulation of insulin receptors in target cells and to assist the liver in extracting insulin from the blood.This oscillation is important to consider when administering insulin-stimulating medication, since it is the oscillating blood concentration of insulin release which should, ideally, be achieved, not a constant high concentration.It is also important to consider in that all methods of insulin replacement can never hope to replicate this delivery mechanism precisely. This may be achieved by delivering insulin rhythmically to the portal vein or by islet cell transplantation to the liver.
Signal transduction
There are special transporter proteins in cell membranes through which glucose from the blood can enter a cell. These transporters are, indirectly, under blood insulin's control in certain body cell types (e.g., muscle cells). Low levels of circulating insulin, or its absence, will prevent glucose from entering those cells (e.g., in Type 1 diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (e.g., the reduced insulin sensitivity characteristic of Type 2 diabetes), resulting in decreased glucose absorption. In either case, there is 'cell starvation', weight loss, sometimes extreme. In a few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is, characteristically, the same: elevated blood glucose levels.
Activation of insulin receptors leads to internal cellular mechanisms that directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane that transport glucose into the cell. The genes that specify the proteins that make up the insulin receptor in cell membranes have been identified and the structure of the interior, cell membrane section, and now, finally after more than a decade, the extra-membrane structure of receptor.Two types of tissues are most strongly influenced by insulin, as far as the stimulation of glucose uptake is concerned: muscle cells (myocytes) and fat cells (adipocytes). The former are important because of their central role in movement, breathing, circulation, etc, and the latter because they accumulate excess food energy against future needs. Together, they account for about two-thirds of all cells in a typical human body.
Effects
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
The actions of insulin on the global human metabolism level include:
•Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about ⅔ of body cells).
•Increase of DNA replication and protein synthesis via control of amino acid uptake.
•Modification of the activity of numerous enzymes.
The actions of insulin on cells include:
•Increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin which is directly useful in reducing high blood glucose levels as in diabetes.
•Increased fatty acid synthesis – insulin forces fat cells to take in blood lipids which are converted to triglycerides; lack of insulin causes the reverse.
•Increased esterification of fatty acids – forces adipose tissue to make fats (i.e., triglycerides) from fatty acid esters; lack of insulin causes the reverse.
•Decreased proteolysis – decreasing the breakdown of protein.
•Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse.
•Decreased gluconeogenesis – decreases production of glucose from non-sugar substrates, primarily in the liver (remember, the vast majority of endogenous insulin arriving at the liver never leaves the liver); lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.
•Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption.
•Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Thus lowers potassium levels in blood.
•Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract.
Degradation
Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule that is produced endogenously by the pancreatic beta cells is finally degraded about 71 minutes after its initial release into circulation.
Hypoglycemia
Although other cells can use other fuels for a while (most prominently fatty acids), neurons depend on glucose as a source of energy in the non-starving human. They do not require insulin to absorb glucose, unlike muscle and adipose tissue, and they have very small internal stores of glycogen. Glycogen stored in liver cells (unlike glycogen stored in muscle cells) can be converted to glucose, and released into the blood, when glucose from digestion is low or absent, and the glycerol backbone in triglycerides can also be used to produce blood glucose.
Sufficient lack of glucose and scarcity of these sources of glucose can dramatically make itself manifest in the impaired functioning of the central nervous system; dizziness, speech problems, and even loss of consciousness, can occur. Low glucose is known as hypoglycemia or, in cases producing unconsciousness, "hypoglycemic coma" (sometimes termed "insulin shock" from the most common causative agent). Endogenous causes of insulin excess (such as an insulinoma) are very rare, and the overwhelming majority of insulin-excess induced hypoglycemia cases are iatrogenic and usually accidental. There have been a few reported cases of murder, attempted murder, or suicide using insulin overdoses, but most insulin shocks appear to be due to errors in dosage of insulin (e.g., 20 units of insulin instead of 2) or other unanticipated factors (didn't eat as much as anticipated, or exercised more than expected, or unpredicted kinetics of the subcutaneously injected insulin itself).
Possible causes of hypoglycemia include:
•External insulin (usually injected subcutaneously).
•Oral hypoglycemic agents (e.g., any of the sulfonylureas, or similar drugs, which increase insulin release from beta cells in response to a particular blood glucose level).
•Ingestion of low-carbohydrate sugar substitutes (animal studies show these can trigger insulin release (albeit in much smaller quantities than sugar) according to a report in Discover magazine, August 2004, p 18, although this is only an issue in people who do not have diabetes, or those who have type 2 diabetes because type 1 diabetes is caused by a complete absence of insulin. As a result, this can never be a cause of hypoglycemia in patients with type 1 diabetes since there is no endogenous insulin production to stimulate.
Diseases and syndromes
There are several conditions in which insulin disturbance is pathologic:
•Diabetes mellitus – general term referring to all states characterized by hyperglycemia.
oType 1 – autoimmune-mediated destruction of insulin producing beta cells in the pancreas resulting in absolute insulin deficiency.
oType 2 – multifactoral syndrome with combined influence of genetic susceptibility and influence of environmental factors, the best known being obesity, age, and physical inactivity, resulting in insulin resistance in cells requiring insulin for glucose absorption. This form of diabetes is strongly inherited.
oOther types of impaired glucose tolerance (see the diabetes article).
•Insulinoma - a tumor of pancreatic beta cells producing excess of insulin or reactive hypoglycemia.
•Metabolic syndrome – a poorly understood condition first called Syndrome X by Gerald Reaven, Reaven's Syndrome after Reaven, CHAOS in Australia (from the signs which seem to travel together), and sometimes prediabetes. It is currently not clear whether these signs have a single, treatable cause, or are the result of body changes leading to type 2 diabetes. It is characterized by elevated blood pressure, dyslipidemia (disturbances in blood cholesterol forms and other blood lipids), and increased waist circumference (at least in populations in much of the developed world). The basic underlying cause may be the insulin resistance of type 2 diabetes which is a diminished capacity for insulin response in some tissues (e.g., muscle, fat) to respond to insulin. Commonly, morbidities such as essential hypertension, obesity, Type 2 diabetes, and cardiovascular disease (CVD) develop.
•Polycystic ovary syndrome – a complex syndrome in women in the reproductive years where there is anovulation and androgen excess commonly displayed as hirsutism. In many cases of PCOS insulin resistance is present.
Testosterone
Testosterone is a steroid hormone from the androgen group. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. It is the principal male sex hormone and an anabolic steroid.
In both men and women, testosterone plays a key role in health and well-being as well as in sexual functioning. Examples include enhanced libido, increased energy, increased production of red blood cells and protection against osteoporosis. On average, an adult human male body produces about forty to sixty times more testosterone than an adult female body, but females are, from a behavioral perspective (rather than from an anatomical or biological perspective), more sensitive to the hormone.However the overall ranges for male and female are very wide, such that the ranges actually overlap at the low end and high end respectively.
Like other steroid hormones, testosterone is derived from cholesterol. The largest amounts of testosterone are produced by the testes in men. It is also synthesized in far smaller quantities in women by the thecal cells of the ovaries, by the placenta, as well as by the zona reticularis of the adrenal cortex in both sexes.
In the testes, testosterone is produced by the Leydig cells. The male generative glands also contain Sertoli cells which require testosterone for spermatogenesis. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein, sex hormone binding globulin (SHBG).
In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone effects can be classified as virilizing and anabolic, although the distinction is somewhat artificial, as many of the effects can be considered both.
•Anabolic effects include growth of muscle mass and strength, increased bone density and strength, and stimulation of linear growth and bone maturation.
•Virilizing effects include maturation of the sex organs, particularly the penis and the formation of the scrotum in unborn children, and after birth (usually at puberty) a deepening of the voice, growth of the beard and axillary hair. Many of these fall into the category of male secondary sex characteristics.
Early postnatal effects
Early postnatal effects are the first visible effects of rising androgen levels in childhood, and occur in both boys and girls in puberty.
•Adult-type body odour
•Increased oiliness of skin and hair, acne
•Pubarche (appearance of pubic hair)
•Axillary hair
•Growth spurt, accelerated bone maturation
•Develop hair on upper lip and sideburns.
Advanced postnatal effects
Advanced postnatal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the blood.
•Enlargement of sebaceous glands. This might cause acne.
•Phallic enlargement or clitoromegaly
•Increased libido and frequency of erection or clitoral engorgement
•Pubic hair extends to thighs and up toward umbilicus
•Facial hair (sideburns, beard, moustache)
•Chest hair, periareolar hair, perianal hair
•Subcutaneous fat in face decreases
•Increased muscle strength and mass
•Deepening of voice
•Growth of the Adam's apple
•Growth of spermatogenic tissue in testes, male fertility
•Growth of jaw, brow, chin, nose, and remodeling of facial bone contours
•Shoulders become broader and rib cage expands
•Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women.
Adult testosterone effects
Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels decline in the later decades of adult life.
•Libido and clitoral engorgement/penile erection frequency.
•Mental and physical energy
•The most recent and reliable studies have shown that testosterone does not cause Prostate cancer, but that it can increase the rate of spread of any existing prostate cancer.Recent studies have also shown its importance in maintaining cardio vascular health.
•Increase eumelanin and reduce pheomelanin
Testosterone regulates the population of thromboxane A2 receptors on megakaryocytes and platelets and hence platelet aggregation in humans.
Mechanism
The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors.
Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T.[citation needed] The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. It is important to note that if there is a 5-alpha reductase deficiency, the body (of a human) will continue growing into a female with testicles.
Androgen receptors occur in many different vertebrate body system tissues, and both males and females respond similarly to similar levels. Greatly differing amounts of testosterone prenatally, at puberty, and throughout life account for a share of biological differences between males and females.
The bones and the brain are two important tissues in humans where the primary effect of testosterone is by way of aromatization to estradiol. In the bones, estradiol accelerates maturation of cartilage into bone, leading to closure of the epiphyses and conclusion of growth. In the central nervous system, testosterone is aromatized to estradiol. Estradiol rather than testosterone serves as the most important feedback signal to the hypothalamus (especially affecting LH secretion). In many mammals, prenatal or perinatal "masculinization" of the sexually dimorphic areas of the brain by estradiol derived from testosterone programs later male sexual behavior.
The human hormone testosterone is produced in greater amounts by males, and less by females. The human hormone estrogen is produced in greater amounts by females, and less by males. Testosterone causes the appearance of masculine traits (i.e., deepening voice, pubic and facial hairs, muscular build, etc.) Like men, women rely on testosterone to maintain libido, bone density and muscle mass throughout their lives. In men, inappropriately high levels of estrogens lower testosterone, decrease muscle mass, stunt growth in teenagers, introduce gynecomastia, increase feminine characteristics, and decrease susceptibility to prostate cancer, reduces libido and causes erectile dysfunction and can cause excessive sweating and hot flushes. However, an appropriate amount of estrogens is required in the male in order to ensure well-being, bone density, libido, erectile function, etc.
Free Androgen Index or FAI is a ratio used to determine abnormal androgen status in humans. The ratio is the total testosterone level divided by the sex hormone binding globulin (SHBG) level, and then multiplying by a constant, usually 100. The concentrations of testosterone and SHBG are normally measured in nanomols per liter. FAI has no units.
The majority of testosterone in the blood does not exist as the free molecule. Instead around half is tightly bound to sex hormone binding globulin, and the other half is weakly bound to albumin. Only a small percentage is unbound, under 3% in females, and less than 0.7% in males. Since only the free testosterone is able to bind to tissue receptors to exert its effects, it is believed that free testosterone is the best marker of a person's androgen status. However, free testosterone is difficult and expensive to measure, and many laboratories do not offer this service.
The free androgen index is intended to give a guide to the free testosterone level, but it is not very accurate. Consequently, there are no universally agreed 'normal ranges', and levels slightly above or below quoted laboratory reference ranges may not be clinically significant.
Reference ranges depend on the constant in the calculation - 100 is used in the formula above, and the following suggested ranges are based on this. As with any laboratory measurement, however, it is vital that results are compared against the reference range quoted for that laboratory. Neither FAI nor free or total testosterone measurements should be interpreted in isolation; as a bare minimum, gonadotropin levels should also be measured.
As a guide, in healthy adult men typical FAI values are 30-150. Values below 30 may indicate testosterone deficiency, which may contribute to fatigue, erectile dysfunction, weight gain, osteoporosis and loss of secondary sex characteristics. In women, androgens are most often measured when there is concern that they may be raised (as in hirsutism or the polycystic ovary syndrome). Typical values for the FAI in women are <7.
Dehydroepiandrosterone
Dehydroepiandrosterone (DHEA) is a natural steroid hormone precursor (prohormone) produced from cholesterol by the adrenal glands, the gonads, adipose tissue, brain and in the skin (by an autocrine mechanism). DHEA is the precursor of androstenedione, which can undergo further conversion to produce the androgen testosterone and the estrogens estrone and estradiol. DHEA is also a potent sigma-1 agonist.
Dehydroepiandrosterone sulfate
Dehydroepiandrosterone sulfate (DHEAS) is the sulfated version of DHEA. This conversion is reversibly catalyzed by sulfotransferase (SULT2A1) primarily in the adrenals, the liver, and small intestine. In the blood, most DHEA is found as DHEAS with levels that are about 300 times higher than those of free DHEA. Orally-ingested DHEA is converted to its sulfate when passing through intestines and liver. Whereas DHEA levels naturally reach their peak in the early morning hours, DHEAS levels show no diurnal variation. From a practical point of view, measurement of DHEAS is preferable to DHEA, as levels are more stable.
DHEA is produced from cholesterol through two cytochrome P450 enzymes. Cholesterol is converted to pregnenolone by the enzyme P450 scc (side chain cleavage); then another enzyme, CYP17A1, converts pregnenolone to 17α-Hydroxypregnenolone and then to DHEA. In humans, DHEA is the dominant steroid hormone and precursor of all sex steroids.
Role
DHEA can be understood as a prohormone for the sex steroids. DHEAS may be viewed as buffer and reservoir. As most DHEA is produced by the zona reticularis of the adrenal, it is argued that there is a role in the immune and stress response.[who?]
As almost all DHEA is derived from the adrenal glands, blood measurements of DHEAS/DHEA are useful to detect excess adrenal activity as seen in adrenal cancer or hyperplasia, including certain forms of congenital adrenal hyperplasia. Women with polycystic ovary syndrome tend to have elevated levels of DHEAS.
Sex hormone-binding globulin
Sex hormone-binding globulin (SHBG) is a glycoprotein that binds to sex hormones, specifically testosterone and estradiol. Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound by transcortin.
SHBG is produced by the liver cells and is released into the bloodstream. Other sites that produce SHBG are the brain, uterus, and placenta and vagina. In addition SHBG is produced by the testes; testes-produced SHBG is also called androgen-binding protein. The gene for SHBG is located on chromosome 17.
Conditions with high or low levels
Conditions with low SHBG include polycystic ovary syndrome, diabetes, and hypothyroidism. Conditions with high SHBG include pregnancy, hyperthyroidism, and anorexia nervosa. There has recently been research to link high SHBG levels with breast and testicular cancer as well.
When determining levels of circulating estradiol or testosterone, either a total measurement could be done that includes the "free" and the bound fractions, or only the "free" hormone could be measured. A free androgen index expresses the ratio of testosterone to the sex hormone binding globulin and can be used to summarise the activity of free testosterone.
The total testosterone is likely the most accurate measurement of testosterone levels and should always be measured at 8 o'clock in the morning. Sex hormone binding globulin can be measured separate from the total fraction of testosterone.
Growth hormone (GH)
Growth hormone (GH) or somatotropin (STH) is a protein hormone which stimulates growth and cell reproduction in humans and other animals. It is a 191-amino acid, single chain polypeptide hormone which is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland. Several molecular forms of GH circulate. Much of the growth hormone in the circulation is bound to a protein (growth hormone binding protein, GHBP) which is derived from the growth hormone receptor.
GH is secreted into the blood by the somatotrope cells of the anterior pituitary gland, in larger amounts than any other pituitary hormone. Secretion levels are highest during puberty. The transcription factor PIT-1 stimulates both the development of these cells and their production of GH. Failure of development of these cells, as well as destruction of the anterior pituitary gland, results in GH deficiency.
Regulation
Peptides released by neurosecretory nuclei of the hypothalamus into the portal venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes. However, although the balance of these stimulating and inhibiting peptides determines GH release, this balance is affected by many physiological stimulators and inhibitors of GH secretion.
Stimulators of GH secretion include:
growth hormone releasing hormone (GHRH) from the arcuate nucleus
ghrelin
sleep
exercise
low levels of blood sugar (hypoglycemia)
dietary protein
estradiol
arginine
Inhibitors of GH secretion include:
somatostatin from the periventricular nucleus
circulating concentrations of GH and IGF-1 (negative feedback)
dietary carbohydrate
glucocorticoids
In addition to control by endogenous processes,a number of foreign compounds (xenobiotics)are now known to influence GH secretion and function,highlighting the fact that the GH-IGF axis is an emerging target for certain endocrine disrupting chemicals.
Functions of GH
Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones GH acts by interacting with a specific receptor on the surface of cells.
Increasing height
Height growth in childhood is the best known effect of GH action, and appears to be stimulated by at least two mechanisms.GH directly stimulates division and multiplication of chondrocytes of cartilage. These are the primary cells in the growing ends (epiphyses) of children's long bones (arms, legs, digits).
GH also stimulates production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process, and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it apparently both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.
Other functions
Although height growth is the best known effect of GH, it serves many other metabolic functions as well.
It increases calcium retention, and strengthens and increases the mineralization of bone.
It increases muscle mass through the creation of new muscle cells (i.e. hyperplasia, which differs from hypertrophy)
It promotes lipolysis, which results in the reduction of adipose tissue (body fat).
It increases protein synthesis and stimulates the growth of all internal organs excluding the brain.
It plays a role in fuel homeostasis.
It reduces liver uptake of glucose, an effect that opposes that of insulin.
It promotes liver gluconeogenesis.
It contributes to the maintenance and function of pancreatic islets.
It stimulates the immune system.
Clinical problems
Growth hormone excess: (acromegaly and pituitary gigantism): The most common disease of GH excess is a pituitary tumor comprised of somatotroph cells of the anterior pituitary. These somatotroph adenomas are benign and grow slowly, gradually producing more and more GH. For years, the principal clinical problems are those of GH excess. Eventually the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement.
Prolonged GH excess thickens the bones of the jaw, fingers and toes. Resulting heaviness of the jaw and increased thickness of digits is referred to as acromegaly. Accompanying problems can include pressure on nerves (e.g., carpal tunnel syndrome), muscle weakness, insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.
GH-secreting tumors are typically recognized in the 5th decade of life. It is extremely rare for such a tumor to occur in childhood, but when it does the excessive GH can cause excessive growth, traditionally referred to as pituitary gigantism.
Surgical removal is the usual treatment for GH-producing tumors. In some circumstances focused radiation or a GH antagonist such as bromocriptine or octreotide may be employed to shrink the tumor or block function.
Growth hormone deficiency: Deficiency of GH produces significantly different problems at various ages. In children, growth failure and short stature are the major manifestations of GH deficiency. In adults the effects of deficiency are more subtle, and may include deficiencies of strength, energy, and bone mass, as well as increased cardiovascular risk.
There are many causes of GH deficiency, including mutations of specific genes, congenital malformations involving the hypothalamus and/or pituitary gland, and damage to the pituitary from injury, surgery or disease.
Diagnosis of GH deficiency involves a multiple step diagnostic process, usually culminating in GH stimulation test(s) to see if the patient's pituitary gland will release a pulse of GH when provoked by various stimuli.
GH deficiency is treated by replacing GH. All GH in current use is a biosynthetic version of human GH, manufactured by recombinant DNA technology. As GH is a large protein molecule, it must be injected into subcutaneous tissue to get it into the blood (injections no longer have to enter muscle mass since 1985 with the production of synthetic GH). When the patient has had a long-standing deficiency of GH, benefits of treatment are often dramatic and gratifying and side effects of treatment are rare. Increased growth in childhood can result in dramatically improved adult height.
GH is used as replacement therapy in adults with GH deficiency of either childhood-onset (after completing growth phase) or adult-onset (usually as a result of an acquired pituitary tumor). In these patients, benefits have variably included reduced fat mass, increased lean mass, increased bone density, improved lipid profile, reduced cardiovascular risk factors, and improved psychosocial well-being.
Endocrine glands are glands that secrete their product (hormones) directly into the blood rather than through a duct. This group contains the glands of the Endocrine system.
Chemistry
1. Most hormones are steroids or amino acid based.
2. Hormones alter cell activity by stimulating or inhibiting characteristic cellular processes of their target cells.
3. Cell responses to hormone stimulation may involve changes in membrane permeability; enzyme synthesis, activation, or inhibition; secretory activity; gene activation; and mitosis.
4. Second-messenger mechanisms employing intracellular messengers and transduced by G proteins are a common means by which amino acid–based hormones interact with their target cells. In the cyclic AMP system, the hormone binds to a plasma membrane receptor that couples to a G protein. When the G protein is activated it, in turn, couples to adenylate cyclase, which catalyzes the synthesis of cyclic AMP from ATP. Cyclic AMP initiates reactions that activate protein kinases and other enzymes, leading to cellular response. The PIP-calcium signal mechanism, involving phosphatidyl inositol, is another important second-messenger system. Other second messengers are cyclic GMP and calcium.
5. Steroid hormones (and thyroid hormone) enter their target cells and effect responses by activating DNA, which initiates messenger RNA formation leading to protein synthesis. Target Cell Specificity
6. The ability of a target cell to respond to a hormone depends on the presence of receptors, within the cell or on its plasma membrane, to which the hormone can bind.
7. Hormone receptors are dynamic structures. Changes in number and sensitivity of hormone receptors may occur in response to high or low levels of stimulating hormones.
8. Blood levels of hormones reflect a balance between secretion and degradation/excretion. The liver and kidneys are the major organs that degrade hormones; breakdown products are excreted in urine and feces.
9. Hormone half-life and duration of activity are limited and vary from hormone to hormone.
Interaction of Hormones at Target Cells
10. Permissiveness is the situation in which a hormone cannot exert its full effects without the presence of another hormone.
11. Synergism occurs when two or more hormones produce the same effects in a target cell and their results are amplified.
12. Antagonism occurs when a hormone opposes or reverses the effect of another hormone.
Control of Hormone Release
13. Endocrine organs are activated to release their hormones by humoral, neural, or hormonal stimuli. Negative feedback is important in regulating hormone levels in the blood.
14. The nervous system, acting through hypothalamic controls, can in certain cases override or modulate hormonal effects.
Table of endocrine glands and secreted hormones
Hypothalamus
Secreted hormone
Abbreviation
From cells
Effect
Thyrotropin-releasing hormone
TRH
Parvocellular neurosecretory neurons
Release thyroid-stimulating hormone from anterior pituitary (primarily)Stimulate prolactin release from anterior pituitary.
Gonadotropin-releasing hormone
GnRH
Neuroendocine cells of the Preoptic area
Release of FSH and LH from anterior pituitary.
Growth hormone-releasing hormone
GHRH
Neuroendocrine neurons of the Arcuate nucleus
Release GH from anterior pituitary
Corticotropin-releasing hormone
CRH
Parvocellular neurosecretory neurons
Release ACTH from anterior pituitary
Vasopressin
Parvocellular neurosecretory neurons
Increases permeability of distal convoluted tubule and collecting duct to water in the nephrons of the kidney, thus increasing water reabsorbiton.
Somatostatin, also growth hormone-inhibiting hormone
SS or GHIH
Neuroendocrince cells of the Periventricular nucleus
Inhibit release of GH and TSH from anterior pituitary
Prolactin inhibiting hormone or Dopamine
PIH or DA
Dopamine neurons of the arcuate nucleus
Inhibit release of prolactin and TSH from anterior pituitary
Prolactin-releasing hormone
PRH
Release prolactin from anterior pituitary
Pineal body
Secreted hormone
From cells
Effect
Melatonin (Primarily)
Pinealocytes
antioxidant and causes drowsiness
Pituitary gland (hypophysis)
Anterior pituitary lobe (adenohypophysis)
Secreted hormone
From cells
Effect
Growth hormone
Somatotropes
stimulates growth and cell reproduction
Release Insulin-like growth factor 1 from liver
Prolactin
Lactotropes
milk production in mammary glandssexual gratification after sexual acts
Adrenocorticotropic hormone or corticotropin
Corticotropes
synthesis of corticosteroids (glucocorticoids and androgens) in adrenocortical cells
Lipotropin
Corticotropes
lipolysis and steroidogenesis,stimulates melanocytes to produce melanin
Thyroid-stimulating hormone or thyrotropin
Thyrotropes
stimulates thyroid gland to secrete thyroxine (T4) and triiodothyronine (T3)
Follicle-stimulating hormone
Gonadotropes
In female: stimulates maturation of Graafian follicles in ovary.
In male: spermatogenesis, enhances production of androgen-binding protein by the Sertoli cells of the testes
Luteinizing hormone
Gonadotropes
In female: ovulation
In male: stimulates Leydig cell production of testosterone
Posterior pituitary lobe (neurohypophysis)
Secreted hormone
From cells
Effect
Oxytocin
Magnocellular neurosecretory cells
Contraction of cervix and vagina
Involved in orgasm, trust between people.and circadian homeostasis (body temperature, activity level, wakefulness) release breast milk
Vasopressin or antidiuretic hormone
Magnocellular neurosecretory cells
retention of water in kidneys
moderate vasoconstriction
Oxytocin and Anti-Diuretic Hormone are not secreted in the posterior lobe, merely stored.
Intermediate pituitary lobe (pars intermedia)
Secreted hormone
From cells
Effect
Melanocyte-stimulating hormone
Melanotroph
melanogenesis by melanocytes in skin and hair.
Thyroid
Secreted hormone
From cells
Effect
Triiodothyronine
Thyroid epithelial cell
potent form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines,
affect protein synthesis
Thyroxine or tetraiodothyronine
Thyroid epithelial cells
less active form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines,
affect protein synthesis, often functions as a prohormone
Calcitonin
Parafollicular cells
Construct bone
reduce blood Ca2+
Parathyroid
Secreted hormone
From cells
Effect
Parathyroid hormone
Parathyroid chief cell
increase blood Ca2+: *indirectly stimulate osteoclasts
Ca2+ reabsorption in kidney
activate vitamin D
(Slightly) decrease blood phosphate:
(decreased reuptake in kidney but increased uptake from bones
activate vitamin D)
Heart
Secreted hormone
From cells
Effect
Atrial-natriuretic peptide
Cardiac myocytes
Reduce blood pressure by:
reducing systemic vascular resistance, reducing blood water, sodium and fats
Brain natriuretic peptide
Cardiac myocytes
(To a minor degree than ANP) reduce blood pressure by:
reducing systemic vascular resistance, reducing blood water, sodium and fats
Striated muscle
Secreted hormone
From cells
Effect
Thrombopoietin
Myocytes
stimulates megakaryocytes to produce platelets
Skin
Secreted hormone
Effect
Calcidiol (25-hydroxyvitamin D3)
Inactive form of Vitamin D3
Adipose tissue
Secreted hormone
From cells
Effect
Leptin (Primarily)
Adipocytes
decrease of appetite and increase of metabolism.
Estrogens(mainly Estrone)
Adipocytes
Stomach
Secreted hormone
From cells
Effect
Gastrin(Primarily)
G cells
Secretion of gastric acid by parietal cells
Ghrelin
P/D1 cells
Stimulate appetite,
secretion of growth hormone from anterior pituitary gland
Neuropeptide Y
increased food intake and decreased physical activity
Secretin
S cells
Secretion of bicarbonate from liver, pancreas and duodenal Brunner's glands
Enhances effects of cholecystokinin Stops production of gastric juice
Somatostatin
D cells
Suppress release of gastrin, cholecystokinin (CCK), secretin, motilin, vasoactive intestinal peptide(VIP), gastric inhibitory polypeptide(GIP), enteroglucagon
Lowers rate of gastric emptying Reduces smooth muscle contractions and blood flow within the intestine
Histamine
ECL cells
stimulate gastric acid secretion
Endothelin
X cells
Smooth muscle contraction of stomach
Duodenum
Secreted hormone
From cells
Effect
Cholecystokinin
I cells
Release of digestive enzymes from pancreas
Release of bile from gallbladder, hunger suppressant
Liver
Secreted hormone
From cells
Effect
Insulin-like growth factor (or somatomedin) (Primarily)
Hepatocytes
insulin-like effects
regulate cell growth and development
Angiotensinogen and angiotensin
Hepatocytes
vasoconstriction
release of aldosterone from adrenal cortex dipsogen.
Thrombopoietin
Hepatocytes
stimulates megakaryocytes to produce platelets
Pancreas
Secreted hormone
From cells
Effect
Insulin (Primarily)
ß Islet cells
Intake of glucose, glycogenesis and glycolysis in liver and muscle from blood
intake of lipids and synthesis of triglycerides in adipocytes Other anabolic effects
Glucagon (Also Primarily)
a Islet cells
glycogenolysis and gluconeogenesis in liver
increases blood glucose level
Somatostatin
d Islet cells
Inhibit release of insulin
Inhibit release of glucagon Suppress the exocrine secretory action of pancreas.
Pancreatic polypeptide
PP cells
Unknown
Kidney
Secreted hormone
From cells
Effect
Renin (Primarily)
Juxtaglomerular cells
Activates the renin-angiotensin system by producing angiotensin I of angiotensinogen
Erythropoietin (EPO)
Extraglomerular mesangial cells
Stimulate erythrocyte production
Calcitriol (1,25-dihydroxyvitamin D3)
Active form of vitamin D3
Increase absorption of calcium and phosphate from gastrointestinal tract and kidneys inhibit release of PTH
Thrombopoietin
stimulates megakaryocytes to produce platelets
Adrenal glands
Adrenal cortex
Secreted hormone
From cells
Effect
Glucocorticoids (chiefly cortisol)
zona fasciculata and zona reticularis cells
Stimulation of gluconeogenesis
Inhibition of glucose uptake in muscle and adipose tissue Mobilization of amino acids from extrahepatic tissues Stimulation of fat breakdown in adipose tissue anti-inflammatory and immunosuppressive
Mineralocorticoids (chiefly aldosterone)
Zona glomerulosa cells
Increase blood volume by reabsorption of sodium in kidneys (primarily)
Potassium and H+ secretion in kidney.
Androgens (including DHEA and testosterone)
Zona fasciculata and Zona reticularis cells
Virilization, anabolic
Adrenal medulla
Secreted hormone
From cells
Effect
Adrenaline (epinephrine) (Primarily)
Chromaffin cells
Fight-or-flight response:
Boost the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasodilation, increasing catalysis of glycogen in liver, breakdown of lipids in fat cells)
Dilate the pupils
Suppress non-emergency bodily processes (e.g., digestion)
Suppress immune system
Noradrenaline (norepinephrine)
Chromaffin cells
Fight-or-flight response:
Boost the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasoconstriction and increased blood pressure, breakdown of lipids in fat cells)
Increase skeletal muscle readiness.
Dopamine
Chromaffin cells
Increase heart rate and blood pressure
Enkephalin
Chromaffin cells
Regulate pain
Testis
Secreted hormone
From cells
Effect
Androgens (chiefly testosterone)
Leydig cells
Anabolic: growth of muscle mass and strength, increased bone density, growth and strength,
Virilizing: maturation of sex organs, formation of scrotum, deepening of voice, growth of beard and axillary hair.
Estradiol
Sertoli cells
Prevent apoptosis of germ cells
Inhibin
Sertoli cells Inhibit production of FSH
Ovary
These originate either from the ovarian follicle or the corpus luteum.
Secreted hormone
From cells
Effect
Progesterone
Granulosa cells, theca cells
Support pregnancy:
Convert endometrium to secretory stage
Make cervical mucus permeable to sperm.
Inhibit immune response, e.g., towards the human embryo
Decrease uterine smooth muscle contractility
Inhibit lactation
Inhibit onset of labor
Other:
Raise epidermal growth factor-1 levels
Increase core temperature during ovulation
Reduce spasm and relax smooth muscle
(widen bronchi and regulate mucus)
Anti-inflammatory
Reduce gall-bladder activity
Normalize blood clotting and vascular tone, zinc
and copper levels,
cell oxygen levels, and use of fat stores for energy
Assist in thyroid function and bone growth by osteoblasts
Increase resilience in bone, teeth, gums, joint, tendon,
ligament, and skin
Promote healing by regulating collagen
Provide nerve function and healing by regulating myelin
Prevent endometrial cancer by regulating effects of estrogen
Androstenedione
Theca cells
Substrate for estrogen
Estrogens (mainly estradiol)
Granulosa cells
Structural:
Promote formation of female secondary sex characteristics
Accelerate height growth
Accelerate metabolism (burn fat)
Reduce muscle mass
Stimulate endometrial growth
Increase uterine growth
Maintain blood vessels and skin
Reduce bone resorption, increase bone formation
Protein synthesis:
Increase hepatic production of binding proteins
Coagulation:
Increase circulating level of factors 2, 7, 9, 10, antithrombin III, plasminogen
Increase platelet adhesiveness
Increase HDL, triglyceride, height growth
Decrease LDL, fat deposition
Fluid balance:
Regulate salt (sodium) and water retention
Increase growth hormone
Increase cortisol, SHBG
Gastrointestinal tract:
Reduce bowel motility
Increase cholesterol in bile
Melanin:
Increase pheomelanin, reduce eumelanin
Cancer:
Support hormone-sensitive breast cancers (Suppression of production in the body of estrogen is a treatment for these cancers.)
Lung function:
Promote lung function by supporting alveoli
Inhibin
Granulosa cells
Inhibit production of FSH from anterior pituitary
Placenta (when pregnant)
Secreted hormone
From cells
Effect
Progesterone (Primarily)
Support pregnancy
Inhibit immune response, towards the fetus.
Decrease uterine smooth muscle contractility
Inhibit lactation
Inhibit onset of labor.
Support fetal production of adrenal mineralo-
and glucosteroids.
Other effects on mother similar to ovarian
follicle-progesterone
Estrogens (mainly Estriol) (Also Primarily)
Effects on mother similar to ovarian follicle estrogen
Human chorionic gonadotropin
Syncytiotrophoblast
promote maintenance of corpus luteum during
beginning of pregnancy
Inhibit immune response, towards the human embryo.
Human placental lactogen
Syncytiotrophoblast
increase production of insulin and IGF-1
increase insulin resistance and carbohydrate intolerance
Inhibin
Fetal Trophoblasts
suppress FSH
Uterus (when pregnant)
Secreted hormone
From cells
Effect
Prolactin
Decidual cells
milk production in mammary glands
Relaxin
Decidual cells
Unclear in humans
Estradiol
Estradiol (17β-estradiol) (also oestradiol) is a sex hormone. Mislabelled the "female" hormone, it is also present in males; it represents the major estrogen in humans. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs including bone structure.
Estradiol, like other steroids, is derived from cholesterol. After side chain cleavage and utilizing the delta-5 pathway or the delta-4 pathway androstenedione is the key intermediary. A fraction of the androstenedione is converted to testosterone, which in turn undergoes conversion to estradiol by an enzyme called aromatase. Alternatively, androstenedione is "aromatized" to estrone, which is subsequently converted to estradiol.
Production
During the reproductive years, most estradiol in women is produced by the granulosa cells of the ovaries by the aromatization of androstenedione (produced in the theca folliculi cells) to estrone, followed by conversion of estrone to estradiol by 17β-hydroxysteroid reductase. Smaller amounts of estradiol are also produced by the adrenal cortex, and (in men), by the testes.
Estradiol is not only produced in the gonads: in both sexes, precursor hormones, specifically testosterone, are converted by aromatization to estradiol. In particular, fat cells are active to convert precursors to estradiol, and will continue to do so even after menopause. Estradiol is also produced in the brain and in arterial walls.
Mechanism of action
Estradiol enters cells freely and interacts with a cytoplasmic target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell.
Estradiol binds well to both estrogen receptors, ERα and ERβ, in contrast to certain other estrogens, notably medications that preferentially act on one of these receptors. These medications are called selective estrogen receptor modulators, or SERMs.
Estradiol is the most potent naturally-occurring estrogen.
Recently there has been speculation about a membrane estrogen receptor, ERX.
Metabolism
In plasma, estradiol is largely bound to sex hormone binding globulin, also to albumin, -only a fraction is free and biologically active. Deactivation includes conversion to less active estrogens such as estrone and estriol. Estriol is the major urinary metabolite. Estradiol is conjugated in the liver by sulfate and glucuronide formation and as such excreted via the kidneys. Some of the watersoluble conjugates are excreted via the bile duct, and partly reabsorbed after hydrolysis from the intestinal tract. This enterohepatic circulation contributes to maintaining estradiol levels.
Measurement
Serum estradiol measurement in women reflects primarily the activity of the ovaries. As such they are useful in the detection of baseline estrogen in women with amenorrhea or menstrual dysfunction and to detect the state of hypoestrogenicity and menopause. Furthermore, estrogen monitoring during fertility therapy assesses follicular growth and is useful in monitoring the treatment. Estrogen-producing tumors will demonstrate persistent high levels of estradiol and other estrogens. In precocious puberty estradiol levels are inappropriately increased.
Estradiol levels (blue line) during the menstrual cycle
In the normal menstrual cycle estradiol levels measure typically <50 ng/ml at menstruation, rise with follicular development, drop briefly at ovulation, and rise again during the luteal phase for a second peak. At the end of the luteal phase estradiol levels drop to their menstrual levels unless there is a pregnancy.
During pregnancy estrogen levels including estradiol rise steadily towards term. The source of these estrogens is the placenta that aromatizes prohormones produced in the fetal adrenal gland.
Effects on Female reproduction
In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of the vagina, the cervical glands, the endometrium and the lining of the fallopian tubes. It enhances growth of the myometrium. Estradiol appears necessary to maintain oocytes in the ovary. During the menstrual cycle, estradiol that is produced by the growing follicle triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to the luteinizing hormone surge, inducing ovulation. In the luteal phase estradiol, in conjunction with progesterone, prepares the endometrium for implantation. During pregnancy estradiol increases due to placental production. In baboons, blocking of estrogen production leads to pregnancy loss suggesting that estradiol has a role in the maintenance of pregnancy. Research is investigating the role of estrogens in the process of initiation of labor.
Sexual development
The development of secondary sex characteristics in women is driven by estrogens, specifically estradiol. These changes are initiated at the time of puberty, most enhanced during the reproductive years, and become less pronounced with declining estradiol support after the menopause. Thus, estradiol enhances breast development, and is responsible for changes in the body shape affecting bones, joints, fat deposition. Fat structure and skin composition are modified by estradiol.
Effects on Male reproduction
The effect of estradiol (and estrogens) upon male reproduction is complex. Estradiol is produced in the Sertoli cells of the testes. There is evidence that estradiol is to prevent apoptosis of male germ cells.
Several studies have noted that sperm counts have been declining in many parts of the world and it has been postulated that this may be related to estrogen exposure in the environment.Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.
Males with sex chromosome genetic conditions such as Klinefelters Syndrome will have a higher level of estradiol.
Bone
There is ample evidence that estradiol has a profound effect on bone. Individuals without estradiol (or other estrogens) will become tall and eunuchoid as epiphysieal closure is delayed or may not take place. Bone structure is affected resulting in early osteopenia and osteoporosis.Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
Liver
Estradiol has complex effects on the liver. It can lead to cholestasis. It affects the production of multiple proteins including lipoproteins, binding proteins, and proteins responsible for blood clotting.
Brain
Estrogens can be produced in the brain from steroid precursors. As antioxidants, they have been found to have neuroprotective function.
The positive and negative feedback loop of the menstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropins.
Estrogen is considered to play a significant role in women’s mental health. A conceptual model of how estrogen affects mood was suggested by Douma et al 2005 based on their extensive literature review relating activity of endogenous, bio-identical and synthetic estrogen with mood and well-being. They concluded that the sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlated with significant mood lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized and/or restored.
Blood vessels
Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in coronary arteries.
Oncogene
Estrogen is suspected to activate certain oncogenes, as it supports certain cancers, notably breast cancer and cancer of the uterine lining. In addition there are several benign gynecologic conditions that are dependent on estrogen such as endometriosis, leiomyomata uteri, and uterine bleeding.
Pregnancy
The effect of estradiol, together with estrone and estriol, in pregnancy is less clear. They may promote uterine blood flow, myometrial growth, sitmulate breast growth and at term, promote cervical softening and expression of myometrial oxytocin receptors.
Hormone replacement therapy
If severe side effects of low levels of estradiol in a woman's blood are experienced (commonly at the beginning of menopause or after oophorectomy), hormone replacement therapy may be prescribed. Often such therapy is combined with a progestin.
Estrogen therapy may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucus or an appropriate uterine lining.
Estrogen therapy is also used to maintain female hormone levels in male-to-female transsexuals.
if (window.runOnloadHook) runOnloadHook();
Follicle-stimulating hormone
Follicle-stimulating hormone (FSH) is a hormone synthesized and secreted by gonadotropes in the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the human body. FSH and Luteinizing hormone (LH) act synergistically in reproduction:
•In females, in the ovary FSH stimulates the growth of immature Graafian follicles to maturation. Graafian follicles are the mature follicle. Primary follicles mature to Graafian follicles. As the follicle grows, it releases inhibin, which shuts off the FSH production.
•In males, FSH enhances the production of androgen-binding protein by the Sertoli cells of the testes, and is critical for spermatogenesis.
Structure
FSH is a glycoprotein. Each monomeric unit is a protein molecule with a sugar attached to it; two of these make the full, functional protein. Its structure is similar to those of LH, TSH, and hCG. The protein dimer contains 2 polypeptide units, labeled alpha and beta subunits. The alpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92 amino acids. The beta subunits vary. FSH has a beta subunit of 118 amino acids (FSHB), which confers its specific biologic action and is responsible for interaction with the FSH-receptor. The sugar part of the hormone is composed of fucose, galactose, mannose, galactosamine, glucosamine, and sialic acid, the latter being critical for its biologic half-life. The half-life of FSH is 3-4 hours. Its molecular wt is 30000.
Activity
FSH regulates the development, growth, pubertal maturation, and reproductive processes of the human body.
• In both males and females, FSH stimulates the maturation of germ cells.
• In males, FSH induces sertoli cells to secrete inhibin and stimulates the formation of sertoli-sertoli tight junctions (zonula occludens).
• In females, FSH initiates follicular growth, specifically affecting granulosa cells. With the concomitant rise in inhibin B, FSH levels then decline in the late follicular phase. This seems to be critical in selecting only the most advanced follicle to proceed to ovulation. At the end of the luteal phase, there is a slight rise in FSH that seems to be of importance to start the next ovulatory cycle.
Like its partner, LH, FSH release at the pituitary gland is controlled by pulses of gonadotropin-releasing hormone (GnRH). Those pulses, in turn, are subject to the oestrogen feed-back from the gonads.
High FSH levels
High levels of Follicle-Stimulating Hormone are indicative of situations where the normal restricting feedback from the gonad is absent, leading to an unrestricted pituitary FSH production. Whereas this is normal in females leading up to and during postmenopause, it is abnormal during the reproductive years.
If the FSH level is high during the reproductive years, this may be a sign of:
1. Premature menopause also known as Premature Ovarian Failure
2. Gonadal dysgenesis, Turner syndrome
3. Castration
4. Swyer syndrome
5. Certain forms of CAH
6. Testicular failure.
Low FSH levels
Diminished secretion of FSH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. In females, cessation of reproductive cycles is commonly observed. Conditions with very low FSH secretions are:
1.Kallmann syndrome
2.Hypothalamic suppression
3.Hypopituitarism
4.Hyperprolactinemia
5.Gonadotropin deficiency
6.Gonadal suppression therapy
1.GnRH antagonist
2.GnRH agonist (downregulation).
Luteinizing hormone
LH surges at ovulation
Luteinizing hormone (LH, also known as lutropin) is a hormone produced by the anterior pituitary gland.
•In the female, an acute rise of LH – the LH surge – triggers ovulation.
•In the male, where LH had also been called Interstitial Cell Stimulating Hormone (ICSH),it stimulates Leydig cell production of testosterone.
Structure
LH is a glycoprotein. Each monomeric unit is a sugar-like protein molecule; two of these make the full, functional protein.
Its structure is similar to the other glycoproteins, follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG). The protein dimer contains 2 polypeptide units, labeled alpha and beta subunits that are connected by two disulfide bridges:
• The alpha subunits of LH, FSH, TSH, and hCG are identical, and contain 92 amino acids.
• The beta subunits vary. LH has a beta subunit of 121 amino acids (LHB) that confers its specific biologic action and is responsible for interaction with the LH receptor. This beta subunit contains the same amino acids in sequence as the beta sub unit of hCG and both stimulate the same receptor, however, the hCG beta subunit contains an additional 24 amino acids, and both hormones differ in the composition of their sugar moieties.
The different composition of these oligosaccharides affects bioactivity and speed of degradation. The biologic half-life of LH is 20 minutes, shorter than that of FSH (3-4 hours) or hCG (24 hours).
Activity
In both males and females, LH is essential for reproduction.
• In females, at the time of menstruation, FSH initiates follicular growth, specifically affecting granulosa cells.[5] With the rise in estrogens, LH receptors are also expressed on the maturing follicle that produces an increasing amount of estradiol. Eventually at the time of the maturation of the follicle, the estrogen rise leads via the hypothalamic interface to the “positive feed-back” effect, a release of LH over a 24-48 hour period. This 'LH surge' triggers ovulation hereby not only releasing the egg, but also initiating the conversion of the residual follicle into a corpus luteum that, in turn, produces progesterone to prepare the endometrium for a possible implantation. LH is necessary to maintain luteal function for the first two weeks. In case of a pregnancy luteal function will be further maintained by the action of hCG (a hormone very similar to LH) from the newly established pregnancy. LH supports thecal cells in the ovary that provide androgens and hormonal precursors for estradiol production.
• In the male, LH acts upon the Leydig cells of the testis and is responsible for the production of testosterone, an androgen that exerts both endocrine activity and intratesticular activity such as spermatogenesis.
The release of LH at the pituitary gland is controlled by pulses of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Those pulses, in turn, are subject to the estrogen feedback from the gonads.
Normal levels
LH levels are normally low during childhood and, in women, high after menopause.
During the reproductive years typical levels are between 5-20 mIU/ml.
Physiologic high LH levels are seen during the LH surge (v.s.); typically they last 48 hours.
Disease states
Relative elevations
In children with precocious puberty of pituitary or central origin, LH and FSH levels may be in the reproductive range instead of the low levels typical for their age.
During the reproductive years, relatively elevated LH is frequently seen in patients with the polycystic ovary syndrome; however it would be unusual for them to have LH levels outside of the normal reproductive range.
High LH levels
Persistently high LH levels are indicative of situations where the normal restricting feedback from the gonad is absent, leading to a pituitary production of both LH and FSH. While this is typical in the menopause, it is abnormal in the reproductive years. There it may be a sign of:
1. Premature menopause
2. Gonadal dysgenesis, Turner syndrome
3. Castration
4. Swyer syndrome
5. Polycystic Ovary Syndrome
6. Certain forms of CAH
7. Testicular failure
Deficient LH activity
Diminished secretion of LH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. In females, amenorrhea is commonly observed. Conditions with very low LH secretions are:
1. Kallmann syndrome
2. Hypothalamic suppression
3. Hypopituitarism
4. Eating disorder
5. Hyperprolactinemia
6. Gonadotropin deficiency
7. Gonadal suppression therapy
1.GnRH antagonist
2.GnRH agonist (downregulation)
Thyroid hormone
The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are tyrosine-based hormones produced by the thyroid gland. An important component in the synthesis is iodine. The major form of thyroid hormone in the blood is thyroxine (T4). The ratio of T4 to T3 released in the blood is roughly 20 to 1. Thyroxine is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5'-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a).
Circulation
Most of the thyroid hormone circulating in the blood is bound to transport proteins. Only a very small fraction of the circulating hormone is free (unbound) and biologically active, hence measuring concentrations of free thyroid hormones is of great diagnostic value.
When thyroid hormone is bound, it is not active, so the amount of free T3/T4 is what is important. For this reason, measuring total thyroxine in the blood can be misleading.
Type
Percent
bound to thyroxine-binding globulin (TBG)
70%
bound to transthyretin or "thyroxine-binding prealbumin" (TTR or TBPA)
10-15%
paraalbumin
15-20%
unbound T4 (fT4)
0.03%
unbound T3 (fT3)
0.3%
T3 and T4 cross the cell membrane, probably via amino acid importins, and function via a well-studied set of nuclear receptors in the nucleus of the cell, the thyroid hormone receptors.
T1a and T0a are positively charged and do not cross the membrane; they are believed to function via the trace amine-associated receptor TAAR1 (TAR1, TA1), a G-protein-coupled receptor located in the cell membrane.
Another critical diagnostic tool is measurement of the amount of thyroid-stimulating hormone (TSH) that is present.
Function
The thyronines act on the body to increase the basal metabolic rate, affect protein synthesis and increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness. The thyroid hormones are essential to proper development and differentiation of all cells of the human body. These hormones also regulate protein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds. They also stimulate vitamin metabolism. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.
Thyroid hormone leads to heat generation in humans. However, the thyronamines function via some unknown mechanism to inhibit neuronal activity; this plays an important role in the hibernation cycles of mammals and the moulting behaviour of birds. One effect of administering the thyronamines is a severe drop in body temperature.
Related diseases
Both excess and deficiency of thyroxine can cause disorders.
•Thyrotoxicosis or hyperthyroidism (an example is Graves Disease) is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men.
•Hypothyroidism (an example is Hashimoto's thyroiditis) is the case where there is a deficiency of thyroxine, triiodiothyronine, or both.
•Clinical depression can sometimes be caused by hypothyroidism.Some research has shown that T3 is found in the junctions of synapses, and regulates the amounts and activity of serotonin, norepinephrine, and Gamma-aminobutyric acid (GABA) in the brain.
Medical use of thyroid hormones
Both T3 and T4 are used to treat thyroid hormone deficiency (hypothyroidism). They are both absorbed well by the gut, so can be given orally. Levothyroxine, the most commonly used synthetic thyroxine form, is a stereoisomer of physiological thyroxine, which is metabolised more slowly and hence usually only needs once-daily administration. Natural desiccated thyroid hormones, also under the commercial name Armour Thyroid, is derived from pig thyroid glands, it is a "natural" hypothyroid treatment containing 20% T3 and traces of T2, T1 and calcitonin. Also available are synthetic combinations of T3/T4 in different ratios (such as Thyrolar) and pure-T3 medications (Cytomel).
Thyronamines have no medical usages yet, though their use has been proposed for controlled induction of hypothermia which causes the brain to enter a protective cycle, useful in preventing damage during ischemic shock.
Synthetic thyroxine was first successfully produced by Charles Robert Harington and George Barger in 1926.
Production of the thyroid hormones
Thyroxine (3,5,3',5'-tetra¬iodothyronine) is produced by follicular cells of the thyroid gland. It is produced as the precursor thyroglobulin (this is not the same as TBG), which is cleaved by enzymes to produce active T4.
Thyroxine is produced by attaching iodine atoms to the ring structures of tyrosine molecules. Thyroxine (T4) contains four iodine atoms. Triiodothyronine (T3) is identical to T4, but it has one less iodine atom per molecule.
Iodide is actively absorbed from the bloodstream by a process called 'iodine trapping' and concentrated in the thyroid follicles. (If there is a deficiency of dietary iodine, the thyroid enlarges in an attempt to trap more iodine, resulting in goitre.) Via a reaction with the enzyme thyroperoxidase, iodine is covalently bound to tyrosine residues in the thyroglobulin molecules, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). Linking two moieties of DIT produces thyroxine. Combining one particle of MIT and one particle of DIT produces triiodothyronine.
• DIT + MIT → r-T3 (biologically inactive)
• MIT + DIT → triiodothyronine (usually referred to as T3)
• DIT + DIT → thyroxine (referred to as T4)
Proteases digest iodinated thyroglobulin, releasing the hormones T4 and T3, the biologically active agents central to metabolic regulation. Thyroxine is supposedly a prohormone and a reservoir for the most active and main thyroid hormone T3. T4 is converted as required in the tissues by deiodinases. Deficiency of deiodinase can mimic an iodine deficiency. T3 is more active than T4 and is the final form of the hormone, though it is present in less quantity than T4.
Anti-thyroid drugs
Iodine uptake against a concentration gradient is mediated by a sodium iodine symporter. Perchlorate and thiocyanate are drugs that can compete with iodine at this point.
Effects of thyroxine
• Increases cardiac output
• Increases heart rate
• Increases ventilation rate
• Increases basal metabolic rate
• Potentiates the effects of catecholamines (i.e increases sympathetic activity)
• Potentiates brain development
• Thickens endometrium in females
Thyroid-stimulating hormone
Thyroid-stimulating hormone (also known as TSH or thyrotropin) is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland which regulates the endocrine function of the thyroid gland.
TSH stimulates the thyroid gland to secrete the hormones thyroxine (T4) and triiodothyronine (T3).TSH production is controlled by a Thyrotrophin Releasing Hormone, (TRH), which is manufactured in the hypothalamus and transported to the anterior pituitary gland via the superior hypophyseal artery, where it increases TSH production and release. Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release.
The level of thyroid hormones (T3 and T4) in the blood have an additional effect on the pituitary release of TSH; When the levels of T3 and T4 are low, the production of TSH is increased, and conversely, when levels of T3 and T4 are high, then TSH production is decreased. This effect creates a regulatory negative feedback loop.
Subunits of TSH
TSH is a glycoprotein and consists of two subunits, the alpha and the beta subunit.
•The α (alpha) subunit (i.e., chorionic gonadotropin alpha) is identical to that of human chorionic gonadotropin (HCG), luteinizing hormone (LH), follicle-stimulating hormone (FSH).
•The β (beta) subunit is unique to TSH, and therefore determines its function.
The TSH receptor
The TSH receptor is found mainly on thyroid follicular cells.Stimulation of the receptor increases T3 and T4 production and secretion.
Stimulating antibodies to this receptor mimic TSH action and are found in Graves' disease.
Diagnostic use
TSH levels are tested in the blood of patients suspected of suffering from excess (hyperthyroidism), or deficiency (hypothyroidism) of thyroid hormone. Generally, a normal range for TSH for adults is between 0.4 and 5.0 uIU/mL
Source of pathology
TSH level
thyroid hormone level
Disease causing conditions
hypothalamus/pituitary
high
high
benign tumor of the pituitary (adenoma) or thyroid hormone resistance
hypothalamus/pituitary
low
low
hypopituitarism
thyroid
low
high
hyperthyroidism or Grave's disease
thyroid
high
low
congenital hypothyroidism (cretinism), hypothyroidism
Clearly, both TSH and T3 and T4 should be measured to ascertain where a specific thyroid dysfunction is caused by primary pituitary or by a primary thyroid disease. If both are up (or down) then the problem is probably in the pituitary. If the one component (TSH) is up, and the other (T3 and T4) is down, then the disease is probably in the thyroid itself. The same holds for a low TSH, high T3 and T4 finding.
A TSH assay is now also the recommended screening tool for thyroid disease. Recent advances in increasing the sensitivity of the TSH assay make it a better screening tool than free T4
Progesterone
Progesterone is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.Progesterone should not be confused with progestins, which are synthetically produced progestogens.
Synthesis
Progesterone, * like all other steroid hormones, is synthesized from pregnenolone, a derivative of cholesterol. This conversion takes place in two steps. The 3-hydroxyl group is converted to a keto group and the double bond is moved to C-4, from C-5.
Conversion of Pregnenolone to Progesterone
Progesterone is the precursor of the mineralocorticoid aldosterone, and after conversion to 17-hydroxyprogesterone (another natural progestogen) of cortisol and androstenedione. Androstenedione can be converted to testosterone, estrone and estradiol.
Progesterone is important for aldosterone (mineralocorticoid) synthesis, as 17-hydroxyprogesterone is for cortisol (glucocorticoid), and androstenedione for sex steroids.
Sources
Progesterone is produced in the ovaries, the gonads (specifically after ovulation in the corpus luteum), the brain, and, during pregnancy, in the placenta.
In humans, increasing amounts of progesterone are produced during pregnancy:
•Initially, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropins (hCG) from the conceptus.
•However, after the 8th week production of progesterone shifts to the placenta. The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term the placenta produces about 250 mg progesterone per day.
•An additional source of progesterone is milk products. They contain much progesterone because on dairy farms cows are milked during pregnancy, when the progesterone content of the milk is high. After consumption of milk products the level of bioavailable progesterone goes up.This observation has resulted in concern that diets high in dairy products might induce pet and human diseases.
Progesterone levels during the menstrual cycle
In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. Progesterone levels tend to be <> 5 ng/ml after ovulation. If pregnancy occurs, progesterone levels are initially maintained at luteal levels. With the onset of the luteal-placental shift in progesterone support of the pregnancy, levels start to rise further and may reach 100-200 ng/ml at term. Whether a decrease in progesterone levels is critical for the initiation of labor has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.
Progesterone levels are relatively low in children and postmenopausal women.[8] Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.
Effects
Progesterone exerts its action primarily through the intracellular progesterone receptor although a distinct, membrane bound progesterone receptor has also been postulated.Progesterone has a number of physiological effects which are amplified in the presence of estrogen. Estrogen through estrogen receptors upregulates the expression of progesterone receptors.
Reproductive system
Progesterone is sometimes called the "hormone of pregnancy",and it has many roles relating to the development of the fetus:
•Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus, making the mucus thick and impermeable to sperm. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. Normal menstrual bleeding is progesterone withdrawal bleeding.
•During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.
•Progesterone decreases contractility of the uterine smooth muscle.
•In addition progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.
•A drop in progesterone levels is possibly one step that facilitates the onset of labor.
The fetus metabolizes placental progesterone in the production of adrenal mineralo- and glucosteroids.
Nervous system
Progesterone, like pregnenolone and dehydroepiandrosterone, belongs to the group of neurosteroids that are found in high concentrations in certain areas in the brain and are synthesized there.
Neurosteroids affect synaptic functioning, are neuroprotective, and affect myelination.They are investigated for their potential to improve memory and cognitive ability.
Progesterone as neuroprotectant affects regulation of apoptotic genes.
Its effect as a neurosteroid works predominantly through the GSK-3 beta pathway, as an inhibitor. (Other GSK-3 beta inhibitors include bipolar mood stabilizers, lithium and valproic acid.)
Other systems
•It raises epidermal growth factor-1 levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.
•It increases core temperature (thermogenic function) during ovulation.
•It reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated. (Progesterone receptors are widely present in submucosal tissue.)
•It acts as an antiinflammatory agent and regulates the immune response.
•It reduces gall-bladder activity.
•It normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy.
•It assists in thyroid function, in bone building by osteoblasts, in bone, teeth, gums, joint, tendon, ligament and skin resilience and in some cases healing by regulating various types of collagen, and in nerve function and healing by regulating myelin.
•It appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen.
Specific uses
•Progesterone is used to support pregnancy in Assisted Reproductive Technology (ART) cycles such as In-vitro Fertilization (IVF). While daily intramuscular injections of progesterone have been the standard route of administration, a recent meta-analysis showed that the intravaginal route with an appropriate dose and dosing frequency is equivalent to daily intramuscular injections.
•Progesterone is used to control anovulatory bleeding. It is also used to prepare uterine lining in infertility therapy and to support early pregnancy. Patients with recurrent pregnancy loss due to inadequate progesterone production may receive progesterone.
•Progesterone is being investigated as potentially beneficial in treating multiple sclerosis, since the characteristic deterioration of nerve myelin insulation halts during pregnancy, when progesterone levels are raised; deterioration commences again when the levels drop.
•Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. The initial study by Fonseca suggested that vaginal progesterone could prevent preterm birth in women with a history of preterm birth.
A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth,but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care.In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline.An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.
•Progesterone is used in hormone replacement therapy for transwomen, and some women with intersex conditions - especially when synthetic progestins have been ineffective or caused side-effects - since normal breast tissue cannot develop except in the presence of both progestogen and estrogen. Mammary glandular tissue is otherwise fibrotic, the breast shape conical and the areola immature. Progesterone can correct those even after years of inadequate hormonal treatment. Research usually cited against such value was conducted using Provera, a synthetic progestin. Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually-dimorphic proportions of those.
•Progesterone receptor antagonists, or selective progesterone receptor modulators (SPRM)s, such as RU-486 (Mifepristone), can be used to prevent conception or induce medical abortions.
Note that methods of hormonal contraception do not contain progesterone but a progestin.
Progesterone may affect male behavior.
Aging
Since most progesterone in males is created during testicular production of testosterone, and most in females by the ovaries, the shutting down (whether by natural or chemical means), or removal, of those inevitably causes a considerable reduction in progesterone levels. Previous concentration upon the role of progestagens (progesterone and molecules with similar effects) in female reproduction, when progesterone was simply considered a "female hormone", obscured the significance of progesterone elsewhere in both sexes.
The tendency for progesterone to have a regulatory effect, the presence of progesterone receptors in many types of body tissue, and the pattern of deterioration (or tumor formation) in many of those increasing in later years when progesterone levels have dropped, is prompting widespread research into the potential value of maintaining progesterone levels in both males and females.
Brain damage
It has been observed in animal models that females have reduced susceptibility to traumatic brain injury and this protective effect has been hypothesized to be caused by increased circulating levels of estrogen and progesterone in females.[26] A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury.Encouraging results have also been reported in human clinical trials.
The mechanism of progesterone protective effects may be the reduction of inflammation which follows brain trauma.
Prolactin
Prolactin (PRL) or Luteotropic hormone (LTH) is a peptide hormone primarily associated with lactation. In breastfeeding, the act of an infant suckling the nipple stimulates the production of prolactin, which fills the breast with milk via a process called lactogenesis, in preparation for the next feed. Oxytocin, another hormone, is also released, which triggers milk let-down.
Production and regulation
Prolactin or luteotropic hormone is synthesised and secreted by lactotrope cells in the adenohypophysis (anterior pituitary gland). It is also produced in other tissues including the breast, the decidua, parts of the central nervous system and the immune system.The gene encoding prolactin in humans is located on chromosome 6.
Pituitary prolactin secretion is regulated by neuroendocrine neurons in the hypothalamus, the most important ones being the neurosecretory tuberoinfundibulum (TIDA) neurons of the arcuate nucleus, which secrete dopamine to act on the dopamine-2 receptors (D2-R) of lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing factor has a stimulatory effect on prolactin release.
Vasoactive intestinal peptide and peptide histidine isoleucine help to regulate prolactin secretion in humans, but the functions of these hormones in birds can be quite different.
Effects
Prolactin has many effects including regulating lactation, orgasms, and stimulating proliferation of oligodendrocyte precursor cells.
It stimulates the mammary glands to produce milk (lactation): Increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands of the breasts and increases the production of milk. However, the high levels of progesterone during pregnancy act directly on the breasts to stop ejection of milk. It is only when the levels of this hormone fall after childbirth that milk ejection is possible. Sometimes, newborn babies (males as well as females) secrete a milky substance from their nipples. This substance is commonly known as Witch's milk. This is caused by the fetus being affected by prolactin circulating in the mother just before birth, and usually stops soon after birth.
Prolactin provides the body with sexual gratification after sexual acts: The hormone counteracts the effect of dopamine, which is responsible for sexual arousal. This is thought to cause the sexual refractory period.The amount of prolactin can be an indicator for the amount of sexual satisfaction and relaxation. Unusually high amounts are suspected to be responsible for impotence and loss of libido (see hyperprolactinemia Symptoms). Prolactin also stimulates proliferation of oligodendrocyte precursor cells. These cells differentiate into oligodendrocytes, the cells responsible for the formation of myelin coatings on axons in the central nervous system.
Prolactin also has a number of other effects including contributing to surfactant synthesis of the fetal lungs at the end of the pregnancy and immune tolerance of the fetus by the maternal organism during pregnancy;it also decreases normal levels of sex hormones — estrogen in women and testosterone in men."Prolactin delays hair regrowth in mice.
Variance in levels
There is a diurnal as well as an ovulatory cycle in prolactin secretion.
During pregnancy, high circulating concentrations of estrogen promote prolactin production. The resulting high levels of prolactin secretion cause further maturation of the mammary glands, preparing them for lactation.
After childbirth, prolactin levels fall as the internal stimulus for them is removed. Sucking by the baby on the nipple then promotes further prolactin release, maintaining the ability to lactate. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland cause increased prolactin secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk let-down: Prolactin controls milk production (lactogenesis) but not the milk-ejection reflex; the rise in prolactin fills the breast with milk in preparation for the next feed.
In usual circumstances, in the absence of galactorrhea, lactation will cease within one or two weeks of the end of demand breastfeeding.
High prolactin levels also tend to suppress the ovulatory cycle by inhibiting the secretion of both follicle-stimulating hormone (FSH) and gonadotropic-releasing hormone (GnRH).
Prolactin levels peak during REM sleep, and in the early morning. Levels can rise after exercise, meals, sexual intercourse, or minor surgical procedures.
Diagnostic use
Prolactin levels may be checked as part of a sex hormone workup, as elevated prolactin secretion can suppress the secretion of FSH and GnRH, leading to hypogonadism, and sometimes causing erectile dysfunction in men.
Prolactin levels may be of some use in distinguishing epileptic seizures from psychogenic non-epileptic seizures. The serum prolactin level usually rises following an epileptic seizure.
Conditions causing elevated prolactin secretion
Hyperprolactinaemia is the term given to having too-high levels of prolactin in the blood.
• Prolactinoma
• Excess thyrotropin-releasing hormone (TRH), usually in primary hypothyroidism
• Many anti-psychotic medications
• Emotional stress
• Pregnancy and Lactation.
Conditions causing decreased prolactin
• Bulimia
• Excess dopamine
Cortisol
Cortisol is a corticosteroid hormone or glucocorticoid produced by the adrenal gland (in the Zona fasciculata and the Zona Reticularis of the adrenal cortex). It is often referred to as the "stress hormone" as it is involved in response to stress. It increases blood pressure and blood sugar, and reduces immune responses. In pharmacology, the synthetic form of cortisol is referred to as hydrocortisone, and is used to treat allergies and inflammation, and to supplement natural cortisol when its production is too low.
When first introduced as a treatment for rheumatoid arthritis, it was referred to as Compound E.
Physiology
The amount of cortisol present in the blood undergoes diurnal variation, with the highest levels present in the early morning, and the lowest levels present around midnight, 3-5 hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. The pattern is not present at birth (estimates of when it starts vary from two weeks to 9 months).
Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of temperature.There is also significant individual variation, although a given person tends to have consistent rhythms.
Effects
In normal release, cortisol (like other glucocorticoid agents) has widespread actions which help restore homeostasis after stress. (These normal endogenous functions are the basis for the physiological consequences of chronic stress - prolonged cortisol secretion.). It has been proposed that its primary function is to inversely mobilize the immune system to fight potassium-depleting diarrhea diseases.Its odd attributes all support this.
Insulin
Cortisol counteracts insulin by increasing gluconeogenesis and promotes breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood) by increasing gluconeogenesis. There is an increased glycogen breakdown in the liver.Prolonged cortisol secretion causes hyperglycemia. Cortisol has no effect on insulin.The reason why in vivo experiments seem to deny this is that cortisone (a cortisol metabolite) greatly inhibits insulin. So the cortisone-cortisol equilibrium may explain why in vivo experiments contradict the cortisol effect.Cortisol does cause serum glucose to rise, but this is probably an indirect effect caused by stimulation of amino acid degradation, especially that derived from collagen in the skin. Loss of collagen from skin by cortisol is ten times greater than from all other tissue in the rat.
Amino acids
Cortisol raises the free amino acids in the serum. It does this by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis. Cortisol (as opticortinol) probably inversely inhibits IgA precursor cells in the intestines of calves.[8] Cortisol also inhibits IgA in serum, as it does IgM, but not IgE.
Gastric secretion
Cortisol stimulates gastric acid secretion.Gastric acid secretion would increase loss of potassium into the stomach during diarrhea as well as acid loss. Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to stimulate excretion of ammonium ion by inactivation of renal glutaminase enzyme.Net chloride secretion in the intestines is inversely decreased by cortisol in vitro (methylprednisolone).
Sodium
Cortisol inhibits loss of sodium from small intestines of mammals.However, sodium depletion does not affect cortisol,so cortisol is not used to regulate serum sodium. Cortisol's purpose may originally have been centered around moving sodium because cortisol is used to stimulate sodium inward for fresh water fish and outward for salt-water fish.
Potassium
Sodium load augments the intense potassium excretion by cortisol, and corticosterone is comparable to cortisol in this case.In order for potassium to move out of the cell, cortisol moves in an equal number of sodium ions.It can be seen that this should make pH regulation much easier, unlike the normal potassium deficiency situation in which about 2 sodium ions move in for each 3 potassium ions that move out, which is closer to the deoxycorticosterone effect. Nevertheless, cortisol consistently causes alkalosis of the serum, while in a deficiency pH does not change. Perhaps this may be for the purpose of bringing serum pH to a value most optimum for some of the immune enzymes during infection in those times when cortisol declines. Potassium is also blocked from loss in the kidneys directly somewhat by decline of cortisol (9 alpha fluorohydrocortisone).
Water
Cortisol also acts as a water diuretic hormone. Half the intestinal diuresis is so controlled.Kidney diuresis is also controlled by cortisol in dogs. The decline in water excretion upon decline of cortisol (dexamethasone) in dogs is probably due to inverse stimulation of antidiuretic hormone (ADH or arginine vasopressin), the inverse stimulation of which is not overridden by water loading.Humans also use this mechanism and other different animal mechanisms operate in the same direction.
Copper
It is probable that increasing copper availability for immune purposes is the reason why many copper enzymes are stimulated to an extent which is often 50% of their total potential by cortisol.This includes lysyl oxidase, an enzyme which is used to cross link collagen and elastin.Particularly valuable for immunity is the stimulation of superoxide dismutase by cortisol since this copper enzyme is almost certainly used by the body to permit superoxide to poison bacteria. Cortisol causes an inverse four- or fivefold decrease of metallothionein, a copper storage protein, in mice(however rodents do not synthesize cortisol themselves). This may be to furnish more copper for ceruloplasmin synthesis or release of free copper. Cortisol has an opposite effect on alpha aminoisobuteric acid than on the other amino acids.If alpha aminoisobuteric acid is used to transport copper through the cell wall, this anomaly would possibly be explained.
Immune system
Cortisol can weaken the activity of the immune system. Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1(IL-1), and unable to produce the T-cell growth factor.Cortisol has a negative feedback effect on interleukin-1which must be especially useful in combating diseases, such as the endotoxin bacteria, that gain an advantage by forcing the hypothalamus to secrete a hormone called CRH. The suppressor cells are not affected by GRMF,[29] so that the effective set point for the immune cells may be even higher than the set point for physiological processes. It reflects leukocyte redistribution to lymph nodes, bone marrow, and skin. Acute administration of corticosterone (the endogenous Type I and Type II receptor agonist), or RU28362 (a specific Type II receptor agonist), to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are not affected by cortisol.
Bone metabolism
It lowers bone formation thus favoring development of osteoporosis in the long term. Cortisol moves potassium out of cells in exchange for an equal number of sodium ions as mentioned above.This can cause a major problem with the hyperkalemia of metabolic shock from surgery.
Memory
It cooperates with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future. However, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning. The desirability of inhibiting activity during infection is no doubt the reason why cortisol is responsible for creating euphoria.The desirability of not disturbing tissues weakened by infection or of not cutting off their blood supply could explain the inhibition of pain widely observed for cortisol.
Additional effects
•It increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine. In the absence of cortisol, widespread vasodilation occurs.
•It inhibits the secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH (Adrenocorticotropic hormone or corticotropin) secretion. Some researchers believe that this normal feedback system may become dysregulated when animals are exposed to chronic stress.
•It increases the effectiveness of catecholamines.
•It allows for the kidneys to produce hypotonic urine.
•It has anti-inflammatory effects by reducing histamine secretion and stabilizing lysosomal membranes. The stabilization of lysosomal membranes prevents their rupture, thereby preventing damage to healthy tissues.
•It stimulates hepatic detoxification by inducing tryptophan oxygenase (to reduce serotonin levels in the brain), glutamine synthase (reduce glutamate and ammonia levels in the brain), cytochrome P-450 hemoprotein (mobilizes arachidonic acid), and metallothionein (reduces heavy metals in the body).
•In addition to the effects caused by cortisol binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone, it also binds to the mineralocorticoid receptor. Aldosterone and cortisol have similar affinity for the mineralocorticoid receptor however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids and allow selective mineralocorticoid action. This enzyme, 11-beta hydroxysteroid dehydrogenase type II (Protein:HSD11B2), catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites.
Regulation
The primary control of cortisol is the pituitary gland peptide, adrenocorticotropic hormone (ACTH). ACTH probably controls cortisol by controlling movement of calcium into the cortisol secreting target cells. ACTH is in turn controlled by the hypothalamic peptide, corticotropin releasing hormone (CRH), which is under nervous control. CRH acts synergistically with arginine vasopressin, angiotensin II, and epinephrine. When activated macrophages start to secrete interleukin-1 (IL-1), which synergistically with CRH increases ACTH,T-cells also secrete glucosteroid response modifying factor (GRMF or GAF) as well as IL-1, both of which increase the amount of cortisol required to inhibit almost all the immune cells. Thus immune cells take over their own regulation, but at a higher cortisol set point. Even so, the rise of cortisol in diarrheic calves is minimal over healthy calves and drops below with time. The cells do not lose all of the fight or flight override because of interleukin-1's synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1 which must be especially useful against those diseases which gain an advantage by forcing the hypothalamus to secrete too much CRH, such as the endotoxin bacteria..The suppressor immune cells are not affected by GRMF, [39] so that the effective set point for the immune cells may be even higher than the set point for physiological processes. GRMF (called GAF in this reference) primarily affects the liver rather than the kidneys for some physiological processes.
A high potassium media, which stimulates aldosterone secretion in vitro, also stimulates cortisol secretion from the fasciculata zone of dog adrenals unlike corticosterone, upon which potassium has no effect. Potassium loading increases ACTH and cortisol in people also. This is no doubt the reason why a potassium deficiency causes cortisol to decline (as just mentioned) and why a potassium deficiency causes a decrease in conversion of 11deoxycortisol to cortisol . This probably contributes to the pain in rheumatoid arthritis since cell potassium is always low in that disease.
Diseases and disorders
Hypercortisolism: Excessive levels of cortisol in the blood result in Cushing's syndrome.
Hypocortisolism, or adrenal insufficiency: If on the other hand the adrenal glands do not produce sufficient amounts of cortisol, Addison's disease is the consequence.
The relationship between cortisol and ACTH is as follows:
THE DISORDERS OF CORTISOL SECRETION
Plasma Cortisol
Plasma ACTH
Primary Hypercortisolism (Cushing's syndrome)
↑
↓
Secondary Hypercortisolism (pituitary or ectopic tumor, Cushing's disease)
↑
↑
Primary Hypocortisolism (Addison's disease)
↓
↑
Secondary Hypocortisolism (pituitary tumor)
↓
↓
Biosynthesis
Cortisol is synthesized from cholesterol. The synthesis takes place in the zona fasciculata of the cortex of the adrenal glands.While the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion. The medulla of the adrenal gland lies under the cortex and mainly secretes the catecholamines, adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation (more epinephrine is produced than norepinephrine, in a ratio 4:1).
The synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with adrenocorticotropic hormone (ACTH); production of ACTH is in turn stimulated by corticotropin-releasing hormone (CRH), released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane (via regulation of STAR (steroidogenic acute regulatory) protein). The cholesterol is converted to pregnenolone, catalysed by Cytochrome P450SCC (side chain cleavage).
Metabolism
Cortisol is metabolized by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2.
•11-beta HSD1 utilizes the cofactor NADPH to convert biologically inert cortisone to biologically active cortisol.
•11-beta HSD2 utilizes the cofactor NAD+ to convert cortisol to cortisone.
Overall the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically active cortisol in a given tissue, while 11-beta HSD2 serves to decrease the local concentrations of biologically active cortisol.
Cortisol is also metabolized by 5-alpha reductase and 5-beta reductase into 5-alpha tetrahydrocortisol (5-alpha THF) and 5-beta tetrahydrocortisol (5-beta THF), respectively. 5-beta reductase is also responsible for converting cortisone to tetrahydrocortisone (THE).
The CA3 area of hippocampus (memory) is affected by cortisol.
An alteration in 11-beta HSD1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance, sometimes referred to the metabolic syndrome.
An alteration in 11-beta HSD2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (SAME).
Laboratory tests
Blood and urine tests for cortisol are used to help diagnose Cushing's syndrome and Addison's disease, two serious adrenal disorders. Some physicians are using salivary cortisol to diagnose Cushing's syndrome as well as to evaluate possible stress-related disorders, although these uses are not widespread.Both the urine and saliva tests are most frequently used to evaluate excess cortisol production.
Once an abnormal cortisol concentration has been detected, the doctor will do additional testing to help confirm the excess or deficiency and to help determine its cause.
Dexamethasone Suppression
If there is excess cortisol production, the doctor may perform a dexamethasone suppression test to help determine whether the cause of the cortisol is related to excess ACTH production by the pituitary. This test involves giving the patient oral dexamethasone (a synthetic glucocorticoid) and then measuring their blood and urine cortisol levels. Dexamethasone suppresses ACTH production and should decrease cortisol production if the source of the excess is pituitary related. There are a variety of dosing schedules, but the medication is usually given every 6 hours for either 2 or 4 days prior to blood or urine collection. Separate 24-hour urine samples are collected prior to and throughout the testing period and then the blood and urine samples are measured for cortisol and evaluated.
ACTH Stimulation
If the findings of the initial blood and/or urine tests indicate insufficient cortisol production, the doctor may order an ACTH stimulation test. This test involves measuring the concentration of cortisol in a patient’s blood before and after an injection of synthetic ACTH. If the adrenal glands are functioning normally, then cortisol levels will rise with the ACTH stimulation. If they are damaged, then the response will be limited. A longer version of this test (1-3 days) may be performed to help distinguish between adrenal and pituitary insufficiency.
What does the test result mean?
NOTE: A standard reference range is not available for this test. Because reference values are dependent on many factors, including patient age, gender, sample population, and test method, numeric test results have different meanings in different labs. Your lab report should include the specific reference range for your test. Lab Tests Online strongly recommends that you discuss your test results with your doctor. For more information on reference ranges, please read Reference Ranges and What They Mean.
In normal people, cortisol levels are very low at bedtime and at their highest just after waking. This pattern will change if a person works irregular shifts (such as the night shift) and sleeps at different times of the day. With Cushing’s syndrome, this pattern is typically lost.
Increased or normal cortisol concentrations in the morning along with levels that do not drop in the afternoon and evening suggest an overproduction of cortisol. If this excess cortisol is suppressed during a dexamethasone suppression test, it suggests that the excess cortisol is due to increased pituitary ACTH production. If it is not suppressed, then the increased cortisol could be due to an ACTH-producing tumor outside of the pituitary, due to a problem with the adrenal gland, or due to a medication that the patient is taking.
If the adrenal glands are overactive, then a patient may have Cushing’s syndrome, with symptoms and signs caused by prolonged exposure to the effects of too much cortisol. This may be due to excess production of cortisol by the adrenal glands (which is frequently due to a benign adrenal tumor) or excess ACTH stimulation (due to a pituitary or other ACTH-producing tumor). It can also be seen in patients who must take corticosteroid medications, such as those used to treat asthma. If insufficient cortisol is present and the patient responds to an ACTH stimulation test, then the problem is likely due to insufficient ACTH production by the pituitary. If cortisol levels do not respond to the ACTH stimulation test, then it is more likely that the problem is based in the adrenal glands. If the adrenal glands are underactive, due to adrenal damage or insufficient ACTH production, then the patient is said to have adrenal insufficiency. If decreased cortisol production is due to adrenal damage, then the patient is said to have Addison’s disease.
Once an abnormality has been identified and associated with the pituitary gland, adrenal glands, or other cause, then the doctor may use other testing such as CT (computerized tomography) or MRI (magnetic resonance imaging) scans to locate the source of the excess (such as a pituitary, adrenal, or other tumor) and to evaluate the extent of any damage to the glands.
Pregnancy, physical and emotional stress, and illness can increase cortisol levels. Cortisol levels may also increase as a result of hyperthyroidism or obesity. A number of drugs can also increase levels, particularly oral contraceptives (birth control pills), hydrocortisone (the synthetic form of cortisol), and spironolactone. Adults have slightly higher cortisol levels than children do.
Hypothyroidism may decrease cortisol levels. Drugs that may decrease levels include some steroid hormones.
Salivary cortisol testing is being used more frequently to help diagnose Cushing's syndrome and stress-related disorders but still requires specialized expertise to perform.
Insulin
Insulin is a hormone with intensive effects on both metabolism and several other body systems (eg, vascular compliance). Insulin causes most of the body's cells to take up glucose from the blood (including liver, muscle, and fat tissue cells), storing it as glycogen in the liver and muscle, and stops use of fat as an energy source. When insulin is absent (or low), glucose is not taken up by most body cells and the body begins to use fat as an energy source (ie, transfer of lipids from adipose tissue to the liver for mobilization as an energy source). As its level is a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as amino acid uptake by body cells). It has several other anabolic effects throughout the body. When control of insulin levels fails, diabetes mellitus results.
Insulin is used medically to treat some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. Patients with Type 2 diabetes mellitus are insulin resistant, have relatively low insulin production, or both; some patients with Type 2 diabetes may eventually require insulin when other medications fail to control blood glucose levels adequately.
Insulin is a peptide hormone composed of 51 amino acid residues and has a molecular weight of 5808 Da. It is produced in the islets of Langerhans in the pancreas. The name comes from the Latin insula for "island".
Release
Beta cells in the islets of Langerhans release insulin mostly in response to increased blood glucose levels through the following mechanism
•Glucose enters the beta cells through the glucose transporter GLUT2
•Glucose goes into the glycolysis and the respiratory cycle where multiple high-energy ATP molecules are produced by oxidation
•Dependent on ATP levels, and hence blood glucose levels, the ATP-controlled potassium channels (K+) close and the cell membrane depolarizes
•On depolarization, voltage controlled calcium channels (Ca2+) open and calcium flows into the cells
•An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol.
•Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER). This allows the release of Ca2+ from the ER via IP3 gated channels, and further raises the cell concentration of calcium.
•Significantly increased amounts of calcium in the cells causes release of previously synthesised insulin, which has been stored in secretory vesicles
This is the main mechanism for release of insulin and regulation of insulin synthesis. In addition some insulin synthesis and release takes place generally at food intake, not just glucose or carbohydrate intake, and the beta cells are also somewhat influenced by the autonomic nervous system. The signalling mechanisms controlling these linkages are not fully understood.Other substances known to stimulate insulin release include amino acids from ingested proteins, acetylcholine, released from vagus nerve endings (parasympathetic nervous system), cholecystokinin,released by enteroendocrine cells of intestinal mucosa and glucose-dependent insulinotropic peptide (GIP). Three amino acids (alanine, glycine and arginine) act similarly to glucose by altering the beta cell's membrane potential. Acetylcholine triggers insulin release through phospholipase C, while the last acts through the mechanism of adenylate cyclase.
The sympathetic nervous system (via Alpha2-adrenergic stimulation)inhibit the release of insulin. However, it is worth noting that circulating adrenaline will activate Beta2-Receptors on the Beta cells in the pancreatic Islets to promote insulin release. This is important since muscle cannot benefit from the raised blood sugar resulting from adrenergic stimulation (increased gluconeogenesis and glycogenolysis from the low blood insulin: glucagon state) unless insulin is present to allow for GLUT-4 translocation in the tissue. Therefore, beginning with direct innervation, norepinephrine inhibits insulin release via alpha2-receptors, then subsequently, circulating adrenaline from the adrenal medulla will stimulate beta2-receptors thereby promoting insulin release.When the glucose level comes down to the usual physiologic value, insulin release from the beta cells slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently glucagon from Islet of Langerhans' alpha cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of glycogen. By increasing blood glucose, the hyperglycemic hormones correct life-threatening hypoglycemia. Release of insulin is strongly inhibited by the stress hormone norepinephrine (noradrenaline), which leads to increased blood glucose levels during stress.
Oscillations
Insulin release from pancreas oscillates with a period of 3–6 minutes.
Even during digestion, generally one or two hours following a meal, insulin release from pancreas is not continuous, but oscillates with a period of 3–6 minutes, changing from generating a blood insulin concentration more than ~800 pmol/l to less than 100 pmol/l.This is thought to avoid downregulation of insulin receptors in target cells and to assist the liver in extracting insulin from the blood.This oscillation is important to consider when administering insulin-stimulating medication, since it is the oscillating blood concentration of insulin release which should, ideally, be achieved, not a constant high concentration.It is also important to consider in that all methods of insulin replacement can never hope to replicate this delivery mechanism precisely. This may be achieved by delivering insulin rhythmically to the portal vein or by islet cell transplantation to the liver.
Signal transduction
There are special transporter proteins in cell membranes through which glucose from the blood can enter a cell. These transporters are, indirectly, under blood insulin's control in certain body cell types (e.g., muscle cells). Low levels of circulating insulin, or its absence, will prevent glucose from entering those cells (e.g., in Type 1 diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (e.g., the reduced insulin sensitivity characteristic of Type 2 diabetes), resulting in decreased glucose absorption. In either case, there is 'cell starvation', weight loss, sometimes extreme. In a few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is, characteristically, the same: elevated blood glucose levels.
Activation of insulin receptors leads to internal cellular mechanisms that directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane that transport glucose into the cell. The genes that specify the proteins that make up the insulin receptor in cell membranes have been identified and the structure of the interior, cell membrane section, and now, finally after more than a decade, the extra-membrane structure of receptor.Two types of tissues are most strongly influenced by insulin, as far as the stimulation of glucose uptake is concerned: muscle cells (myocytes) and fat cells (adipocytes). The former are important because of their central role in movement, breathing, circulation, etc, and the latter because they accumulate excess food energy against future needs. Together, they account for about two-thirds of all cells in a typical human body.
Effects
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
The actions of insulin on the global human metabolism level include:
•Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about ⅔ of body cells).
•Increase of DNA replication and protein synthesis via control of amino acid uptake.
•Modification of the activity of numerous enzymes.
The actions of insulin on cells include:
•Increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin which is directly useful in reducing high blood glucose levels as in diabetes.
•Increased fatty acid synthesis – insulin forces fat cells to take in blood lipids which are converted to triglycerides; lack of insulin causes the reverse.
•Increased esterification of fatty acids – forces adipose tissue to make fats (i.e., triglycerides) from fatty acid esters; lack of insulin causes the reverse.
•Decreased proteolysis – decreasing the breakdown of protein.
•Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse.
•Decreased gluconeogenesis – decreases production of glucose from non-sugar substrates, primarily in the liver (remember, the vast majority of endogenous insulin arriving at the liver never leaves the liver); lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.
•Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption.
•Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Thus lowers potassium levels in blood.
•Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract.
Degradation
Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Most insulin molecules are degraded by liver cells. It has been estimated that a typical insulin molecule that is produced endogenously by the pancreatic beta cells is finally degraded about 71 minutes after its initial release into circulation.
Hypoglycemia
Although other cells can use other fuels for a while (most prominently fatty acids), neurons depend on glucose as a source of energy in the non-starving human. They do not require insulin to absorb glucose, unlike muscle and adipose tissue, and they have very small internal stores of glycogen. Glycogen stored in liver cells (unlike glycogen stored in muscle cells) can be converted to glucose, and released into the blood, when glucose from digestion is low or absent, and the glycerol backbone in triglycerides can also be used to produce blood glucose.
Sufficient lack of glucose and scarcity of these sources of glucose can dramatically make itself manifest in the impaired functioning of the central nervous system; dizziness, speech problems, and even loss of consciousness, can occur. Low glucose is known as hypoglycemia or, in cases producing unconsciousness, "hypoglycemic coma" (sometimes termed "insulin shock" from the most common causative agent). Endogenous causes of insulin excess (such as an insulinoma) are very rare, and the overwhelming majority of insulin-excess induced hypoglycemia cases are iatrogenic and usually accidental. There have been a few reported cases of murder, attempted murder, or suicide using insulin overdoses, but most insulin shocks appear to be due to errors in dosage of insulin (e.g., 20 units of insulin instead of 2) or other unanticipated factors (didn't eat as much as anticipated, or exercised more than expected, or unpredicted kinetics of the subcutaneously injected insulin itself).
Possible causes of hypoglycemia include:
•External insulin (usually injected subcutaneously).
•Oral hypoglycemic agents (e.g., any of the sulfonylureas, or similar drugs, which increase insulin release from beta cells in response to a particular blood glucose level).
•Ingestion of low-carbohydrate sugar substitutes (animal studies show these can trigger insulin release (albeit in much smaller quantities than sugar) according to a report in Discover magazine, August 2004, p 18, although this is only an issue in people who do not have diabetes, or those who have type 2 diabetes because type 1 diabetes is caused by a complete absence of insulin. As a result, this can never be a cause of hypoglycemia in patients with type 1 diabetes since there is no endogenous insulin production to stimulate.
Diseases and syndromes
There are several conditions in which insulin disturbance is pathologic:
•Diabetes mellitus – general term referring to all states characterized by hyperglycemia.
oType 1 – autoimmune-mediated destruction of insulin producing beta cells in the pancreas resulting in absolute insulin deficiency.
oType 2 – multifactoral syndrome with combined influence of genetic susceptibility and influence of environmental factors, the best known being obesity, age, and physical inactivity, resulting in insulin resistance in cells requiring insulin for glucose absorption. This form of diabetes is strongly inherited.
oOther types of impaired glucose tolerance (see the diabetes article).
•Insulinoma - a tumor of pancreatic beta cells producing excess of insulin or reactive hypoglycemia.
•Metabolic syndrome – a poorly understood condition first called Syndrome X by Gerald Reaven, Reaven's Syndrome after Reaven, CHAOS in Australia (from the signs which seem to travel together), and sometimes prediabetes. It is currently not clear whether these signs have a single, treatable cause, or are the result of body changes leading to type 2 diabetes. It is characterized by elevated blood pressure, dyslipidemia (disturbances in blood cholesterol forms and other blood lipids), and increased waist circumference (at least in populations in much of the developed world). The basic underlying cause may be the insulin resistance of type 2 diabetes which is a diminished capacity for insulin response in some tissues (e.g., muscle, fat) to respond to insulin. Commonly, morbidities such as essential hypertension, obesity, Type 2 diabetes, and cardiovascular disease (CVD) develop.
•Polycystic ovary syndrome – a complex syndrome in women in the reproductive years where there is anovulation and androgen excess commonly displayed as hirsutism. In many cases of PCOS insulin resistance is present.
Testosterone
Testosterone is a steroid hormone from the androgen group. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. It is the principal male sex hormone and an anabolic steroid.
In both men and women, testosterone plays a key role in health and well-being as well as in sexual functioning. Examples include enhanced libido, increased energy, increased production of red blood cells and protection against osteoporosis. On average, an adult human male body produces about forty to sixty times more testosterone than an adult female body, but females are, from a behavioral perspective (rather than from an anatomical or biological perspective), more sensitive to the hormone.However the overall ranges for male and female are very wide, such that the ranges actually overlap at the low end and high end respectively.
Like other steroid hormones, testosterone is derived from cholesterol. The largest amounts of testosterone are produced by the testes in men. It is also synthesized in far smaller quantities in women by the thecal cells of the ovaries, by the placenta, as well as by the zona reticularis of the adrenal cortex in both sexes.
In the testes, testosterone is produced by the Leydig cells. The male generative glands also contain Sertoli cells which require testosterone for spermatogenesis. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein, sex hormone binding globulin (SHBG).
In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone effects can be classified as virilizing and anabolic, although the distinction is somewhat artificial, as many of the effects can be considered both.
•Anabolic effects include growth of muscle mass and strength, increased bone density and strength, and stimulation of linear growth and bone maturation.
•Virilizing effects include maturation of the sex organs, particularly the penis and the formation of the scrotum in unborn children, and after birth (usually at puberty) a deepening of the voice, growth of the beard and axillary hair. Many of these fall into the category of male secondary sex characteristics.
Early postnatal effects
Early postnatal effects are the first visible effects of rising androgen levels in childhood, and occur in both boys and girls in puberty.
•Adult-type body odour
•Increased oiliness of skin and hair, acne
•Pubarche (appearance of pubic hair)
•Axillary hair
•Growth spurt, accelerated bone maturation
•Develop hair on upper lip and sideburns.
Advanced postnatal effects
Advanced postnatal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the blood.
•Enlargement of sebaceous glands. This might cause acne.
•Phallic enlargement or clitoromegaly
•Increased libido and frequency of erection or clitoral engorgement
•Pubic hair extends to thighs and up toward umbilicus
•Facial hair (sideburns, beard, moustache)
•Chest hair, periareolar hair, perianal hair
•Subcutaneous fat in face decreases
•Increased muscle strength and mass
•Deepening of voice
•Growth of the Adam's apple
•Growth of spermatogenic tissue in testes, male fertility
•Growth of jaw, brow, chin, nose, and remodeling of facial bone contours
•Shoulders become broader and rib cage expands
•Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women.
Adult testosterone effects
Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels decline in the later decades of adult life.
•Libido and clitoral engorgement/penile erection frequency.
•Mental and physical energy
•The most recent and reliable studies have shown that testosterone does not cause Prostate cancer, but that it can increase the rate of spread of any existing prostate cancer.Recent studies have also shown its importance in maintaining cardio vascular health.
•Increase eumelanin and reduce pheomelanin
Testosterone regulates the population of thromboxane A2 receptors on megakaryocytes and platelets and hence platelet aggregation in humans.
Mechanism
The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors.
Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T.[citation needed] The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen effects. It is important to note that if there is a 5-alpha reductase deficiency, the body (of a human) will continue growing into a female with testicles.
Androgen receptors occur in many different vertebrate body system tissues, and both males and females respond similarly to similar levels. Greatly differing amounts of testosterone prenatally, at puberty, and throughout life account for a share of biological differences between males and females.
The bones and the brain are two important tissues in humans where the primary effect of testosterone is by way of aromatization to estradiol. In the bones, estradiol accelerates maturation of cartilage into bone, leading to closure of the epiphyses and conclusion of growth. In the central nervous system, testosterone is aromatized to estradiol. Estradiol rather than testosterone serves as the most important feedback signal to the hypothalamus (especially affecting LH secretion). In many mammals, prenatal or perinatal "masculinization" of the sexually dimorphic areas of the brain by estradiol derived from testosterone programs later male sexual behavior.
The human hormone testosterone is produced in greater amounts by males, and less by females. The human hormone estrogen is produced in greater amounts by females, and less by males. Testosterone causes the appearance of masculine traits (i.e., deepening voice, pubic and facial hairs, muscular build, etc.) Like men, women rely on testosterone to maintain libido, bone density and muscle mass throughout their lives. In men, inappropriately high levels of estrogens lower testosterone, decrease muscle mass, stunt growth in teenagers, introduce gynecomastia, increase feminine characteristics, and decrease susceptibility to prostate cancer, reduces libido and causes erectile dysfunction and can cause excessive sweating and hot flushes. However, an appropriate amount of estrogens is required in the male in order to ensure well-being, bone density, libido, erectile function, etc.
Free Androgen Index or FAI is a ratio used to determine abnormal androgen status in humans. The ratio is the total testosterone level divided by the sex hormone binding globulin (SHBG) level, and then multiplying by a constant, usually 100. The concentrations of testosterone and SHBG are normally measured in nanomols per liter. FAI has no units.
The majority of testosterone in the blood does not exist as the free molecule. Instead around half is tightly bound to sex hormone binding globulin, and the other half is weakly bound to albumin. Only a small percentage is unbound, under 3% in females, and less than 0.7% in males. Since only the free testosterone is able to bind to tissue receptors to exert its effects, it is believed that free testosterone is the best marker of a person's androgen status. However, free testosterone is difficult and expensive to measure, and many laboratories do not offer this service.
The free androgen index is intended to give a guide to the free testosterone level, but it is not very accurate. Consequently, there are no universally agreed 'normal ranges', and levels slightly above or below quoted laboratory reference ranges may not be clinically significant.
Reference ranges depend on the constant in the calculation - 100 is used in the formula above, and the following suggested ranges are based on this. As with any laboratory measurement, however, it is vital that results are compared against the reference range quoted for that laboratory. Neither FAI nor free or total testosterone measurements should be interpreted in isolation; as a bare minimum, gonadotropin levels should also be measured.
As a guide, in healthy adult men typical FAI values are 30-150. Values below 30 may indicate testosterone deficiency, which may contribute to fatigue, erectile dysfunction, weight gain, osteoporosis and loss of secondary sex characteristics. In women, androgens are most often measured when there is concern that they may be raised (as in hirsutism or the polycystic ovary syndrome). Typical values for the FAI in women are <7.
Dehydroepiandrosterone
Dehydroepiandrosterone (DHEA) is a natural steroid hormone precursor (prohormone) produced from cholesterol by the adrenal glands, the gonads, adipose tissue, brain and in the skin (by an autocrine mechanism). DHEA is the precursor of androstenedione, which can undergo further conversion to produce the androgen testosterone and the estrogens estrone and estradiol. DHEA is also a potent sigma-1 agonist.
Dehydroepiandrosterone sulfate
Dehydroepiandrosterone sulfate (DHEAS) is the sulfated version of DHEA. This conversion is reversibly catalyzed by sulfotransferase (SULT2A1) primarily in the adrenals, the liver, and small intestine. In the blood, most DHEA is found as DHEAS with levels that are about 300 times higher than those of free DHEA. Orally-ingested DHEA is converted to its sulfate when passing through intestines and liver. Whereas DHEA levels naturally reach their peak in the early morning hours, DHEAS levels show no diurnal variation. From a practical point of view, measurement of DHEAS is preferable to DHEA, as levels are more stable.
DHEA is produced from cholesterol through two cytochrome P450 enzymes. Cholesterol is converted to pregnenolone by the enzyme P450 scc (side chain cleavage); then another enzyme, CYP17A1, converts pregnenolone to 17α-Hydroxypregnenolone and then to DHEA. In humans, DHEA is the dominant steroid hormone and precursor of all sex steroids.
Role
DHEA can be understood as a prohormone for the sex steroids. DHEAS may be viewed as buffer and reservoir. As most DHEA is produced by the zona reticularis of the adrenal, it is argued that there is a role in the immune and stress response.[who?]
As almost all DHEA is derived from the adrenal glands, blood measurements of DHEAS/DHEA are useful to detect excess adrenal activity as seen in adrenal cancer or hyperplasia, including certain forms of congenital adrenal hyperplasia. Women with polycystic ovary syndrome tend to have elevated levels of DHEAS.
Sex hormone-binding globulin
Sex hormone-binding globulin (SHBG) is a glycoprotein that binds to sex hormones, specifically testosterone and estradiol. Other steroid hormones such as progesterone, cortisol, and other corticosteroids are bound by transcortin.
SHBG is produced by the liver cells and is released into the bloodstream. Other sites that produce SHBG are the brain, uterus, and placenta and vagina. In addition SHBG is produced by the testes; testes-produced SHBG is also called androgen-binding protein. The gene for SHBG is located on chromosome 17.
Conditions with high or low levels
Conditions with low SHBG include polycystic ovary syndrome, diabetes, and hypothyroidism. Conditions with high SHBG include pregnancy, hyperthyroidism, and anorexia nervosa. There has recently been research to link high SHBG levels with breast and testicular cancer as well.
When determining levels of circulating estradiol or testosterone, either a total measurement could be done that includes the "free" and the bound fractions, or only the "free" hormone could be measured. A free androgen index expresses the ratio of testosterone to the sex hormone binding globulin and can be used to summarise the activity of free testosterone.
The total testosterone is likely the most accurate measurement of testosterone levels and should always be measured at 8 o'clock in the morning. Sex hormone binding globulin can be measured separate from the total fraction of testosterone.
Growth hormone (GH)
Growth hormone (GH) or somatotropin (STH) is a protein hormone which stimulates growth and cell reproduction in humans and other animals. It is a 191-amino acid, single chain polypeptide hormone which is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland. Several molecular forms of GH circulate. Much of the growth hormone in the circulation is bound to a protein (growth hormone binding protein, GHBP) which is derived from the growth hormone receptor.
GH is secreted into the blood by the somatotrope cells of the anterior pituitary gland, in larger amounts than any other pituitary hormone. Secretion levels are highest during puberty. The transcription factor PIT-1 stimulates both the development of these cells and their production of GH. Failure of development of these cells, as well as destruction of the anterior pituitary gland, results in GH deficiency.
Regulation
Peptides released by neurosecretory nuclei of the hypothalamus into the portal venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes. However, although the balance of these stimulating and inhibiting peptides determines GH release, this balance is affected by many physiological stimulators and inhibitors of GH secretion.
Stimulators of GH secretion include:
growth hormone releasing hormone (GHRH) from the arcuate nucleus
ghrelin
sleep
exercise
low levels of blood sugar (hypoglycemia)
dietary protein
estradiol
arginine
Inhibitors of GH secretion include:
somatostatin from the periventricular nucleus
circulating concentrations of GH and IGF-1 (negative feedback)
dietary carbohydrate
glucocorticoids
In addition to control by endogenous processes,a number of foreign compounds (xenobiotics)are now known to influence GH secretion and function,highlighting the fact that the GH-IGF axis is an emerging target for certain endocrine disrupting chemicals.
Functions of GH
Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones GH acts by interacting with a specific receptor on the surface of cells.
Increasing height
Height growth in childhood is the best known effect of GH action, and appears to be stimulated by at least two mechanisms.GH directly stimulates division and multiplication of chondrocytes of cartilage. These are the primary cells in the growing ends (epiphyses) of children's long bones (arms, legs, digits).
GH also stimulates production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin. The liver is a major target organ of GH for this process, and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. Additional IGF-1 is generated within target tissues, making it apparently both an endocrine and an autocrine/paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.
Other functions
Although height growth is the best known effect of GH, it serves many other metabolic functions as well.
It increases calcium retention, and strengthens and increases the mineralization of bone.
It increases muscle mass through the creation of new muscle cells (i.e. hyperplasia, which differs from hypertrophy)
It promotes lipolysis, which results in the reduction of adipose tissue (body fat).
It increases protein synthesis and stimulates the growth of all internal organs excluding the brain.
It plays a role in fuel homeostasis.
It reduces liver uptake of glucose, an effect that opposes that of insulin.
It promotes liver gluconeogenesis.
It contributes to the maintenance and function of pancreatic islets.
It stimulates the immune system.
Clinical problems
Growth hormone excess: (acromegaly and pituitary gigantism): The most common disease of GH excess is a pituitary tumor comprised of somatotroph cells of the anterior pituitary. These somatotroph adenomas are benign and grow slowly, gradually producing more and more GH. For years, the principal clinical problems are those of GH excess. Eventually the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement.
Prolonged GH excess thickens the bones of the jaw, fingers and toes. Resulting heaviness of the jaw and increased thickness of digits is referred to as acromegaly. Accompanying problems can include pressure on nerves (e.g., carpal tunnel syndrome), muscle weakness, insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.
GH-secreting tumors are typically recognized in the 5th decade of life. It is extremely rare for such a tumor to occur in childhood, but when it does the excessive GH can cause excessive growth, traditionally referred to as pituitary gigantism.
Surgical removal is the usual treatment for GH-producing tumors. In some circumstances focused radiation or a GH antagonist such as bromocriptine or octreotide may be employed to shrink the tumor or block function.
Growth hormone deficiency: Deficiency of GH produces significantly different problems at various ages. In children, growth failure and short stature are the major manifestations of GH deficiency. In adults the effects of deficiency are more subtle, and may include deficiencies of strength, energy, and bone mass, as well as increased cardiovascular risk.
There are many causes of GH deficiency, including mutations of specific genes, congenital malformations involving the hypothalamus and/or pituitary gland, and damage to the pituitary from injury, surgery or disease.
Diagnosis of GH deficiency involves a multiple step diagnostic process, usually culminating in GH stimulation test(s) to see if the patient's pituitary gland will release a pulse of GH when provoked by various stimuli.
GH deficiency is treated by replacing GH. All GH in current use is a biosynthetic version of human GH, manufactured by recombinant DNA technology. As GH is a large protein molecule, it must be injected into subcutaneous tissue to get it into the blood (injections no longer have to enter muscle mass since 1985 with the production of synthetic GH). When the patient has had a long-standing deficiency of GH, benefits of treatment are often dramatic and gratifying and side effects of treatment are rare. Increased growth in childhood can result in dramatically improved adult height.
GH is used as replacement therapy in adults with GH deficiency of either childhood-onset (after completing growth phase) or adult-onset (usually as a result of an acquired pituitary tumor). In these patients, benefits have variably included reduced fat mass, increased lean mass, increased bone density, improved lipid profile, reduced cardiovascular risk factors, and improved psychosocial well-being.
Subscribe to:
Posts (Atom)