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1. Reproductive Endocrinology
2. Gross and microscopic anatomy of human testis
3. Testis Function:
Androgen synthesis and secretion.
Seminiferous tubules: nurtures the sperm as they develop. Each tubule is made up of germ cells and Sertoli cells
Leydig cells: steroid synthesizing cells.
4. Androgens In males, androgens are secreted by Leydig cells of the testis, with only a small contribution from the adrenal.
In male embryos androgen secretion by the Leydig cells is initiated by human chorionic gonadotropin (hCG).
T is converted to dihydrotestosterone (DHT) by 5a-reductase in peripheral tissues.
Embryonically, T stimulates the male external genitalia, while DHT is responsible for the development of the internal genitalia
In adolescence, androgens stimulate skeletal growth and muscle protein synthesis.
Androgens induce aggression and libido
They also promote the development of both primary and secondary male sexual characteristics
5. Synthesis pathway of gonadal hormones
6. Testicular biosynthesis and hepatic metabolism of testosterone
7. Hormonal control Spermatogenesis requires both FSH and T.
T is released from the Leydig cells and is concentrated in the tubules.
LH binds to Leydig cells and stimulates T synthesis.
FSH binds to Sertoli cells, it also enhances the number of Leydig cell LH receptors.
Prolactin controls the number of Leydig cell LH receptors
Inhibin secreted by Sertoli cells inhibit FSH
Testosterone acts directly on some tissues and must be converted to either DHT or Estradiol to mediate its action in some other tissues
9. Hormonal regulation of steroidogenesis and spermatogenesis in the testis
10. Action of LH and FSH on Sertoli and Leydig Cells
11. Female Gonads
12. Female reproductive system
13. Estrogens Estrogens are secreted by the ovary in women. In men it is formed by the peripheral conversion of androgens.
In the embryo, estrogen production is stimulated by hCG.
During puberty, estrogen stimulates skeletal growth as androgens, but induces muscle protein synthesis far less.
Estrogens cause behavioral changes and promote development of both primary and secondary female sexual characteristics.
14. Oogenesis From birth, the ovaries of the human female contain about one million of immature oocytes, called primordial follicles.
Primordial follicle: oocyte surrounded by a single flat layer of granulosa cells.
Primary follicle: oocyte surrounded by a single cuboidal layer of granulosa cells.
Secondary follicle: Under hormonal stimulation during puberty, bigger oocyte and several layers of granulosa cells. Formation of theca externa and interna layers from the interstitial tissue surrounding the follicle.
15. Graafian Follicle Graafian follicle: it is marked by the formation of a fluid-filled cavity adjacent to the oocyte called the antrum. Granulosa and theca cells continue to undergo division concomitant with an increase in antrum volume.
Graafian follicles are dependent on the availability of FSH
Corpus Luteum: After the egg cell has been released, the follicle remains and the granulosa and thecal cells increase in number and becomes known as the corpus luteum.
It secretes progesterone and estradiol under the effect of LH.
It maintains uterine endometrium in early pregnancy.
If fertilization does not occur, it degenerates until it becomes only as scar tissue called corpus albicans.
17. Ovarian Hormonal synthesis Menstrual Cycle consists of 4 phases: follicular, ovulation, luteal and menstrual phases.
Follicular phase lasts for 10-14 days.
Starts with FSH developing primordial follicles into primary follicles.
LH stimulates steroidogenesis from the follicle?s theca interna. Androstenedione and testosterone are produced due to lack of aromatase.
They are then transported to the adjacent granulosa cells where they are converted to E2 by a FSH-induced aromatase
18. Synthesis of Estrogens
19. Menstrual Cycle The control circuit of the hormonal cycle has two essential control elements:
The pulsatile liberation of GnRH, as well as FSH and LH
The long-loop feedback-effect of estrogen and progesterone on the hypothalamic-hypophysial-system (these two hormones are synthesized in the [ready to rupture] follicle and so originate in the ovary, thus the name "long loop").
20. The menses (bleeding or periods): this commonly lasts from day 1 to day 5.During this phase, if fertilisation of the egg did not occur, the lining of the womb or uterus, which is called the endometrium, comes away from the uterus wall and the blood and tissues pass out via the vagina.
The follicular phase: this phase is so-named because it is when the follicles in the ovary grow and form an egg. About 3 to 30 follicles grow between days 8 and 10. Each follicle contains an egg, but by days 10 to 14 one follicle has overtaken the rest and has reached the correct stage of maturity.
During days 6 to 14, the lining of the uterus is repaired and builds up to be thicker. This is why this phase is also known as the proliferative phase. This is stimulated by oestrogen secreted from the ovaries. The lining of the uterus will now be about 3 mm thick and is also more velvety again.
21. Ovulation: A surge of luteinising hormone occurs roughly just before day 14 in a 28-day cycle. This surge stimulates the mature follicle in one of the ovaries to release its egg (ovulation) 16 to 32 hours later. Oestrogen also peaks during this surge.
An egg is released from the right or left ovary at random and takes about 5 days to travel down the fallopian tube to the uterus.
The luteal or secretory phase: This phase follows ovulation and lasts from about day 15 to day 28. After the follicle ruptures as it releases its egg, it closes and forms a corpus luteum. The corpus luteum secretes more and more progesterone, which acts on glands in the endometrium and causes them to make a secretion. The purpose of this secretion is to feed the embryo for a few days until a placenta has formed. Even if the egg is not fertilised and pregnancy has not happened, the secretion is still produced.
The progesterone secreted by the corpus luteum causes the temperature of the body to rise slightly until the start of the next period.
If the woman has not become pregnant the corpus luteum lasts about 14 days and then starts to break down. This is when progesterone production rapidly drops and the oestrogen level decreases. This lack of hormones causes blood vessels in the endometrium to go into spasm and they cut off the blood supply to the top layers of the endometrium. Without oxygen and nutrients from the blood, the endometrial cells begin to die, tissue breaks down and there is bleeding from the damaged blood vessels and so this is how the new menstrual cycle begins on about day 28.
22. Role of FSH and inhibin in the control of gonadal function
25. Course of hormonal concentrations within the ovarian cycle
26. Hypothalamic-pituitary-gonadal axis hormones and cortisol in both menstrual phases of women with chronic fatigue syndrome and effect of depressive mood on these hormonesRemzi Cevik , Ali Gur , Suat Acar , Kemal Nas and Ayseg?l Jale SaracBMC Musculoskeletal Disorders 2004, 5:47 Stress is known to interfere with the menstrual cycle and may lead to chronic anovulation and amenorrhea
This generally thought to be caused by a decrease in the activity of hypothalamic gonadotropin releasing hormone (GnRH) pulse generator with subsequent inhibition of the pituitary-gonadal axis
Stress-induced activation of hypothalamic-pituitary-adrenal (HPA) hormonal axis plays an important role in suppressing the HPG axis
Studies in primates have demonstrated that intracerebroventricular infusion of CRH as well as proinflammatory cytokines such as interleukin-1 can decrease LH secretion
27. Sex hormones and glucocorticoids: interactions with the immune system. by: JA Da SilvaAnn N Y Acad Sci, Vol. 876 (22 June 1999) Estrogens depress T cell-dependent immune function and diseases, but enhance antibody production and aggravate B cell-dependent diseases.
Androgens suppress both T-cell and B-cell immune responses and virtually always result in the suppression of disease expression.
Defects in the hypothalamic-pituitary-adrenal (HPA) axis have been proposed to play an important role in the pathogenesis of autoimmune diseases.
Glucocorticoid response to stress, including immune challenge, is strongly inhibited by androgens and enhanced by estrogens.
28. Pulsatile growth hormone release in normal women during the menstrual cycleAmllton C. S. Faria 1 Lori Waranch Bekenstein 1 Robert A. Jr Booth 1 Veronica A. Vaccaro 1 Christopher M. Asplin 1 Johannes D. Veldhuls 1 Michael O. Thorner 1 William S. Evans 1Clinical Endocrinology Volume?36,?Issue?6 , Pages591?-?596 1992 GH pulse frequency was higher during the follicular phase of the cycle (P = 0.032), and nocturnal GH was higher in the follicular phase of the cycle
these results suggest that late follicular phase concentrations of oestradiol may enhance circulating GH via an amplitude-modulated rather than a frequency-modulated effect on the endogenous GH pulse. Progesterone may blunt this oestrogen-associated effect, thus resulting in the observed mid-luteal phase concentrations of GH. Whether these gonadal hormones act primarily at the hypothalamus and/or anterior pituitary gland remains to be clarified, but the present observations indicate that pulsatile GH release throughout the normal menstrual cycle is significantly amplitude regulated.
29. Relationship between Aldosterone and Progesterone in the Human Menstrual Cycle Emily D. Szmuilowicz, Gail K. Adler, Jonathan S. Williams, Dina E. Green, Tham M. Yao, Paul N. Hopkins and Ellen W. Seely The Journal of Clinical Endocrinology & Metabolism2006 Vol. 91, No. 10 3981-3987 ALDOSTERONE LEVELS HAVE been reported to increase during the luteal phase of the human menstrual cycle, a time characterized by increased progesterone and estradiol production.
Progesterone may directly contribute to increased luteal phase aldosterone production, independent of the renin-angiotensin system
progesterone is known to have antimineralocorticoid effects. Progesterone is postulated to mediate the luteal phase increase in aldosterone levels. Because progesterone inhibits aldosterone binding to the mineralocorticoid receptor (1, 3, 16), increased progesterone production during the luteal phase likely leads to compensatory activation of the RAS and thus increased aldosterone production
30. Plasma melatonin profile and hormonal interactions in the menstrual cycles of anovulatory infertile women treated with gonadotropins Gynecol Obstet Invest 1998;45:247-252P.L. Tanga, T.Y. Chana, G.W.K. Tangb, S.F. Pangc The patterns of plasma melatonin, gonadotropins, sex steroids and prolactin were studied in anovulatory infertile females undergoing ovulation induction with hMG/hCG. Melatonin levels were found to fluctuate during the menstrual cycle of these subjects with a nadir at mid-cycle and peak occurring at the early follicular/late luteal phases of the cycle (p < 0.05). Melatonin correlated negatively with estradiol during the follicular phase (r = -0.5180, p < 0.05) and positively with LH (5 + 0.6321, p < 0.05) in the luteal phase, respectively. Correlational analyses by partial and multiple correlations suggest that the effects of estradiol and LH on melatonin in the follicular phase are interdependent whereas the effect of LH on melatonin in the luteal phase is independent of the effects of other hormones. The results suggest that hormonal interactions and phases of the cycle are important variables contributing to the fluctuations in melatonin levels during the menstrual cycle.
31. Effects of estrogen versus estrogen and progesterone on cortisol and interleukin-6 K M. Edwards and P J. Mills 2008:Maturatis Vol61, Issue 4 Pages 330-333 Estrogen administration elevated cortisol levels, but this effect may be moderated by progestins. IL-6 was not altered by estradiol or estradiol + progestins in post-menopausal women.
32. Melatonin enhances Cortisol levels in aged women: Reversible by estrogensA. Cagnacci , R. Soldani and S.S.C. YenJ. Pineal Res. 1997; 22:81?85. The administration of melatonin increases Cortisol levels in postmenopausal women. Aging and hypoestrogenism are believed to impair the regulation of the hypothalamo-pituitary-adrenal axis and may participate in the determination of this altered response. In this study the implications of hypoestrogenism were tested. Seven postmenopausal women were studied. At 08.00 hr for 2 consecutive days, each woman received randomly and in a double blind fashion a pill of placebo or melatonin (100 mg). Serum melatonin and Cortisol levels were evaluated at 20 min intervals, for 48 hr. Measurements were performed in the same subjects both during no estrogen supplementation and at least two cycles of conjugated estrogens administration (0.625 mg/day). During estrogen supplementation, postmenopausal women showed slightly lower Cortisol levels at lunch and early night (20.00?01.00 hr). The onset of the nocturnal melatonin rise was not modified, but that of Cortisol was delayed of about 60 min (P<0.02). The administration of melatonin elicited a marked increase in daytime Cortisol levels in postmenopausal women (P<0.02), but this stimulus completely disappeared during estrogen administration. Mean nighttime (20.00?08.00 hr) Cortisol levels were not modified by daytime administration of melatonin. The present data reveal that in aged postmenopausal women, reversal of hypoestrogenism, resulting from supplemental estrogens, may improve the regulation of the hypothalamo-pituitary-adrenal axis.
33. Cortisol disrupts the ability of estradiol-17? to induce the LH surge in ovariectomized ewes Domestic Animal Endocrinology, Volume 36, Issue 4, May 2009, Pages 202-208B.N. Pierce, I.J. Clarke, A.I. Turner, E.T.A. Rivalland and A.J. Tilbrook Stress disrupts the preovulatory luteinizing hormone (LH) surge in females, but the mechanisms are unknown. We conclude that cortisol can interfere with the LH surge in several ways: delay, blunt, and in extreme cases prevent the E2-induced LH surge. Furthermore, the effect of cortisol to delay the E2-induced LH surge is more pronounced in the breeding season. These results show that cortisol disrupts the positive feedback effect of E2 to trigger an LH surge and suggest the involvement of multiple mechanisms.
34. The Complex Role of Estrogens in InflammationEndocrine Reviews 2007 28 (5): 521-574Rainer H. Straub An excellent review
35. The effects of sex-steroid administration on the pituitary?thyroid axis in transsexuals European Journal of Endocrinology, 2006Vol 155, Issue 1, 11-16 Peter H Bisschop1, Arno W Toorians3, Erik Endert2, Wilmar M Wiersinga1, Louis J Gooren3 and Eric Fliers1 Administration of sex hormones can interfere substantially with the hypothalamic?pituitary?thyroid (HPT) axis. Oral estrogen administration increases thyroid-hormone-binding globulin (TBG) concentrations (1). This glycoprotein is produced in the liver and binds about two-thirds of serum thyroxine (T4). The rise in TBG is paralleled by a T4 increase to maintain a physiological concentration of free T4. Therefore, the T4 substitution dose in women with primary hypothyroidism, characterized by impaired endogenous T4 production, must be increased when oral estrogens are administered (1). In contrast to oral administration, transdermal estrogen administration does not raise TBG concentrations (2). It is assumed that this discrepancy is caused by a first-pass effect due to high portal vein estrogen concentrations after oral administration. Opposite to estrogen, androgen administration in women decreases TBG concentrations and requires reduction of T4 substitution in patients with primary hypothyroidism to avoid thyrotoxicosis (3).
Besides the effects on TBG concentrations, sex hormones also affect deiodinase activity. Peripheral conversion of inactive T4 to biologically active triiodothyronine (T3) is catalyzed by 5'-deiodinase activity and is the main source of circulating T3. Two of the three deiodinase subtypes, type 1 (D1) and 2 (D2), have5'-deiodinase capability. D1 is expressed in the liver of rodents and humans. D2 is expressed in brown adipose tissue of rodents and in muscle of humans. It was recently shown that muscle D2 activity is the major source of circulating T3 in euthyroid humans (4).
In rats, hepatic activity of 5'-deiodinase was not altered by ovariectomy (5), but increased after a supraphysiological dose of 17?-estradiol (6). The latter effect was blunted by concurrent administration of progestins (6). In orchidectomized rats, hepatic D1 activity was reduced, but could be restored to normal by the substitution of testosterone (5,6). These observations suggest that physiological concentrations of testosterone stimulate D1 activity in male rats and might provide an explanation for higher D1 activity in the liver of normal male rats than in female rats (7).
The effects of androgens and estrogens on 5'-deiodinase activity in humans are not known. For evident reasons, 5'-deiodinase activity cannot be measured as easily in humans as in rodents, but serum T3/T4 ratios can be used as a marker for 5'-deiodinase activity, since the majority of circulating serum T3 is produced by peripheral conversion of T4 to T3.
To explore the effects of androgens and estrogens on 5'-deiodinase activity, we studied transsexuals receiving standard cross-gender sex-hormone administration and measured the effects on the HPT axis, including T3/T4 ratios and TBG. The standard hormone administration regimens in male-to-female transsexuals include, among others, a regimen with single agent administration of cyproterone acetate (CA). CA is a progestin with anti-androgenic action by competitive binding to the testosterone receptor. The effects of CA administration on the HPT axis in humans have not been described before and will also be presented.