Biochemistry of Reproductive Hormones 2021-22 PDF

Royal College of Surgeons in Ireland – Medical University of Bahrain Biochemistry of main gonadal hormones Module : Renal Endocrine Breast Code :REB30 Class: MedYear1 semester 2 Date 5 April 2022 Lecturer: Paul O’Farrell Learning objectives Recall the precursor relationships...

Royal College of Surgeons in Ireland – Medical University of Bahrain Biochemistry of main gonadal hormones Module : Renal Endocrine Breast Code :REB30 Class: MedYear1 semester 2 Date 5 April 2022 Lecturer: Paul O’Farrell Learning objectives Recall the precursor relationships of the main steroid hormones. Outline the biochemical synthesis pathway of the main gonadal hormones and identify the key enzymes involved. Describe the hormonal inter-relationship in the control of the female and male reproductive system (the hypothalamic-pituitary- gonadal axis) Outline the hormonal control of the normal female menstrual cycle. Describe the actions of the gonadal hormones. Outline the role of pituitary gonadotropins in steroidogenesis in males and females Recognise the defects of steroid hormone synthesis that cause abnormalities of sexual development Female Ovarian cycle – follicular changes At week 11-12 of gestation the oogonia of the female foetus enter prophase of the first meiotic division and are arrested there. This cell is now the primary oocyte, which with the surrounding granulosa cells, forms the primordial follicle. No further development occurs until puberty At birth about 2 million primary follicles; by puberty, there are about 300,000. Puberty There is a good deal of evidence indicating that the peptide hormone, kisspeptin, plays an important role in initiating puberty Kisspeptin → stimulates hypothalamus to secrete GnRH → stimulates anterior pituitary to secrete LH and FSH → production of testosterone (testes) and estradiol (ovaries) →promotes spermatogenesis, development of the oocyte, and development of secondary sexual characteristics. http://www.kisspeptin.com/ Ovarian cycle – follicular changes At the start of each cycle, 10-20 primary follicles begin to develop Follicular cells begin to prolifererate to form the membrana granulosa; Surrounding stromal cells form the theca. Enlargement of the antrum, a fluid filled cavity, and development into the secondary follicle In the graafian follicle, the Brook and Marshall 6.7 ovum is supported in the antrum on a stalk of cells called the cumulus oophorus Ovarian cycle – follicular changes About day 14, ovulation occurs : the graafian follicle migrates to the surface of the ovary and ruptures, releasing the ovum The cells of the ruptured graafian follicle proliferate and develop into the corpus luteum (“yellow body”) The corpus luteum remains active for the second half of the cycle (“luteal phase”, first half is “follicular phase”) Brook and Marshall 6.7 If fertilization and implantation do not occur, the corpus luteum degenerates and is replaced with scar tissue – the corpus albicans (“white body”) Hadley “Endocrinology” 18.3 Ovarian cycle - hormonal changes Menstruation Follicular phase Luteal phase Brook and Marshall 6.10 The changes that occur throughout the cycle are driven by changes in the levels of the various hormones involved. There are feedback and feedforward mechanisms by which one hormone controls the level of another  Gard 11.1 hormones hormones hormone source function Peptide Gonadotrophin hypothalmus stimulate pituitary to release hormone releasing hormone gonadotrophins; pulsatile (GnRH) release follicle stimulating pituitary stimulate ovary to release hormone (FSH) steroids, follicle maturation Gonadotrophins leutenizing hormone pituitary stimulate ovary to release (glycoprotein) (LH) steroids, ovulation, maintenance of CL Human Chorionic placenta Maintenance of CL in Gonadotrophin pregnancy (HCG) estradiol Follicle, CL inhibition of LH and FSH release, follicle maturation, Steroid repair of endometrium hormones progesterone CL inhibition of LH and FSH release, prepare and maintenance of endometrium for implantation Peptide inhibin Follicle, CL inhibition of LH and FSH hormone release Production of ovarian steroid hormones Theca cells are stimulated by LH to produce androgens LH stimulates conversion of cholesterol to pregnenolone …. Aromatase in granulosa cells converts androgens to estrogens In early cycle, granulosa cells do not have LH receptors and do not convert cholesterol to pregnenolone Hormones in the cycle Follicular phase : – FSH stimulates development of primary follicle, increases number of granulosa cells, increases number of FSH receptors – LH increases number of theca cells As the follicle develops, increased production of estradiol begins to reduce levels of FSH As FSH levels fall, only the follicle with the most FSH receptors continues to develop Estradiol levels continue to rise. Estradiol levels reach a threshold value which triggers a temporary spike in LH levels (also FSH) The spike in LH triggers ovulation Just before ovulation, granulosa cells develop LH receptors, and begin to produce progesterone Hormones in the cycle Luteal phase : Corpus luteum continues to produce progesterone and estradiol after ovulation, under the stimulus of LH LH levels continue to fall after ovulation Corpus luteum needs LH for maintenance; → as LH levels fall CL degenerates Degeneration of Corpus Luteum causes drop in estradiol and progesterone levels; drop in progesterone levels leads to menstruation Drop in steroid hormone levels removes inhibition of gonadotrophin production and cycle begins again Ovarian cycle - uterus Menstruation – the endometrium After menstruation, estradiol promotes repair and proliferation of uterine endometrium and synthesis of progesterone and estradiol receptors – proliferative phase After ovulation, progesterone leads to changes in endometrium necessary for implantation – secretory phase Maintenance of secretory phase depends on progesterone from CL; when progesterone levels fall due to degeneration of CL, endometrium sloughs off. If implantation occurs: human Chorionic Gonadotrophin –hCG- (which has LH like activity) from trophoblast maintains CL, and thus maintains progesterone levels Placenta eventually takes over progesterone production Cervical mucus: - consistancy and pH changes during cycle Follicular phase: less viscous and higher pH → promotes sperm motility and survival Luteal phase: more viscous and lower pH; opposes sperm entry into uterus ovarian cycle Target tissue effects of estrogens Widening of pelvis Breast development Maturation of genitalia Female pattern pubic hair Suncutaneous fat deposition Menstrual cycle and ovulation Male Testes structure and function male gonads that produce the male gametes or sperm and testes secretes testosterone tissue in the testes that divide it into lobules or regions that septa contain seminiferous tubules sperm producing factories seminiferous tubules site of spermatogenesis  Brook and Marshall 6.4 Testosterone Produced in Leydig cells of testes Under stimulation by LH Steroid synthesis pathway in testes produces testosterone - (enzymes not available for other products) testosterone Converted to DHT (a much more potent androgen) in various tissues by 5α-reductase In utero effects of testosterone Presence of Sry in male embryo suppresses expression of aromatase and steroid production from gonad ends at testosterone (not estrogen). Testosterone : development of wolffian duct into epididymus, vas deferens and seminal vesicles (Sry also directs production of anti-Mullerian hormone) Spermatogenesis Germ cells laid down in testes in foetal period – committed to becoming spermatogonia No further development until puberty In adolescent and adult, spermatogonia increase numbers by mitosis Spermatozoa are produced by meiosis Sertoli cells in testes sectrete nutrients and growth factors that ‘nurse’ developing spermatozoa Puberty Kisspeptin → increase in GnRH →increase in LH and FSH from hypothalamus → Puberty FSH stimulates sertoli cells LH stimulates Leydig cells Initiation of spermatogenesis requires both FSH and LH Testesterone (induced by LH) is able to maintain spermatogenesis, but cannot initiate it Hormones in male hormones hormone source function Peptide Gonadotrophin hypothalmus stimulate pituitary to release releasing hormone gonadotrophins hormone (GnRH) follicle stimulating pituitary stimulate Sertoli cells, hormone (FSH) initiation of spermatogenesis Gonadotrophins (glycoprotein) leutenizing hormone pituitary stimulate Leydig cells; (LH) induction of testerone production testosterone Leydig Cells inhibition of LH and FSH Steroid release hormone inhibin Sertoli cells inhibition of FSH release Peptide hormone Target tissue effects of androgens Testerone/DHT Foetal development of male Increased agression and libido Enlargement of larynx Male pattern pubic hair Male physique Promotion of anabolic metabolism Beard growth Maturation of genitalia Sperm production Defects of steroid hormone synthesis cause abnormalities of sexual development Inherited deficiency of 5alpha-reductase –Prevents synthesis of DHT from testosterone –Affected boys born with ambiguous external genitalia, although testes and internal wolffian ducts structures (epididymis, vas deferens, seminal vesicles) are present. –Full virilization takes place at puberty –‘penis-at-12’ syndrome Congenital adrenal hyperplasia (CAH) –Deficiency of e.g. 21-a-hydroxylase or 11b-hydroxylase –Enzymes required for synthesis of corticosteroids but not androgens –Corticosteroid synthesis blocked, overproduced progestins are diverted into androgen synthesis 1.Life threatening electrolyte imbalance 2.Ambiguous external genitalia in girls, precocious puberty in boys Other resources: Reading Gard “ Human endocrinology” Chp. 10 & 11 Brook and Marshall “Essential Endrocrinology” Chp. 6 Guevedoce Video: summary of ovarian/uterine cycle Oogenesis spermatogenesis