Reproductive Hormones 2022 PDF

Reproductive hormones Brinnell Caszo Sr Lecturer MBBS, MD, Human Biology/Physiology August 2023  OUTCOMES 1. Outline the synthesis, metabolism and regulation of the secretion of sex hormones 2. Describe the mechanism of action and effects of sex hormones during puberty and in...

Reproductive hormones Brinnell Caszo Sr Lecturer MBBS, MD, Human Biology/Physiology August 2023  OUTCOMES 1. Outline the synthesis, metabolism and regulation of the secretion of sex hormones 2. Describe the mechanism of action and effects of sex hormones during puberty and in an adult 3. Describe the hormonal basis of ovular and anovular menstrual cycles, and signs of ovulation 4. Discuss the hormonal manipulation of the menstrual cycle 5. Describe the effects of 5-apha- reductase deficiency, orchidectomy before and after puberty, and congenital adrenal hyperplasia Synthesis: Oestrogens  Metabolism and excretion Main Site: In the liver, Oestrogens are converted to glucuronide and sulfate conjugates. All these compounds, along with other metabolites, are excreted in the urine Appreciable amounts are secreted in the bile and reabsorbed into the bloodstream (enterohepatic circulation)  Actions of Oestrogens Female Secondary Sex Characteristics: narrow shoulders and broad hips, thighs that converge, and arms that diverge (wide carrying angle). the female distribution of fat in the breasts and buttocks the larynx retains its prepubertal proportions and the voice stays high-pitched. flat-topped pattern (female escutcheon) Growth of pubic and axillary hair in both sexes is due primarily to androgens. Sebaceous gland secretions more fluid, countering the effect of testosterone and inhibit formation of comedones Female reproductive tract: Proliferation of endometrium Uterine glands lengthen Estrogen makes the mucus thinner and more alkaline, changes that promote the survival and transport of sperm Cervical mucus dries in an arborizing, fern-like pattern vaginal epithelium becomes cornified,  Actions of Oestrogens Breast: proliferation of mammary ducts facilitate the growth of the ovarian follicles and increase the motility of the uterine tubes. hey increase uterine blood flow and have important effects on the smooth muscle of the uterus. increase the amount of uterine muscle and its content of contractile proteins “estrogen-dominated” uterus is also more sensitive to oxytocin. Other systemic effects: Retain salt and water and gain weight just before menstruation significant plasma cholesterol-lowering action Prevent action of osteoclasts and reduce rate of bone resorbtion they increase libido in humans Synthesis: Progesterone Secretion, transport and metabolism: Progesterone Site of secretion: corpus luteum, the placenta, and (in small amounts) the follicle 80% is bound to albumin and 18% is bound to corticosteroid binding globulin. converted in the liver to pregnanediol, which is conjugated to glucuronic acid and excreted in the urine. principal target organs of progesterone are the uterus, the breasts, and the brain Endometrium: secretory phase, increased tortuosity and secretion by glands, increased tortuosity of spiral arteries Cervix: thickening of cervical mucus and inhibits the ferning caused by oestrogen Vagina; the epithelium proliferates and becomes infiltrated with leukocytes  Effects of Progesterone In pregnancy: Progesterone has an antiestrogenic effect on the myometrial cells, decreasing their excitability, sensitivity to oxytocin, and spontaneous electrical activity Decreases the number of estrogen receptors in the endometrium and increases the rate of conversion to less active estrogens. In the breast: progesterone causes growth of lobules and alveoli Others: Large doses of progesterone inhibit LH secretion and potentiate the inhibitory effect of estrogens, preventing ovulation. Progesterone is thermogenic; is probably responsible for the rise in basal body temperature at the time of ovulation. It stimulates respiration, and the alveolar PCO2  Mechanism of action Two types of estrogen receptors: estrogen receptor α (ERα) (chromosome 6) and estrogen receptor β (ERβ), (chromosome 14) Most of the effects of estrogens are genomic; but some are so rapid Importance: selective estrogen receptor modulators (SERMs); “tailormade” estrogens that have selective effects in humans like tamoxifen The effects of progesterone, like those of other steroids, are brought about by an action on DNA to initiate synthesis of new mRNA. The progesterone receptor is bound to a heat shock protein in the absence of the steroid, and progesterone binding releases the heat shock protein, exposing the DNAbinding domain of the receptor. two isoforms of the progesterone receptor—PRA and PRB; significance not known Regulation or ovarian hormone secretion by the hypothalamo-pituitary axis Secretion and regulation Episodic secretion of LH (s) and FSH (d) during the follicular stage (top) and the luteal stage (bottom) of the menstrual cycle. The numbers above each graph indicate the numbers of LH pulses per 12 hours and the plasma estradiol (E2) and progesterone (P) concentrations at these two times of the cycle. (Reproduced with permission from Marshall JC, Kelch RO: Gonadotropin-releasing hormone: Role of pulsatile secretion in the regulation of reproduction. N Engl J Med 1986; Dec 4; 315(23):1459–1468.) Citation: Chapter 22 Reproductive Development & Function of the Female Reproductive System, Barrett KE, Barman SM, Brooks HL, Yuan JJ. Ganong's Review of Medical Physiology, 26e; 2019. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2525&sectionid=204295862 Accessed: May 12, 2022 Copyright © 2022 McGraw-Hill Education. All rights reserved Synthesis of Male reproductive hormones  Synthesis Testosterone the principal hormone of the testes, synthesized from cholesterol Site of secretion: Leydig cells and also formed from androstenedione secreted by the adrenal cortex. under the control of luteinizing hormone (LH), involves increased formation of cAMP via the G-protein-coupled LH receptor and Gs. increases formation of cholesterol and conversion of cholesterol to pregnenolone  Metabolism Most (98%) of the testosterone in plasma is bound to protein 65% is bound to a β-globulin called gonadal steroid– binding globulin (GBG) or sex steroid–binding globulin, and 33% to albumin Small amount plasma testosterone is converted to estradiol Most is converted androsterone and excreted in the urine.  Actions Schematic diagram of the actions of testosterone (solid arrows) and dihydrotestosterone (dashed arrows). Note that they both bind to the same receptor, but DHT binds more effectively. (Reproduced with permission of Wilson JD, Griffin JE, Russell DW: Steroid 5 alpha-reductase 2 deficiency. Endocr Rev 1993 Oct; 14(5):577–593.) Citation: Chapter 23 Function of the Male Reproductive System, Barrett KE, Barman SM, Brooks HL, Yuan JJ. Ganong's Review of Medical Physiology, 26e; 2019. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2525&sectionid=204296105 Accessed: May 12, 2022 Copyright © 2022 McGraw-Hill Education. All rights reserved  Actions Testosterone–receptor the maturation of Wolffian duct structures formation of male internal genitalia during development DHT–receptor complexes enlargement of the external genitalia: prostate and probably of the penis at the time of puberty, increase growth of facial hair, the acne due to effects on sebum, and the temporal recession of the hairline.  Actions: Secondary Sex Characteristics Site Effect External genitalia: Penis increases in length and width. Scrotum becomes pigmented and rugose. Internal genitalia: Seminal vesicles enlarge and secrete and begin to form fructose. Prostate and bulbourethral glands enlarge and secrete. Voice: Larynx enlarges, vocal cords increase in length and thickness, and voice becomes deeper. Hair growth: Beard appears. Hairline on scalp recedes anterolaterally. Pubic hair grows with male (triangle with apex up) pattern. Hair appears in axillas, on chest, and around anus; general body hair increases. Mental: More aggressive, active attitude. Interest in opposite sex develops. Body Shoulders broaden; muscles enlarge. conformation: Skin: Sebaceous gland secretion thickens and increases (predisposing to acne) Effect on hair line  Actions: Anabolic effects Anabolic effects increase the synthesis and decrease the breakdown of protein leading to an increase in the rate of growth. Secondary to this, causes moderate Na+, K+, H2O, Ca2+, SO42−, and PO43− retention, Can also increase the size of the kidneys. Exogenous testosterone that exert significant anabolic effects are also masculinizing and increase libido, which limits the usefulness of the hormone as an anabolic agent in patients with wasting diseases. Testicular Production of Estrogens Most of the estrogens in adult men are formed by extragonadal and extra-adrenal aromatization of circulating testosterone and androstenedione. Rest comes from the testes, from the Leydig cells, and some by aromatization of androgens in Sertoli cells.  Spermatogenesis Sufficient concentration of testosterone is required in the seminiferous tubules to maintain spermatogenesis Sertoli cells secrete ABP into the tubules which helps to keep local concentration of testosterone high Testosterone reaches the seminiferous tubules after diffusing through the Leydig cells and the Sertoli cells; it can easily cross the blood testes barrier Regulation Systemically administered testosterone does not raise androgen level in testes sufficiently to increase sperm count Instead it inhibits LH secretion. Which has the net effect of decreasing Testosterone synthesis which decreases the sperm count. This effect is true of analogues of Testosterone as well  Mechanism Testosterone binds to an intracellular receptor, androgen receptor (or NR3C4) Receptor/steroid complex then binds to DNA in the nucleus, facilitating transcription of various genes. Testosterone is converted to DHT by 5α-reductase in some target cells DHT binds to the same intracellular receptor as testosterone. Testosterone–receptor complexes are less stable than DHT–receptor complexes Helps to amplifying the action of testosterone in target tissues. ABNORMALITIES OF TESTICULAR FUNCTION  Figure 1 Hypergonadotropic Hypogonadotropic The Lancet 2014 3831250-1263DOI: (10.1016/S0140-6736(13)61126-5) Copyright © 2014 Elsevier Ltd Terms and Conditions  Abnormalities of testicular function Cryptorchidism Male Hypogonadism In adults, it may be – hypergonadotropic hypogonadism (High LH but low testosterone ie testicular failure) – hypogonadotropic hypogonadism. (Low testosterone with normal or low LH) Long term effects: may not have a prominent effect on secondary sex characteristics (very little androgen is needed to to maintain them), Others: loss of libido, with flushes and general irritability, passive, and depressed In adolescents: effects are usually permanent, if from childhood, “eunuchoid” tall, narrow shoulders, small muscles, a body configuration resembling the female. The genitalia may be small, high-pitched voice Pubic hair and axillary hair are present because of adrenocortical androgen secretion the hair is sparse, Androgen-Secreting Tumours Androgen-secreting Leydig cell tumors are rare and symptoms affect only prepubertal boys who develop precocious pseudopuberty Some carcinomas of the prostate are androgen-dependent  Congenital 5α-Reductase Deficiency Congenital 5α-reductase deficiency, or pseudohermaphroditism. (gene for type 2 5α-reductase is mutated) Born with male internal genitalia including testes, but they have female external genitalia and are usually raised as girls. At puberty, LH secretion and circulating testosterone levels are increased. Begin to develop male body contours and male libido. At this point, they usually change their gender identities The clitoris enlarges (“penis-at-12 syndrome”) to the point that some of the individuals can have intercourse with women. This enlargement probably occurs because, with the high LH, enough testosterone is produced to overcome the need for DHT amplification in the genitalia. Prostatic hyperplasia Rx: 5α-Reductase–inhibiting drugs are being used clinically to treat benign prostatic hyperplasia, and finasteride, the most extensively used drug, has its greatest effect on type 2 5α-reductase.  Actions Schematic diagram of the actions of testosterone (solid arrows) and dihydrotestosterone (dashed arrows). Note that they both bind to the same receptor, but DHT binds more effectively. (Reproduced with permission of Wilson JD, Griffin JE, Russell DW: Steroid 5 alpha-reductase 2 deficiency. Endocr Rev 1993 Oct; 14(5):577–593.) Citation: Chapter 23 Function of the Male Reproductive System, Barrett KE, Barman SM, Brooks HL, Yuan JJ. Ganong's Review of Medical Physiology, 26e; 2019. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2525&sectionid=204296105 Accessed: May 12, 2022 Copyright © 2022 McGraw-Hill Education. All rights reserved  Other hormones Inhibins: Testosterone can inhibit LH secretion except in large doses, it has no effect on plasma FSH. There are two inhibins in extracts of testes in men and in antral fluid from ovarian follicles in women; Inhibin A and Inhibin B Both αβA (inhibin A) and αβB (inhibin B) inhibit FSH secretion by a direct action on the pituitary, although it appears that it is inhibin B that is the FSH-regulating inhibin in adult men and women. Inhibins are produced by Sertoli cells in males and granulosa cells in females. So FSH can be controlled by Inhibins in both men and women FSH can be controlled by high levels of testosterone in men Activins: also produced from the same precursor and STIMULATE FSH secretion, role not known  Other hormones Relaxin polypeptide hormone produced in the corpus luteum, uterus, placenta, and mammary glands in women and in the prostate gland in men. During pregnancy, it facilitates delivery by relaxes the pubic symphysis and other pelvic joints and softens and dilates the uterine cervix It also inhibits uterine contractions and may play a role in the development of the mammary glands. In nonpregnant women, relaxin is found in the corpus luteum and the endometrium during the secretory phase, effects unknown In men, it is found in semen, may help maintain sperm motility penetration of ovum. Link for applied questions will be shared in the class/elearn portal  References Widmaier EP, Raff H, Strang KT. Vander’s Human Physiology. 15th Edition. USA: McGrawHill Education; 2019, Chapter 17, Pages 604- 655. Barret KE, Brooks HL, Brown S, Yuan J X-J Ganong's Review of Medical Physiology, 26th ed. USA: McGrawHill Education; 2019, Chapter 22 and 23 https://accessmedicine.mhmedical.com.ezp.imu.edu.my/content.aspx ?bookid=2525&sectionid=204295758 https://accessmedicine.mhmedical.com.ezp.imu.edu.my/content.aspx ?bookid=2525&sectionid=204296105 Kibble JD, Halsey CR, The Big Picture: Medical Physiology, USA: McGrawHill Education; 2009, Chapter 9 https://accessmedicine.mhmedical.com.ezp.imu.edu.my/content.aspx ?bookid=1291&sectionid=75578033 Thank you for your participation