Lesson 34 - Gonadal Hormones PDF

Lesson 34 Gonadal Hormones 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  GONADAL HORMONES Gonadal hormones are primarily produced by the testes and ovaries, but a small amount of these hormones is also produced by the zona reticularis of the...

Lesson 34 Gonadal Hormones 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  GONADAL HORMONES Gonadal hormones are primarily produced by the testes and ovaries, but a small amount of these hormones is also produced by the zona reticularis of the adrenal glands (Dehydroepiandrosterone (DHEA) and androstenedione: can be converted into testosterone or estrogen in peripheral tissues) Gonadal hormones play crucial roles in regulating sexual development, reproduction, and the maintenance of secondary sexual characteristics Types of gonadal hormones: Estrogens Progesterone Testosterone Luteinizing Hormone Follicle-stimulating hormone  1. Neurohormonal control of the FEMALE reproductive system Gonadotrophin-releasing hormone (GnRH), released from the hypothalamus acts on the anterior pituitary to release follicle-stimulating hormone (FSH) and luteinising hormone (LH). FSH and LH stimulate follicle development in the ovary. FSH is the main hormone stimulating oestrogen release. LH stimulates ovulation at mid-cycle and is the main hormone controlling progesterone secretion from the corpus luteum. 1. Neurohormonal control of the FEMALE reproductive system Increased secretion of GnRH (Gonadotropin-releasing ormone) stimulates secretion of oestrogen from the ovaries. Maturation of the reproductive organs Development of secondary sexual characteristics Closure of the epiphyses of the long bones 1. Neurohormonal control of the FEMALE reproductive system Oestrogen controls the proliferative phase of the endometrium and has negative feedback effects on the anterior pituitary. Progesterone controls the later secretory phase, and has negative feedback effects on both the hypothalamus and anterior pituitary. HORMONAL CHANGES AND PHASES OF THE MENSTRUAL CYCLE ovulación 2. Neurohormonal control of the MALE reproductive system GnRH controls the secretion of gonadotrophins by the anterior pituitary Pulsatile secretion in both sexes FSH is responsible for the integrity of the seminiferous tubules, and it is important in gametogenesis ICSH stimulates the interstitial cells to secret androgens – in particular testosterone Testosterone has marked anabolic effects, causing development of the musculature and increased bone growth 3. Drugs affecting reproductive function INACTIVE 3. Drugs affecting reproductive function OESTROGENS Oestrogens are synthesised by the ovary and placenta, and in small amounts by the testis and adrenal cortex. The starting substance for synthesis of oestrogen (and other steroids) is cholesterol There are three main endogenous oestrogens in humans: OESTRADIOL, OESTRONE, OESTRIOL OESTRADIOL is the most potent and is the principal oestrogen secreted by the ovary. There are numerous exogenous synthetic forms: ETHINYLESTRADIOL 3. Drugs affecting reproductive function OESTROGENS The effects of exogenous oestrogen depend on the state of sexual maturity when the oestrogen is administered: In primary hypogonadism: oestrogen stimulates development of secondary sexual characteristics and accelerates growth. In adults with primary amenorrhoea: oestrogen, given cyclically with a progestogen, induces an artificial cycle. In sexually mature women: oestrogen (with a progestogen) is contraceptive. At or after the menopause: oestrogen replacement prevents menopausal symptoms and bone loss. 3. Drugs affecting reproductive function OESTROGENS They have several metabolic actions, (like mineralocorticoid→retention of salt and water) and mild anabolic actions. Reduce the risk of atheromatous disease in premenopausal women compared with men of the same age. Decrease LDL and lipoprotein a while increasing the levels of HDL Increase the coagulability of blood, and increase the risk of thromboembolism. Sensitization of the myometrium to oxytocin facilitates labour Prevent osteoporosis by inhibiting bone resorption. Estrogens are responsible for epiphyseal closure in both males and females, which halts linear bone growth. 3. Drugs affecting reproductive function OESTROGENS Mechanism of action Binds to nuclear receptors: two types of oestrogen receptor ERα and ERβ. Upon binding, the resulting complexes interact with specific nuclear sites, leading to genomic effects. Additionally, some oestrogen effects-particularly its rapid vascular actions, such as vasodilation mediated by nitric oxide (NO)- are initiated through interactions with membrane receptors. 3. Drugs affecting reproductive function OESTROGENS Pharmacokinetics Many preparations (oral, transdermal, intramuscular, implantable, intravaginal, topical) of oestrogens are available for a wide range of indications. May be given as intravaginal creams or pessaries for local effect. In the plasma, natural oestrogens are bound to albumin and to a sex steroid-binding globulin Natural and synthetic oestrogens are well absorbed in the gastrointestinal tract but after absorption are metabolised in the liver. 3. Drugs affecting reproductive function OESTROGENS ADRs: Breast tenderness, nausea, vomiting, anorexia, retention of salt and water with resultant oedema, and increased risk of thromboembolism. Gallbladder disease Oestrogen administration to pregnant women can cause genital abnormalities in their offspring: vaginal carcinoma Used intermittently for postmenopausal replacement therapy cause menstruation-like withdrawal bleeding. Oestrogen causes endometrial hyperplasia unless given cyclically with a progestogen Contraindicated during pregnancy and should be avoided in women with uterine fibroids.  3. Drugs affecting reproductive function Selective Oestrogen Receptor Modulators (SERMs) TAMOXIFEN Antioestrogenic action on mammary tissue Oestrogenic actions on plasma lipids, endometrium and bone. Mechanism of action Partial agonist of estrogen receptors: upregulates TGF-β, a cytokine that retards the progression of malignancy In bones controlling the balance between bone-producing osteoblasts and bone-resorbing osteoclasts Mild oestrogen-like adverse effects consistent with partial agonist activity. An adjuvant to surgery and radiation therapy for the treatment of breast cancer in postmenopausal women 3. Drugs affecting reproductive function Selective Oestrogen Receptor Modulators (SERMs) CLOMIPHEN Mechanism of action Inhibits oestrogen binding to its receptors in the anterior pituitariy preventing negative feedback Increases secretion of GnRH and gonadotrophins: stimulates and enlarges the ovaries, increases oestrogen secretion and induces ovulation It is administered by mouth as a 5-day course starting around day 5 of a menstrual cycle for the treatment of infertility caused by failure of ovulation. ADRs: Approximately 5% to 7% of women treated with clomiphene have multiple births (twins in the vast majority of cases). 3. Drugs affecting reproductive function Selective Oestrogen Receptor Modulators (SERMs) RALOXIFEN Antioestrogenic effects on breast and uterus Oestrogenic effects on bone, lipid metabolism and blood coagulation. FDA has supported its use to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. ADRs: menopausal symptoms are common adverse effects Increases the risk of thromboembolic disease 3. Drugs affecting reproductive function Selective Estrogen Receptor Degrader FULVESTRANT ER antagonist that acts as a selective estrogen receptor degrader (SERD). Unlike SERMs which may have agonist or antagonist effects at ERs depending on the tissue, fulvestrant is a pure ER antagonist in all tissues tested. Indicated for ER-positive, metastatic breast cancer and is given by intramuscular injection every 2 weeks for three times then monthly thereafter 3. Drugs affecting reproductive function Aromatase Inhibitors ANASTROZOLE Mechanism of action Block oestrogen synthesis in the adrenal but not in the ovary and are an alternative to receptor antagonists in postmenopausal but not in premenopausal women with breast cancer. CLINICAL USES Oestrogens Replacement therapy: – primary ovarian failure (e.g. Turner’s syndrome); – secondary ovarian failure (menopause) for flushing, vaginal dryness and to preserve bone mass. Such use should be short term because of an excess risk of thromboembolism. Contraception Antioestrogens/SERMs and aromatase inhibitors To treat oestrogen-sensitive breast cancer (tamoxifen , raloxifene, fulvestrant ). Aromatase inhibitors (e.g. anastrozole ) are an alternative for breast cancer in post-menopausal women. To induce ovulation ( clomiphene ) in treating infertility caused by anovulation.  4. Progestogens Secreted by the corpus luteum in the second part of the menstrual cycle, and by the placenta during pregnancy. Small amounts are also secreted by the testis and adrenal cortex. Progestogens act on nuclear receptors. The density of progesterone receptors is controlled by oestrogens  4. Progestogens There are two main groups of progestogens: 1.The naturally occurring hormone and its derivatives HYDROXYPROGESTERONE , MEDROXYPROGESTERONE , DYDROGESTERONE. Progesterone itself is inactive orally due to presystemic hepatic metabolism. Other derivatives are available as oral preparations 2. Testosterone derivatives NORETHISTERONE , NORGESTREL, ETHYNODIOL can be given orally. The first two have some androgenic activity and are metabolised to give oestrogenic products. Newer progestogens used in contraception: desogestrel and gestodene Option for women who experience adverse effects but have been associated with higher risks of venous thromboembolic disease 4. Progestogens ADRs: Weak androgenic actions Other unwanted effects: Acne Fluid retention Weight change Depression Change in libido Breast discomfort Premenstrual symptoms Irregular menstrual cycles Breakthrough bleeding Increased incidence of thromboembolism 5. Antiprogestogens MIFEPRISTONE Partial agonist at progesterone receptors: sensitizes the uterus to the action of prostaglandins Administered orally and has a plasma half-life of 21 h. It sensitizes the uterus to the action of prostaglandins. Mifepristone is used, in combination with a prostaglandin analogue, as a medical alternative to surgical termination of pregnancy ULIPRISTAL Selective progesterone receptor modulator which blocks ovulation It is available over the counter (OTC) and is used for emergency contraception within 120 h of vaginal intercourse To reduce the size of uterine fibroids (benign tumours of the uterus) preoperatively. CLINICAL USES Progestogens Contraception: – with oestrogen (usually ethinylestradiol) in combined oral contraceptive pill) – as progesterone-only contraceptive pill – as injectable or implantable progesterone-only contraception – as part of an intrauterine contraceptive system. Combined with oestrogen for oestrogen replacement therapy in women with an intact uterus, to prevent endometrial hyperplasia and carcinoma. For endometriosis. In endometrial carcinoma Antiprogestogens Medical termination of pregnancy: mifepristone (partial agonist) combined with a PG Emergency contraception (morning-after pill): ulipristal  6. Oral contraceptives Oral contraceptives can be started at any point during the menstrual cycle, provided there is reasonable certainty that the woman is not pregnant. If initiation occurs after day 5 of the menstrual cycle, the use of a backup barrier method of contraceptionmay be recommended for additional protection. 1. Progestogen alone (the progestogen-only pill) 2. Combinations of an oestrogen with a progestogen (the combined pill). The combined pill contains an oestrogen (ETHINYLESTRADIOL) and a progestogen (LEVONORGESTREL , ETHYNODIOL) It is taken for 21 consecutive days out of 28. “Third-generation” pills –>NORGESTREL, DESOGESTREL OR GESTODENE  6. Oral contraceptives Combined pill Mechanism of action Oestrogen inhibits secretion of FSH via negative feedback on the anterior pituitary, and thus suppresses development of the ovarian follicle. Progestogen inhibits secretion of LH and thus prevents ovulation; it also makes the cervical mucus less suitable for the passage of sperm. Oestrogen and progestogen act in concert to alter the endometrium in such a way as to discourage implantation.  6. Oral contraceptives Combined pill Administration Usually contain 21 active ingredient tablets that are administered once a day, beginning on day 5 of the menstrual cycle Extended-cycle (menstrual suppression) preparations are now available for continuous daily administration for 84 days followed by 7 days of inactive tablets: ethinyl estradiol and levonorgestrel Preparations containing drospirenone and ethinyl estradiol are available for either a 21-day or 24-day hormone regimen. Recent studies found that the 24-day regimen is associated with slightly lower rates of contraceptive failure. 6. Oral contraceptives Combined pill Contraindications Contraindicated women with certain medical conditions including but not limited to: Breast cancer Current or history of venous thromboembolism Severe hereditary thrombophilia Migraine with aura ADRs: Weight gain, owing to fluid retention or an anabolic effect Mild nausea, flushing, dizziness, depression or irritability Skin changes (e.g. acne and/or an increase in pigmentation) Amenorrhoea of variable duration on cessation of taking the pill. Reversible hypertension Increase breast cancer and cervical cancer increased risk of thromboembolism with third-generation pills, especially in women with additional risk factors 6. Oral contraceptives Transdermal patch or vaginal ring are methods of delivering continuous combined hormonal contraception as an alternative to oral contraceptives NuvaRing is a vaginal ring commercially available for combined hormonal contraception  6. Oral contraceptives Progestogen-only pill NORETHISTERONE , LEVONORGESTREL, ETHYNODIOL The progestogen-only pill is taken continuously. The contraceptive effect is less reliable and is mainly a result of the alteration of cervical mucus. Irregular bleeding is common. Considered contraceptive of choice for: Women who prefer oral contraceptive but have contraindications to combined oral contraceptives (smokers) For women whose blood pressure increases unacceptably during treatment with oestrogen. 6. Oral contraceptives Interactions Combined and progestogen-only oral contraceptives are metabolized by hepatic cytochrome P450 enzymes Any increase in its clearance may result in contraceptive failure, enzyme- inducing drugs can have this effect: -Rifampicin and rifabutin , carbamazepine , phenytoin and others, including the herbal preparation St John’s Wort  6. Oral contraceptives Emergency contraception LEVONORGESTREL (morning after pill) Progestogen-only oral contraceptive available in single-dose (1.5 mg) or double-dose regimens Considered most effective when administered within 72 hours (3 days) of intercourse and associated with about 1.1%-2.4% failure rate ULIPRISTAL ACETATE (morning after pill) Emergency oral contraceptive in single 30 mg dose Considered most effective when taken up to 120 hours (5 days) after unprotected intercourse. Repeat dosing with ulipristal acetate (UPA) not recommended 6. Oral contraceptives Emergency contraception MEDROXYPROGESTERONE Intramuscularly as a contraceptive. Infertility may persist for many months after the final dose. MIFEPRISTONE (MIFEGYNE) (abortion pill) Antagonist of progestagen´s receptor, promotes abortion first days after conception Used up to week 9 Combined with prostaglandins. 7. Clinical uses of drugs acting on the uterus MYOMETRIAL STIMULANTS (OXYTOCICS) OXYTOCIN To induce or augment labour when the uterine muscle is not functioning adequately. Vasodilator action: its weak antidiuretic action can result in water retention, which can be problematic in patients with cardiac or renal disease, or with pre-eclampsia. ADRs: Dose-related hypotension, due to vasodilatation, with associated reflex tachycardia. Anti-diuretic effect: hyponatraemia  7. Clinical uses of drugs acting on the uterus MYOMETRIAL STIMULANTS (OXYTOCICS) ERGOMETRINE can be used to treat postpartum haemorrhage. Contracts the human uterus: this action depends partly on the contractile state of the organ if the uterus is inappropriately relaxed, ergometrine initiates strong contraction and reduces bleeding from the placental bed Rapid onset of action and its effect lasts for 3–6 h. ADRs: Produce vomiting, probably by an effect on dopamine D 2 receptors in the CTZ Vasoconstriction with an increase in blood pressure associated with nausea, blurred vision and headache can occur, as can vasospasm of the coronary arteries, resulting in angina.  7. Clinical uses of drugs acting on the uterus MYOMETRIAL STIMULANTS (OXYTOCICS) PROSTAGLANDINES Prostaglandins PGE and PGF promote coordinated uterine contractions and cervical relaxation, facilitating the expulsion of uterine contents. Unlike oxytocin, they are effective in inducing abortion during early and mid-pregnancy stages. Menorrhagia can occur when we have an imbalance in the production of PGI2. PGI2 (prostaglandin I2) can exacerbate this condition by both inhibiting platelet aggregation and causing vasodilation, thereby impairing haemostasis. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as mefenamic acid, are commonly used to manage menorrhagia and associated conditions like dysmenorrhoea due to their ability to reduce prostaglandin production. 7. Clinical uses of drugs acting on the uterus MYOMETRIAL STIMULANTS (OXYTOCICS) PROSTAGLANDINES The PGs used in obstetrics are DINOPROSTONE (PGE 2) CARBOPROST and GEMEPROST or MISOPROSTOL (PGE 1 analogues) Carboprost can be used if patients do not respond to ergometrine Preparation of oxytocin and ergometrine for the management of the third stage of labour (to control bleeding) GEMEPROST (intravaginally) or MISOPROSTOL (intravaginally or orally) are used in therapeutic abortion. 7. Clinical uses of drugs acting on the uterus MYOMETRIAL RELAXANTS RITODRINE β2-adrenoceptor agonist used to delay preterm labour. Used in selected patients to prevent premature labour occurring between 22 and 33 weeks of gestation in otherwise uncomplicated pregnancies ADRs: Toxicity in the neonate ATOSIBAN (oxytocin antagonist) also delays preterm labour. 8. Postmenopausal hormone replacement therapy (HRT) HRT normally involves the cyclic or continuous administration of low doses of one or more oestrogens, with or without a progestogen. Short-term HRT has some clear-cut benefits: Improvement of symptoms caused by reduced oestrogen, for example hot flushes and vaginal dryness Prevention and treatment of osteoporosis Drawbacks include: Does not reduce the risk of coronary heart disease. Not reduces age-related decline in cognitive function. Cyclical withdrawal bleeding Increased risk of endometrial cancer Increased risk of breast cancer, related to the duration and disappearing within 5 years of stopping Increased risk of venous thromboembolism (two-fold increase in women using combined hrt for 5 years). 8. Postmenopausal hormone replacement therapy (HRT) Oestrogens used in HRT can be given orally (conjugated oestrogens, oestradiol, oestriol), vaginally (oestriol), by transdermal patch (oestradiol) or by subcutaneous implant (oestradiol). TIBOLONE is marketed for the short term treatment of symptoms of oestrogen deficiency. It has oestrogenic, progestogenic and weak androgenic activity. 9. Androgens Testosterone is the main natural androgen. It is synthesized mainly by the interstitial cells of the testis, and in smaller amounts by the ovaries and adrenal cortex. Adrenal androgen production is influenced by adrenocorticotrophic hormone (ACTH, corticotrophin). As for other steroid hormones, cholesterol is the precursor Actions In general, the effects of exogenous androgens are the same as those of testosterone, and depend on the age and sex. 9. Androgens Administration of testosterone: Prepubertal boys: cause premature closure of the epiphyses of the long bones. Pubertal boys: promotes development of secondary sexual characteristics (i.e. growth of facial, axillary and pubic hair, deepening of the voice), maturation of the reproductive organs and a marked increase in muscular strength. Adults: the anabolic effects can be accompanied by retention of salt and water. The skin thickens and may darken, and sebaceous glands become more active which can result in acne. Body weight and muscle mass increase, partly due to water retention. Well-being and an increase in physical vigor, and libido Male fertility  9. Androgens Administration: Subcutaneous implantation or by transdermal patches intramuscular depot injection and orally. Pharmacokinetic aspects The elimination half-life of the free hormone is short (10–20 min). Synthetic androgens are less rapidly metabolised, and some are excreted in the urine unchanged. ADRs: Continued use infertility, and salt and water retention leading to oedema. Adenocarcinoma of the liver has been reported. 10. Antiandrogens OESTROGENS PROGESTAGENS ANDROGENS CYPROTERONE is a derivative of progesterone Used as an adjunct in the treatment of prostatic cancer together with GnRH agonists It is also used in the therapy of precocious puberty in males, and of masculinisation and acne in women. It also has a central nervous system effect, decreasing libido, and has been used to treat hypersexuality in male sexual offenders 10. Antiandrogens FLUTAMIDE It is a non-steroidal antiandrogen used with GnRH agonists in the treatment of inoperable prostate cancer. FINASTERIDE It inhibits the enzyme (5α-reductase) that converts testosterone to its active metabolite dihydrotestosterone It is used to treat benign prostatic hyperplasia (BPH) CLINICAL USES 1. Androgens ( testosterone preparations) as hormone replacement in: – male hypogonadism due to pituitary or testicular disease. 2. Anti-androgens (e.g. flutamide , cyproterone ) are used as part of the treatment of prostatic cancer. 5α-Reductase inhibitors (e.g. finasteride ) are used in benign prostatic hyperplasia 49 11. Anabolic steroids NANDROLONE It increase protein synthesis and muscle development disproportionately, but clinical use (e.g. in debilitating disease) has been disappointing. They are used in the therapy of APLASTIC ANAEMIA (to stimulate erytropoyesis) ADRs: Cholestatic jaundice liver tumors increased risk of coronary heart disease at high-dose anabolic steroids. 12. GnRH analogues GnRH analogues given by subcutaneous infusion Mechanism of action Given in pulsatile fashion, GnRHs stimulate gonadotrophin release; given continuously, they inhibit it. Indications Treatment of inoperable prostate cancer GnRH agonists are used by specialists in infertility treatment Treatment is started only after the patient has received an androgen receptor antagonist such as flutamide 12. GnRH analogues DANAZOL Synthetic steroid inhibits gonadotrophin secretion Indications Danazol is used in sex hormone-dependent conditions including endometriosis, breast dysplasia and gynaecomastia. An additional special use is to reduce attacks of swelling in hereditary angio- oedema ADRs: Gastrointestinal disturbances and weight gain fluid retention Dizziness menopausal symptoms muscle cramps