Gonadal Hormones & Inhibitors PDF

# The Gonadal Hormones & Inhibitors ## The Ovary - Estrogens - Progestins - Oral contraceptives - Inhibitors & antagonists - Ovulation inducing agents ## The Estrogens Hypothalamus → GnRH ⇨ Pituitary ⇨ FSH ◦ Estrogen **Pharmacokinetic aspects:** - Natural and synthetic estrogens are well absor...

# The Gonadal Hormones & Inhibitors ## The Ovary - Estrogens - Progestins - Oral contraceptives - Inhibitors & antagonists - Ovulation inducing agents ## The Estrogens Hypothalamus → GnRH ⇨ Pituitary ⇨ FSH ◦ Estrogen **Pharmacokinetic aspects:** - Natural and synthetic estrogens are well absorbed after oral administration, but natural are rapidly metabolized. - Most estrogens are absorbed from skin and mucous membrane and can be given as transdermal patches. - Can be given topically in the vagina as pessaries or creams for local effect but some of the drug can be absorbed. **Preparations** 1. **Natural estrogens:** Estradiol - The naturally occurring steroids undergo first-pass metabolism and so when taken orally have low bioavailability. 2. **Semisynthetic estrogens (Steroidal synthetic):** - **Ethinyl estradiol:** Highly potent, taken orally because ethinyl group protects from in activation by the liver. - **Mestranol:** rapidly oxidized to ethinyl estradiol. - Fat soluble, stored in adipose tissue: long duration. 3. **Synthetic estrogens:** - Non-steroidal, Effective orally, e.g. Diethylstilbestrol ## Mechanism of Action 1. **Genomic Mechanism:** - Steroid hormones diffuse across the cell membrane and bind with high affinity to specific nuclear-receptor proteins. - The activated steroid-receptor complex interacts with nuclear chromatin to initiate hormone-specific RNA synthesis. - This results in the synthesis of specific proteins that mediate a number of physiologic functions. 2. **Non-genomic Mechanism:** lead to more rapid actions: - Activation of an estrogen receptor in the membranes of hypothalamic cells has been shown to couple to a G protein, thereby initiating a 2nd messenger cascade. - Estrogen-mediated dilation of coronary arteries occurs by the increased formation and release of nitric oxide and prostacyclin in endothelial cells. ## Therapeutic Uses 1. Contraception with progestogens. 2. Postmenopausal hormonal therapy (HT): - For menopausal symptoms" hot flushes & vaginal atrophy". - With intact uterus add progestogen to decrease risk of endometrial carcinoma. - Doses of HT are less than that in oral contraception: less side effects. - Lowest effective doses for the shortest possible time (for risk of side effect). - If only vaginal atrophy: use vaginal estrogen. 3. Replacement therapy: (estrogen & progestogen) in: - 1ry hypogonadism (ovarian failure). - Premature menopause. - Surgical menopause. ## Adverse Effects 1) Nausea and Breast tenderness (most common). 2) Thromboembolic events & myocardial infarction. Estrogens enhance the coagulability of blood by increasing levels of factors II, VII, IX and X resulting in high incidence of thromboembolic disease. 3) Salt & water retention leading to edema & hypertension which causes increased weight gain. 4) Increased blood sugar levels. 5) Risk of breast cancer. 6) Risk of endometrial carcinoma: add progesterone to decrease risk ## Contraindications 1) Carcinomas of endometrium, certain types of cancer breast, both are estrogen dependent. 2) History of thromboembolic disorders. ## Drug Interactions - Hepatic microsomal enzyme inducers as phenytoin and rifampicin increase estrogens metabolism and decrease their effect as contraception. ## The Progestins - Progesterone is the natural progestational Hormone (Progestogens). ## Therapeutic Uses 1. Oral contraception: alone or with estrogen: main use. 2. Functional uterine bleeding. 3. Dysmenorrhea. 4. Amenorrhea: artificial cycle: estrogen for 25 days supplemented with progesterone 15th to 25th day. Menstruation occurs on withdrawal. 5. Endometriosis. ## Preparations 1. **Natural:** Rapidly Metabolized (IM injection) - Progesterone: oily IM. - Rapidly metabolized. - May be implanted IM as pellets or microcrystals. - Hydroxyprogesterone caproate: IM, weekly. 2. **Synthetic progestin preparations:** (effective orally) - **Derivatives of progesterone:** - Medroxyprogesterone acetate: orally, daily. - IM/3 months - **Derivatives of nortestosterone (androgenic precursor):** - Norethindrone: orally, daily. - Norgestrel: orally or SC implantation. ## Adverse Effects - Weak androgenic actions of some of the progestogens derived from testosterone. - Edema. - Psychic depression. - Increase Cholesterol: atherosclerosis. # Contraception - Hormonal: Oral or by injection - Chemical - Mechanical - Intrauterine device - Physiological methods - Male or female sterilization. ## Hormonal Contraception (ORAL, PARENTERAL, & IMPLANTED CONTRACEPTIVES) Drugs taken to prevent conception; **Types:** - A) Combination oral contraceptives - B) Progestin - only contraceptives. - C) Postcoital or "morning after" contraceptives. **A) Combination oral contraceptives:** Combination of: 1. Estrogen mainly ethinyl estradiol, sometimes mestranol. 2. Progestogen: as Norethisterone, Levonorgestrel, Newer compounds with less androgenic activity as desogestrel. - This combination form is the most effective available but have side effects. - They are taken for 21 days followed by a 7-day withdrawal period to induce menses. - They are available as monophasic, biphasic or triphasic preparations. **Triphasic combination preparations:** There are 3 different pills containing varying amounts of estrogen and progestin taken in a certain schedule. * **Advantages:** - Reduces the total amount of steroids. - Approximates the estrogen/ progestogen ratios that occur during the menstrual cycle to give better control of conception with minimal adverse effects as: - Minimize spotting and breakthrough bleeding. - Thromboembolic manifestation is less. * **Example:** Triovlar: is a triphasic preparation, the course is: - **First phase:** Start on day 5, for 6 days. - Reduced estrogen (30 mg ethinyl estradiol) reduced progestogen (50ug Levonorgestrel). - **Second phase:** next 5 days - Estrogen raised (40 ug) progestogen raised (75 ug). - **Third phase:** 10 days - Estrogen dropped (30 ug) progestogen further increased (125 ug). ## Mechanism of action: 1. Estrogen inhibits the release of FSH and so suppresses the development of the ovarian follicle. 2. The progestogen inhibits the release of LH and thus prevents ovulation and it also increases viscosity of cervical mucus so impair penetration of sperms. 3. They both alter the endometrium in such a way as to discourage implantation. - When administration ceases it is the withdrawal of progestogen which causes bleeding. **B) Progestin only contraceptives:** ## Mechanism of action: 1) Increases viscosity of cervical mucus so impair penetration of sperms. 2) Hinder implantation through effect on endometrium & on motility and secretions of the fallopian tubes. **Types:** 1) **Oral progestogens:** Minipill - Norethindrone or L-norgestrel are given in relatively small doses (minipill) starting on the first day of the cycle and continued without interruption. - Does not inhibit ovulation. - Does not inhibit the cycle. - Does not inhibit lactation. * **Mechanism of contraception:** thick cervical mucus & endometrial changes. * **Disadvantages:** - Break-through bleeding is common. - Irregular menstrual cycles. - Less effective than the combined method. Missing a dose: conception. 2) **Long acting (depot therapy):** - Injection of a long acting progestogen: medroxyprogesterone acetate 150 mg every 3 months. - Used in women after delivery as it does not affect lactation. - Menstrual irregularities are very common; infertility persists for many months after stop. 3) **Subcutaneous implants:** - L-Norgestrel by SC implants will release the hormone very slowly, effective over several years (5 years). - Six capsules are placed SC in the upper arm. * **Advantages:** - The implant is cheaper than oral contraceptives. - Nearly reliable as sterilization. - Totally reversible if the implants are surgically removed. - Once implantation occurs, the method does not depend on patient compliance. So lower rates of new pregnancies compared to oral contraceptives. * **Adverse effects:** Irregular menstrual bleeding & headaches. 4) **Progesterone Releasing Intrauterine Device(IUDs):** - Progestasert: is an IUD, its vertical stem contains a reservoir of 38 mg progesterone. - Low amounts of progesterone is released locally per day. **C) Post coital or "morning after" contraceptive:** - **Estrogen alone:** - Diethylstilbestrol, within 72 hrs after intercourse in a large dose of 25 mg twice daily for 5 consecutive days. - **Estrogen + progestogen** - Taken twice, 12 hrs apart, within 72 hrs after intercourse. * **Mechanism of action of large dose of estrogens:** - Large dose of estrogen (postcoital pills): Increase motility of oviduct & endometrial changes and decreased fertilization & implantation - Withdrawal of large dose of estrogens: Withdrawal bleeding then expel fertilized ovum. * **Disadvantage:-** Nausea and vomiting occur frequently. ## Adverse effects of oral contraceptives: **The most common adverse effects:** 1) Headache, and nausea. 2) Fluid retention → Weight gain & Increased blood pressure may also occur. 3) Breast fullness & mastalgia. 4) Progestins may be associated with: depression, changes in libido, hirsutism, and acne. Also, Break-through bleeding (common with progestogens alone or low dose combination method). **Severe adverse effects:** Although rare 1) Thromboembolism, myocardial infarction, and stroke (most common among women who are over 35 years and smoke). 2) Increased incidence of cervical cancer and breast cancer. 3) cholecystitis, gall stones & jaundice. ## Contra-indications of oral contraceptives: 1. History of thromboembolic disease or varicose veins. 2. Breast Cancer. 3. Liver disease. 4. Diabetes. 5. Cardiovascular diseases e.g. hypertension, coronary heart disease. 6. Uterine fibromyomata (may increase). 7. Migraine. 8. Women over 35 years. 9. Undiagnosed vaginal bleeding. ## Drug interactions: - Oral contraceptives antagonize the effect of: - 1. Oral anticoagulants: oral contraceptives increased level of blood clotting factors. - 2. Some antihypertensive: oral contraceptives may increase Bl. pr. - 3. Antihypercholesterolemic drugs: oral contraceptives increase level of blood cholesterol & triglycerides. - Oral contraceptives effect may be reduced → breakthrough bleeding, and pregnancy may occur with: - 1. Enzyme inducers: phenytoin, phenobarbitone, rifampicin - 2. Mineral oil: decrease intestinal absorption of oral steroids. - 3. Tobacco smoking and antifibrinolytics increase the incidence of thromboembolism. # Estrogen & Progesterone Inhibitors & Antagonists ## Anti-Estrogens 1. **Selective Estrogen Receptor Modulators (SERMS)** - SERMs are a class of estrogen-related compounds that display selective agonism or antagonism for estrogen receptors depending on the tissue type. - This category includes tamoxifen, raloxifene, clomiphene citrate. * **Tamoxifen:** - **Indications:** - 1- treatment of metastatic Breast Cancer. - 2- adjuvant therapy after mastectomy or radiation - **Adverse effects:** - hot flushes - increase risk of endometrial cancer - Increase risk of DVT & pulmonary embolism * **Raloxifene:** - **Adverse effects:** - No effect on endometrium. - Effective for prevention & treatment of osteoporosis. - Reduction in risk of breast cancer. - Does not relieve Post-Menopausal hot flushes. - Increase risk of venous thromboembolism (high). * **Clomiphene Citrate:** - Estrogen Receptor Modulators at estrogen receptors. - Used as Ovulation-inducing agent 2. **Estrogen Synthesis Inhibitors:** - **Aromatase Inhibitors (Als):** Decrease the production of estrogen. - The aromatase reaction is responsible for the extra-adrenal synthesis of estrogen from androstenedione, which takes place in liver, fat, muscle, skin, and breast tissues, including breast malignancies. Peripheral aromatization is an important source of estrogen in postmenopausal women. - They are of 2 types: - **Steroidal Als:** which binds permanently to aromatase enzyme (suicide inhibition), example: exemestane - **Non-steroidal Als:** which bind reversibly to aromatase, example: letrezole - Can be used in treatment of breast cancer & induction of ovulation. - It is devoid from the androgenic side effect of steroidal Als. ## Anti-Progestogens 1. **Mifepristone:** inhibits the activity of progesterone. - It binds to progesterone receptors with no progesterone activity (progesterone antagonist). - It also binds to glucocorticoid receptors - It interferes with the progesterone & proved very effective in terminating early pregnancy and often combined with the prostaglandin analog misoprostol (administered orally or intravaginally) to induce uterine contractions. - It is used as postcoital contraceptive e.g. in rape. 2. **Danazol (Anti - gonadotrophins)** - Weak androgen, anti-progestin and anti-estrogenic effects. - Inhibits the mid-cycle surge of LH and FSH, but with no effect on basal level. - Inhibits steroid synthesis in the ovary: reduces ovarian function leading to atrophic changes in the endometrium. - Used in treatment of endometriosis & fibrocystic disease of breast. * **Adverse effects:** - Androgenic: acne, hirsutism & Deepening of voice - Weight gain - Decrease breast size - Libido changes # Ovulation-Inducing Agents Treatment of infertility due to ovulatory failure: 1. **Clomiphene citrate:** - Nonsteroidal compound used to induce ovulation - It blocks ER in hypothalamus preventing the usual negative feedback effect of estrogen on GnRH leading to increased FSH→ marked stimulation and enlargement of ovaries & increase estrogen secretion & induction of ovulation. - Dose: 50 mg daily for 5 days orally. If no ovulation 100 mg daily for 5 days. - **Adverse-effects:** - Hot flushes, Headache, Visual disturbances and reversible hair loss. - Ovarian enlargement Multiple Ovulation & multiple pregnancies. - Constipation. 2. **Human Menopausal Gonadotrophins** - It has FSH and LH activities - Its use must be followed by human chorionic gonadotrophin with LH activity only. 3. **Metformin:** - It lowers insulin, androgen and cholesterol levels - It is useful in restoring regular menstrual cycle and starting ovulation in about 50% of women with polycystic ovary syndrome. 4 **Aromatase Inhibitors (e.g. Letrezole)** - The drug inhibits estrogen synthesis → increases GnRH release → increases FSH release ➡induction of ovulation. - Better to be given with small dose of FSH ## Self-assessment 1. Mention 3 selective estrogen receptor modulators, for each one enumerate 1 clinical use and 1 side effect. 2. Mention 5 side effects of combined oral contraceptive pills. 3. Enumerate 3 drugs that may interact with combined oral contraceptive pills and the result of this interaction.