[PHT] P.06 THE GONADAL HORMONES AND INHIBITORS.pdf

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.06 THE GONADAL HORMONES AND INHIBITORS PHARMACOLOGY LECTURE LECTURER: Dr. Sharon Gawigawen DATE: January 25, 2024 HYPOTHALAMIC PITUITARY GONADAL AXIS TOPIC OUTLINE I. FEMALE GONADAL HORMONES, ORAL CONTRACEPTIVES, INHIBITORS AND ANTAGONIST, AND OVULATION I...

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.06 THE GONADAL HORMONES AND INHIBITORS PHARMACOLOGY LECTURE LECTURER: Dr. Sharon Gawigawen DATE: January 25, 2024 HYPOTHALAMIC PITUITARY GONADAL AXIS TOPIC OUTLINE I. FEMALE GONADAL HORMONES, ORAL CONTRACEPTIVES, INHIBITORS AND ANTAGONIST, AND OVULATION INDUCING AGENTS II. HORMONAL CONTRACEPTION III. ESTROGEN AND PROGESTERONE INHIBITORS AND ANTAGONISTS IV. THE TESTIS V. APPENDIX CASE A 25-year old woman with menarche at 13 years and menstrual periods until about 1 year ago complaints of hot lushes, skin and vaginal dryness, weakness, poor sleep, and scanty and infrequent menstrual periods of a year’s duration. She visits her gynecologist, who obtains plasma levels of FSH and LH, both of which are moderately elevated. She is diagnosed with premature ovarian failure, and estrogen and progesterone replacement therapy is recommended. A dual energy absorptiometry scan (DEXA) reveals a bone density tscore of 24 hours) can be taken once a day o Approved in the United States for the prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in women with risk factors. BAZEDOXIFENE o Newer SERMs o Approved for treatment of menopausal symptoms and prophylaxis of postmenopausal osteoporosis. CLOMIPHENE o An older partial agonist o A weak estrogen that also acts as a competitive inhibitor of endogenous estrogens o It has found use as an ovulation-inducing agent for those who want to get pregnant N O T E T A K E R : Y N O T | C U T A Y | S A N G D A A N | A B U L E N C I A | B A L D O S | F E R R E R | B A S T I A N P a g e 10 | 17 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.06 THE GONADAL HORMONES AND INHIBITORS B. MIFEPRISTONE (RU – 486) Binds strongly to the progesterone and glucocorticoid receptors Inhibits the activity of progesterone and that of glucocorticoids The drug has luteolytic properties in 80% of women when given in the mid luteal period providing the basis for its use as a contraceptive Major use: terminate early pregnancy (in combination with misoprostol) C. DANAZOL An isoxazole derivative of ethisterone (17αethinyltestosterone) with weak progestational, androgenic, and glucocorticoid activities Used as an inhibitor of gonadal function and has found its major use in the treatment of endometriosis. OVULATION INDUCING AGENTS CLOMIPHENE CITRATE o MECHANISM OF ACTION ▪ A partial estrogen agonist receptor blocks the feedback inhibitory influence of estrogens on the hypothalamus ► surge of gonadotropins ► ovulation o EFFECT ▪ Stimulate ovulation in women with oligomenorrhea or amenorrhea and ovulatory dysfunction o CLINICAL USE ▪ Used in the treatment of disorders of ovulation in patients who wish to become pregnant – ovulation inducing. o ADVERSE EFFECTS ▪ Hot flushes ▪ Headache ▪ Constipation o CONTRAINDICATION/CAUTIONS ▪ Patients with enlarged ovaries THE TESTIS (ANDROGENS AND ANABOLIC STEROIDS, ANTIANDROGENS AND MALE CONTRACEPTION) ANDROGENS Male sex hormones Testosterone (T) o Principal androgen o Secreted by the testes (95%) and adrenal cortex (5%) o Small amounts of dihydrotestosterone (DHT), androstenedione and dehydroepiandrosterone are also secreted by the testes o Production of testosterone (LH stimulation) begins during fetal development, continues for a short time after birth (mini puberty), nearly ceases during childhood, and then resumes at puberty. o 65% of circulating T is bound to SHBG, remaining are albumin-bound. o Approx. 2% is free and available to enter cells and bind to receptors ||METABOLISM AND PHYSIOLOGIC EFFECTS|| *ENLARGED IMAGE – APPENDIX ||SYNTHETIC STEROIDS WITH ANDROGENIC AND ANABOLIC ACTIONS|| Rapidly absorbed orally but only about sixth of the dose administered is available in active form Parenteral form has a more prolonged absorption time Testosterone and its derivative have been used for their anabolic effects as well as in the treatment of testosterone deficiency N O T E T A K E R : Y N O T | C U T A Y | S A N G D A A N | A B U L E N C I A | B A L D O S | F E R R E R | B A S T I A N P a g e 11 | 17 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.06 THE GONADAL HORMONES AND INHIBITORS ||PHARMACOLOGIC EFFECTS: ANDROGENS|| MECHANISM OF ACTION o Testosterone and dihydrotestosterone bind to the intracellular androgen receptor ►initiating a series of events like those of estradiol and progesterone ► leading to growth, differentiation, and synthesis of a variety of enzymes and other functional proteins EFFECTS o Male at Puberty ▪ Androgens cause development of the Secondary sex characteristics o Adult male ▪ Suppression of gonadotropins when given in large doses ||PHARMACOLOGIC EFFECTS: ANDROGENS|| A. ANDROGEN REPLACEMENT THERAPY IN MEN o Used to replace or augment endogenous androgen secretion in hypogonadal men o Pituitary deficiency ▪ Androgens are used rather than gonadotropin except when normal spermatogenesis is to be achieved (You need a LHFSH need to stimulate spermatogenesis) o In children (with hypopituitarism) ▪ Start treatment with low dose at puberty → gradually increasing doses to achieve the growth spurt and the development of secondary sex characteristics (use of longacting agents, given intramuscularly) ANDROGEN PREPARATION FOR REPLACEMENT THERAPY B. GYNECOLOGIC DISORDERS o Used to reduce breast engorgement during the postpartum period ▪ Usually in conjunction with estrogens. o Sometimes given in combination with estrogens for replacement therapy in the postmenopausal period in an attempt to ▪ Eliminate the endometrial bleeding that may occur when only estrogens are used and to enhance libido. o Used for chemotherapy of breast tumors in premenopausal women. C. USE OF PROTEIN ANABOLIC AGENTS o Androgens and anabolic steroids have been used in conjunction with dietary measures and exercises in an attempt to reverse protein loss after trauma, surgery, or prolonged immobilization. D. ANEMIA o Large doses of androgens were used in the treatment of refractory anemias such as ▪ Aplastic anemia, Fanconi’s anemia, sickle cell anemia, myelofibrosis, and hemolytic anemias o Recombinant erythropoietin has largely replaced androgens for this purpose. E. OSTEOPOROSIS o Used in the treatment of osteoporosis, either alone or in conjunction with estrogens. F. USE OF GROWTH STIMULATORS o Used to stimulate growth in boys with delayed puberty. o If treatment is too vigorous, the patient may grow rapidly at first but will not achieve full predicted final stature because epiphyseal closure is accelerated. G. AGING o Androgen production falls with age in men and may contribute to the decline in muscle mass, strength, and libido. H. ANABOLIC STEROID AND ANDROGEN ABUSE IN SPORTS o Many athletes and their coaches believe that: ▪ Anabolic steroids—in doses 10– 200 times larger than the daily N O T E T A K E R : Y N O T | C U T A Y | S A N G D A A N | A B U L E N C I A | B A L D O S | F E R R E R | B A S T I A N P a g e 12 | 17 PCC SOM 2026 o PHARMACOLOGY AND THERAPEUTICS P.06 THE GONADAL HORMONES AND INHIBITORS normal physiologic production— increase strength and aggressiveness, thereby improving competitive performance. Adverse effects of these drugs clearly make their use inadvisable. ||ADVERSE EFFECTS: ANDROGENS|| Women and prepubertal children o Masculinization o Hirsutism, acne, amenorrhea, clitoral enlargement, and deepening of the voice Some of the androgenic steroids exert progestational activity o Leading to endometrial bleeding upon discontinuation Alter serum lipids and could conceivably increase susceptibility to atherosclerotic disease in women Cholestatic jaundice ||CONTRAINDICATION AND CAUTION: ANDROGENS|| Contraindicated in pregnant women or women who may become pregnant during the course of therapy Should not be administered to male patients with carcinoma of the prostate or breast Special caution is required in giving these drugs to children to produce a growth spurt Caution in patients with renal or cardiac disease predisposed to edema. Caution: Several cases of hepatocellular carcinoma have been reported in patients with aplastic anemia treated with androgen anabolic therapy. o Erythropoietin and colony-stimulating factors should be used instead ANTI-ANDROGENS STEROID SYNTHESIS INHIBITORS KETOCONAZOLE o Used primarily in the treatment of fungal disease o An inhibitor of adrenal and gonadal steroid synthesis o It reduces human placental aromatase activity INHIBITION OF CONVERSION OF STEROID PRECURSORS TO ANDROGENS ABIRATERONE o A newer 17α-hydroxylase inhibitor o Has been approved for use in metastatic prostate cancer FINASTERIDE o An inhibitor of 5α-reductase o A steroid-like inhibitor of this enzyme, is orally active o Decreases conversion of testosterone to dihydrotestosterone o Moderately effective in reducing prostate size in men with benign prostatic hyperplasia DUTASTERIDE o A similar orally active steroid derivative with a slow onset of action and a much longer half-life than finasteride o It is approved for treatment of benign prostatic hyperplasia RECEPTOR INHIBITORS FLUTAMIDE o A potent antiandrogen o Has been used in the treatment of prostatic carcinoma o Although not a steroid, it behaves like a competitive antagonist at the androgen receptor. BICALUTAMIDE, NILUTAMIDE AND ENZALUTAMIDE o Potent orally active antiandrogens o Administered as a single daily dose and are used in patients with metastatic carcinoma of the prostate. CYPROTERONE AND CYPROTERONE ACETATE o Effective antiandrogens o Inhibit the action of androgens at the target organ. o Used in women to treat hirsutism and in men to decrease excessive sexual drive SPIRONOLACTONE o A competitive inhibitor of aldosterone o Competes with dihydrotestosterone for the androgen receptors in target tissues. N O T E T A K E R : Y N O T | C U T A Y | S A N G D A A N | A B U L E N C I A | B A L D O S | F E R R E R | B A S T I A N P a g e 13 | 17 PCC SOM 2026 o PHARMACOLOGY AND THERAPEUTICS P.06 THE GONADAL HORMONES AND INHIBITORS Used in the treatment of hirsutism in women ▪ Appears to be as effective as finasteride, flutamide, or cyproterone in this condition. ||CHEMICAL CONTRACEPTION IN MEN|| Testosterone and testosterone enanthate, in a dosage of 400 mg per month o Produced azoospermia in less than half the men treated. Preliminary studies indicate that the intramuscular administration of 100 mg of testosterone enanthate weekly together with 500 mg of levonorgestrel daily orally can produce azoospermia in 94% of men. CYPROTERONE ACETATE o A very potent progestin and antiandrogen, also produces oligospermia o However, it does not cause reliable contraception. CASE STUDY ANSWER The patient should be advised to start daily transdermal estradiol therapy (100 mcg/d) along with oral natural progesterone (200 mg/d) for the last 12 days of each 28-day cycle. On this regimen, her symptoms should disappear and normal monthly uterine bleeding resume. She should also be advised to get adequate exercise and increase her calcium and vitamin D intake as treatment for her osteoporosis 1.The main female hormone after menopause 2.Main female hormone in non-pregnant women. 3.T/F: Estrogen decreases the coagulability of blood. 4.T/F: Estrogen increases plasminogen levels and decreases platelet adhesiveness. 5.The most important progestin in humans 6.Used in palliative treatment of breast cancer in postmenopausal women and is approved for chemoprevention of breast cancer in high-risk women. a. Tamoxifen b. Toremifen c. Raloxifene 7.Approved for prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in women with risk factors a. Tamoxifen b. Toremifen c. Raloxifene d. Bazedoxifene 8. Approved for treatment of menopausal symptoms and prophylaxis of postmenopausal osteoporosis a. Tamoxifen b. Toremifen c. Raloxifene d. Bazedoxifene 9. An inhibitor of adrenal and gonadal steroid synthesis that is used primarily in the treatment of fungal disease a. Ketoconazole b. Abiraterone c. Finasteride d. Dutasteride 10. A newer 17a- hydroxylase inhibitor that is used in metastatic prostate cancer a. Ketoconazole b. Abiraterone c. Finasteride d. Dutasteride 11. A competitive inhibitor of aldosterone that is used in the treatment of hirsutism in women a. Flutamide b. Bicalutamide c. Spironolactone d. Cyproterone Acetate 12. A very potent progestin and antiandrogen that produces oligospermia but does not cause reliable contraception. a. Flutamide b. Bicalutamide c. Spironolactone d. Cyproterone Acetate 1.Estrone(E1) 2. Estradiol(E2) 3. F 4. T 5. Progesterone 6. A 7. C 8. D 9. A 10. B 11. C 12. D N O T E T A K E R : Y N O T | C U T A Y | S A N G D A A N | A B U L E N C I A | B A L D O S | F E R R E R | B A S T I A N P a g e 14 | 17 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.06 THE GONADAL HORMONES AND INHIBITORS APPENDIX PROPERTIES OF SOME PROGESTATIONAL AGENTS METABOLISM AND PHYSIOLOGIC EFFECTS OF ANDROGEN N O T E T A K E R : Y N O T | C U T A Y | S A N G D A A N | A B U L E N C I A | B A L D O S | F E R R E R | B A S T I A N P a g e 15 | 17 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.06 THE GONADAL HORMONES AND INHIBITORS ORAL AND IMPLANTABLE CONTRACEPTIVE AGENTS IN USE N O T E T A K E R : Y N O T | C U T A Y | S A N G D A A N | A B U L E N C I A | B A L D O S | F E R R E R | B A S T I A N P a g e 16 | 17 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.06 THE GONADAL HORMONES AND INHIBITORS N O T E T A K E R : Y N O T | C U T A Y | S A N G D A A N | A B U L E N C I A | B A L D O S | F E R R E R | B A S T I A N P a g e 17 | 17