Female sex hormones

Gonadotropin releasing hormone (GnRH) Released in “pulsalite manner” from the hypothalamus and acts on Pituitary to stimulate the secretion of gonadotropins- FSH & LH

1. GnRH analogs A. Short-acting analogs Gonadorelin (t 1/2 = 4 min.) It can be used in “Pulsatile” manner to stimulate pituitary to secrete FSH and LH. Uses: Diagnostic purpose In infertility: Hypothalamic amenorrhea

B. Long-acting analogs Goserelin, Nafarelin, Leuprolide After initial stimulation, they will cause suppression of gonadotropin (FSH, LH) secretion. (down-regulation) Therapeutic Uses: For Medical castration: In precocious puberty Breast Ca Prostate Ca Leiomyoma Endometriosis Adverse effects: Gonadal steroidal inhibition in females can cause: Hot flashes, Vaginal atrophy, Decreased bone density

2. GnRH antagonist Ganirelix Cetrorelix These are pure GnRH antagonists and do not cause initial increase in gonadotropin secretion.

3. Gonadotropins: FSH & LH Gonadotropin preparations: Menotropins (LH + FSH) Recombinant FSH and LH hCG (Human chorionic gonadotropin)

Follicle-Stimulating Hormone (FSH) Therapeutic uses: Treatment of infertility caused by hypogonadism in both sexes. To stimulate ovulation as a part of in-vitro fertilization (IVF) programs. Side effects: Hyperstimulation syndrome (enlarged ovaries, ascites, fever, embolism, etc.). Multiple births. Gynecomastia in men.

Human chorionic gonadotropin (hCG) It is glycoprotein produced by the placenta hCG can be used as LH substitute. Therapeutic uses: Treatment of infertility both sexes. In females hCG is used as a part of invitro fertilization (IVF) programs to induce ovulation when mature follicles are present (ovulation occurs 36-40hrs from injection). HCG injections are used to stimulate the Leydig cells to synthesize testosterone. Treatment hypogonadism

4. Estrogens Physiological Role: Development of genital tract and breast. Secondary sex characters. Menstrual cycle During follicular phase it cause endometrium to grow Metabolic effects: Increase bone mass and prevent bone resorption. Increase blood glucose. Increase serum TGs and decrease cholesterol. Salt and water retention. Increase blood coagulation and platelet adhesiveness.

Types of estrogen Natural estrogens Estradiol Estriol Estrone Synthetic estrogens Ethinyl estradiol Routes of adminstration Oral IM Transdermal

Uses of Estrogens: Hormone Replacement therapy: Primary hypogonadism Premature ovarian failure; surgical removal of ovaries Menopause Oral contraception Osteoporosis Atrophic vaginitis

Adverse effects Nausea, vomiting Thromboembolic problems Myocardial infarction Breast Ca Endometrial Ca Postmenopausal uterine bleeding Diethylstilbestrol: Clear cell Ca (cervical & vagina)

Prolonged administrations of estrogen  abnormal endometrial hyperplasia, abnormal bleeding patterns, associated with high incidence of endometrial cancer. This can be prevented by administration of progesterone accompanies the estrogen. Thus, women taking HRT must also take a progesterone unless they have had a hysterectomy.

5. Selective estrogen receptor modulators (SERMs) Tamoxifen, Raloxifene These are drugs that interact with estrogen receptors but have different effects on different tissues. They can show agonism or antagonism depending upon the tissue type.

A. Tamoxifen Antiestrogenic effect: on Breast Effective in the treatment of breast Ca in patients with tumor cells that are estrogen receptor- positive. can be given after surgery to eradicate micrometastases Estrogenic effect: on Endometrium Can cause endometrial Ca Not prescribed to treat breast Ca for longer than 3-5 years in non-hysterectomized women

Adverse effects: Nausea/Vomiting Hot flashes Vaginal bleeding Risk of Endometrial Ca Thromboembolic disorders

B. Raloxifene Antiestrogenic effect: Breast, Endometrium Estrogenic effect: Bones, lipid metabolism Unlike Tamoxifen, it does not increase the risk of endometrial Ca. Approved to be used for the prevention of osteoporosis in postmenopausal women

6. Estrogen antagonists Clomiphene (Ovulation inducer): It blocks estrogen receptors in the hypothalamus and anterior pituitary so reduces negative feedback ↑ FSH and LH secretion leads to ovarian follicle development and ovulation Side effects include; Multiple pregnancies, Enlarged cystic ovaries. Used for Inadequate ovulation or low sperm count in males

7. Aromatase inhibitors Anastrozole : non-steroidal agents; competitive inhibitors Exemestane : steroidal agent; irreversible inhibitor Estriol Estrone Estradiol

Mechanism of action: Aromatase inhibitors block the synthesis of estrogens from androgen precursors by inhibiting aromatase enzyme. Uses: it can be used to inhibit the growth of estrogen-dependent tumors e.g., breast cancer. Used in postmenopausal women with advanced breast cancer. Unlike tamoxifen, they DO NOT increase the risk of endometrial carcinoma or venous thromboembolism. Endometriosis

8. Progestins The physiological role of progesterone is maintenance of pregnancy Progestins are often combined with estrogen in various formulations to counteract the harmful effects of estrogens (Estrogen can cause endometrial carcinoma)

Types Progestins: Natural progestins: Progesterone, 17-alpha hydroxyprogesterone Synthetic progestins: Medroxyprogesterone (Oral-daily, IM every 1-3 month) Norgestrel, Levonorgestrel Norgestimate (less androgenic) Desogestrel (less androgenic)

Uses: As contraceptive and menopausal hormone therapy Combined with estrogen (in COCPs & menopausal hormonal therapy) Progestin only contraceptive preparations As postcoital contraception Dysmenorrhea Dysfunctional uterine bleeding Endometriosis

Adverse effects: Edema Depression Breakthrough bleeding ADRs of progestins having Androgen-like activity: Increase the ratio of LDL to HDL cholesterol Thrombophlebitis Pulmonary embolism Acne Hirsutism Weight gain Liver dysfunction

9. Progesterone antagonist Mifepristone: Progesterone receptor antagonist Glucocorticoid receptor antagonist Therapeutic uses: Medical termination of pregnancy (Mifepristone followed 48 hrs later by Misoprostol)

10. Progesterone receptor modulators Ulipristal   Mechanism of action: Progesterone receptor modulators It inhibit or delay ovulation Inhibit implantation Pharmacokinetics Rapidly absorbed after oral administration Metabolized by CYP 3A4 to active metabolites Adverse events Headache, nausea, abdominal pain, upper abdominal pain, dysmenorrhea, dizziness, and back pain

Infertility Clomifene Safest & cheapest , Antiestrogens Gonadotropins Used in women with hypopituitarism or do not respond to clomifene therapy. Treatment starts with daily injection of menotrophin (LH = FSH ) or (FSH), followed by 1-2 large doses of chorionic gonadotropin (mostly LH) to induce ovulation. Adverse Effects: Multiple births, Ovarian hyperstimulation syndrome (OHSS), Bleeding, Low birth weight, Birth defects In men with hypogonadism, both LH and FSH are given to stimulate spermatogenesis and androgen release.

Bromocriptine Dopamine agonist that inhibits prolactin release GnRH releasing hormone (Gn-RH) analogs Aromatase inhibitors Metformin

Drugs affecting uterine smooth muscle 1.Stimulatants of uterus Include Oxytocin, Ergot alkaloid, Prostaglandins A. Oxytocin Enhances uterine contraction Adverse Effects: Uterine rupture, fetal hypoxia or trauma, hypertension, CVA. Uses: Post-partum hemorrhage, induce and maintain labor.

B. Ergot alkaloid : Ergometrine, Methylergometrine Effects: Contract uterus Vasoconstriction: Damage vascular endothelial cells at high dose can lead to dry gangrene of the extremities after long term use. Uses: Postpartum hemorrhage To enhance the delivery of the placenta. Migraine

Adverse effects GI disturbances: diarrhea, nausea, and vomiting prolonged vasospasm Contraindications Cerebrovascular diseases; pregnancy

C. Prostaglandins Dinoprostone，(PGE2） Dinoprost and carboprost (PGF2） Used in Medical abortion: combined with mifepristone Induction of labor Adverse effects GI disturbances: nausea, vomiting, Fever and abdominal pain

2. Relaxants of uterus (tocolytics): Ritodrine, Terbutaline, Salbuterol, Magnesium sulfate, nifedipine Used to delay Premature birth or preterm labor Ritodrine Selective β2 adrenergic receptor agonist that relaxes uterus Used in preterm labor Adverse Effects: palpitations, tachycardia

Hormonal Contraceptives

A. Hormonal Contraceptives Combined Oral Contraceptive Pills (COCPs) Contain both estrogen and progesterone Progestin only preparations Progestin-only pills (“mini-pill”) Progestin implants/depot (Levonorgestrel, medroxyprogesterone) Progestin containing Intrauterine device Emergency contraception Postcoital contraception

1. Combined Oral Contraceptive Pills (COCPs) Mechanism of action: Estrogen and progesterone causes feedback inhibition of FSH and LH secretion from the pituitary gland to inhibit ovulation. (main mechanism) Progestins thicken the cervical mucous and prevent the entry of sperm. 3. Effects on uterine tubes and endometrium decrease the likelihood of fertilization and implantation Feedback inhibition ↓ LH surge No Ovulation

Adverse effects: Nausea, vomiting, mastalgia, Breakthrough bleeding Migraine headache Wt. gain Acne and Hirsutism (19-nortestosterone derivatives) Chloasma (skin pigmentation) Thromboembolism Ischemic heart disease Hypertension Increase TAG Cholecystitis and gall stones. Hepatotoxicity

Contraindications: Absolute contraindications Thromboembolic, coronary, cerebrovascular disease. Greater risk for : Women > 35 years of age Heavy smokers Obese Active liver disease Suspected or overt malignancy of genitals/breast Undiagnosed vaginal bleeding

Relative contraindications: Hypertension Migraine Diabetes mellitus Uterine leiomyoma Mental illness Gall bladder disease Drug Interactions: Enzyme inducers (Phenytoin, barbiturates, carbamazapine, Rifampin) cause contraceptive failure Antibiotics (Tetracyclines, ampicillin, etc.) cause contraceptive failure by suppressing intestinal microflora

2. Progestin-only preparations Progestin-only pill (“Mini-pill”) norethindrone or levonorgestrel Progestin implants/depot Levonorgestrel: subcutaneous implant, 5 years Medroxyprogesterone acetate (DMPA): IM, every 3 months. Progestin containing Intrauterine devices Progestasert contains progesterone & mirena contains levonorgestrel

Uses: Progestin-only preparations are suitable for women when estrogens are contraindicated : Smokers Age > 35 years H/O cardiovascular disease Migraine Liver impairment

Disadvantages of progestins: Frequent spotting Irregular and unpredictable menstrual cycles Failure rate is higher as compared to combined COCPs Unfavorable effect on lipid profile

Emergency contraception Postcoital or “morning after” contraception Combined oral contraceptive pills: 2 pills within 72 hours of unprotected sexual intercourse and 2 exactly 12 hours later. Progestin-only pills (Levonorgestrel): one tablet within 72 hours of unprotected sexual intercourse followed by second dose exactly 12 hrs later. Ulipristal: a selective progesterone receptor modulator; taken within 120 hrs of unprotected sexual intercourse

Menopausal hormone therapy (HRT) Used to treat estrogen deficiency symptoms: Hot flashes, chills, night sweats, mood swings, insomnia, headache, palpitation Vaginal and urethral atrophy Osteoporosis (others drugs are preferred) Lowest effective dose of estrogen for the shortest duration to relieve estrogen deficiency symptoms in postmenopausal period.

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