Estrogens, progestins and antiestrogens. Androgens and antiandrogens. Estrogens and progestins: •two major classes of female sex hormones •functions in the development of female secondary sex characteristics •control of pregnancy •control of ovulatory-menstrual cycle •modulation of many metabolic processes ESTROGENS •17β-estradiol, estriol, estrone •responsible for the development of secondary sex characteristics •initiate breast development by increasing ductal and stromal growth •contribute to accelerated growth at puberty •stimulate closure of the epiphyses in the shafts of the long bones •stimulate the synthesis and secretion of prolactin from pituitary lactotrophs •accelerate cellular proliferation of uterine endometrium and stroma in the absence of progesterone, as occurs in the follicular phase of the menstrual cycle •induce RNA and protein synthesis in cells •generate thickening of the vaginal mucosa and thinning of cervical mucus •aid in maintaining bone mass, as evidenced by substantial but preventable with estrogen replacement therapy) bone loss in postmenopausal women •stimulate hepatic production of sex hormonebinding globulin, thyroid-binding globulin, bloodclotting factors (VII, VIII, IX, X), plasminogen, HDL •inhibit antithrombin III, LDL formation •increase retention of sodium and water (edema) •decrease bowel motility •role in the progression of some endometrial tumors •risk factor for breast cancer •endometrial hyperplasia, increased risk of endometrial cancer Clinical uses Hypogonadism Relief of menopausal symptoms – in postmenopausal hormonal therapy Hot flushes Relief of atrophic vaginitis Preventing bone loss and osteoporosis In combination with progestins for contraception Contraindications endometrial cancer, breast cancer, undiagnosed genital bleeding, liver disease, history of thromboembolic disorder, histories of coronary or cerebrovascular disease, heavy smokers Adverse effects Cancer: breast cancer, endometrial cancer, adenocarcinoma of the vagina Thromboembolic disease, myocardial infarction, strokes, Uterine bleeding, Excessive bleeding, Amenorrhea, Breast tenderness, Migraine, headaches, Depression Acne, Hirsutism Elevated triglycerides, serum glucose PROGESTINS Progesterone – the major progestin in humans Synthetic progestins - eg Medroxyprogesterone, Desogestrel, Gestodene, Norgestimate •partially responsible for mediating mammary glandular development, role in ductal growth •high concentrations in the luteal phase of the menstrual cycle – modulation of estrogen’s action on the uterus •without estrogen, progesterone receptor concentrations are low and estrogen priming is necessary for progesterone receptor induction in almost all progesterone-responsive tissues •increased basal body temperature (luteal phase) •aid in the maintenance of pregnancy •inhibits uterine contraction •increase sodium and water elimination by competing with aldosterone for binding to mineralocorticosteroid receptor Therapeutic applications: Hormone replacement therapy (HRT) o Micronized form used orally o Progesterone-containg vaginal creams Hormonal contraception (alone or in combination with an estrogen), In combination with an estrogen in HRT to prevent estrogen-induced endometrial cancer Diagnostic uses: As a test of estrogen secretion – the administration of progesterone is followed by withdrawal bleeding in amenorrheic patients only when the endometrium has been stimulated by estrogens A combination of estrogen and progestin can be given to test the responsiveness of the endometrium in patients with amenorrhea Contraindications: Thromboembolic disorder, Liver disease, Undiagnosed genital bleeding, Adverse effects The toxicity of progestins is low •decrease HDL and increase LDL concentration Oral contraceptives Two types of oral contraceptives are available: • Combinations of estrogen and progestins • Progestins only Action: -Inhibition of ovulation by altering the hypothalamic-gonadotropin axis -Alteration in cervical mucus to prevent sperm entry and uterine endometrium to prevent implantation -Suppression of ovarian function -Breast stimulation Progestogen-only pill: Makes endometrium unsuitable for implantation and cervical mucus hostile to sperm May inhibit ovulation in 40% of women Contraindications: • Not to be used in clients with history of thromboembolic or cerebrovascular disease • Avoid in clients with estrogen-dependent neoplasms (breast cancer, endometrial cancer) • Women with bleeding for which a cause is not known Used with caution in clients with: • hepatic disease, • migraines, • diabetes, • hypertension, • seizure disorders because exacerbation of the above may occur Used with caution in women with fibroids (may worsen) Used with caution in coronary artery disease Pregnancy Smoking will increase the likelihood of pulmonary embolic disease Oral contraceptives-Estrogenic effect • Nausea • Increased breast size • Cyclic weight gain due to fluid retention • Leukorrhea (discharge of white mucous material from the vagina) • Cervical eversion or ectopy • Hypertension • Rise in cholesterol concentration in gallbladder bile • Growth of leiomyoma • Telangiectasia • Hepatocellular adenomas or hepatocellular cancer (rare) • Cerebrovascular accidents (rare) • Thromboembolic complications including pulmonary emboli (rare) • Stimulation of breast neoplasia (exceedingly rare) Progestogenic and estrogenic effect: • Headaches • Hypertension • Breast tenderness • Myocardial infarction (rare) Androgenic effect/antiandrogenic effect: • All low-dose combined pills suppress a woman’s production of testosterone, which has beneficial effect on acne, oily skin, and hirsutism (excessive hairiness in females). Androgenic effect : • • • • • • • Increased appetite and weight gain Depression, fatigue, tiredness Acne, oily skin Increased breast size or breast tenderness Decreased HDL Increased LDL concentration Increased insulin resistance Oral contraceptives-Postcoital contraceptives • Administration progestins alone or in combination with estrogens • „morning after” pill • EMERGENCY CONTRACEPTION • May reduce the risk of pregnancy by: -Preventing ovulation -Preventing fertilization -Preventing imlantation ANTIESTROGENS SERMs - selective estrogen receptor modulators – agonists/antagonists Tamoxifen •Partial agonist inhibitor of estradiol at the estrogen receptor •Used in the palliative treatment of advanced breast cancer in postmenopausal women •Nonsteroidal agent, given orally •Adverse effects - hot flushes, nausea, vomiting Agonistic effects on • bone, • serum lipid profiles • endometrial tissues (cancer!) Antagonistic effects on • breast tissue Raloxifene •Another partial estrogen agonist-antagonist at some but not all target tissues, •Similar effects on lipids and bone •Not stimulates the endometrium or breast •Prevention of postmenopausal osteoporosis Agonistic effects on • bone, • serum lipid profiles Antagonistic effects on • endometrial, • breast tissues Danazol - Inhibits FSH and LH release from the pituitary gland Indications • Endometriosis • Fibrocystic breast disease • Hereditary angioedema • Hemophilia Adverse effects • Hot flushes • Weight gain • Acne and oily skin • Hirsutism • Changes in libido • Impaired renal, liver function • Vaginal bleeding Anastrozole & Letrozole: Selective nonsteroidal inhibitors of aromatase, Are effective if breast tumors have become resistant to tamoxifen ANDROGENS •Known as anabolic steroids because they are steroid compounds that have the ability to exhibit te tissue building and masculinization characteristics of the male hormone testosterone •Testosterone – the most important androgen produced by the Leydig cells and adrenal gland responsible for the development of secondary sex characteristics in the male Synthetic steroid drugs related to testosterone are known as anabolic steroids, and these drugs tend to have similar actions as testosterone Indications: Androgen replacement in hypogonadism, Protein anabolic agent (severe injury or debilitating illness), Refractory anemia, Adverse effects: Females - virilization and mentrual irregularityty in pregnancy with a female fetus – virilization of the fetus’s external genitalia paradoxically, excessive doses in men – feminization both sexes – cholestatic jaundice, elevation of liver enzyme levels, hepatocellular carcinoma (possibly) Common androgen inhibitors Finasteride: Blocks conversion of testosterone to its most active intracellular form (dihydrotestosterone), shrinks prostate size Indications • Prostatic hypertrophy Adverse effects • Decreased libido • Impotence Receptor inhibitors: Cyproterone, Cyproterone acetate, Flutamide Cyproterone & Cyproterone acetate • Effective antiandrogens that inhibit the action of androgens at the target organ • Acetate form – progestational effect that suppresses the feedback enhancement of LH and FSH – more effective antiandrogen effect • Women – treatment of hirsutism • Men – to decrease excessive sexual drive Flutamide • Treatment of prostatic carcinoma • Causes gynecomastia • (probably by increasing testicular estrogen production) • Reversible hepatic toxicity