Estrogens and Anti-Estrogens PDF

Estrogens Natural human estrogens Phytoestrogens Soy and saw palmetto Estrogens in ocean sediments Phenols Used in plastic manufacturing Associated with increased breast cancer risk in both sexes Natural estrogens Estradiol (E2), Estrone(E1), Estriol(E3) E2 is the major...

Estrogens Natural human estrogens Phytoestrogens Soy and saw palmetto Estrogens in ocean sediments Phenols Used in plastic manufacturing Associated with increased breast cancer risk in both sexes Natural estrogens Estradiol (E2), Estrone(E1), Estriol(E3) E2 is the major estrogen secreted by ovaries E1 and E3: Most formed by liver conversion, or from adrenal androgens in peripheral tissues Estrogen is produced by ovarian follicles by theca and granulosa cells ( preovulation) Post ovulation: from the theca and granulosa cells of corpus luteum Also produces progesterone Pregnancy: Placenta and fetus Estrogen levels vary monthly with the ovarian cycle Lowest in early follicular phase and highest right before ovulation ER affinity: E2>E1>E3  Ovaries are main source in premenopausal women Estradiol is the major product Adrenal glands in post menopausal women Estrone is the major product Produced from adrenal DHEA Estrogen produced from ovarian follicles, corpus luteum, placenta Smaller amounts from liver, breast tissue , and adrenal glands Pharmacokinetics Estrogen binds SHBG in plasma with high affinity and albumin with lower affinity Estradiol converted to estrone and estriol in liver and other tissues Also forms derivatives that are excreted into bile Estrone and Estriol have lower affinity for the estrogen receptor Conjugates can be hydrolyzed into active reabsorbable products in the intestines via enterohepatic circulation Oral estrogens will have a high ratio of liver to peripheral effects Increased clotting factors and renin in plasma Can be minimized by dosage forms that avoid first pass metabolism Transdermal forms, creams Depot forms also Estrogens are excreted into breast milk Synthetic estrogens Chemical alterations to improve oral efficacy Both steroidal and non-steroidal forms Ethinyl estradiol Quinestrol (Estrovis) is a prodrug of Ethinyl estradiol Estradiol Cypionate Conjugated equine estrogens (Premarin, Enjuvia, Cenastin) Combination of estrogens with estradiol In combination with progesterone (Prempro) Esterified forms also Non steroid forms also diethylstilbestrol ( Stilbestrol), only used for prostate cancer today dienestrol, benzestrol, hexestrol, and chlorotrianisene. Mechanism of action Bound to SHBG in plasma Dissociate to enter cell – travel to nucleus and bind ER ER in nucleus is bound to HSP 90 Estrogen binding causes dissociation from HSPs R/L complex dimerizes and binds EREs on DNA Two half sites separated by spacer region A transactivation complex forms through recruitment of co-regulators and TFs Two receptor subtypes ER alpha and ER beta Alpha has effects on uterus, breast tissue, maintenance of bone and metabolism Beta appears to have effects on Immune function and nervous system ER beta also reduces the effects of ER alpha on growth of breast and uterine tissue Growth inhibiting effects Also non-genomic effects Responsible for rapid effects Physiological effects Sexual maturation and growth of females Stimulate development of vagina, uterus, uterine tubes and secondary sex characteristics Stimulate breast growth and maturation Accelerated growth phase and epiphyseal plate closure Fat distribution characteristic of females Endometrial effects Development of endometrial lining In conjunction with progesterone Metabolic and cardiovascular effects Maintain normal skin and blood vessel structures in women Causes osteoclast apoptosis and inhibit PTH osteoclast stimulation Stimulate adipose production of leptin Increase levels of circulation binding globulins ( thyroid, corticosteroid, steroid) Increases circulating levels of these substances Increase levels of fibrinogen and renin Increase HDL, lower LDL, increase TGs and lower total plasma cholesterol Affects coagulation Increase several clotting factors, decrease ATIII, decrease platelet adhesion and increase plasminogen Other effects Increase progesterone receptors Influence libido and behavior including a sense of well-being Produce edema Fluid leaves ECF Plasma volume reduction stimulates renal fluid and water retention Uses Primary hypogonadism Initiated at 11-13 yoa Attempts to mimic physiology changes at puberty Doses slowly titrated up and then maintained until menopausal age ( 50s) Progestin added Post-menopausal HRT Menopause associated with many changes Osteoporosis, hot flashes, thinning skin,sleep and memory disturbances and on and on Cardiovascular changes less clear LDL increases but HDL still remains higher than males HRT and whether to initiate comes down to risk vs rewards Considerations include age, risk of osteoporosis, cardiovascular disease, breast or endometrial cancer, symptoms,  Breast cancer risk Minimal if initiated immediately after menopause for first 7 years of therapy Women with premature menopause HRT is recommended Endometrial cancer risk Can be minimized if a progesterone is also given Reduces endometrial hyperplasia Estrogen given first 25 days of each month Progesterone added last 10-14 days for those with intact uterus Estrogen alone for HRT in women who have had a hysterectomy If to reduce symptoms of hot flashes, sleep disturbances etc Lowest dose given that provides relief for briefest amount of time Minimizes breast cancer risk If for osteoporosis prevention Smallest therapeutic dose should be used  Suppression of ovulation in intractable dysmenorrhea Suppression of increased ovarian androgen production to reduce hirsutism Higher doses often required in combo with a GnRH inhibitor Adverse effects Uterine bleeding Common but must be taken seriously as this can also indicate endometrial cancer at menopausal age Smallest dose given Dosed cyclically ( first 21 -25 days of each month) Cancer Breast Breast cancer risk minimal with short duration therapy Increases with prolonged courses Adding progesterone does not help Endometrial cancer Risk increases greatly with dose and duration if estrogen given alone Addition of progesterone reduces risk and may be protective Ie risk may be reduced below general population  Nausea , breast tenderness , migraines, gallstones, HTN Contraindications Estrogen dependent cancers High risk for breast cancer Undiagnosed vaginal bleeding Risk for thromboembolic disorders Liver disease Heavy smokers Estrogen Inhibitors Tamoxifen (Nolvadex) Partial agonist inhibitor at estrogen receptor Antiestrogenic in breast tissue , estrogenic in endometrial tissue First SERM to be introduced Mechanism of inhibition unclear May tie up coregulatory proteins, may increase ER beta activity Use Breast cancer, and prevention of breast cancer in high risk patients Non-steroidal agent Oral dosing Half life of 7-14 hours  Liver metabolism by Cyp2D6 Produces a more active metabolite Cyp2D6 inhibition should be avoided Adverse effects N/V, not flashes When used as adjuvant therapy in breast cancer 35 % reduction in contralateral breast cancer Therapies extended >5 years show no further benefit cause antagonist to agonist conversion in resistant cell lines Toremifine Similar in most aspects  Raloxifene(Evista) Partial ER agonist at some, but not all, target tissues Estrogenic effects on liver and bone, but not endometrium or breast Large first pass metabolism However large Vd and long half life ( 24 h) Use: prevention of postmenopausal osteoporosis Tamoxifen resistant breast cancer Prophylaxis of breast cancer in high risk patients Good choice for osteoporosis prevention in this group Contraindicated with history or risk of DVT or thromboembolic disorders Bezedoxifene Newer SERM Approved for prevention of osteoporosis associated with menopause and menopausal symptoms in combination with conjugated estrogens (Duavive) Viviant, Bezedoxifene monotherapy not approved in US  Fulvestrant (Faslodex) ER antagonist No oral dosage form ( IM, IV) Downregulates and degrades ER Use: ER+ metastatic breast cancer in postmenopausal women with disease progression following estrogen therapy  Clomiphene (Clomid) Older drug Partial agonist Weak estrogen Competitive inhibitor of endogenous estrogen Use Ovulation inducing agent Danazol (Danocrine) 17 alpha-ethinyl-testosterone derivative Weak androgen progesterone and glucocorticoid activity also Suppresses ovarian function Inhibits midcycle surge in LH and FSH but does not inhibit basal FSH or LH levels in normal women Binds AR, PR, and GR. Does not bind ER and does not inhibit aromatase Does cause AR nuclear translocation causing mild activation of AR regulated genes Ethisterone ( a major metabolite) has progesterone and androgenic effects  Use Endometriosis to inhibit gonadal function Fibrocystic disease of the breast Hematological or allergic disorders Adverse effects Weight gain, edema, reduced breast size, acne , oily skin, increased hair growth, voice deepening, libido changes, muscle cramps and hot flashes Most are virilizing effects Adrenal suppression possible due to GR activity  Anastrozole (Arimidex) Aromatase inhibitor (Converts androgens to estrogen) Letrozole (Femara) and Exemestane(Aromasin) also Approved for use in advanced breast cancer Ovulation inducers Clomiphene (Clomid) Partial ER agonist Inhibits action of estrogen Inhibits estradiol induced negative feedback on gonadotropin release Elevates LH and FSH Elevations seen within days Used most in PCOS Gonadotropin dependent ovarian hyperandrogenism Anovulation and infertility Menopausal like adverse effects due to ER inhibition May cause ovary enlargement Ovarian cancer risk with prolonged therapy ( > 1 year) Contraindicated in patients with enlarged ovaries PCOS mechanism