Estrogen, Progesterone and Contraceptives BY: DR MEHERUNISA CIMS ASSOCIATE PROFESSOR ESTROGEN Actions • Female reproductive system: 1. Growth and development • CNS: 1. Feedback inhibition of gonadotropin (LH/FSH) secretion. 2. stimulation of CTZ to cause nausea and vomiting. • BLOOD: 1. Increased predisposition to deep vein thrombosis and pulmonary embolism due to increased synthesis of factor VII, VIII, IX and X and decreased production of antithrombin III by the liver. 2. Favourable effect on lipid profile by decreasing LDL and increasing HDL. ESTROGEN • METABOLIC 1. Glucose intolerance 2. Sodium and water retention. 3. Maintain bone mass by decreasing the bone resorption. • Increased risk of gall bladder stones and cholestatic jaundice. • Can result in hepatic adenoma on prolonged use. • Vasodilation by increasing the production of NO. ESTROGEN PREPARATIONS • Natural steroidal estrogen ✓Estrone, Estradiol ( maximum), Estriol • Synthetic steroidal estrogen ✓Ethinyl estradil ✓Mestranol ✓Tibolone • Synthetic non steroidal estrogens ✓Diethylstilbesterol ✓Dienestrol Pharmacokinetics ✓Natural estrogens: orally inactive due to first pass metabolism ✓Synthetic estrogens: orally active ✓Estradiol is converted to estrone and estriol in liver/ peripheral tissue ✓Orally administered estrogen → absorbed from intestine→ enterohepatic circulation → high hepatic to peripheral ratio→ hepatic side effects Therapeutic uses • Oral contraceptive pills ( OCP) • Postmenopausal Hormone Replacement Therapy ( HRT) • No progesterone/estrogen production after menopause. • Leading to osteoporosis, hot flushes( due to LH), vaginal atrophy, insomnia • in HRT:Estrogen + Progesterone are given Therapeutic uses • Estrogen Replacement Therapy ( ERT) in primary ovarian failure • Dysmenorrhoea : painful menstrual bleeding • Acne, hirsuitism • Carcinoma prostrate • DUB: dysfunctional uterine bleeding Adverse effects • In males: gynaecomastia, feminisation and decreased libido • In females: • breast tenderness, breast cancer risk • withdrawal bleeding, amenorrhoea, endometrial hyperplasia • Risk of vaginal, cervical adenocarcinoma • Migraine, nausea • In both genders: • Gall stones, hepatic dysfunction • Thromboembolic disorders • Diabetes and fluid retention Contraindications • Pregnancy • Thromboembolic disorders • Diabetes • Estrogen dependent breast carcinoma • Endometrial carcinoma PROGESTERONE Actions • Progesterone increases basal insulin levels. • decrease in Na+ reabsorption. • Progesterone increases LDL and opposes beneficial effect of estrogen on lipid profile. • growth of breast tissue and also participates in LH surge. • Progestins decrease the chances of endometrial carcinoma due to estrogen Progesterone preparations Pharmacokinetics • Natural progesterone orally ineffective due to first pass metabolism • Synthetic progesterones are orally active Therapeutic uses • Oral contraceptive pills, HRT : Progestins are added to decrease the risk of endometrial and ovarian carcinoma. • DUB: dysfunctional uterine bleeding • Endometriosis : presence of ectopic endometrial cells outside uterus causing bleeding • Infertility treatment Adverse effects • Breast engorgement • Irregular mensturation cycle, breakthrough bleeding • Depression, irritability • Weight gain, decreased libido Oral contraceptive pills • Oral contraceptives are medicines taken by mouth to help prevent pregnancy. • they are also known as birth control pills • Types: ✓ combined pills: estrogen+ progesterone ✓ progesterone only pills Formulations of OCPs 1. Monophasic (each tablet containsa fixed amount of estrogen and progestin); 2. Biphasic (each tablet contains a fixed amount of estrogen, while the amount of progestin increases in the second half of the cycle); or 3. Triphasic (the amount of estrogen may be fixed or variable, while the amount of progestin increases in 3 equal phases). Mechanism of action Oestrogen inhibits secretion of FSH via negative feedback on the anterior pituitary, and thus suppresses development of the ovarian follicle. Progestogen inhibits secretion of LH and thus prevents ovulation; It also makes the cervical mucus less suitable for the passage of sperm. The oestrogen in most combined preparations (second- generation pills) is ethinylestradiol, or mestranol The progestogen may be norethisterone, levonorgestrel, or- in 'third- generation' pills-desogestrel or gestodene Adverse effects ➢ Weight gain, owing to fluid retention ➢ Glucose intolerance ➢ Mild nausea, flushing, dizziness, depression or irritability ➢ Skin changes (e.g. acne and/or an increase in pigmentation) ➢ Amenorrhoea of variable duration on cessation of taking the pill. Adverse effects ➢ CVS: thromboembolism, hypertension ➢ Increase risk of Breast carcinoma. Decrease risk of ovarian and endometrial cancer Non contraceptive beneficial effects decreases menstrual symptoms such as irregular periods and intermenstrual bleeding. Iron deficiency anaemia and premenstrual tension are reduced, Reduce benign breast disease, uterine fibroids and functional cysts of the ovaries. Progesterone only pills / mini pills These contain low dose of progestins (norethisterone or levonorgestrel or ethynodiol ) without any estrogen. These are less effective than combined OCPs. • Minipills are preferred in women where estrogen is contra-indicated e.g. –– Smokers; >35 years of age; Risk factors of thromboembolism • Progesterone only pills are given daily without any break. Mifepristone • Anti-progestin • Binds to progesterone receptors, blocking activity of progesterone Uses: • Termination of pregnancy, • Contraceptive, • Softening of cervix, • Induction of labour SERM • Selective Estrogen Receptor Modulator • Synthetic agents with tissue selective agonist and antagonist activities on estrogen receptor ( ER) • Beneficial estrogenic effects on some tissues: bone, brain, liver SERM • Prevent deleterious estrogenic effects on some tissues: endometrium, breast • Example: clomiphene, tamoxifen, raloxifene • Uses: breast cancer ( raloxifene), HRT ( tamoxifen), infertility ( clomiphene) THANKYOU.