REPRODUCTIVE DRUGSESTROGEN RECEPTOR MODULATORS Not hormones/ replacement Affect specific estrogen receptor sites Develop to produce the positive effects of estrogenDRUGS: Raloxifene (Evista) Toremifene (Fareston) Given oral C/I: venous thrombosis; smoking - risk for blood clotsA/R: Headache; dizziness visual changes Hot flashes Vaginal bleeding

Drugs Affecting the Reproductive System Female hormones:Estrogen and Progesterone Example: Oral contraceptives (OCPs) Estrogen prevents ovulation Impt for development of female repro system & secondary characteristics. Progesterone prevents implantation of ovum decreases amount and increases viscosity of cervical mucous to impair sperm motility impedes motility of the ova by affecting peristalsis of the ovaduct.ESTROGENSPROGESTINS

Replacement therapy Palliation of menopause discomfort Treat female hypogonadism Prevent postpartum breast engorgement Slow bone loss in osteoporosis Affect release of FSH and LH Cause capillary dilation Fluid retention Thin cervical mucus Conserve calcium and phosphorus Inhibit ovulation Proliferate endometrial lining Protect heart from atherosclerosis Cross placenta Enter breast milk Used as contraceptives; combined with estrogens Treat primary and secondary amenorrhea Treat functional uterine bleeding Treat specific cancers Make endometrium secretory Inhibit secretion of FSH and LH Prevent follicle m maturation and ovulation Inhibit uterine contractions Cross placenta Enter breast milk

C/I: Idiopathic vaginal bleeding Breast cancer Estrogen-dependent cancers Hx of thromboembolism CVA Smokers Pregnancy;breastfeeding Metabolic bone dsC/I: PID STIs Endometriosis Migraine headaches Asthma Cardiac ds Renal dysfunction

A/R: Breakthrough bleeding Menstrual irregularities Dysmenorrhea Amenorrhea Changes in libido

A/R: Nervousness Constipation Breast enlargement Perineal pain Endometriosis Abortion PID Expulsion of IUD Irritation (vaginal use)

Progestogens Used for hormonal contraception and for producing long-term ovarian suppression for other purposes (e.g., dysmenorrhea, endometriosis, hirsutism and bleeding disorders) when estrogens are contra-indicated Estrogens Estradiol (estrace) Conjugated estrogens (premarin) Esterified estrogen (menest) Estropipate (orthoEst)

Progestins Drospirenone (Yasmin) Medroxyprogesterone (provera) Norgestrel (ovrette) Levonorgestrel (mirena) Etonogestrel vaginal ring Stimulate female reproductive system

FERTILITY DRUGS - Stimulate female reproductive system Cetrorelix (Cetrotide) - inj Clomiphene (clomid) - oral Follitropin beta (follistim) - inj Menotropins (pergonal) - inj Infertility Drugs Example: Clomid Stimulates secretion of FSH and LH, which stimulates maturation of follicles, ovulation and development of the corpus luteum. Uses: Inadequate ovulation, low sperm count in males. Adverse Effects: Similar to those of OCPs. Increased incidence of early abortion and multiple births, pelvic pain.

Clomifene and Tamoxifen anti-estrogens work by inhibiting the negative feedback of estrogens in the hypothalamus Incr release of LH and FSH.Gonadotropins used in women who lack approp pit function or do not respond to clomifene therapy. Treatment starts with daily inj of menotrophin (LH = FSH amts) or urofollitropin (FSH), followed by 1-2 large doses of chorionic gonadotropin (mostly LH) to induce ovulation.Adverse Effects? Multiple birthsIn men with hypogonadotrophichypogonadism, both LH and FSH are given to stim spermatogenesis and androgen release. Directly stimulate follicles and ovulation Stimulate functioning ovaries Stimulate the hypothalamus to increase FSH and LH Given in sequence with HCG Menotropins stimulate spermatogenesis in males Check estrogen and estradiol levels d/c drug ovarian overstimulationC/I: Primary ovarian failure Thyroid or adrenal dysfunction Ovarian cysts Pregnancy IUB

A/R: Multiple births Birth defects Ovarian overstimulation abdl pain, distention, ascites, pleural effusion Fluid retention Uterine bleeding Ovarian enlargement gynecomastia

Oxytoxics Examples: Pitocin (oxytocin) Enhances contractile activity of the uterine smooth muscle. Adverse Effects: Uterine rupture, fetal hypoxia or trauma, hypertension, CVA. Uses: Post-partum hemorrhage only. Premature Labor Inhibitor Examples: Yutopar (rotodrine) Selective 2 adrenergic receptor antagonist that prevents smooth muscle contractions. Uses: Preterm labor if gestation > 20 weeks. Adverse Effects: palpitations, tachycardia, hypotension.

Oral Contraceptives Uses: Contraception, menstrual irregularities. Adverse Effects: hypertension, diabetes, high LDL, dizziness, numbness, weight gain, fluid retention, breast tenderness, breakthrough bleeding. Contraindications: ABSOLUTE: Thromboplebitis, CVA, breast cancer, pregnancy, liver disease or impairment, CAD, > 35, smoker. Combination Pills contain estrogen: ethinylestradiol and progestogen, taken for ~ 21 days and discontinued for the following 6-7 days to allow menstruation to occur. Progestogen-only Pills contain low dose of progestogen, taken continuously.

Fertilization Oral Contraceptives - Mechanism Combination pills act by feedback inhibition on the hypothal to supressGnRH and hence plasma gonadotropin secretion. Produce an endometrium that is unreceptive to implantation. Alter ovaduct motility. Change the composition of cervical mucous. These latter effects also caused by progestogen-only pills and appear to be the basis of their contraceptive actions. Block ovulation in only ~ 25% of women. Menstruation often stops initially with progestogens, but usually returns with prolonged use. But the length and duration of bleeding highly variable. Combination of both E and P most potent and effective way to suppress GnRH, LH, and FSH secretion. The combined effects on previous slide >99% efficacy. Ethinylestradiol or mestranol the E in the combination contraceptives. The progestins all are potent PR agonists, but also have some androgenic cross-reactivity.Norgestrel and levonorgestrel>norethindrone and norethindrone acetate >ethynodiol, norgestimate, gestodene, anddegestrel in androgenic activity. Oral Contraceptives 3 Delivery systems are available: vaginal ring, transdermal patches, oral tablets.Ring contains ethinylestradiol and a progestin, etonogestrel.Has zero-order pkinetics over 21 days.Dermal patch has ethinylestradiol and a progestin, norelgestromin. Changed weekly for 3 weeks. Oral Contraceptives Adverse EffectsNon-life Threatening Breakthrough bleeding and irregular menses (most women who take combo pills). Abdominal pain Chest pain, cough, dyspnea, dizziness, numbness, headache, nausea, changes in libido, breast soreness. Eye problems: vision loss or blurred. Severe leg pain (calves, thighs). Hirsutism, vaginal yeast infections and depression. ~ 20-30 % women experience some of these effects. Oral Contraceptives Adverse Effects Serious Rare. Cholestatic jaundice and thromboembolic disease. Thromboembolism (~ 25/10,000 women). Emergency (morning-after) Contraception levenorgestrel a single high dose can be taken up to 3 days after unprotected intercourse. Blocks the LH surge.Therapeutic Termination of Pregnancy mifepristone a progesterone ant highly effective in terminating early pregnancy (up to 63 days gestation) when used with a PG-cervical ripening agent (e.g., gemeprostpessaries). [Recall Progesterone supports endometrial implantation of fertilized ovum].-Main adverse effect: pain and bleeding. Stimulate uterine contraction Effective in gravid uterus Stimulate lacteal glands Prevent uterine atony after delivery Cross placenta Enter breast milk Cross placenta Enter breast milkC/I: CPD Uterine atony Early pregnancy CAD; HPN - BP

A/R: Uterine hypertonicity Uterine spasms Uterine rupture Hemorrhage Fetal distress Male Hormones Example: Testosterone Secreted by the testes. Uses: Treatment of low sperm count and impotence caused by any kind of deficiency.Aromatase Inhibitors Used to inhibit estrogen-dependent tumors, metastatic breast cancer. But, serious estrogen-lacking side-effects: increased risk of osteoporosis.Anastrozole, letrozole, exemestane, formestane. Selective Estrogen Receptor Modulators(SERMs) class of compounds that act on theestrogen receptor. Are mixed agonists/antagonists. ER and ER types are tissue-specific.The actions of SERMs on various tissues: Boneturnover and postmenopausalosteoporosisrespond favorably to most SERMs, although premenopausal women may experience bone loss with some SERMs including tamoxifen. Breast- all SERMs decrease breast cancer risk, and tamoxifen is mainly used for its ability to inhibit growth in estrogen receptor-positive breast cancer. Cholesterolandtriglycerides- levels respond favorably to SERMs. Deep venous thrombosis- the risk may be elevated in at least some SERMs. Hot flashesare increased by some SERMs. Pituitary gland- clomifene blocks estrogen action, leading to an increase offollicle-stimulating hormoneandluteinizing hormone. Uterus- tamoxifen may increaseendometrial carcinomarisk, but raloxifene and femarelle do not. Data on toremifene and clomifene is insufficient.

NameUsesEffects/location

clomifene used inanovulation antagonist at hypothalamus

femarelle managingmenopausesymptoms,osteoporosis agonist at brain and bone

ormeloxifene contraceptionagonist at bone; antagonist at breast and uterus

raloxifene osteoporosis,breast canceragonist at bone; antagonist at breast and uterus

toremifene breast cancer

lasofoxifene osteoporosis,breast cancer,vaginal atrophyagonist at the bone, antagonist at breast and uterus

tamoxifen breast canceragonist at bone and uterus, antagonist at breast

Undescended testicles.Anabolic action in conditions such as osteoporosis, anemia, and debilitated states. Inoperable breast cancer in postmenopausal women.Adverse Effects: Edema, acne, hirsutism, voice deepening, polycythemia, increased LDL, depression.Contraindications: Pregnancy, prostate cancer, breast cancer in males. Sex hormones; produced in the adrenal glands Indicated for hypogonadism (underdevelop testes) Treat certain breast cancers Adrenal Sex Hormones Androgens male hormones secreted by the adrenal cortex in both sexes and are responsible for the physiological effects exerted by adrenal sex hormones. The incr protein synthesis (anabolism), which incr muscle and bone mass and strength, affect development of male 2 characteristics. They incr hair growth and libido in women. Excessive secretion: masculine effects in women. Female sex hormones exert few effects. Excessive secretion: feminine characteristics in men. Androgen Receptor AntagonistsFlutamide and spironolactone used to treat metastatic prostate cancer and BPH.Progesterone Receptor Antagonists Mifepristone (aka RU-486) used to induce 1st-trimester abortion.Often admin with misoprostol (PG analogue) stimulates uterine contractions.Asoprisnil does not cause abortion, but inhibits the growth of tissue derived from the endometrium and myometrium.May be used to treat endometriosis and uterine fibroids. Estrogenic compounds span a spectrum of activity ranging from: full agonists (agonistic in all tissues) such as the natural endogenous hormoneestrogen mixed agonists/antagonistics (agonistic in some tissues while antagonist in others) such as tamoxifen (a SERM) pure antagonists (antagonistic in all tissues) such asfulvestrant The mechanism of mixed agonism/antagonism may differ: depending on the chemical structure of the SERM, but, for at least for some SERMs, it appears to be related to the ratio ofco-activatortoco-repressorproteins in different cell types and theconformationof the estrogen receptor induced by drug binding, which in turn determines how strongly the drug/receptor complex recruits co-activators (resulting in an agonist response) relative to co-repressors (resulting in antagonism). retention of nitrogen, Na, K, phosphorus excretion of Ca CHON anabolism CHON catabolism production of RBCs Long acting depot forms; patch; oralA/R: Hirsutism Deepening of voice Oily skin Weight gain Decreased breast size Testicular atrophyDRUGS: Prostaglandin alprostadil (caverject, muse) Phosphodiesterase type 5 (PDE5) Sildenafil (Viagra) Tadalafil (cialis) Vardenafil (levitra) relax smooth muscles filling of corpus cavernosum with blood Onset: 27 minutes Duration: 4 hoursC/I: Priapism Penile implants WomenA/R: Priapism Fibrosis rash Male Contraception Tried suppressing sperm production.- Very unsuccessful.- Most promising to date: testosterone enanthate + daily oral levonorgestrel; and parenternalptestosteroneundecanoate + injectablemedroxyprogesteroneascetate. But,- Highly variable results from clinical trials only ~ 60% of men became azoospermic.Significant adverse effects: acne, weight gain, polycythemia, potential increase in prostate size. back to the drawing board