1HORMONE REPLACEMENT THERAPY and FERTILITY DRUGS Richard Minshall, Ph.D Postmenopausal Hormone Replacement Therapy for: Osteoporosis: ! a disorder of the skeleton associated with the loss of both hydroxyapatite (calcium phosphate complexes) and protein matrix or colloid ! thinning and weakening of the bones and an increased incidence of fractures, particularly compression fractures of the vertebrae and minimal trauma fractures of the hip and wrist ! twenty percent of patients who sustain hip fractures die within the first 12 months ! Osteoporosis is a major indication for ERT, and it is clearly efficacious for this purpose ! primary mechanism by which E act is to decrease bone resorption, and consequently are more effective at preventing rather than restoring bone loss ! most effective if treatment is initiated before significant bone loss occurs ! beneficial effects require continuous use; bone loss resumes when treatment is discontinued ! diet with adequate calcium intake and weight-bearing exercise support the effects of E ! higher doses of E may lead to some increase in bone mass, and combinations of E with calcium, fluoride, and/or other agents that increase bone mass are under study at present Vasomotor Symptoms: ! decline in ovarian function at menopause is associated with vasomotor symptoms in most women due to deficiency of estrogen ! characteristic hot flashes may alternate with chilly sensations, inappropriate sweating, and paresthesias ! MPA may provide some relief of vasomotor symptoms for certain patients ! "2-adrenergic agonist clonidine diminishes vasomotor symptoms in some women, presumably by blocking the CNS outflow that regulates blood flow to cutaneous vessels Prevention of Cardiovascular Disease: ! the leading cause of death in women in the US over 65 years old is cardiovascular disease, particularly MI ! there is a lower incidence of heart attacks in premenopausal women relative to age-matched men ! epidemiological studies show decreased coronary artery disease in postmenopausal women receiving estrogens, thus it is (WAS) widely accepted that estrogens have major cardiovascular health benefits ! mechanisms responsible are not fully established, but beneficial effects on plasma lipoprotein profiles are thought to play a major role Vaginitis: ! decreased E levels in the menopause leads to decreased thickness of the vaginal epithelium and increased risk of secondary inflammation due to trauma or infection ! severe atrophy or vaginitis may cause painful coitus ! responds to systemic treatment and vaginal creams that contain estrogen ! Kraurosis vulvae, an itchy condition due in part to estrogen deficiency, also responds to hormone treatment Other Therapeutic Effects: ! Estrogen replacement may help alleviate or lessen some of these via direct actions or secondary effects: general thinning of the skin; changes in the urethra, vulva, and external genitalia; a decrease in height, camel hump on the back, and a protuberant abdomen; and a variety of changes including headache, tiredness, and difficulty concentrating, many of which may derive from the chronic lack of sleep created by hot flashes and other vasomotor symptoms Hormone Replacement Regimens: ! 1960s and 1970s: estrogen replacement therapy (i.e., estrogens alone) to reduce vasomotor symptoms, vaginitis, and osteoporosis ! 1980, epidemiological studies indicated that this treatment was associated with a large increase in the incidence of endometrial carcinoma, presumably due in part to the continuous stimulation of endometrial hyperplasia by unopposed estrogens, which led to the use of hormone replacement therapy that includes both an estrogen and a progestin to limit endometrial hyperplasia ! HRT with both an estrogen and progestin is now recommended for most postmenopausal women with a uterus2! for those women with a uterus who are unable to tolerate progestins or have a high risk of cardiovascular disease due to unfavorable lipoprotein profiles, E alone may be preferable ! for women who have undergone a hysterectomy, endometrial carcinoma is not a concern, and E alone is more commonly used because of possible deleterious effects of progestins ! Medroxyprogesterone acetate (MPA) is the progestin most commonly used in HRT ! has less androgenic activity than the 19-nor compounds used in combination Ocs ! concern that the inclusion of a progestin opposes the beneficial effects of E on lipoprotein profiles Regimens: ! "cyclic": (1) administration of an E for 25 days (2) inclusion of MPA for the last 10 to 13 days of E treatment (3) 5 to 6 days with no hormone treatment during which withdrawal bleeding normally occurs ! "continuous": (1) E is given continuously on a daily basis (2) progestin is jointly administered during the first 10 to 13 days of each month this decreases endometrial hyperplasia and the incidence of endometrial carcinoma, yet minimizes the total amount of progestin administered Route of estrogen administration: ! oral administration exposes the liver to high concentrations of estrogens via the portal circulation and causes a more rapid conversion of estradiol or conjugated estrone to estrone ! these effects are lessened with transdermal estradiol ! either route effectively relieves vasomotor symptoms and protects against bone loss ! oral, but not transdermal E may increase sex steroid binding globulin, other binding globulins, and renin substrate ! oral route expected to cause greater increases in the cholesterol content of the bile ! transdermal estrogen appears to cause smaller beneficial changes in lipoprotein profiles (approximately 50% of those seen with the oral route3 ANTI-ESTROGENS ! tamoxifen and clomiphene used primarily for treatment of breast cancer and female infertility, respectively ! can produce estrogenic as well as anti-estrogenic effects ! competitively block estradiol binding to its receptor; act as antagonists, agonists, or partial agonists depending upon the context in which they are used Chemistry: ! triphenylethylene compounds ! trans conformations have antiestrogenic activity; cis has estrogenic activity ! Tamoxifen (NOLVADEX) is marketed as the pure trans isomer ! clomiphene (SEROPHENE, CLOMID) is a racemic mixture of both trans (enclomiphene) and cis (zuclomiphene) isomers ! 7"-alkylamide derivatives of estradiol (e.g., ICI 164,384) are more purely anti-estrogenic but not yet approved for use in the United
View Full Document
Unlocking...