Steroidal Drugs I Estrogens Progestins Hormonal Contraception Estrogens Physiological Role o Promote development function of reproductive organs o promote development of secondary sex characteristics o exert cyclical control over menstruation o affect sexual behavior Organizational actions permanent sexual differentiation Activational effects increase in sexual activity in adult Sources of Estrogens o Naturally occurring endogenous Estradiol E2 major product of ovary premenopausal most potent endogenous estrogen produced by granulosa cells stimulated by FSH from androgen precursors made by theca cells LH stimulated Estrone E1 principal estrogen in post menopausal women and in men synthesized in adipose tissue stroma from DHEA secreted by adrenal cortex interconvertible to E2 in the liver Estriol E3 relatively short acting Not long enough to have a mjor effect Sites of Production of Endogenous Estrogens o Ovaries E2 theca granulosa cells o Placenta E3 E1 o Fat tissues both sexes o Minor players Adrenal cortex both sexes Testes CNS involved in local effects Endogenous Estrogens Target Tissues o Uterus stimulates overall development cyclical growth secretory activity of endometrial cells o Fallopian tubes cervix vagina o Breasts increase stromal tissue duct development o Hypothalamus negative feedback receptors control GnRH secretion Physiological Actions of Estrogens o Growth development of sexual organs in females o Promote endometrial growth secretory phase o Promote feminization secondary sex characteristics Estrogenic Agents Dosage Forms during follicular proliferative phase and increases no of progesterone receptors during o Estradiol micronized prep Estrace low bioavailability multiple dosage forms p o s c I M topical creams transdermal patch less lipoprotein effects extensive first pass effect o Various esters of estradiol in oil for I M estradiol valerate estradiol cypionate o Ethinyl estradiol improved oral bioavailability E component in most oral O C s o Mestranol used in some O C s Conjugated estrogens equine mixtures of sulfate esters of estrone equilin Estropipate estrone solubilized as sulfate stabilized with piperazine enzymes in gut remove sulfate groups Diethylstilbesterol DES most potent non steroidal Chlorotrianisene Raloxifene Evista selective estrogen receptor modulator SERM Pharmacological Actions of Estrogens Metabolic Effects o Direct and or indirect o Preservation of bone mass decrease resorbtion by osteoclasts decrease no activity o Lipid metabolism slight increase of serum triglycerides slightly reduce serum cholesterol increase HDL decrease LDL increase cholesterol o CHO metabolism no major effects o Protein metabolism and lipoprotein a secretion decrease bile acid secretion by gall bladder risk of gallstones increase many serum proteins produced by liver o CBG transcortin TBG SSBG transferrin renin substrate increase circulating levels of thyroxine estrogen testosterone iron copper no net effect on coagulation usually BUT What are the risk factors for venous thrombosis with estrogens Estrogen have the potential to cause venous thrombosis Doses how the exposure of the is sustained and differences in estrogens given o Pharmacologic o Patient Specific Age Obesity Patient can be more vulnerable to estrogen or if they smoke Estrogens Undesirable Effects o Nausea vomiting tolerance may develop take with food or at bedtime o Fullness tenderness of breasts edema lower dose Severe migraine in some o Reactivation or aggravation of endometriosis related pain o Hyperpigmentation chloasma melasma o Post menopausal bleeding o Increased frequency of monilia infection o Potential carcinogenicity risk of vaginal cervical adenocarcinoma in offsprings of mothers exposed 0 01 0 1 incidence non malignant genital abnormalities in offspring exposed during pregnancy DES unopposed use in ERT 5 15 fold increase risk of endometrial cancer reversible with discontinuation breast cancer risk may be increased ovarian cancer risk may be increased Estrogens Undesirable Effects o Metabolic Cardiovascular Issues 2 to 3 fold increase in gallbladder disease 3 fold increase risk of venous thrombosis in healthy women 1 35 factor increase risk of stroke no increase risk of hypertension Estrogens Contraindications o Estrogen dependent cancers o undiagnosed vaginal bleeding o liver disease gallbladder disease o history of thromboembolic disorders o pregnancy o Drug Interactions blocks effects of bromocriptine cigarette smoking increases risk of serious cardiac adverse reactions inhibits metabolism of cyclosporin Estrogens Therapeutic Uses o Post menopausal Hormone Replacement Therapy conjugated estrogens most commonly used lower dose than OC s less side effects o Prevention of osteoporosis related bone fractures o Treatment of vasomotor symptoms of menopause hot flashes alternating chills inappropriate sweating parasthesias o See summary of findings from WHI page 1145 Aschenbrenner 3rd ed o Reversal of urogenital atrophy effective to treat vaginal dryness itching pain during intercourse genital swelling pain on urination sudden unexpected urinary incontinence o Neuroprotective effects none opposite effect Seemed to slow Alzheimer s disease progression in first clinical reports but benefits could not be reproduced harm uncovered in recent WHI prospective study increased risk of dementia improve skin texture o Other benefits o Other uses oral contraceptives treatment of primary hypogonadism Progesterone Physiological Role o Produced during luteal phase reduces estrogen driven endometrial proliferation leading into secretory phase endocervical secretions changed from watery profuse to scant viscid progesterone on top of estrogen causes secretion difference o Post luteal decline main determinant of menstruation o Placental production during pregnancy suppresses menstruation uterine contraction with estrogen proliferation of acini of mammary gland progestin has the opposite effect of oxytoxin will relax uterine contractions Sources of Progesterone o Ovary corpus luteum during luteal phase o Placenta starting 2 3 wks into gestation to end hCG stimulated hCG is similar to LH binds to same receptor o Adrenal cortex precursor of corticosteroids o Testes precursor of androgens Progesterone Synthesis Release o LH stimulated during menstrual cycles activates rate limiting step in P synthesis conversion of cholesterol to pregnenolone o hCG stimulated during pregnancy o Typical rates of secretion