Contraceptives and Pro Fertility Agents Richard Minshall Ph D rminsh uic edu Neuroendocrine control of gonadotropin secretion in females 1 Hormonal relationships of the human menstrual cycle Structural Formulas of Selected Estrogens 2 The biosynthetic pathway for the estrogens 19 carbon precursors are synthesized primarily in the ovaries testes and adrenals Physiological and Pharmacological Actions Developmental Actions Puberty and secondary sexual characteristics of females growth and development of the vagina uterus and fallopian tubes with other hormones cause enlargement of the breasts promotion of ductal growth stromal development and the accretion of fat molding body contours shaping the skeleton and growth spurt of the long bones growth of axillary and pubic hair and pigmentation of the genital region regional pigmentation of the nipples and areolae that occur after the first term of pregnancy Metabolic Effects of E blocks bone resorption and increases bone formation increases the level of the hydroxylase that converts vitamin D to 1 25 dihydroxyvitamin D3 in the kidney slightly elevates serum triglycerides and reduces total serum cholesterol levels increases HDL levels and decreases LDL values alters bile composition by increasing cholesterol secretion and decreasing bile acid secretion leading to increased saturation of bile with cholesterol which may be the basis for increased gallstone formation decrease slightly fasting levels of glucose and insulin increase plasma levels of cortisol binding globulin CBG or transcortin thyroxine binding globulin TBG and sex steroid binding globulin SSBG which binds both androgens and estrogens 3 Physiologic Effects of Estrogen Alters liver metabolism Affects on clotting and fibrinolysis fibrinogen levels synthesis of clotting factors VII IX X XIII plasminogen levels plasminogen activator inhibitor Alters metabolism of lipoproteins HDL TG LDL total cholesterol Other increases angiotensinogen and transport proteins Physiological Effects of Estrogen Alters vascular reactivity endothelial mediators of contraction and relaxation endothelin 1 TXA2 receptors angiotensin II receptors superoxide free radicals nitric oxide synthase expression and activity therefore nitric oxide 4 Estrogen Receptor Isoforms Estrogen Receptor Signaling 5 Mechanisms of Steroid Hormone Signaling AP 1 Sp1 6 Elimination 17 estradiol is primarily converted by 17b hydroxysteroid dehydrogenase to estrone and converted by 16a hydroxylation and 17 keto reduction to estriol which is the major urinary metabolite sulfate and glucuronide conjugates also are excreted in the urine Estrone also is converted to the catechol estrogen 2 hydroxyestrone which is methylated to 2 methoxyestrone Untoward Responses the decision to use estrogens is largely a matter of analyzing the the riskrisk totobenefit ratio for each patient the major concerns about the use of estrogens have been cancer thromboembolic disease changes in carbohydrate and lipid metabolism hypertension gallbladder disease nausea migraine changes in mood the untoward effects of estrogens are dosedose dependent some of the deleterious effects of oral contraceptives originally originally attributed to E are due to progestins the amount of E and P in oral contraceptives has decreased which which has diminished the risks usage in the 1960s and 1970s established that unopposed estrogens estrogens caused endometrial carcinoma since then E has been used with P which greatly greatly diminished this risk 7 Therapeutic Uses pharmacological considerations for E use in OC and HRT are different because of the dose conjugated estrogens for HRT 0 625 mg day for most women 1 25 mg in some patients combination oral contraceptives in current use employ 20 to 35 mg day of ethinyl estradiol Conjugated estrogens and ethinyl estradiol differ widely in their oral potencies for example a dose of 0 625 mg of conjugated estrogens generally is considered equivalent to 5 to 10 mg of ethinyl estradiol Physiological and Pharmacological Actions Neuroendocrine Actions P decreases the frequency of the hypothalamic pulse generator and and increases the amplitude of LH pulses Reproductive Tract P released during the luteal phase of the cycle decreases estrogenestrogen driven endometrial proliferation and leads to the development of a secretory endometrium decline in P release from the corpus luteum at the end of the cycle determines onset of menstruation P influences the endocervical glands the abundant watery secretion of the estrogenestrogen stimulated structures is changed to a scant viscid material decreasing penetration of of the cervix by sperm E induced maturation of the vaginal epithelium is modified toward the condition of pregnancy by P P is very important for the maintenance of pregnancy suppress menstruation menstruation and uterine contractility which led to the use of progestins to prevent threatened abortion However such treatment is of questionable benefit because diminished P is rarely the cause of spontaneous abortion Mammary Gland P acting with E induces proliferation of the acini of the mammary gland during the normal menstrual cycle the mitotic activity in the breast breast epithelium is very low in the follicular phase and then peaks in the luteal phase P triggers a single round of mitotic activity in contrast in the endometrium endometrium proliferation is greatest in the follicular phase due to increasing increasing E and is opposed by P in the second half of the cycle hormonal control of proliferation is thus different in breast and and endometrium endometrium these cellcell specific effects should be kept in mind when interpreting therapeutic and untoward untoward effects of E and P 8 Physiological and Pharmacological Actions CNS Effects an increase of about 1 F may be noted midway through the normal menstrual cycle at the time of ovulation the temperature rise persists for the remainder of the cycle until until the onset of the menstrual and thus clearly due to P The mechanism of this effect is unknown P increases the ventilatory response of the respiratory centers to carbon dioxide and leads to reduced arterial and alveolar PCO2 in the luteal phase of the menstrual cycle and during pregnancy P may have depressant and hypnotic actions perhaps inducing drowsiness drowsiness after administration Metabolic Effects P increases basal insulin levels and the rise in insulin after carbohydrate carbohydrate ingestion longlong term
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