Follicular maturation and ovulation, as well as the associated production of female gonadal hormones, are controlled by the hypophyseal gonadotropins FSH (follicle-stimulating hormone) and LH (luteinizing hormone). In the first half of the menstrual cycle, FSH promotes growth and maturation of ovarian follicles that respond with accelerating synthesis of estradiol. Estradiol stimulates endometrial growth and increases the permeability of cervical mucus for sperm cells. When the estradiol blood level approaches a predetermined setpoint, FSH release is inhibited due to feedback action on the anterior hypophysis. Since follicle growth and estrogen production are correlated, hypophysis and hypothalamus can "monitor" the follicular phase of the ovarian cycle through their estrogen receptors. Within hours after ovulation, the tertiary follicle develops into the corpus luteum, which then also releases progesterone in response to LH. The former initiates the secretory phase of the endometrial cycle and lowers the permeability of cervical mucus. Nonruptured follicles continue to release estradiol under the influence of FSH. After 2 wk, production of progesterone and estradiol subsides, causing the secretory endometrial layer to be shed (menstruation).
The natural hormones are unsuitable for oral application because they are subject to presystemic hepatic elimination. Estradiol is converted via estrone to estriol; by conjugation, all three can be rendered water soluble and amenable to renal excretion. The major metabolite of progesterone is pregnan-diol, which is also conjugated and eliminated renally.
Estrogen preparations. Depot preparations for i.m. injection are oily solutions of esters of estradiol (3- or 17-OH group). The hydrophobicity of the acyl moiety determines the rate of absorption, hence the duration of effect
(p. 252). Released ester is hydrolyzed to yield free estradiol.
Orally used preparations. Ethinylestradiol (EE) is more stable metaboli-cally, passes largely unchanged through the liver after oral intake and mimics estradiol at estrogen receptors. Mestranol itself is inactive; however, cleavage of the C-3 methoxy group again yields EE. In oral contraceptives, one of the two agents forms the estrogen component (p. 256). (Sulfate-)conjugated estrogens can be extracted from equine urine and are used for the prevention of post-menopausal osteoporosis and in the therapy of climacteric complaints. Because of their high polarity (sulfate, glu-curonide), they would hardly appear suitable for this route of administration. For transdermal delivery, an adhesive patch is available that releases estradiol transcutaneously into the body.
Progestin preparations. Depot formulations for i.m. injection are 17-a-hydroxyprogesterone caproate and medroxyprogesterone acetate. Preparations for oral use are derivatives of 17a-ethinyltestosterone = ethisterone (e.g., norethisterone, dimethisterone, lynes-trenol, desogestrel, gestoden), or of 17a-hydroxyprogesterone acetate (e.g., chlormadinone acetate or cyproterone acetate). These agents are mainly used as the progestin component in oral contraceptives.
Indications for estrogens and progestins include: hormonal contraception (p. 256), hormone replacement, as in postmenopausal women for prophylaxis of osteoporosis; bleeding anomalies, menstrual complaints. Concerning adverse effects, see p. 256.
Estrogens with partial agonist activity (raloxifene, tamoxifene) are being investigated as agents used to replace estrogen in postmenopausal osteoporosis treatment, to lower plasma lipids, and as estrogen antagonists in the prevention of breast cancer. Raloxi-fen—in contrast to tamoxifen—is an antagonist at uterine estrogen receptors.
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