Goodman and Gilman Manual of Pharmacology and Therapeutics

Section V
Hormones and Hormone Antagonists

chapter 40
Estrogens and Progestins

Estrogens and progestins are hormones that produce myriad physiological actions. In women, these include developmental effects, neuroendocrine actions involved in the control of ovulation, the cyclical preparation of the reproductive tract for fertilization and implantation, and major actions on mineral, carbohydrate, protein, and lipid metabolism. Estrogens also have important actions in males, including effects on bone, spermatogenesis, and behavior. The most common uses of these agents are menopausal hormone therapy and contraception in women, but the specific compounds and dosages used in these 2 settings differ substantially. Anti-estrogens are used in the treatment of hormone-responsive breast cancer and infertility. Selective estrogen receptor modulators (SERMs) that display tissue-selective agonist or antagonist activities are useful to prevent breast cancer and osteoporosis. The main use of antiprogestins has been for medical abortion.

ESTROGENS

Estrogens interact with 2 receptors of the nuclear receptor superfamily, termed estrogen receptors α (Erα) and β (ERβ). The most potent naturally occurring estrogen in humans, for both ERα- and ERβ-mediated actions, is 17β-estradiol, followed by estrone and estriol. Steroidal estrogens arise from androstenedione or testosterone (Figure 40–1) by a reaction catalyzed by aromatase (CYP19).

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Figure 40–1 The biosynthetic pathway for estrogens.

The ovaries are the principal source of circulating estrogen in premenopausal women, with estradiol the main secretory product. Gonadotropins, acting via receptors that couple to the Gs-adenylyl cyclase–cyclic AMP pathway, increase the activities of aromatase and facilitate the transport of cholesterol (the precursor of all steroids) into the mitochondria of cells that synthesize steroids. In the ovary, type I17β-hydroxysteroid dehydrogenase favors the production of testosterone and estradiol from androstenedione and estrone, respectively. In the liver, the type II enzyme favors oxidation of circulating estradiol to estrone, and both of these steroids are then converted to estriol (see Figure 40–1). All 3 of these estrogens are excreted in the urine along with their glucuronide and sulfate conjugates.

In postmenopausal women, the principal source of circulating estrogen is adipose tissue stroma, where estrone is synthesized from dehydroepiandrosterone secreted by the adrenals. In men, estrogens are produced by the testes, but extragonadal production by aromatization of circulating C19 steroids (e.g., androstenedione and dehydroepiandrosterone) accounts for most circulating estrogens. Local production of estrogens by aromatization of androgens may play a causal or promotional role in the development of certain diseases such as breast cancer. Estrogens also may be produced from androgens via aromatase in the central nervous system (CNS) and other tissues and exert local effects near their production site (e.g., in bone they affect bone mineral density).

Human urine during pregnancy is an abundant source of natural estrogens. Pregnant mare’s urine is the source of conjugated equine estrogens, which have been widely used therapeutically for many years.

PHYSIOLOGICAL AND PHARMACOLOGICAL ACTIONS

DEVELOPMENTAL ACTIONS. Estrogens are largely responsible for pubertal changes in girls and secondary sexual characteristics.

Estrogens cause growth and development of the vagina, uterus, and fallopian tubes, and contribute to breast enlargement. They also contribute to molding the body contours, shaping the skeleton, and causing the pubertal growth spurt of the long bones and epiphyseal closure. Growth of axillary and pubic hair, pigmentation of the genital region, and the regional pigmentation of the nipples and areolae that occur after the first trimester of pregnancy are also estrogenic actions. Androgens may also play a secondary role in female sexual development (see Chapter 41). Estrogens also play important developmental roles in males. In boys, estrogen deficiency diminishes the pubertal growth spurt and delays skeletal maturation and epiphyseal closure so that linear growth continues into adulthood. Estrogen deficiency in men leads to elevated gonadotropins, macroorchidism, and increased testosterone levels and also may affect carbohydrate and lipid metabolism and fertility in some individuals.

NEUROENDOCRINE CONTROL OF THE MENSTRUAL CYCLE. A neuroendocrine cascade involving the hypothalamus, pituitary, and ovaries controls the menstrual cycle (Figure 40–2). A neuronal oscillator, or “clock,” in the hypothalamus fires at intervals that coincide with the release of gonadotropin-releasing hormone (GnRH) into the hypothalamic-pituitary portal vasculature (see Chapter 38). GnRH interacts with its receptor on pituitary gonadotropes to cause release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The frequency of the GnRH pulses, which varies in the different phases of the menstrual cycle, controls the relative synthesis of FSH and LH.

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Figure 40–2 Neuroendocrine control of gonadotropin secretion in females. The hypothalamic pulse generator located in the arcuate nucleus of the hypothalamus functions as a neuronal “clock” that fires at regular hourly intervals (A). This results in the periodic release of gonadotropin-releasing hormone (GnRH) from GnRH-containing neurons into the hypothalamic-pituitary portal vasculature (B). GnRH neurons (B) receive inhibitory input from opioid, dopamine, and GABA neurons and stimulatory input from noradrenergic neurons (NE, norepinephrine). The pulses of GnRH trigger the intermittent release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from pituitary gonadotropes (C), resulting in the pulsatile plasma profile (D). FSH and LH regulate ovarian production of estrogen and progesterone, which exert feedback controls (E). (See text and Figure 40–3 for additional details.)

The gonadotropins (LH and FSH) regulate the growth and maturation of follicles in the ovary and the ovarian production of estrogen and progesterone, which exert feedback regulation on the pituitary and hypothalamus. Because the release of GnRH is intermittent, secretion of LH and FSH is pulsatile. The pulse frequency is determined by the neural “clock” (see Figure 40–2), termed the hypothalamic GnRH pulse generator, but the amount of gonadotropin released in each pulse (i.e., the pulse amplitude) is largely controlled by the actions of estrogens and progesterone on the pituitary. The intermittent, pulsatilenature of hormone release is essential for the maintenance of normal ovulatory menstrual cycles because constant infusion of GnRH results in a cessation of gonadotropin release and ovarian steroid production (see Chapter 38). Although the precise mechanism that regulates the timing of GnRH release (i.e., pulse frequency) is unclear, hypothalamic cells appear to have an intrinsic ability to release GnRH episodically. Ovarian steroids, primarily progesterone, regulate the frequency of GnRH release. At puberty the pulse generator is activated and establishes cyclic profiles of pituitary and ovarian hormones. Although the mechanism of activation is not entirely established, it may involve increases in circulating insulin-like growth factor 1 (IGF)-1 and leptin levels, the latter acting to inhibit neuropeptide Y (NPY) in the arcuate nucleus to relieve an inhibitory effect on GnRH neurons.

Figure 40–3 provides a schematic diagram of the profiles of gonadotropin and gonadal steroid levels in the menstrual cycle. In the early follicular phase of the cycle: (1) the pulse generator produces bursts of neuronal activity with a frequency of about 1/h that correspond with pulses of GnRH secretion, (2) these cause a corresponding pulsatile release of LH and FSH from pituitary gonadotropes, and (3) FSH in particular causes the graafian follicle to mature and secrete estrogen. The effects of estrogens on the pituitary are inhibitory at this time and cause the amount of LH and FSH released from the pituitary to decline, so gonadotropin levels gradually fall. Estrogens act primarily on the pituitary to control the amplitude of gonadotropin pulses and may also contribute to the amplitude of GnRH pulses secreted by the hypothalamus. Inhibin, produced by the ovary, exerts negative feedback to selectively decrease serum FSH.

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Figure 40–3 Hormonal relationships of the human menstrual cycleA. Average daily values of LH, FSH, estradiol (E2), and progesterone in plasma samples from women exhibiting normal 28-day menstrual cycles. Changes in the ovarian follicle (top) and endometrium (bottom) also are illustrated schematically. Frequent plasma sampling reveals pulsatile patterns of gonadotropin release. Characteristic profiles are illustrated schematically for the follicular phase (day 9, inset on left) and luteal phase (day 17, inset on right). Both the frequency (number of pulses per hour) and amplitude (extent of change of hormone release) of pulses vary throughout the cycle. (Redrawn with permission from Thorneycroft et al., 1971. © Elsevier). B. Major regulatory effects of ovarian steroids on hypothalamic-pituitary function. Estrogen decreases the amount of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) released (i.e., gonadotropin pulse amplitude) during most of the cycle and triggers a surge of LH release only at mid-cycle. Progesterone decreases the frequency of GnRH release from the hypothalamus and thus decreases the frequency of plasma gonadotropin pulses. Progesterone also increases the amount of LH released (i.e., the pulse amplitude) during the luteal phase of the cycle.

At mid-cycle, serum estradiol rises above a threshold level of 150-200 pg/mL for ~36 h, exerting a brief positive feedback effect on the pituitary to trigger the preovulatory surge of LH and FSH. This effect primarily involves a change in pituitary responsiveness to GnRH. Progesterone may contribute to the mid-cycle LH surge. The mid-cycle surge in gonadotropins stimulates follicular rupture and ovulation within 1-2 days. The ruptured follicle then develops into the corpus luteum, which produces large amounts of progesterone and lesser amounts of estrogen under the influence of LH during the second half of the cycle. In the absence of pregnancy, the corpus luteum ceases to function, steroid levels drop, and menstruation occurs. When steroid levels drop, the pulse generator reverts to a firing pattern, the entire system then resets, and a new ovarian cycle occurs.

In the follicular phase of the cycle, estrogens inhibit gonadotropin release but then have a brief mid-cycle stimulatory action that increases the amount released and causes the LH surge. Progesterone, acting on the hypothalamus, exerts the predominant control of the frequency of LH release. It decreases the firing rate of the hypothalamic pulse generator, an action thought to be mediated largely via inhibitory opioid neurons (containing progesterone receptors) that synapse with GnRH neurons. Progesterone also exerts a direct effect on the pituitary to oppose the inhibitory actions of estrogens and thus enhance the amount of LH released (i.e., to increase the amplitude of the LH pulses). These steroid feedback effects, coupled with the intrinsic activity of the hypothalamic GnRH pulse generator, lead to relatively frequent LH pulses of small amplitude in the follicular phase of the cycle, and less frequent pulses of larger amplitude in the luteal phase.

In males, testosterone regulates the hypothalamic-pituitary-gonadal axis at both the hypothalamic and pituitary levels, and its negative feedback effect is mediated to a substantial degree by estrogen formed via aromatization.

EFFECTS OF CYCLICAL GONADAL STEROIDS ON THE REPRODUCTIVE TRACT

The cyclical changes in estrogen and progesterone production by the ovaries regulate corresponding events in the fallopian tubes, uterus, cervix, and vagina. Physiologically, these changes prepare the uterus for implantation, and the proper timing of events in these tissues is essential for pregnancy. If pregnancy does not occur, the endometrium is shed as the menstrual discharge (see Figure 40–3).

Menstruation marks the start of the menstrual cycle. During the follicular (or proliferative) phase of the cycle, estrogen begins the rebuilding of the endometrium by stimulating proliferation and differentiation. An important response to estrogen in the endometrium and other tissues is induction of the progesterone receptor (PR), which enables cells to respond to this hormone during the second half of the cycle. In the luteal (or secretory) phase of the cycle, elevated progesterone limits the proliferative effect of estrogens on the endometrium by stimulating differentiation. Major effects include stimulation of epithelial secretions important for implantation of the blastocyst and the characteristic growth of the endometrial blood vessels seen at this time. These effects are mediated by PR-A in animal models. Progesterone is thus important in preparation for implantation and for the changes that take place in the uterus at the implantation site (i.e., the decidual response). There is a narrow “window of implantation,” spanning days 19-24 of the endometrial cycle, when the epithelial cells of the endometrium are receptive to blastocyst implantation. If implantation occurs, human chorionic gonadotropin (hCG), produced initially by the trophoblast and later by the placenta, interacts with the LH receptor of the corpus luteum to maintain steroid hormone synthesis during the early stages of pregnancy. Later the placenta becomes the major site of estrogen and progesterone synthesis.

METABOLIC EFFECTS. Estrogens affect myriad tissues. Many nonreproductive tissues, including bone, vascular endothelium, liver, CNS, immune system, the GI tract, and heart, express low levels of both estrogen receptors (ERs), and the ratio of ERe to ERβ varies in a cell-specific manner. The effects of estrogens on selected aspects of mineral, lipid, carbohydrate, and protein metabolism are particularly important for understanding their pharmacological actions.

Long-term administration of estrogen is associated with decreased plasma renin, angiotensin-converting enzyme, and endothelin-1; expression of the AT1 receptor for AngII is also decreased. Estrogen actions on the vascular wall include increased production of NO and prostacyclin. All of these changes promote vasodilation and retard atherogenesis. Estrogens alter a number of metabolic pathways that affect the clotting cascade. Systemic effects include changes in hepatic production of plasma proteins. Estrogens cause a small increase in coagulation factors II, VII, IX, X, and XII, and they decrease the anticoagulation factors protein C, protein S, and antithrombin III (see Chapter 30). Fibrinolytic pathways also are affected, and several studies of women treated with estrogen alone or estrogen with a progestin have demonstrated decreased levels of plasminogen-activator inhibitor 1 (PAI-1) protein with a concomitant increase in fibrinolysis. Thus, estrogens increase both coagulation and fibrinolytic pathways, and imbalance in these 2 opposing activities may cause adverse effects.

Estrogens increase bone mass. Bone is continuously remodeled by the resorptive action of osteoclasts and the bone-forming action of osteoblasts. Estrogens directly regulate osteoblasts and increase osteocyte survival by inhibiting apoptosis. The major effect of estrogens is to decrease the number and activity of osteoclasts.

Estrogens slightly elevate serum triglycerides and slightly reduce total serum cholesterol levels. They increase high-density lipoprotein (HDL) levels and decrease the levels of low-density lipoprotein (LDL) and lipoprotein A (LPA) (see Chapter 31). The presence of ERs in the liver suggests that the beneficial effects of estrogen on lipoprotein metabolism may be due partly to direct hepatic actions. Estrogens also alter bile composition by increasing cholesterol secretion and decreasing bile acid secretion. This leads to increased saturation of bile with cholesterol and appears to be the basis for increased gallstone formation in some women receiving estrogens. In general, estrogens increase plasma levels of cortisol-binding globulin, thyroxine-binding globulin, and sex hormone-binding globulin (SHBG), which binds both androgens and estrogens.

ESTROGEN RECEPTORS

Estrogens exert their effects by interaction with receptors that are members of the superfamily of nuclear receptors. The 2 estrogen receptor genes are located on separate chromosomes: ESR1 encodes ERα, and ESR2 encodes ERβ. Both ERs are estrogen-dependent nuclear transcription factors that have different tissue distributions and transcriptional regulatory effects on a wide number of target genes. Both ERα and ERβ exist as multiple mRNA isoforms due to differential promoter use and alternative splicing. There are significant differences between the 2 receptor isoforms in the ligand-binding domains and in both transactivation domains. Human ERβ does not appear to contain a functional AF-1 domain. The receptors appear to have different biological functions and respond differently to various estrogenic compounds. However, their high homology in the DNA-binding domains suggests that both receptors recognize similar DNA sequences and hence regulate many of the same target genes.

ERα is expressed most abundantly in the female reproductive tract—especially the uterus, vagina, and ovaries—as well as in the mammary gland, the hypothalamus, endothelial cells, and vascular smooth muscle. ERβ is expressed most highly in the prostate and ovaries, with lower expression in lung, brain, bone, and vasculature. Both forms of ER are expressed on breast cancers, although ERβ is believed to be the predominant form responsible for growth regulation (see Chapter 63). Polymorphic variants of ER have been identified, but attempts to correlate specific polymorphisms with the frequency of breast cancer, bone mass, endometrial cancer, or cardiovascular disease have led to contradictory results.

A cloned G protein-coupled receptor, GPR30, also appears to interact with estrogens in some cell systems, and its participation in the rapid effects of estrogen is an attractive idea. There may be interaction/cross-talk between membrane-associated ERα and membrane-localized GPR30 in some cancer cells, but in vivo confirmation is lacking.

MECHANISM OF ACTION

Both ERs are ligand-activated transcription factors that increase or decrease the transcription of target genes (Figure 40–4). After entering the cell by passive diffusion through the plasma membrane, the hormone binds to an ER in the nucleus. In the nucleus, the ER is present as an inactive monomer bound to heat-shock protein 90 (HSP90), and upon binding estrogen, a change in ER conformation dissociates the heat-shock proteins and causes receptor dimerization, which increases the affinity and the rate of receptor binding to DNA. Homodimers of ERα or ERβ and ERα/ERβ heterodimers can be produced depending on the receptor complement in a given cell. The ER dimer binds to estrogen response elements (EREs), typically located in the promoter region of target genes. The ER/DNA complex recruits a cascade of coactivator and other proteins to the promoter region of target genes (Figure 40–4B and legend) and allows the proteins that make up the general transcription apparatus to assemble and initiate transcription.

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Figure 40–4 Molecular mechanism of action of nuclear estrogen receptorA. Unliganded estrogen receptor (ER) exists as a monomer within the nucleus. B. Agonists such as 17β-estradiol (E) bind to the ER and cause a ligand-directed change in conformation that facilitates dimerization and interaction with specific estrogen response elements in DNA. The ER-DNA complex recruits coactivators such as SWI/SNF that modify chromatin structure, and coactivators such as steroid-receptor coactivator-1 (SRC-1) that has histone acetyltransferase (HAT) activity that further alters chromatin structure. This remodeling facilitates the exchange of the recruited proteins such that other coactivators (e.g., p300 and the TRAP complex) associate on the target gene promoter and proteins that comprise the general transcription apparatus (GTA) are recruited, with subsequent synthesis of mRNA. C. Antagonists such as tamoxifen (T) also bind to the ER but produce a different receptor conformation. The antagonist-induced conformation also facilitates dimerization and interaction with DNA, but a different set of proteins called corepressors, such as nuclear-hormone receptor corepressor (NcoR), are recruited to the complex. NcoR further recruits proteins such as histone deacetylase I (HDAC1) that act on histones to stabilize nucleosome structure and prevent interaction with the GTA.

Some ERs are located on the plasma membrane of cells. These ERs are encoded by the same genes that encode ERα and ERβ but are transported to the plasma membrane and reside mainly in caveolae. Translocation to the membrane by all sex steroid receptors is mediated by palmitoylation of a 9–amino acid motif common to these receptors. Membrane-localized ERs mediate the rapid activation of some proteins such as MAPK (phosphorylated in several cell types) and the rapid increase in cyclic AMP caused by the hormone. These membrane interactions and sequelae provide additional levels of cross-talk and complexity in estrogen signaling.

ADME. Various estrogens are available for oral, parenteral, transdermal, or topical administration. Given the lipophilic nature of estrogens, absorption generally is good with the appropriate preparation. Aqueous or oil-based esters of estradiol are available for intramuscular injection, ranging in frequency from every week to once per month. Conjugated estrogens are available for IV or IM administration. Transdermal patches that are changed once or twice weekly deliver estradiol continuously through the skin. Preparations are available for topical use in the vagina or for application to the skin. Estrogen preparations also are available in combination with a progestin. All estrogens are labeled with precautionary statements urging the prescribing of the lowest effective dose and for the shortest duration consistent with the treatment goals and risks for each individual patient.

Oral administration is common and may use estradiol, conjugated estrogens, esters of estrone and other estrogens, and ethinyl estradiol (in combination with a progestin). Estradiol is available in nonmicronized (FEMTRACE) and micronized preparations (ESTRACE, others). The micronized formulations yield a large surface for rapid absorption to partially overcome low absolute oral bioavailability due to first-pass metabolism. Addition of the ethinyl substituent at C17 (ethinyl estradiol) inhibits first-pass hepatic metabolism. Other common oral preparations contain conjugated equine estrogens (PREMARIN), which are primarily the sulfate esters of estrone, equilin, and other naturally occurring compounds; esterified esters (MENEST); or mixtures of synthetic conjugated estrogens prepared from plant-derived sources (CENESTIN;ENJUVIA). These are hydrolyzed by enzymes present in the lower gut that remove the charged sulfate groups and allow absorption of estrogen across the intestinal epithelium. In another oral preparation, estropipate (ORTHO-EST, OGEN, others), estrone is solubilized as the sulfate and stabilized with piperazine. Due largely to differences in metabolism, the potencies of various oral preparations differ widely; e.g., ethinyl estradiol is much more potent than conjugated estrogens.

Administration of estradiol via transdermal patches (ALORA, CLIMARA, ESTRADERM, VIVELLE, others) provides slow, sustained release of the hormone, systemic distribution, and more constant blood levels than oral dosing. Estradiol is also available as a topical emulsion (ESTRASORB) or as a gel (ESTROGEL). The transdermal route does not lead to the high level of the drug in the portal circulation after oral administration, and thus should minimize hepatic effects of estrogens. Preparations available for intramuscular injection include compounds such as estradiol valerate (DELESTROGEN, others) or estradiol cypionate (DEPO-ESTRADIOL, others), which may be absorbed over several weeks following a single intramuscular injection. Preparations of estradiol (ESTRACE) and conjugated estrogen (PREMARIN) creams are available for topical administration to the vagina. A 3-month vaginal ring (ESTRING, FEMRING) may be used for slow release of estradiol, and tablets are also available for vaginal use (VAGIFEM).

Estradiol, ethinyl estradiol, and other estrogens are extensively bound to plasma proteins. Estradiol and other naturally occurring estrogens are bound mainly to SHBG; ethinyl estradiol is bound extensively to serum albumin but not SHBG. Due to their size and lipophilic nature, unbound estrogens distribute rapidly and extensively. Estrogens undergo rapid hepatic biotransformation, with a plasma t1/2measured in minutes. Estrogens also undergo enterohepatic recirculation via (1) sulfate and glucuronide conjugation in the liver, (2) biliary secretion of the conjugates into the intestine, and (3) hydrolysis in the gut (largely by bacterial enzymes) followed by reabsorption. Estradiol is converted primarily by 17β-hydroxysteroid dehydrogenase to estrone, which undergoes conversion by 16α-hydroxylation and 17-keto reduction to estriol, the major urinary metabolite; myriad sulfate and glucuronide conjugates appear in the urine. Ethinyl estradiol is cleared much more slowly than estradiol due to decreased hepatic metabolism with t1/2 of 13-27 h. Mestranol, a component of some combination oral contraceptives, is the 3-methyl ether of ethinyl estradiol.

Many drugs, environmental agents (e.g., cigarette smoke), and nutraceuticals (e.g., St. John’s wort) act as inducers or inhibitors of the various enzymes that metabolize estrogens, and thus have the potential to alter their clearance. Consideration of the impact of these factors on efficacy and untoward effects is important with the decreased doses of estrogens currently employed for both menopausal hormone therapy and contraception. A number of foodstuffs and plant-derived products, largely from soy, are available as nonprescription items and often are touted as providing benefits similar to those from compounds with established estrogenic activity. These products may contain flavonoids such as genistein, which display estrogenic activity in laboratory tests, albeit generally much less than that of estradiol; their efficacy at relevant doses has not been established in human trials.

UNTOWARD RESPONSES. Oral contraceptives now contain much lower amounts of both estrogen and progestins, and this has significantly diminished the risks associated with their use.

CONCERN ABOUT CARCINOGENIC ACTIONS. Early studies established that the use of estrogens is associated with the risk of developing breast, endometrial, cervical, and vaginal cancer. Estrogen use during pregnancy also can increase the incidence of cancer and nonmalignant genital abnormalities in both male and female offspring. The use of unopposed estrogen for hormone treatment in postmenopausal women increases the risk of endometrial carcinoma by 5- to 15-fold. This increased risk can be prevented if a progestin is coadministered with the estrogen, and this is now standard practice.

The association between estrogen and/or estrogen-progestin use and breast cancer is of great concern. The results of 2 large randomized clinical studies (the Women’s Health Initiative study [WHI], and the Million Women Study [MWS]) of estrogen/progestin and estrogen-only in postmenopausal women clearly established a small but significant increase in the risk of breast cancer, apparently due to the medroxyprogesterone. In the WHI study, an estrogen-progestin combination increased the total risk of breast cancer by 25%; the absolute increase in attributable cases of disease was 6 per 1000 women and required 3 or more years of treatment. In women without a uterus who received estrogen alone, the relative risk of breast cancer was actually decreased. Thus, the data suggest that the progestin component in combined hormone-replacement therapy plays a major role in this increased risk of breast cancer. Importantly, the excess risk of breast cancer associated with menopausal hormone use appears to abate 5 years after discontinuing therapy. Thus, hormone replacement therapy for ≥5 years is often prescribed to mitigate hot flashes and likely has a minimal effect on the risk of breast cancer.

METABOLIC AND CARDIOVASCULAR EFFECTS. Although they may slightly elevate plasma triglycerides, estrogens themselves generally have favorable overall effects on plasma lipoprotein profiles. However, addition of progestins may reduce the favorable actions of estrogens. Estrogens do increase cholesterol levels in bile and cause a relative 2- to 3-fold increase in gallbladder disease. Many studies and clinical trials suggest that estrogen therapy in postmenopausal women would reduce the risk of cardiovascular disease. However, 2 recent randomized clinical trials have not found such protection. In women with established coronary heart disease (CHD), estrogen plus a progestin increased the relative risk of nonfatal myocardial infarction or CHD death within 1 year of treatment, but there was no overall change in 5 years. In women without existing CHD, treated with an estrogen plus progestin, protective effects were seen but only when hormone replacement was initiated within 10 years of menopause. It is clear, however, that oral estrogens increase the risk of thromboembolic disease in healthy women and in women with preexisting cardiovascular disease.

EFFECTS ON COGNITION. Several retrospective studies had suggested that estrogens had beneficial effects on cognition and delayed the onset of Alzheimer disease. However, in more recent studies, estrogen-progestin therapy was associated with increased incidence of dementia, and no benefit of hormone treatment on global cognitive function was observed.

OTHER POTENTIAL UNTOWARD EFFECTS. Nausea and vomiting are an initial reaction to estrogen therapy in some women, but these effects may disappear with time and may be minimized by taking estrogens with food or just before sleep. Fullness and tenderness of the breasts and edema may occur but sometimes can be diminished by lowering the dose. A more serious concern is that estrogens may cause severe migraine in some women. Estrogens also may reactivate or exacerbate endometriosis.

THERAPEUTIC USES. The 2 major uses of estrogens are for menopausal hormone therapy (MHT) and as components of combination oral contraceptives, The “effective” dose of estrogen used for MHT is less than that in oral contraceptives when one considers potency. The doses of estrogens employed in both settings have decreased substantially, thereby reducing the incidence of untoward effects.

MENOPAUSAL HORMONE THERAPY. The established benefits of estrogen therapy in postmenopausal women include amelioration of vasomotor symptoms and the prevention of bone fractures and urogenital atrophy.

Vasomotor Symptoms. The decline in ovarian function at menopause is associated with vasomotor symptoms in most women. The characteristic hot flashes may alternate with chilly sensations, inappropriate sweating, and (less commonly) paresthesias. Treatment with estrogen is specific and is the most efficacious pharmacotherapy. Medroxyprogesterone acetate (discussed in the section on progestins) may provide some relief of vasomotor symptoms; the α2 adrenergic agonist clonidine diminishes vasomotor symptoms in some women, presumably by blocking the CNS outflow that regulates blood flow to cutaneous vessels. In many women, hot flashes diminish within several years; the dose and duration of estrogen use should thus be the minimum necessary to provide relief.

Osteoporosis. Osteoporosis is a disorder of the skeleton associated with the loss of bone mass (see Chapter 44). The result is thinning and weakening of the bones and an increased incidence of fractures. Osteoporosis is an indication for estrogen therapy. Most fractures in the postmenopausal period occur in women without a prior history of osteoporosis, and estrogens are the most efficacious agents available for prevention of fractures at all sites in such women. Estrogens act primarily to decrease bone resorption; consequently, estrogens are more effective at preventing rather than restoring bone loss and are most effective if treatment is initiated before significant bone loss occurs. Maximal benefit requires continuous use; bone loss resumes when treatment is discontinued. An appropriate diet with adequate intake of Ca2+ and vitamin D and weight-bearing exercise enhance the effects of estrogen treatment. The bisphosphonates (see Chapter 44) can also be considered.

Vaginal Dryness and Urogenital Atrophy. Loss of tissue lining the vagina or bladder leads to a variety of symptoms in many postmenopausal women, including vaginal dryness and itching, painful intercourse, swelling of tissues in the genital region, pain during urination, a need to urinate urgently or often, and sudden or unexpected urinary incontinence. For relief of vulvar and vaginal atrophy, local administration as a vaginal cream, ring device, or tablets may be considered.

Cardiovascular Disease. The incidence of cardiovascular disease is low in premenopausal women, rising rapidly after menopause; epidemiological studies show an association between estrogen use and reduced cardiovascular disease in postmenopausal women. Estrogens produce a favorable lipoprotein profile, promote vasodilation, inhibit the response to vascular injury, and reduce atherosclerosis. However, estrogens also promote coagulation and thromboembolic events. Randomized prospective studies unexpectedly indicated that the incidence of heart disease and stroke in older postmenopausal women, treated with conjugated estrogens and a progestin, was initially increased, although the trend reversed with time. Combined estrogen-progestin therapy is associated with a decrease in heart attacks in younger women.

MENOPAUSAL HORMONE REGIMENS. The use of hormone-replacement therapy, or HRT, that includes a progestin in addition to estrogen, limits estrogen-related endometrial hyperplasia. Postmenopausal HRT, when indicated, should include both an estrogen and progestin for women with a uterus. For women who have undergone a hysterectomy, endometrial carcinoma is not a concern, and estrogen alone avoids the possible deleterious effects of progestins. Menopausal hormone therapy with estrogens should use the lowest dose and shortest duration necessary to achieve an appropriate therapeutic goal.

Conjugated estrogens and medroxyprogesterone acetate (MPA) have been used most commonly in menopausal hormone regimens, although estradiol, estrone, and estriol have been used as estrogens, andnorethindrone, norgestimate, levonorgestrel, norethisterone, and progesterone also have been widely used (especially in Europe). Various “continuous” or “cyclic” regimens have been used; the latter regimens include drug-free days. An example of a cyclic regimen is as follows: (1) administration of an estrogen for 25 days; (2) the addition of MPA for the last 12-14 days of estrogen treatment; and (3) 5-6 days with no hormone treatment, during which withdrawal bleeding normally occurs due to breakdown and shedding of the endometrium. Continuous administration of combined estrogen plus progestin does not lead to regular, recurrent endometrial shedding but may cause intermittent spotting or bleeding, especially in the first year of use. Other regimens include a progestin intermittently (e.g., every third month), but the long-term endometrial safety of these regimens remains to be firmly established. PREMPRO (conjugated estrogens plus MPA given as a fixed dose daily) and PREMPHASE (conjugated estrogens given for 28 days plus MPA given for 14 of 28 days) are widely used combination formulations. Other combination products available in the U.S. are FEMHRT (ethinyl estradiol plus norethindrone acetate), ACTIVELLA (estradiol plus norethindrone), PREFEST (estradiol and norgestimate), and ANGELIQ (estradiol and drospirenone). Doses and regimens are usually adjusted empirically based on control of symptoms, patient acceptance of bleeding patterns, and/or other untoward effects.

Another pharmacological consideration is the route of estrogen administration. Oral administration exposes the liver to higher concentrations of estrogens than does transdermal administration and may increase SHBG, other binding globulins, angiotensinogen; and possibly the cholesterol content of the bile. Transdermal estrogen appears to cause smaller beneficial changes in LDL and HDL profiles (~50% of those seen with the oral route).

Tibolone (LIVIAL) is widely used in the E.U. for treatment of vasomotor symptoms and prevention of osteoporosis but is not currently approved in the U.S. The parent compound itself is devoid of activity, but it is metabolized in a tissue-selective manner to 3 metabolites that have predominantly estrogenic, progestogenic, and androgenic activities.

ESTROGEN TREATMENT IN THE FAILURE OF OVARIAN DEVELOPMENT. In several conditions (e.g., Turner syndrome), the ovaries do not develop and puberty does not occur. Therapy with estrogen at the appropriate time replicates the events of puberty, and androgens (see Chapter 41) and/or growth hormone (see Chapter 38) may be used concomitantly to promote normal growth. Although estrogens and androgens promote bone growth, they also accelerate epiphyseal fusion, and their premature use can thus result in a shorter ultimate height.

SELECTIVE ESTROGEN RECEPTOR MODULATORS AND ANTI-ESTROGENS

SELECTIVE ESTROGEN RECEPTOR MODULATORS: TAMOXIFEN, RALOXIFENE, AND TOREMIFENE. Selective estrogen receptor modulators, or SERMs, are compounds with tissue-selective actions. The pharmacological goal of these drugs is to produce beneficial estrogenic actions in certain tissues (e.g., bone, brain, and liver) but antagonist activity in tissues such as breast and endometrium. Currently approved drugs in the U.S. in this class are tamoxifen citrate, raloxifene hydrochloride (EVISTA), and toremifene (FARESTON).

ANTI-ESTROGENS: CLOMIPHENE AND FULVESTRANT. These compounds are distinguished from the SERMs in that they are pure antagonists in all tissues studied. Clomiphene (CLOMID, SEROPHENE, others) is approved for the treatment of infertility in anovulatory women, and fulvestrant (FASLODEX) is used for the treatment of breast cancer in women with disease progression after tamoxifen.

PHARMACOLOGICAL EFFECTS. All of these agents bind to the ligand-binding pocket of both ERα and ER and competitively block estradiol binding. However, the conformation of ligand-bound ERs is different with different ligands, and this has 2 important mechanistic consequences. The distinct ER-ligand conformations recruit different coactivators and corepressors onto the promoter of a target gene. The tissue-specific actions of SERMs thus can be explained in part by the distinct conformation of the ER when occupied by different ligands, in combination with different coactivator and corepressor levels in different cell types.

Tamoxifen exhibits anti-estrogenic, estrogenic, or mixed activity depending on the species and target gene measured. In clinical tests or laboratory studies with human cells, the drug’s activity depends on the tissue and end point measured. For example, tamoxifen inhibits the proliferation of cultured human breast cancer cells and reduces tumor size and number in women, and yet it stimulates proliferation of endometrial cells and causes endometrial thickening. The drug has an antiresorptive effect on bone, and in humans it decreases total cholesterol, LDL, and LPA but does not increase HDL and triglycerides. Tamoxifen treatment increases the relative risk of deep vein thrombosis, pulmonary embolism, and endometrial carcinoma. Tamoxifen produces hot flashes and other adverse effects, including cataracts and nausea. Due to its agonist activity in bone, it does not increase the incidence of fractures when used in this setting. Whereas 17α estradiol induces a conformation that recruits coactivators to the receptor, tamoxifen induces a conformation that permits the recruitment of the corepressor to both ERα and ERβ. The agonist activity of tamoxifen seen in tissues such as the endometrium is mediated by the ligand-independent AF-1 transactivation domain of ER α; because ERβ does not contain a functional AF-1 domain, tamoxifen does not activate ERβ.

Raloxifene is an estrogen agonist in bone, where it exerts an antiresorptive effect. The drug also acts as an estrogen agonist in reducing total cholesterol and LDL, but it does not increase HDL. Raloxifene does not cause proliferation or thickening of the endometrium. Studies indicate that raloxifene significantly reduces the risk of ER-positive but not ER-negative breast cancer. Raloxifene does not alleviate the vasomotor symptoms associated with menopause. Adverse effects include hot flashes, leg cramps, and a 3-fold increase in deep vein thrombosis and pulmonary embolism.

Clomiphene increases gonadotropin secretion and stimulates ovulation. Clomiphene’s major pharmacological use is to induce ovulation in women with amenorrhea, polycystic ovarian syndrome, or dysfunctional bleeding with anovulatory cycles, but who have a functional hypothalamic-hypophyseal-ovarian system and adequate endogenous estrogen production.

Fulvestrant is anti-estrogenic. In clinical trials it is efficacious in treating tamoxifen-resistant breast cancers. Fulvestrant binds to ERα and ERβ with a high affinity comparable to estradiol but represses transactivation. It also increases dramatically the intracellular proteolytic degradation of ERα while apparently protecting ERβ from degradation. This effect on ERα protein levels may explain fulvestrant’s efficacy in tamoxifen-resistant breast cancer.

ADME. Tamoxifen is given orally, and peak plasma levels are reached within 4-7 h. It has 2 elimination phases with half-lives of 7-14 h and 4-11 days; thus, 3-4 weeks of treatment are required to reach steady-state plasma levels. Tamoxifen is metabolized in humans by multiple hepatic CYPs, some of which it also induces. In humans, the more potent anti-estrogen metabolite 4-hydroxytamoxifen is produced in the liver. The major route of elimination from the body involves N-demethylation and deamination. The drug undergoes enterohepatic circulation, and excretion is primarily in the feces as conjugates of the deaminated metabolite.

Oral Raloxifene is absorbed rapidly with a bioavailability of ~2%. The drug has a t1/2 of ~28 h and is eliminated primarily in the feces after hepatic glucuronidation. Clomiphene is well absorbed following oral administration, and the drug and its metabolites are eliminated primarily in the feces. The long plasma t1/2 (5-7 days) is due largely to plasma-protein binding, enterohepatic circulation, and accumulation in fatty tissues. Fulvestrant is administered monthly by intramuscular depot injections. Plasma concentrations reach maximal levels in 7 days and are maintained for a month. The drug is eliminated primarily (90%) via the feces in humans.

THERAPEUTIC USES

BREAST CANCER. Tamoxifen is highly efficacious in the palliation of advanced breast cancer in women with ER-positive tumors, and it is now indicated as the hormonal treatment of choice for both early and advanced breast cancer in women of all ages. Response rates are ~50% in women with ER-positive tumors. Tamoxifen increases disease-free survival and overall survival; treatment for 5 years is more efficacious than shorter 1- to 2-year treatment periods in reducing cancer recurrence and death. Prophylactic treatment should be limited to 5 years because effectiveness decreases thereafter. The most frequent side effect is hot flashes. Tamoxifen has estrogenic activity in the uterus, increases the risk of endometrial cancer by 2- to 3-fold, and also causes a comparable increase in the risk of thromboembolic disease that leads to serious risks for women receiving anticoagulant therapy and women with a history of deep vein thrombosis or stroke. Toremifene has therapeutic actions similar to tamoxifen, and fulvestrant may be efficacious in women who become resistant to tamoxifen. Untoward effects of fulvestrant include hot flashes, GI symptoms, headache, back pain, and pharyngitis.

OSTEOPOROSIS. Raloxifene reduces the rate of bone loss and may increase bone mass at certain sites. Raloxifene does not appear to increase the risk of developing endometrial cancer. The drug has beneficial actions on lipoprotein metabolism, reducing both total cholesterol and LDL; HDL is not increased. Adverse effects include hot flashes, deep vein thrombosis, and leg cramps.

INFERTILITY. Clomiphene is used primarily for treatment of female infertility due to anovulation. By increasing gonadotropin levels, primarily FSH, it enhances follicular recruitment. It is relatively inexpensive, orally active, and requires less extensive monitoring than other treatment protocols. Untoward effects include ovarian hyperstimulation, increased incidence of multiple births, ovarian cysts, hot flashes, and blurred vision. Prolonged use (e.g., ≥12 cycles) may increase the risk of ovarian cancer. The drug should not be administered to pregnant women due to reports of teratogenicity in animals, but there is no evidence of this when used to induce ovulation.

ESTROGEN SYNTHESIS INHIBITORS

Continual administration of GnRH agonists prevents ovarian synthesis of estrogens but not their peripheral synthesis from adrenal androgens (see Chapter 38). The recognition that locally produced as well as circulating estrogens may play a significant role in breast cancer has greatly stimulated interest in the use of aromatase inhibitors to selectively block production of estrogens (see Chapter 63). Both steroidal (e.g., formestane and exemestane [AROMASIN]) and nonsteroidal agents (e.g., anastrozole [ARIMIDEX], letrozole [FEMARA], and vorozole) are available. Steroidal, or type I, agents are substrate analogs that act as suicide inhibitors to irreversibly inactivate aromatase, whereas the nonsteroidal, or type II, agents interact reversibly with the heme groups of CYPs. Exemestane, letrozole, and anastrozole are currently approved in the U.S. for the treatment of breast cancer. These agents may be used as first-line treatment of breast cancer or as second-line drugs after tamoxifen (see Chapter 62). They are highly efficacious and actually superior to tamoxifen in adjuvant use for postmenopausal women, and are indicated either following tamoxifen for 2-5 years or as initial agents. They have the added advantage of not increasing the risk of uterine cancer or venous thromboembolism. Because they dramatically reduce circulating as well as local levels of estrogens, they produce hot flashes. They lack the beneficial effect of tamoxifen to maintain bone density.

PROGESTINS

Progesterone is secreted by the ovary, mainly from the corpus luteum, during the second half of the menstrual cycle (see Figure 40–3). LH, acting via its G protein-coupled receptor, stimulates progesterone secretion during the normal cycle.

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After fertilization, the trophoblast secretes hCG into the maternal circulation, which then stimulates the LH receptor to sustain the corpus luteum and maintain progesterone production. During the second or third month of pregnancy, the developing placenta begins to secrete estrogen and progesterone in collaboration with the fetal adrenal glands, and thereafter the corpus luteum is not essential to continued gestation. Estrogen and progesterone continue to be secreted in large amounts by the placenta up to the time of delivery.

The progestins are widely used with estrogens for MHT. Depot MPA is used as a long-acting injectable contraceptive. The 19-nortestosterone derivatives (estranes) were developed for use as progestins in oral contraceptives, but they also exhibit androgenic and other activities. The gonanes are the “19-nor” compounds that have diminished androgenic activity relative to the estranes. These 2 classes of 19-nortestosterone derivatives are the progestational components of most oral and some long-acting injectable contraceptives. The remaining oral contraceptives contain a class of progestins derived from spironolactone (e.g., drospirenone) that have anti-mineralocorticoid and anti-androgenic properties. Other steroidal progestins include the gonane dienogest; 19-nor-progestin derivatives (e.g., nomegestrol, Nestorone, and trimegestone), which have increased selectivity for the progesterone receptor and less androgenic activity than estranes; and the spironolactone derivative drospirenone, which is used in combination with oral contraceptives. Like spironolactone, drospirenone is also a mineralocorticoid and androgen receptor antagonist.

PHYSIOLOGICAL AND PHARMACOLOGICAL ACTIONS

NEUROENDOCRINE ACTIONS. Progesterone produced in the luteal phase of the cycle decreases the frequency of GnRH pulses. This progesterone-mediated decrease in GnRH pulse frequency is critical for suppressing gonadotropin release and resetting the hypothalamic-pituitary-gonadal axis to transition from the luteal back to the follicular phase. Furthermore, GnRH suppression is the major mechanism of action of progestin-containing contraceptives.

Reproductive Tract. Progesterone decreases estrogen-driven endometrial proliferation and leads to the development of a secretory endometrium (see Figure 40–3); the abrupt decline in progesterone at the end of the cycle is the main determinant of the onset of menstruation. If the duration of the luteal phase is artificially lengthened, either by sustaining luteal function or by treatment with progesterone, decidual changes in the endometrial stroma similar to those seen in early pregnancy can be induced. Under normal circumstances, estrogen antecedes and accompanies progesterone in its action on the endometrium and is essential to the development of the normal menstrual pattern. Progesterone also influences the endocervical glands, and the abundant watery secretion of the estrogen-stimulated structures is changed to a scant viscid material. These and other effects of progestins decrease penetration of the cervix by sperm. The estrogen-induced maturation of the human vaginal epithelium is modified toward the condition of pregnancy by the action of progesterone. Progesterone is very important for the maintenance of pregnancy. Progesterone suppresses menstruation and uterine contractility.

Mammary Gland. Development of the mammary gland requires both estrogen and progesterone. During pregnancy and to a minor degree during the luteal phase of the cycle, progesterone, acting with estrogen, brings about a proliferation of the acini of the mammary gland. Toward the end of pregnancy, the acini fill with secretions and the vasculature of the gland notably increases; however, only after the levels of estrogen and progesterone decrease at parturition does lactation begin. During the luteal phase of the menstrual cycle, progesterone triggers a single round of mitotic activity in the mammary epithelium. This effect is transient; continued exposure to the hormone is rapidly followed by arrest of growth of the epithelial cells.

CNS. During a normal menstrual cycle, an increase in basal body temperature of ~0.6°C (1°F) may be noted at mid-cycle; this correlates with ovulation. This increase is due to progesterone, but the exact mechanism of this effect is unknown. Progesterone also 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. Progesterone also may have depressant and hypnotic actions in the CNS, possibly accounting for reports of drowsiness after hormone administration. This potential untoward effect may be abrogated by giving progesterone preparations at bedtime, which may help some patients sleep.

Metabolic Effects. Progesterone itself increases basal insulin levels and the rise in insulin after carbohydrate ingestion but does not normally alter glucose tolerance. However, long-term administration of more potent progestins, such as norgestrel, may decrease glucose tolerance. Progesterone stimulates lipoprotein lipase activity and seems to enhance fat deposition. Progesterone and analogs such as MPA have been reported to increase LDL and cause either no effects or modest reductions in serum HDL levels. MPA decreases the favorable HDL increase caused by conjugated estrogens during postmenopausal hormone replacement, but not the beneficial effect of estrogens to lower LDL. In contrast, micronized progesterone does not significantly alter beneficial estrogen effects on either HDL or LDL profiles; the spironolactone derivative drospirenone may actually have advantageous effects on the cardiovascular system due to its anti-androgenic and anti-mineralocorticoid activities. Progesterone also may diminish the effects of aldosterone in the renal tubule and cause a decrease in sodium reabsorption that may increase mineralocorticoid secretion from the adrenal cortex.

CELLULAR MECHANISM OF ACTION. A single gene encodes 2 isoforms of the progesterone receptor, PR-A and PR-B. The first 164 N-terminal amino acids of PR-B are missing from PR-A. Because the ligand-binding domains of the 2 PR isoforms are identical, their ligand-binding properties are also the same. However, the structural differences outside the ligand-binding region contribute to different interactions with coactivators and corepressors and thus differential activities of PR-A and PR-B. The biological activities of PR-A and PR-B are distinct and depend on the target gene. In most cells, PR-B mediates the stimulatory activities of progesterone; PR-A strongly inhibits this action of PR-B and is also a transcriptional inhibitor of other steroid receptors. Several uterine genes appear to be regulated exclusively by PR-A, including calcitonin and amphiregulin, and the antiproliferative effect of progesterone on the estrogen-stimulated endometrium. In contrast, PR-B may be responsible for mediating progesterone’s effects in the mammary gland.

In the absence of ligand, PR is present primarily in the nucleus in an inactive monomeric state bound to heat-shock proteins. When receptors bind progesterone, the heat-shock proteins dissociate and the receptors are phosphorylated and form dimers (homo- and hetero-) that bind to PREs (progesterone response elements) located on target genes. Transcriptional activation by PR occurs primarily via recruitment of coactivators. The receptor/coactivator complex then favors further interactions that mediate processes such as histone acetylase activity. Histone acetylation causes a remodeling of chromatin that increases the accessibility of general transcriptional proteins, including PolII, to the target promoter. Progesterone antagonists also facilitate receptor dimerization and DNA binding, but, as with ER, the conformation of antagonist-bound PR is different from that of agonist-bound PR. This different conformation favors PR interaction with corepressors that recruit histone deacetylases, reducing accessibility of a target promoter to the transcriptional apparatus. In general mechanistic terms, the PR functions similarly to the ER (see Figure 40–4).

Certain effects of progesterone, such as increased Ca2+ mobilization in sperm, can be seen in as little as 3 min and are therefore considered transcription-independent. Similarly, progesterone can promote oocyte maturation (meiotic resumption) independently of transcription.

ADME. The t1/2 of progesterone is ~5 min, and the hormone is metabolized primarily in the liver to hydroxylated metabolites and their sulfate and glucuronide conjugates, which are eliminated in the urine. A major metabolite specific for progesterone is pregnane-3α, 20 α-diol; its measurement in urine and plasma is used as an index of endogenous progesterone secretion. The synthetic progestins have much longer half-lives (e.g., ~7 h for norethindrone, 16 h for norgestrel, 12 h for gestodene, and 24 h for MPA). The metabolism of synthetic progestins is primarily hepatic, and elimination is generally via the urine as conjugates and various polar metabolites.

Even though progesterone undergoes rapid first-pass metabolism, high-dose (e.g., 100-200 mg) preparations of micronized progesterone (PROMETRIUM) are available for oral use. The absolute bioavailability of these preparations is low but efficacious plasma levels can be obtained. Progesterone also is available in oil solution for injection, as a vaginal gel (CRINONE, PROCHIEVE), as a slow-release intrauterine device (PROGESTASERT) for contraception, and as a vaginal insert (ENDOMETRIN) for assisted reproductive technology. Esters such as MPA (DEPO-PROVERA) are available for intramuscular administration, and MPA (PROVERA, others) and megestrol acetate (MEGACE, others) may be used orally. The 19-nor steroids have good oral activity because the ethinyl substituent at C17 significantly slows hepatic metabolism. Implants and depot preparations of synthetic progestins are available in many countries for release over very long periods of time.

THERAPEUTIC USES. Progestins are mainly used for contraception, either alone or with an estrogen, and in combination with estrogen for hormone therapy of postmenopausal women. Progestins also are used diagnostically for secondary amenorrhea. Combinations of estrogens and progestins can also be given to test for endometrial responsiveness in patients with amenorrhea. Progestins are highly efficacious in decreasing the occurrence of endometrial hyperplasia and carcinoma caused by unopposed estrogens. Local intrauterine application via a hormone-releasing intrauterine device (IUD) containing levonorgestrel can be used to decrease estrogen-induced endometrial hyperplasia while reducing untoward effects of systemically administered progestins. Finally, levonorgestrel is used as so-called emergency contraception after known or suspected unprotected intercourse. The medication is given orally within 72 h after intercourse as either a single 1.5-mg dose (PLAN B ONE-STEP) or as 2 0.75-mg doses (PLAN B) separated by 12 h. The mechanism of action may involve several factors, including the prevention of ovulation, fertilization, and implantation.

ANTIPROGESTINS AND PROGESTERONE-RECEPTOR MODULATORS

The antiprogestin, RU 38486 (often referred to as RU-486) or mifepristone is available for the termination of pregnancy. Ulipristal acetate [ELLA (U.S.), ELLA ONE (E.U.)], a partial agonist at the progesterone receptor, is used for emergency contraception.

MIFEPRISTONE

Mifepristone is a derivative of the 19-norprogestin norethindrone containing a dimethyl-aminophenol substituent at the 11 β-position. It effectively competes with both progesterone and glucocorticoids for binding to their respective receptors. Mifepristone is considered a progesterone-receptor modulator (PRM) due to its context-dependent activity. Onapristone(or ZK 98299) is a pure progesterone antagonist, similar in structure to mifepristone but with a methyl substituent in the 13α rather than 13β orientation.

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PHARMACOLOGICAL ACTIONS. Mifepristone acts primarily as a competitive receptor antagonist for both progesterone receptors, although it may have some agonist activity in certain contexts. When administered in the early stages of pregnancy, mifepristone causes decidual breakdown by blockade of uterine progesterone receptors. This leads to detachment of the blastocyst, which decreases hCG production. This in turn causes a decrease in progesterone secretion from the corpus luteum, which further accentuates decidual breakdown. Decreased endogenous progesterone coupled with blockade of progesterone receptors in the uterus increases uterine prostaglandin levels and sensitizes the myometrium to their contractile actions. Mifepristone also causes cervical softening, which facilitates expulsion of the detached blastocyst. Mifepristone can delay or prevent ovulation depending on the timing and manner of administration. If administered for 1 or several days in the mid- to late luteal phase, mifepristone impairs the development of a secretory endometrium and produces menses. Mifepristone also binds glucocorticoid and androgen receptors and exerts anti-glucocorticoid and anti-androgenic actions. Thus, mifepristone blocks the feedback inhibition by cortisol of ACTH secretion from the pituitary, thereby increasing plasma levels of corticotropin and adrenal steroids.

ADME. Mifepristone is orally active with good bioavailability. Peak plasma levels occur within several hours. In plasma, it is bound by α1 acid glycoprotein, which contributes to the drug’s long t1/2 (20-40 h). Metabolites are primarily the mono- and di-demethylated products (thought to have pharmacological activity) formed via CYP3A4. The drug undergoes hepatic metabolism and enterohepatic circulation; metabolic products are found predominantly in the feces.

THERAPEUTIC USES. Mifepristone (MIFEPREX), in combination with misoprostol or other prostaglandins, is available for the termination of early pregnancy. When mifepristone is used to produce a medical abortion, a prostaglandin is given 48 h after the antiprogestin to further increase myometrial contractions and ensure expulsion of the detached blastocyst. Intramuscular sulprostone, intravaginalgemeprost, and oral misoprostol have been used. The most severe untoward effect is vaginal bleeding, which most often lasts 8-17 days but is only rarely (0.1% of patients) severe enough to require blood transfusions. High percentages of women also have experienced abdominal pain and uterine cramps, nausea, vomiting, and diarrhea due to the prostaglandin. Women receiving chronic glucocorticoid therapy should not be given mifepristone because of its antiglucocorticoid activity. In fact, due to its high affinity for the glucocorticoid receptor, high doses of mifepristone can result in adrenal insufficiency.

ULIPRISTAL

Ulipristal, a derivative of 19-norprogesterone, functions as a selective progesterone receptor modulator (SPRM), acting as a partial agonist at progesterone receptors. Unlike mifepristone, ulipristal appears to be a relatively weak glucocorticoid antagonist.

PHARMACOLOGICAL ACTIONS. In high doses, ulipristal has antiproliferative effects in the uterus; however, its most relevant actions to date involve its capacity to inhibit ovulation. Ulipristal’s anti-ovulatory actions likely occur due to progesterone regulation at many levels, including inhibition of LH release through the hypothalamus and pituitary, and inhibition of LH-induced follicular rupture within the ovary. A 30-mg dose of ulipristal can inhibit ovulation when taken up to 5 days after intercourse. Ulipristal can block ovarian rupture at or even just after the time of the LH surge. Ulipristal may also block endometrial implantation of the fertilized egg, although whether this contributes to its effects as an emergency contraceptive is not clear.

THERAPEUTIC USES. Ulipristal acetate [ELLA, ELLA ONE] has recently been licensed in the E.U. and the U.S. as an emergency contraceptive. Studies comparing ulipristal to levonorgestrel (progesterone-only emergency contraception, or POEC) demonstrate that ulipristal is at least as effective when taken up to 72 h after unprotected sexual intercourse. In addition, ulipristal remains effective up to 120 h (5 days) after intercourse, making ulipristal a more versatile emergency contraceptive than levonorgestrel, which does not work well beyond 72 h after unprotected intercourse. The most severe side effect in clinical trials has been a headache and abdominal pain.

HORMONAL CONTRACEPTIVES

The incredible growth of the earth’s human population stands out as one of the fundamental events of the last 2 centuries. The Old Testament dictum “Be fruitful and multiply” (Genesis 9:1) has been followed too religiously by readers and nonreaders of the Bible alike. In 1798, Malthus started a great controversy by opposing the prevailing view of unlimited progress for humankind by making 2 postulates and a conclusion. Malthus postulated “that food is necessary for the existence of man” and that sexual attraction between female and male is necessary and likely to persist, since “toward the extinction of the passion between the sexes, no progress whatever has hitherto been made,” barring “individual exceptions.” Malthus concluded that “the power of populations is infinitely greater than the power of the earth to produce subsistence for man,” producing a “natural inequality” that would someday loom “insurmountable in the way to perfectibility of society.”

Malthus was right: passion between the sexes persists and the power of populations is very great indeed, so much so that our sheer numbers have increased to the point that they are straining the earth’s capacity to supply food, energy, and raw materials, and to absorb the detritus of its human burden. Marine fisheries are being depleted, forests and aquifers are disappearing, and the atmosphere is accumulating greenhouse gases from combustion of the fossil fuels that provide the energy needs of 7 billion people, up from 1 billion in Malthus’ day. Perhaps some of the blame can be laid at the feet of medical science: advances in public health and medicine have led to a significant decline in mortality and an increased life expectancy. However, medical science has also begun to assume a portion of the responsibility for overpopulation and its adverse effects. To this end, drugs in the form of hormones and their analogs have been developed to control human fertility.

COMBINATION ORAL CONTRACEPTIVES. The most frequently used agents in the U.S. are combination oral contraceptives containing both an estrogen and a progestin. Their theoretical efficacy is 99.9%. Combination oral contraceptives are available in many formulations. Monophasic, biphasic, or triphasic pills are generally provided in 21-day packs. (Virtually all preparations come as 28-day packs, with the pills for the last 7 days containing only inert ingredients.) For the monophasic agents, fixed amounts of the estrogen and progestin are present in each pill, which is taken daily for 21 days, followed by a 7-day “pill-free” period. The biphasic and triphasic preparations provide 2 or 3 different pills containing varying amounts of active ingredients, to be taken at different times during the 21-day cycle. This reduces the total amount of steroids administered and more closely approximates the estrogen-to-progestin ratios that occur during the menstrual cycle. With these preparations, predictable menstrual bleeding generally occurs during the 7-day “off” period each month. However, several oral contraceptions are now available whereby progestin withdrawal is only induced every 3 months.

The estrogen content of current preparations ranges from 20-50 µg; most contain 30-35 µg. Preparations containing ≥35 µg of an estrogen are generally referred to as “low-dose” or “modern” pills. The dose of progestin is more variable because of differences in potency of the compounds used. A transdermal preparation of norelgestromin and ethinyl estradiol (ORTHO EVRA) is marketed for weekly application to the buttock, abdomen, upper arm, or torso for the first 3 consecutive weeks followed by a patch-free week for each 28-day cycle. A similar 3-week on/1-week off cycle is employed for the intravaginal ring containing ethinyl estradiol and etonogestrel (NUVARING).

PROGESTIN-ONLY CONTRACEPTIVES. Several agents are available with theoretical efficacies of 99%. Specific preparations include the “minipill”; low doses of progestins (e.g., 350 µg of norethindrone [NOR-QD, ORTHO MICRONOR, others]) taken daily without interruption; subdermal implants of 216 mg of norgestrel (NORPLANT II, JADELLE) for long-term contraceptive action (e.g., up to 5 years) or 68 mg of etonogestrel (IMPLANON) for contraception lasting 3 years; and crystalline suspensions of medroxyprogesterone acetate for intramuscular injection of 104 mg (DEPO-SUBQ PROVERA 104) or 150 mg (DEPO-PROVERA, others) of drug; each provides effective contraception for 3 months. An IUD (PROGESTASERT) that releases low amounts of progesterone locally is available for insertion on a yearly basis. Its effectiveness is considered to be 97-98%, and contraceptive action probably is due to local effects on the endometrium. An IUD (MIRENA) releases levonorgestrel for up to 5 years.

MECHANISM OF ACTION

COMBINATION ORAL CONTRACEPTIVES. Combination oral contraceptives act by preventing ovulation. Direct measurements of plasma hormone levels indicate that LH and FSH levels are suppressed, a mid-cycle surge of LH is absent, endogenous steroid levels are diminished, and ovulation does not occur. Hypothalamic actions of steroids play a major role in the mechanism of oral contraceptive action. Progesterone diminishes the frequency of GnRH pulses. Because the proper frequency of LH pulses is essential for ovulation, this effect of progesterone likely plays a major role in the contraceptive action of these agents.

Multiple pituitary effects of both estrogen and progestin components are likely to contribute to oral contraceptive action. Oral contraceptives seem likely to decrease pituitary responsiveness to GnRH. Estrogens also suppress FSH release from the pituitary during the follicular phase of the menstrual cycle, and this effect seems likely to contribute to the lack of follicular development in oral contraceptive users. The progestin component may also inhibit the estrogen-induced LH surge at mid-cycle. Other effects may contribute to a minor extent to the extraordinary efficacy of oral contraceptives. Transit of sperm, the egg, and fertilized ovum are important to establish pregnancy, and steroids are likely to affect transport in the fallopian tube. In the cervix, progestin effects also are likely to produce a thick viscous mucus to reduce sperm penetration and in the endometrium to produce a state that is not receptive to implantation.

PROGESTIN-ONLY CONTRACEPTIVES. Progestin-only pills and levonorgestrel implants are highly efficacious but block ovulation in only 60-80% of cycles. Their effectiveness is thought to be due largely to a thickening of cervical mucus, which decreases sperm penetration, and to endometrial alterations that impair implantation; such local effects account for the efficacy of IUDs that release progestins. Depot injections of MPA are thought to exert similar effects, but they also yield plasma levels of drug high enough to prevent ovulation, presumably by decreasing the frequency of GnRH pulses.

UNTOWARD EFFECTS

COMBINATION ORAL CONTRACEPTIVES. Untoward effects of early hormonal contraceptives fell into several major categories: adverse cardiovascular effects; breast, hepatocellular, and cervical cancers; and a number of endocrine and metabolic effects. The current consensus is that low-dose preparations pose minimal health risks in women who have no predisposing risk factors.

Cardiovascular Effects. For nonsmokers without other risk factors such as hypertension or diabetes, there is no significant increase in the risk of myocardial infarction or stroke. There is a 28% increase in relative risk for venous thromboembolism, but the estimated absolute increase is very small because the incidence of these events in women without other predisposing factors is low (e.g., roughly half that associated with the risk of venous thromboembolism in pregnancy). The risk is significantly increased in women who smoke or have other factors that predispose to thrombosis or thromboembolism. Postmarketing studies indicate that women using transdermal contraceptives have a higher than expected exposure to estrogen and are at increased risk for the development of venous thromboembolism.

Early high-dose combination oral contraceptives caused hypertension in 4-5% of normotensive women and increased blood pressure in 10-15% of those with preexisting hypertension. This incidence is much lower with newer low-dose preparations, and most reported changes in blood pressure are not significant. The cardiovascular risk associated with oral contraceptive use does not appear to persist after use is discontinued. Estrogens increase serum HDL and decrease LDL levels; progestins tend to have the opposite effect. Recent studies of several low-dose preparations have not found significant changes in total serum cholesterol or lipoprotein profiles, although slight increases in triglycerides have been reported.

Cancer. Given the growth-promoting effects of estrogens, there has been a long-standing concern that oral contraceptives might increase the incidence of endometrial, cervical, ovarian, breast, and other cancers. There is not a widespread association between oral contraceptive use and cancer. Epidemiological evidence suggests that combined oral contraceptive use may increase the risk of cervical cancer by about 2-fold but only in long-term users (>5 years) with persistent human papilloma virus infection. There have been reports of increases in the incidence of hepatic adenoma and hepatocellular carcinoma. Current estimates indicate there is about a doubling in the risk of liver cancer after 4-8 years of use; these are rare cancers, and the absolute increases are small.

The effects of oral contraceptives on breast cancer are a concern. The risk of breast cancer in women of childbearing age is very low, and current oral contraceptive users in this group have only a very small increase in relative risk of 1.1-1.2, depending on other variables. This small increase is not substantially affected by duration of use, dose, or type of component, age at first use, or parity. Importantly, 10 years after discontinuation of oral contraceptive use, there is no difference in breast cancer incidence between past users and never users. Combination oral contraceptives decrease the incidence of endometrial cancer by 50%, an effect that lasts 15 years after the pills are stopped. This is thought to be due to the inclusion of a progestin throughout the entire 21-day cycle of administration. These agents also decrease the incidence of ovarian cancer. There are accumulating data that oral contraceptive use decreases the risk of colorectal cancer.

Metabolic and Endocrine Effects. The effects of sex steroids on glucose metabolism and insulin sensitivity are complex and may differ among agents in the same class. Early studies with high-dose oral contraceptives generally reported impaired glucose tolerance; these effects have decreased as steroid dosages have been lowered; current low-dose combination contraceptives may even improve insulin sensitivity. Similarly, the high-dose progestins in early oral contraceptives raised LDL and reduced HDL levels, but modern low-dose preparations do not produce unfavorable lipid profiles. There also have been periodic reports that oral contraceptives increase the incidence of gallbladder disease, but any such effect appears to be weak and associated with very long-term use.

The estrogenic component of oral contraceptives may increase hepatic synthesis of a number of serum proteins, including those that bind thyroid hormones, glucocorticoids, and sex steroids. Although physiological feedback mechanisms generally adjust hormone synthesis to maintain normal “free” hormone levels, these changes can affect the interpretation of endocrine function tests that measure totalplasma hormone levels, and may necessitate dose adjustment in patients receiving thyroid-hormone replacement. The ethinyl estradiol present in oral contraceptives appears to cause a dose-dependent increase in several serum factors known to increase coagulation. However, in healthy women who do not smoke, there also is an increase in fibrinolytic activity that exerts a counter effect so that overall there is a minimal effect on hemostatic balance. This compensatory effect is diminished in smokers.

Miscellaneous Effects. Nausea, edema, and mild headache occur in some individuals; migraine headaches may be precipitated in a smaller fraction of women. Breakthrough bleeding may occur during the 21-day cycle when the active pills are being taken. Withdrawal bleeding may fail to occur in a small fraction of women during the 7-day “off” period, thus causing confusion about a possible pregnancy. Acne and hirsutism may be due to the androgenic activity of the 19-nor progestins.

PROGESTIN-ONLY CONTRACEPTIVES. Episodes of irregular, unpredictable spotting and breakthrough bleeding are the most frequently encountered untoward effect and the major reason women discontinue use of progestin-only contraceptives. With time, the incidence of these bleeding episodes decreases. No evidence indicates that the progestin-only minipill preparations increase thromboembolic events. Acne may be a problem because of the androgenic activity of norethindrone-containing preparations. These preparations may be attractive for nursing mothers because they do not decrease lactation.

Headache is a commonly reported untoward effect of depot MPA. Mood changes and weight gain also have been reported. Many studies have found decreases in HDL levels and increases in LDL levels, and there have been reports of decreased bone density. These effects may be due to reduced endogenous estrogens because depot MPA lowers gonadotropin levels. Because of the time required to completely eliminate the drug, the contraceptive effect of this agent may remain for 6-12 months after the last injection. Implants of norethindrone may be associated with infection, local irritation, pain at the insertion site, and, rarely, expulsion of the inserts. Headache, weight gain, and mood changes have been reported. Acne is seen in some patients. Ovulation occurs fairly soon after implant removal, reaching 50% in 3 months and almost 90% within 1 year.

CONTRAINDICATIONS. Modern oral contraceptives are considered generally safe in most healthy women; however, these agents can contribute to the incidence and severity of cardiovascular, thromboembolic, or malignant disease, particularly if other risk factors are present. Contraindications for combination oral contraceptive use include: the presence or history of thromboembolic disease, cerebrovascular disease, myocardial infarction, coronary artery disease, or congenital hyperlipidemia; known or suspected carcinoma of the breast, carcinoma of the female reproductive tract; abnormal undiagnosed vaginal bleeding; known or suspected pregnancy; and past or present liver tumors or impaired liver function. The risk of serious cardiovascular side effects is particularly marked in women >35 years of age who smoke heavily (e.g., >15 cigarettes per day); even low-dose oral contraceptives are contraindicated in such patients.

Other relative contraindications include migraine headaches, hypertension, diabetes mellitus, obstructive jaundice of pregnancy or prior oral contraceptive use, and gallbladder disease. If elective surgery is planned, discontinuation of oral contraceptives for several weeks to a month is recommended to minimize the possibility of thromboembolism after surgery. These agents should be used with care in women with prior gestational diabetes or uterine fibroids, and low-dose forms should generally be used in such cases. Progestin-only contraceptives are contraindicated in the presence of undiagnosed vaginal bleeding, benign or malignant liver disease, and known or suspected breast cancer. Depot MPA and levonorgestrel inserts are contraindicated in women with a history or predisposition to thrombophlebitis or thromboembolic disorders.

CHOICE OF CONTRACEPTIVE PREPARATIONS

Treatment should generally begin with preparations containing the minimum dose of steroids that provides effective contraceptive coverage. This is typically a pill with 30-35 µg of estrogen, but preparations with 20 µg may be adequate for lighter women or >40 years of age with perimenopausal symptoms; a preparation containing 50 µg of estrogen may be required for heavier women. In women for whom estrogens are contraindicated or undesirable, progestin-only contraceptives may be an option. The progestin-only minipill may have enhanced effectiveness in several such types of women (e.g., nursing mothers and women >40 years of age, in whom fertility may be decreased). The choice of a preparation also may be influenced by the specific 19-nor progestin component because this component may have varying degrees of androgenic and other activities. The androgenic activity of this component may contribute to untoward effects such as weight gain, acne due to increased sebaceous gland secretions, and unfavorable lipoprotein profiles. These side effects are greatly reduced in newer low-dose contraceptives that contain progestins with little to no androgenic activity.

NONCONTRACEPTIVE HEALTH BENEFITS

Combination oral contraceptives have substantial health benefits unrelated to their contraceptive use. Oral contraceptives significantly reduce the incidence of ovarian and endometrial cancer within 6 months of use. Depot MPA injections reduce substantially the incidence of uterine cancer. These agents also decrease the incidence of ovarian cysts and benign fibrocystic breast disease. Oral contraceptives have major benefits related to menstruation in many women, including more regular menstruation, reduced menstrual blood loss, less iron-deficiency anemia, and decreased frequency of dysmenorrhea. There also is a decreased incidence of pelvic inflammatory disease and ectopic pregnancies, and endometriosis may be ameliorated.