Chapter 40: Estrogens and Progestins

History. The hormonal nature of the ovarian control of the female reproductive system was firmly established in 1900 by Knauer when he found that ovarian transplants prevented the symptoms of gonadectomy, and by Halban, who showed that normal sexual development and function occurred when glands were transplanted. In 1923, Allen and Doisy devised a bioassay for ovarian extracts based on the vaginal smear of the rat. Frank and associates in 1925 detected an active sex principle in the blood of sows in estrus, and Loewe and Lange discovered in 1926 that a female sex hormone varied in the urine of women throughout the menstrual cycle. The excretion of estrogen in the urine during pregnancy also was reported by Zondek in 1928 and enabled Butenandt and Doisy in 1929 to crystallize an active substance.

Early investigations indicated that the ovary secretes two substances. Beard had postulated in 1897 that the corpus luteum serves a necessary function during pregnancy, and Fraenkel showed in 1903 that destruction of the corpora lutea in pregnant rabbits caused abortion. Several groups then isolated progesterone from mammalian corpora lutea in the 1930s.

In the early 1960s, pioneering studies by Jensen and colleagues suggested the presence of intracellular receptors for estrogens in target tissues. This was the first demonstration of receptors of the steroid/thyroid superfamily and provided techniques to identify receptors for the other steroid hormones. A second estrogen receptor was identified in 1996 and termed estrogen receptor β (ERβ) to distinguish it from the receptor identified by Jensen and others, termed estrogen receptor α (ERα). Two protein isoforms, A and B, of the progesterone receptor arise from a single gene by transcription initiation from different promoters. For the primary literature references about the history of this subject, consult the ninth and tenth editions of this text.

Chemistry. Many steroidal and nonsteroidal compounds, some of which are shown in Table 40–1 and Figure 40–1, possess estrogenic activity. The most potent naturally occurring estrogen in humans, for both ERα- and ERβ-mediated actions, is 17β-estradiol, followed by estrone and estriol. Each contains a phenolic A ring with a hydroxyl group at carbon 3, and a β-OH or ketone in position 17 of ring D.

The phenolic A ring is the principal structural feature responsible for selective high-affinity binding to both receptors. Most alkyl substitutions on the A ring impair binding, but substitutions on ring C or D may be tolerated. Ethinyl substitutions at the C17 position greatly increase oral potency by inhibiting first-pass hepatic metabolism. Models for the ligand-binding sites of both estrogen receptors have been determined from structure–activity relationships (Harrington et al., 2003) and structural analysis (Pike et al., 2000).

Diethylstilbestrol (DES), which is structurally similar to estradiol when viewed in the trans conformation, binds with high affinity to both estrogen receptors and it is as potent as estradiol in most assays but has a much longer t_1/2. DES no longer has widespread use, but it was important historically as an inexpensive orally active estrogen.

Selective ligands for ERα and ERβ are available for experimental studies but are not yet used therapeutically (Harrington et al., 2003).

Nonsteroidal compounds with estrogenic or anti-estrogenic activity—including flavones, isoflavones (e.g., genistein), and coumestan derivatives—occur in plants and fungi. Synthetic agents—including pesticides (e.g., p,p′-DDT), plasticizers (e.g., bisphenol A), and a variety of other industrial chemicals (e.g., polychlorinated biphenyls)—also have hormonal or antihormonal activity. Although their affinity is relatively weak, their large number, bioaccumulation, and persistence in the environment have raised concerns about their potential toxicity in humans and wildlife. Over-the-counter and prescription preparations containing naturally occurring estrogenlike compounds from plants (i.e., phytoestrogens) now are available (Fitzpatrick, 2003).

Biosynthesis. Steroidal estrogens arise from androstenedione or testosterone (Figure 40–1) by aromatization of the A ring. The reaction is catalyzed by aromatase (CYP19) that uses nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen as co-substrates. A ubiquitous flavoprotein, NADPH–cytochrome P450 reductase, also is essential. Both proteins are localized in the endoplasmic reticulum of ovarian granulosa cells, testicular Sertoli and Leydig cells, adipose stroma, placental syncytiotrophoblasts, preimplantation blastocysts, bone, various brain regions, and many other tissues (Simpson et al., 2002).

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 G_s-adenylyl cyclase–cyclic AMP pathway, increase the activities of aromatase and the cholesterol side-chain cleavage enzyme and facilitate the transport of cholesterol (the precursor of all steroids) into the mitochondria of cells that synthesize steroids. The ovary contains a form of 17β-hydroxysteroid dehydrogenase (type I) that favors the production of testosterone and estradiol from androstenedione and estrone, respectively. However, in the liver, another form of this enzyme (type II) favors oxidation of circulating estradiol to estrone (Peltoketo et al., 1999), and both of these steroids are then converted to estriol (Figure 40–1). All three 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. Thus, the level of estrogens is regulated in part by the availability of androgenic precursors (Simpson, 2003).

Estrogenic effects most often have been attributed to circulating hormones, but locally produced estrogens also may have important actions (Simpson et al., 2002). For example, estrogens may be produced from androgens by the actions of aromatase or from estrogen conjugates by hydrolysis. Such local production of estrogens could play a causal or promotional role in the development of certain diseases such as breast cancer because mammary tumors contain both aromatase and hydrolytic enzymes. 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).

The placenta uses fetal dehydroepiandrosterone and its 16α-hydroxyl derivative to produce large amounts of estrone and estriol. Human urine during pregnancy is thus an abundant source of natural estrogens, and pregnant mare's urine is the source of conjugated equine estrogens, which have been widely used therapeutically for many years.

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. The overall pattern of GnRH release likely is regulated by the interplay of intrinsic mechanism(s) and extrinsic synaptic inputs from opioid, catecholamine, and GABAergic neurons (Figure 40–2). Ovarian steroids, primarily progesterone, regulate the frequency of GnRH release, but the cellular and molecular mechanisms of this regulation are not well established. Some GnRH cells have immunoreactive steroid receptors. Some nerve cells that synapse with GnRH neurons also contain steroid receptors, and neighboring glial cells may contain estrogen and progesterone receptors. Steroids may thus directly and indirectly modulate GnRH neuronal function.

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 (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.

In the early follicular phase of the cycle, (1) the pulse generator produces bursts of neuronal activity with a frequency of about one per hour 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 (i.e., the amplitude of the LH pulse decreases), so gonadotropin levels gradually fall, as seen in Figure 40–3. Inhibin, produced by the ovary, also exerts a negative feedback to selectively decrease serum FSH at this time (Chapter 38). Activin and follistatin, two other peptides released from the ovary, may also regulate FSH production and secretion to a lesser extent, although their levels do not vary appreciably during the menstrual cycle.

At mid-cycle, serum estradiol rises above a threshold level of 150-200 pg/mL for ∼36 hours. This sustained elevation of estrogen no longer inhibits gonadotropin release but exerts 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. In some species, estrogens may also exert a positive effect on hypothalamic neurons that contributes to a mid-cycle "surge" of GnRH release; this is not yet established in humans. 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 characteristic of the follicular phase, the entire system then resets, and a new ovarian cycle occurs.

Regulation of the frequency and amplitude of gonadotropin secretions by steroids may be summarized as follows: Estrogens act primarily on the pituitary to control the amplitude of gonadotropin pulses, and they may also contribute to the amplitude of GnRH pulses secreted by the hypothalamus.

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. Studies in knockout mice indicate that ERα (Hewitt and Korach, 2003) and the progesterone receptor PR-A (Conneely et al., 2002) mediate the major actions of estrogens and progestins, respectively, on the hypothalamic-pituitary axis.

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. Thus, exogenous estrogen administration decreases LH and testosterone levels in men, and anti-estrogens such as clomiphene cause an elevation of serum LH, which can be used to evaluate the male reproductive axis.

When the ovaries are removed or cease to function, there is overproduction of FSH and LH, which are excreted in the urine. Measurement of urinary or plasma LH is valuable to assess pituitary function and the effectiveness of therapeutic doses of estrogen. Although FSH levels will also decline upon estrogen administration, they do not return to normal, secondary to production of inhibin by the ovary (Chapter 38). Consequently, the measurement of FSH levels as a means to monitor the effectiveness of hormone therapy is not clinically useful. Additional features of the regulation of gonadotropin secretion and actions are discussed in Chapters 38 and 66.

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.

The uterus is composed of an endometrium and a myometrium. The endometrium contains an epithelium lining the uterine cavity and an underlying stroma; the myometrium is the smooth muscle component responsible for uterine contractions. These cell layers, the fallopian tubes, cervix, and vagina display a characteristic set of responses to both estrogens and progestins. The changes typically associated with menstruation occur largely in the endometrium (Figure 40–3).

The luminal surface of the endometrium is a layer of simple columnar epithelial secretory and ciliated cells that is continuous with the openings of numerous glands that extend through the underlying stroma to the myometrial border. Fertilization normally occurs in the fallopian tubes, so ovulation, transport of the fertilized ovum through the fallopian tube, and preparation of the endometrial surface must be temporally coordinated for successful implantation.

The endometrial stroma is a highly cellular connective-tissue layer containing a variety of blood vessels that undergo cyclic changes associated with menstruation. The predominant cells are fibroblasts, but macrophages, lymphocytes, and other resident and migratory cell types also are present.

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. Numerous mitoses become visible, the thickness of the layer increases, and characteristic changes occur in the glands and blood vessels. In rodent models, ERα mediates the uterotrophic effects of estrogens (Hewitt and Korach, 2003). The overall endometrial response involves estrogen- and progesterone-mediated expression of peptide growth factors and receptors, cell cycle genes, and other regulatory signals. 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 (Conneely et al., 2002). 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. Because endometrial status is regulated by estrogens and progestins, the efficacy of some contraceptives may be due in part to production of an endometrial surface that is not receptive to implantation. If pregnancy does not occur, the corpus luteum regresses due to lack of continued LH secretion, estrogen and progesterone levels fall, and the endometrium is shed (Figure 40–3).

If implantation occurs, human chorionic gonadotropin (hCG) (Chapter 38), 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. In later stages the placenta itself becomes the major site of estrogen and progesterone synthesis.

Estrogens and progesterone have important effects on the fallopian tube, myometrium, and cervix. In the fallopian tube, estrogens stimulate proliferation and differentiation, whereas progesterone inhibits these processes. Also, estrogens increase and progesterone decreases tubal muscular contractility, which affects transit time of the ovum to the uterus. Estrogens increase the amount of cervical mucus and its water content to facilitate sperm penetration of the cervix, whereas progesterone generally has opposite effects. Estrogens favor rhythmic contractions of the uterine myometrium, and progesterone diminishes contractions. These effects are physiologically important and may also play a role in the action of some contraceptives.

At relatively high concentrations, estrogens have antioxidant activity and may inhibit the oxidation of LDL by affecting superoxide dismutase. Long-term administration of estrogen is associated with decreased plasma renin, angiotensin-converting enzyme, and endothelin-1; expression of the AT₁ receptor for angiotensin II is also decreased. Estrogen actions on the vascular wall include increased production of nitric oxide (NO), which occurs within minutes via a mechanism involving activation of Akt (protein kinase B) (Simoncini et al., 2000), induction of NO synthase, and increased production of prostacyclin. All of these changes promote vasodilation and retard atherogenesis. Estrogens also promote endothelial cell growth while inhibiting the proliferation of vascular smooth muscle cells.

The presence of estrogen receptors in the liver suggests that the beneficial effects of estrogen on lipoprotein metabolism are due partly to direct hepatic actions, but other sites of action cannot be excluded. 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. The decline in bile acid biosynthesis may contribute to the decreased incidence of colon cancer in women receiving combined estrogen-progestin treatment. 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. ERα deficiency or aromatase enzyme deficiency in mice is associated with impaired glucose tolerance and other elements of the metabolic syndrome due to increased insulin resistance (Simpson, 2003).

Estrogens alter a number of metabolic pathways that affect the clotting cascade (Mendelsohn and Karas, 1999). 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 (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 (Koh et al., 1997). Thus, estrogens increase both coagulation and fibrinolytic pathways, and imbalance in these two opposing activities may cause adverse effects.

ERα, the first discovered, 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. Many cells express both ERα and ERβ, which can form either homo- or heterodimers. Both forms of ER are expressed on breast cancers, although ERα is believed to be the predominant form responsible for growth regulation (Chapter 63). When co-expressed with ERα, ERβ can inhibit ERα-mediated transcriptional activation in many cases (Hall and McDonnell, 1999). Polymorphic variants of ER have been identified, but attempts to correlate specific polymorphisms with the frequency of breast cancer (Han et al., 2003), bone mass (Kurabayashi et al., 2004), endometrial cancer (Weiderpass et al., 2000), or cardiovascular disease (Herrington and Howard, 2003) 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. However, four GPR30 knockout (KO) mice strains show inconsistent data with few stress or developmental phenotypes, and there is no consistent overlap of these models with ERα and ERβ KO phenotypes. There may be interaction/cross-talk between membrane-associated ERα and membrane-localized GPR30 in some cancer cells, but in vivo confirmation is lacking (Levin, 2008; Olde et al. 2009).

Besides co-activators and co-repressors, both ERα and ERβ can interact physically with other transcription factors such as Sp1 (Saville et al., 2000) or AP-1 (Paech et al., 1997), and these protein-protein interactions provide an alternate mechanism of action. In these circumstances, ER-ligand complexes interact with Sp1 or AP-1 that is already bound to its specific regulatory element, such that the ER complex does not interact directly with an ERE. This may explain how estrogens are able to regulate genes that lack a consensus ERE. Responses to agonists and antagonists mediated by these protein-protein interactions also are ER isoform- and promoter-specific. For example, 17β-estradiol induces transcription of a target gene controlled by an AP-1 site in the presence of an ER α/AP-1 complex but inhibits transcription in the presence of an ERβ/AP-1 complex. Conversely, anti-estrogens are potent activators of ERβ/AP-1 but not of ERα/AP-1 complexes.

Other signaling systems may activate nuclear ER by ligand-independent mechanisms. Phosphorylation of ERα at serine 118 by MAP kinase activates the receptor (Kato et al., 1995). Similarly, PI-3-kinase–activated Akt directly phosphorylates ERα, causing ligand-independent activation of estrogen-target genes (Simoncini et al., 2000). This provides a means of cross-talk between membrane-bound receptor pathways (i.e., EGF/IGF-1) that activate MAPK and the nuclear ER. In a reciprocal fashion ER may interact directly with members of the Src-Shc/Erk signaling pathway. Activation of Erk by an estren that is a novel ER and androgen receptor (AR) agonist is thought to be responsible for the anti-apoptotic action of this drug in bone (reviewed in Manolagas et al., 2002).

Numerous studies indicate that some estrogen receptors are located on the plasma membrane of cells. This cellular pool form of the ER is encoded by the same genes that encode ERα and ERβ (Pedram, 2006) 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 nine–amino acid motif in the respective E domains of the receptors (reviewed in Levin, 2008). These 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 (Aronica and Katzenellenbogen, 1993). The finding that MAPK is activated by estradiol provides an additional level of cross-talk with growth factor receptors for IGF-1 and EGF, which can activate multiple kinase pathways.

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 (Fotherby, 1996). 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; ethinyl estradiol, e.g., is much more potent than conjugated estrogens.

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 (Table 40–1), which display estrogenic activity in laboratory tests, albeit generally much less than that of estradiol. In theory, these preparations could produce appreciable estrogenic effects, but their efficacy at relevant doses has not been established in human trials (Fitzpatrick, 2003).

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), applied to the upper thigh and calf, or as a gel (estrogel), applied once daily to the arm. The transdermal route does not lead to the high level of the drug that occur in the portal circulation after oral administration, and it is thus expected to minimize hepatic effects of estrogens (e.g., effects on hepatic protein synthesis, lipoprotein profiles, and triglyceride levels).

Other preparations are available for intramuscular injection. When dissolved in oil and injected, esters of estradiol are well absorbed. The aryl and alkyl esters of estradiol become less polar as the size of the substituents increases; correspondingly, the rate of absorption of oily preparations is progressively slowed, and the duration of action can be prolonged. A single therapeutic dose of compounds such as estradiol valerate (delestrogen, others) or estradiol cypionate (depo-estradiol, others) 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. These are effective locally, but systemic effects also are possible due to significant absorption. 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 and to a lesser degree to serum albumin. In contrast, ethinyl estradiol is bound extensively to serum albumin but not SHBG. Due to their size and lipophilic nature, unbound estrogens distribute rapidly and extensively.

Variations in estradiol metabolism occur and depend on the stage of the menstrual cycle, menopausal status, and several genetic polymorphisms (Herrington and Klein, 2001). In general, the hormone undergoes rapid hepatic biotransformation, with a plasma t_1/2 measured in minutes. 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. A variety of sulfate and glucuronide conjugates also are excreted in the urine. Lesser amounts of estrone or estradiol are oxidized to the 2-hydroxycatechols by CYP3A4 in the liver and by CYP1A in extrahepatic tissues or to 4-hydroxycatechols by CYP1B1 in extrahepatic sites, with the 2-hydroxycatechol being formed to a greater extent. The 2- and 4-hydroxycatechols are largely inactivated by catechol-O-methyl transferases (COMTs). However, smaller amounts may be converted by CYP- or peroxidase-catalyzed reactions to yield semiquinones or quinones that are capable of forming DNA adducts or of generating (via redox cycling) reactive oxygen species that could oxidize DNA bases (Yue et al., 2003).

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.

Many other drugs and environmental agents (e.g., cigarette smoke) 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 increasingly important with the decreased doses of estrogens currently employed for both menopausal hormone therapy and contraception.

Ethinyl estradiol is cleared much more slowly than estradiol due to decreased hepatic metabolism, and the elimination-phase t_1/2 in various studies ranges from 13 to 27 hours. Unlike estradiol, the primary route of biotransformation of ethinyl estradiol is via 2-hydroxylation and subsequent formation of the corresponding 2- and 3-methyl ethers. Mestranol, another semisynthetic estrogen and a component of some combination oral contraceptives, is the 3-methyl ether of ethinyl estradiol. In the body it undergoes rapid hepatic demethylation to ethinyl estradiol, which is its active form (Fotherby, 1996).

Concern About Carcinogenic Actions. The risk of developing breast, endometrial, cervical, and vaginal cancer is probably the major concern for the use of estrogens and oral contraceptives. Landmark studies (Greenwald et al., 1971; Herbst et al., 1971) reported an increased incidence of vaginal and cervical adenocarcinoma in female offspring of mothers who had taken diethylstilbestrol (DES) during the first trimester of pregnancy. The incidence of clear cell vaginal and cervical adenocarcinoma in women who were exposed to DES in utero was 0.01-0.1% (Food and Drug Administration, 1985); these findings established for the first time that developmental exposure to estrogens was associated with an increase in a human cancer. Estrogen use during pregnancy also can increase the incidence of nonmalignant genital abnormalities in both male and female offspring. Thus, pregnant patients should not be given estrogens because of the possibility of such reproductive tract toxicities.

The use of unopposed estrogen for hormone treatment in postmenopausal women increases the risk of endometrial carcinoma by 5- to 15-fold (Shapiro et al., 1985). This increased risk can be prevented if a progestin is co-administered with the estrogen (Pike et al., 1997), 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 two large randomized clinical trials of estrogen/progestin and estrogen-only (i.e., the two arms of WHI) in postmenopausal women clearly established a small but significant increase in the risk of breast cancer, apparently due to the medroxyprogesterone (Anderson et al., 2004; Rossouw et al., 2002). 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 by 23%, and the decrease only narrowly missed reaching statistical significance. Interestingly, the incidence of colon cancer was reduced by 26% in the WHI trial.

The Million Women Study (MWS) in the U.K. was a cohort study rather than a clinical trial (Beral et al., 2003). It surveyed >1 million women; about half had received some type of hormone treatment and half had never used them. Those receiving an estrogen-progestin combination had an increased relative risk of invasive breast cancer of 2, and those receiving estrogen alone had an increased relative risk of 1.3, but the increase in actual attributable cases of the disease was again small.

Both the WHI and MWS data are thus consistent with earlier studies indicating that the progestin component (e.g., medroxyprogesterone) in combined hormone-replacement therapy plays a major role in this increased risk of breast cancer (Ross et al., 2000; Schairer et al., 2000). Importantly, although long-term data have not accumulated for the WHI trials, the available data suggest that 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.

Historically, the carcinogenic actions of estrogens were thought to be related to their trophic effects. An increase in cell proliferation would be expected to cause an increase in spontaneous errors associated with DNA replication, and estrogens would then enhance the growth of clones with mutations introduced by this or other mechanisms (e.g., chemical carcinogens). More recently, another mechanism has been proposed. If catechol estrogens, especially the 4-hydroxycatechols, are converted to semiquinones or quinones prior to "inactivation" by COMT, these products, or reactive oxygen species generated during subsequent biotransformations, may cause direct chemical damage to DNA bases (Yue et al., 2003). In this regard, CYP1B1, which has specific estrogen-4-hydroxylase activity, is present in tissues such as uterus, breast, ovary, and prostate, which often give rise to hormone-responsive cancers (Yue et al., 2003).

Metabolic and Cardiovascular Effects. Although they may slightly elevate plasma triglycerides, estrogens themselves generally have favorable overall effects on plasma lipoprotein profiles. However, as noted in a later section dealing with hormone-replacement regimens, progestins may reduce the favorable actions of estrogens. In contrast, estrogens do increase cholesterol levels in bile and cause a relative 2- to 3-fold increase in gallbladder disease. Currently prescribed doses of estrogens generally do not increase the risk of hypertension, and estrogen engaging the ERβ receptor typically reduces blood pressure.

A number of observational studies, clinical trials using intermediate markers of cardiovascular disease, and numerous animal studies suggested that estrogen therapy in postmenopausal women would reduce the risk of cardiovascular disease by 35-50% (Manson and Martin, 2001). However, two recent randomized clinical trials have not found such protection. HERS (Hulley et al., 1998) followed women with established coronary heart disease (CHD) and found that estrogen plus a progestin increased the relative risk of nonfatal myocardial infarction or CHD death within 1 year of treatment, and found no overall change in 5 years. The HERS II follow-up (Grady et al., 2002) found no overall change in the incidence of CHD after 6.8 years of the treatment. These results indicate no role for hormone replacement in the secondary prevention of atherosclerotic heart disease. In the WHI trials, women without existing CHD were treated with an estrogen plus progestin (Rossouw et al., 2002); 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 (Grady et al., 2000). The increase in absolute risk is small but significant. In the WHI, e.g., an estrogen-progestin combination led to an increase in eight attributable cases of stroke per 10,000 older women and a similar increase in pulmonary embolism (Rossouw et al., 2002).The latter was seen mainly in women who concomitantly smoked cigarettes.

Effects on Cognition. Several retrospective studies had suggested that estrogens had beneficial effects on cognition and delayed the onset of Alzheimer's disease (Green and Simpkins, 2000). However, the Women's Health Initiative Memory Study (WHIMS) of a group of women ≥65 years of age (Shumaker et al., 2003) found that estrogen-progestin therapy was associated with a doubling in the number of women diagnosed with probable dementia, and no benefit of hormone treatment on global cognitive function was observed (Rapp et al., 2003). Women in the estrogen-only arm also showed a comparable decrease in cognitive function (Espeland et al., 2004), implicating estrogens in these cognitive changes.

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.

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 for these symptoms (Belchetz, 1994). If estrogen is contraindicated or otherwise undesirable, other options may be considered. Medroxyprogesterone acetate (discussed in the later section on progestins) may provide some relief of vasomotor symptoms for certain patients, and 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; when prescribed for this purpose 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 (Chapter 44). The result is thinning and weakening of the bones and an increased incidence of fractures, particularly compression fractures of the vertebrae and minimal-trauma fractures of the hip and wrist. The frequency and severity of these fractures and their associated complications (e.g., death and permanent disability) are a major public health problem, especially as the population continues to age. Osteoporosis is an indication for estrogen therapy, which clearly is efficacious in decreasing the incidence of fractures. However, because of the risks associated with estrogen use, first-line use of other drugs, such as bisphosphonates, should be considered (Chapter 44). Nevertheless, it is important to note that 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 (Anderson et al., 2004; Rossouw et al., 2002).

The primary mechanism by which estrogens act is to decrease bone resorption; consequently, estrogens are more effective at preventing rather than restoring bone loss (Belchetz, 1994; Prince et al., 1991). Estrogens are most effective if treatment is initiated before significant bone loss occurs, and their maximal beneficial effects require continuous use; bone loss resumes when treatment is discontinued. Other options for treatment of osteoporosis are presented in Chapter 44. An appropriate diet with adequate intake of Ca²⁺ and vitamin D and weight-bearing exercise enhance the effects of estrogen treatment. Public health efforts to improve diet and exercise patterns in girls and young women also are rational approaches to increase bone mass.

Vaginal Dryness and Urogenital Atrophy. Loss of tissue lining the vagina or bladder leads to a variety of symptoms in many postmenopausal women (Robinson and Cardozo, 2003). These include dryness and itching of the vagina, dyspareunia, swelling of tissues in the genital region, pain during urination, a need to urinate urgently or often, and sudden or unexpected urinary incontinence. When estrogens are being used solely 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, and epidemiological studies consistently showed an association between estrogen use and reduced cardiovascular disease in postmenopausal women. Furthermore, estrogens produce a favorable lipoprotein profile, promote vasodilation, inhibit the response to vascular injury, and reduce atherosclerosis. Studies such as these led to the widespread use of estrogen for prevention of cardiovascular disease in postmenopausal women (Mendelsohn and Karas, 1999). As discussed earlier, estrogens promote coagulation and thromboembolic events. Randomized prospective studies (Grady et al., 2002; Rossouw et al., 2002) unexpectedly have 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. However, as mentioned, combined estrogen-progestin therapy is associated with a decrease in heart attacks in younger women.

Other Therapeutic Effects. Many other changes occur in postmenopausal women, including a general thinning of the skin; changes in the urethra, vulva, and external genitalia; and a variety of changes including headache, fatigue, and difficulty concentrating. Chronic lack of sleep created by hot flashes and other vasomotor symptoms may be contributing factors. Estrogen replacement may help alleviate or lessen some of these via direct actions (e.g., improvement of vasomotor symptoms) or secondary effects resulting in an improved feeling of well-being (Belchetz, 1994). The WHI demonstrated that a conjugated estrogen in combination with a progestin reduces the risk of colon cancer by roughly one-half in postmenopausal women (Rossouw et al., 2002).

Conjugated estrogens and medroxyprogesterone acetate (MPA) historically have been used most commonly in menopausal hormone regimens, although estradiol, estrone, and estriol have been used as estrogens, and norethindrone, 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. Either route effectively relieves vasomotor symptoms and protects against bone loss. Oral but not transdermal estrogen may increase SHBG, other binding globulins, and angiotensinogen; the oral route might be expected to cause greater increases in 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) (Walsh et al., 1994) but may be preferred in women with hypertriglyceridemia.

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 three metabolites that have predominantly estrogenic, progestogenic, and androgenic activities. The drug appears to increase bone mineral density and decrease vasomotor symptoms without stimulating the endometrium, but its effects on fractures, breast cancer, and long-term outcomes remain to be established (Modelska and Cummings, 2002).

Regardless of the specific agent or regimen, menopausal hormone therapy with estrogens should use the lowest dose and shortest duration necessary to achieve an appropriate therapeutic goal.

Estrogen Treatment in the Failure of Ovarian Development. In several conditions (e.g., Turner's 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 (Chapter 41) and/or growth hormone (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.

Chemistry. The structures of the trans-isomer of tamoxifen, and of raloxifene, trans-clomiphene (enclomiphene), and fulvestrant are:

Tamoxifen is a triphenylethylene with the same stilbene nucleus as DES; compounds of this class display a variety of estrogenic and anti-estrogenic activities. In general, the trans conformations have anti-estrogenic activity, whereas the cis conformations display estrogenic activity. However, the pharmacological activity of the trans compound depends on the species, target tissue, and gene. Hepatic metabolism produces primarily N-desmethyltamoxifen, which has affinity for ER comparable to that of tamoxifen, and lesser amounts of the highly active 4-hydroxy metabolite, which has a 25-50 times higher affinity for both ERα and ERβ than does tamoxifen (Kuiper et al., 1997). Tamoxifen is marketed as the pure trans-isomer. Toremifene is a triphenylethylene with a chlorine substitution at the R2 position.

Raloxifene is a polyhydroxylated nonsteroidal compound with a benzothiophene core. Raloxifene binds with high affinity for both ERα and ERβ (Kuiper et al., 1997).

Clomiphene citrate is a triphenylethylene; its two isomers, zuclomiphene (cis-clomiphene) and enclomiphene (trans-clomiphene), are a weak estrogen agonist and a potent antagonist, respectively. Clomiphene binds to both ERα and ERβ, but the individual isomers have not been examined (Kuiper et al., 1997).

Fulvestrant is a 7α-alkylamide derivative of estradiol that interacts with both ERα and ERβ (Van Den Bemd et al., 1999).

Initial animal studies with clomiphene showed slight estrogenic activity and moderate anti-estrogenic activity, but the most striking effect was the inhibition of pituitary gonadotropes. In contrast, the most prominent effect in women was enlargement of the ovaries and the drug-induced ovulation in many patients with amenorrhea, polycystic ovarian syndrome, and dysfunctional bleeding with anovulatory cycles. This is the basis for clomiphene's major pharmacological use: to induce ovulation in women with a functional hypothalamic-hypophyseal-ovarian system and adequate endogenous estrogen production. In some cases, clomiphene is used in conjunction with human gonadotropins (Chapter 38) to induce ovulation.

Fulvestrant and its less potent forerunner ICI 164,384 have been purely anti-estrogenic in studies to date. In vitro, fulvestrant was more potent than 4-hydroxytamoxifen (DeFriend et al., 1994) in inhibiting proliferation of breast cancer cells, and in clinical trials it is efficacious in treating tamoxifen-resistant breast cancers (Robertson et al., 2003).

All of these agents bind to the ligand-binding pocket of both ERα and ERβ and competitively block estradiol binding. However, the conformation of the ligand-bound ERs is different with different ligands (Smith and O'Malley, 2004), and this has two important mechanistic consequences. The distinct ER-ligand conformations recruit different co-activators and co-repressors onto the promoter of a target gene by differential protein-protein interactions at the receptor surface. 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 co-activator and co-repressor levels in different cell types that together affect the nature of ER complexes formed in a tissue-selective fashion.

The conformation of ERs, especially in the AF-2 domain, determines whether a co-activator or a co-repressor will be recruited to the ER-DNA complex (Smith and O'Malley, 2004). Whereas 17β-estradiol induces a conformation that recruits co-activators to the receptor, tamoxifen induces a conformation that permits the recruitment of the co-repressor 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 (McInerney et al., 1998).

Raloxifene acts as a partial agonist in bone but does not stimulate endometrial proliferation in postmenopausal women. Presumably this is due to some combination of differential expression of transcription factors in the two tissues and the effects of this SERM on ER conformation. Raloxifene induces a configuration in ERα that is distinct from that of tamoxifen-ERβ (Tamrazi et al., 2003), suggesting that a different set of co-activators/co-repressors may interact with ER-raloxifene compared with ER-tamoxifen.

Clomiphene increases gonadotropin secretion and stimulates ovulation. It increases the amplitude of LH and FSH pulses without changing pulse frequency (Kettel et al., 1993). This suggests that the drug is acting largely at the pituitary level to block inhibitory actions of estrogen on gonadotropin release from the gland and/or is somehow causing the hypothalamus to release larger amounts of GnRH per pulse.

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 (Van Den Bemd et al., 1999). This effect on ERα protein levels may explain fulvestrant's efficacy in tamoxifen-resistant breast cancer.

Absorption, Fate, and Excretion

Tamoxifen is given orally, and peak plasma levels are reached within 4-7 hours after treatment. This drug displays two elimination phases with half-lives of 7-14 hours and 4-11 days. Due to the prolonged t_1/2, 3-4 weeks of treatment are required to reach steady-state plasma levels. The parent drug is converted largely to metabolites within 4-6 hours after oral administration. Tamoxifen is metabolized in humans by multiple hepatic CYPs, some of which it also induces (Sridar et al., 2002). In humans and other species, 4-hydroxytamoxifen is produced via hepatic metabolism, and this compound is considerably more potent than the parent drug as an anti-estrogen. 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. Polymorphisms affect the rate of tamoxifen metabolism to its more potent 4-hydroxy metabolite and may impact its therapeutic activity in breast cancer (Chapter 63).

Raloxifene is adsorbed rapidly after oral administration and has an absolute bioavailability of ∼2%. The drug has a t_1/2 of ∼28 hours and is eliminated primarily in the feces after hepatic glucuronidation; it does not appear to undergo significant biotransformation by CYPs.

Clomiphene is well absorbed following oral administration, and the drug and its metabolites are eliminated primarily in the feces and to a lesser extent in the urine. The long plasma t_1/2 (5-7 days) is due largely to plasma-protein binding, enterohepatic circulation, and accumulation in fatty tissues. Other active metabolites with long half-lives also may be produced.

Fulvestrant is administered monthly by intramuscular depot injections. Plasma concentrations reach maximal levels in 7 days and are maintained for a month. Numerous metabolites are formed in vivo, possibly by pathways similar to endogenous estrogen metabolism, but the drug is eliminated primarily (90%) via the feces in humans.

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 (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 (Haynes et al., 2003). Exemestane, letrozole, and anastrozole are currently approved in the U.S. for the treatment of breast cancer.

As discussed in Chapter 62, these agents may be used as first-line treatment of breast cancer or as second-line drugs after tamoxifen. They are highly efficacious and actually superior to tamoxifen in adjuvant use for postmenopausal women (Coombes et al., 2004), 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 and thus are usually administered with bisphosphonates. Their effects on plasma lipids remain to be established.

History. Corner and Allen originally isolated a hormone in 1933 from the corpora lutea of sows and named it "progestin." The next year, several European groups independently isolated the crystalline compound and called it "luteo-sterone," unaware of the previous name. This difference in nomenclature was resolved in 1935 at a garden party in London given by Sir Henry Dale, who helped persuade all parties that the name "progesterone" was a suitable compromise.

Two major advances overcame the early difficulties and expense of obtaining progesterone from animal sources. The first was the synthesis of progesterone by Russel Marker from the plant product diosgenin in the 1940s, which provided a relatively inexpensive and highly pure product. The second was the synthesis of 19-nor compounds, the first orally active progestins, in the early 1950s by Carl Djerassi, who synthesized norethindrone at Syntex, and Frank Colton, who synthesized the isomer norethynodrel at Searle. These advances led to the development of effective oral contraceptives.

Chemistry. The structural features of several progestins are shown in Figure 40–5. Unlike the ER, which requires a phenolic A ring for high-affinity binding, the progesterone receptor (PR) favors a Δ⁴-3-one A-ring structure in an inverted 1β, 2α-conformation (Duax et al., 1988). Other steroid hormone receptors also bind this nonphenolic A-ring structure, although the optimal conformation differs from that for the PR. Thus, some synthetic progestins (especially the 19-nor compounds) display limited binding to glucocorticoid, androgen, and mineralocorticoid receptors, a property that probably accounts for some of their nonprogestational activities. The spectrum of activities of these compounds is highly dependent on specific substituent groups, especially the nature of the C17 substituent in the D ring, the presence of a C19 methyl group, and the presence of an ethyl group at position C13.

One major class of agents is similar to progesterone and its metabolite 17α-hydroxyprogesterone (Figure 40–5). Compounds such as hydroxyprogesterone caproate have progestational activity but must be used parenterally due to first-pass hepatic metabolism. However, further substitutions at the 6-position of the B ring yield orally active compounds such as medroxyprogesterone acetate and megestrol acetate with selective progestational activity.

The second major class of agents is 19-nor testosterone derivatives. These testosterone derivatives, lacking the C19 methyl group, display primarily progestational rather than androgenic activity. An ethinyl substituent at C17 decreases hepatic metabolism and yields orally active 19-nortestosterone analogs such as norethindrone, norethindrone acetate, norethynodrel, and ethynodiol diacetate. The activity of the latter three compounds is due primarily to their rapid in vivo conversion to norethindrone. These compounds are less selective than the 17α-hydroxyprogesterone derivatives just mentioned and have varying degrees of androgenic activity and, to a lesser extent, estrogenic and anti-estrogenic activities.

Replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent yields the gonane norgestrel, which is a more potent progestin than the parent compound but has less androgenic activity. Norgestrel is a racemic mixture of an inactive dextrorotatory isomer and the active levorotatory isomer, levonorgestrel. Preparations containing half as much levonorgestrel as norgestrel thus have equivalent pharmacological activity. Other gonanes—including norgestimate, desogestrel, and gestodene (not available in the U.S.)—have very little if any androgenic activity at therapeutic doses.

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.

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

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.

Progesterone also influences the endocervical glands, and the abundant watery secretion of the estrogen-stimulated structures is changed to a scant viscid material. As noted previously, 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, a change that can be detected in cytological alterations in the vaginal smear. If the quantity of estrogen concurrently acting is known to be adequate, or if it is assured by giving estrogen, the cytological response to a progestin can be used to evaluate its progestational potency.

Progesterone is very important for the maintenance of pregnancy. Progesterone suppresses menstruation and uterine contractility, but other effects also may be important. These effects to maintain pregnancy led to the historical use of progestins to prevent threatened abortion. However, such treatment is of questionable benefit, probably because spontaneous abortion infrequently results from diminished progesterone.

During the normal menstrual cycle, mitotic activity in the breast epithelium is very low in the follicular phase and then peaks in the luteal phase. This pattern is due to progesterone, which triggers a single round of mitotic activity in the mammary epithelium. This effect is transient because continued exposure to the hormone is rapidly followed by arrest of growth of the epithelial cells. Importantly, progesterone may be responsible for the increased risk of breast cancer associated with estrogen-progestin use in postmenopausal women, although controlled studies with only progestin have not been performed (Anderson et al., 2004; Rossouw et al., 2002).

In this regard, a large prospective study has shown that MPA decreases the favorable HDL increase caused by conjugated estrogens during postmenopausal hormone replacement, but it does not significantly affect 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 (Writing Group for the PEPI Trial, 1995); 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.

The biological activities of PR-A and PR-B are distinct and depend on the target gene in question. 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 (McDonnell and Goldman, 1994). Current data suggest that co-activators and co-repressors interact differentially with PR-A and PR-B (e.g., the co-repressor SMRT binds much more tightly to PR-A than to PR-B) (Giangrande et al., 2000), and this may account, at least in part, for the differential activities of the two isoforms. Female PR-A knockout mice are infertile, with impaired ovulation and defective decidualization and implantation. Several uterine genes appear to be regulated exclusively by PR-A, including calcitonin and amphiregulin (Mulac-Jericevic et al., 2000), and the antiproliferative effect of progesterone on the estrogen-stimulated endometrium is lost in PR-A knockout mice. In contrast, knockout studies suggest that PR-B is largely responsible for mediating hormone effects in the mammary gland (Mulac-Jericevic et al., 2003).

Certain effects of progesterone, such as increased Ca²⁺ mobilization in sperm, can be seen in as little as 3 minutes (Blackmore, 1999) and are therefore considered transcription independent. Similarly, progesterone can promote oocyte maturation (meiotic resumption) independent of transcription (Hammes, 2004). There is debate regarding the identity of the receptors mediating these progestin-induced processes, as well as their physiological importance in humans.

Absorption, Fate, and Excretion

Progesterone undergoes rapid first-pass metabolism, but high-dose (e.g., 100-200 mg) preparations of micronized progesterone (prometrium) are available for oral use. Although the absolute bioavailability of these preparations is low (Fotherby, 1996), efficacious plasma levels nevertheless may 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 (see later section on contraceptives).

In the plasma, progesterone is bound by albumin and corticosteroid-binding globulin but is not appreciably bound to SHBG. 19-Nor compounds, such as norethindrone, norgestrel, and desogestrel, bind to SHBG and albumin, and esters such as MPA bind primarily to albumin. Total binding of all these synthetic compounds to plasma proteins is extensive, ≤90%, but the proteins involved are compound specific.

The elimination t_1/2 of progesterone is ∼5 minutes, 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 hours for norethindrone, 16 hours for norgestrel, 12 hours for gestodene, and 24 hours for MPA). The metabolism of synthetic progestins is thought to be primarily hepatic, and elimination is generally via the urine as conjugates and various polar metabolites, although their metabolism is not as clearly defined as that of progesterone.

Progestins also are used diagnostically for secondary amenorrhea. An oral progestin is given to an amenorrheic woman for 5-7 days. If endogenous estrogens are present, withdrawal bleeding will occur. Combinations of estrogens and progestins can also be given to test for endometrial responsiveness in patients with amenorrhea.

In addition, progestins are highly efficacious in decreasing the occurrence of endometrial hyperplasia and carcinoma caused by unopposed estrogens; when used in this setting, there appears to be less irregular uterine bleeding with sequential rather than continuous administration. 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 (e.g., unfavorable lipid profiles and incidence of breast cancer) 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 hours after intercourse as either a single 1.5-mg dose (PLAN B ONE STEP) or as two 0.75-mg doses (PLAN B) separated by 12 hours. The mechanism of action may involve several factors, including the prevention of ovulation, fertilization, and implantation.

Chemistry. Mifepristone is a derivative of the 19-norprogestin norethindrone containing a dimethyl-aminophenol substituent at the 11β-position. It effectively competes with both progesterone and glucocorticoids for binding to their respective receptors. Mifepristone was initially thought to be a pure anti-progestin, although it is now considered a progesterone-receptor modulator (PRM) due to its context-dependent activity.

Other PRMs and pure progesterone antagonists now have been synthesized, and most contain an 11β-aromatic group. Another widely studied anti-progestin is onapristone (or ZK 98299), which is similar in structure to mifepristone but contains a methyl substituent in the 13α rather than 13β orientation. More selective progesterone-receptor modulators, such as asoprisnil, are being studied experimentally (DeManno et al., 2003).

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. These effects are due largely to actions on the hypothalamus and pituitary rather than the ovary, although the mechanisms are unclear.

If administered for one or several days in the mid- to late luteal phase, mifepristone impairs the development of a secretory endometrium and produces menses. Progesterone-receptor blockade at this time is the pharmacological equivalent of progesterone withdrawal, and bleeding normally ensues within several days and lasts for 1-2 weeks after anti-progestin treatment.

Mifepristone also binds to glucocorticoid and androgen receptors and exerts anti-glucocorticoid and anti-androgenic actions. A predominant effect in humans is blockade of the feedback inhibition by cortisol of adenocorticotropic hormone secretion from the pituitary, thus increasing both corticotropin and adrenal steroid levels in the plasma.

Absorption, Fate, and Excretion. Mifepristone is orally active with good bioavailability. Peak plasma levels occur within several hours, and the drug is slowly cleared with a plasma t_1/2 of 20-40 hours. In plasma, it is bound by α₁-acid glycoprotein, which contributes to the drug's long t_1/2. Metabolites are primarily the mono- and di-demethylated products (thought to have pharmacological activity) formed via CYP3A4-catalyzed reactions and, to a lesser extent, hydroxylated compounds. The drug undergoes hepatic metabolism and enterohepatic circulation; metabolic products are found predominantly in the feces (Jang and Benet, 1997).

When mifepristone is used to produce a medical abortion, a prostaglandin is given 48 hours after the anti-progestin to further increase myometrial contractions and ensure expulsion of the detached blastocyst. Intramuscular sulprostone, intravaginal gemeprost, and oral misoprostol have been used. The success rate with such regimens is >90% among women with pregnancies of ≤49 days' duration. 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 anti-glucocorticoid activity. In fact, due to its high affinity for the glucocorticoid receptor, high doses of mifepristone can result in adrenal insufficiency; thus mifepristone is being considered as a chemical treatment for diseases of excess adrenal cortisol secretion.

Chemistry. Ulipristal, a derivative of 19-norprogesterone, functions as a selective progesterone receptor modulator (SPRM), acting as a partial agonist at progesterone receptors. It has a dimethyl-aminophenol group at the 11β position, as does mifepristone, with an additional acetoxy group at the C17. Unlike mifepristone, ulipristal appears to be a relatively weak glucocorticoid antagonist.

A 30-mg dose of ulipristral can inhibit ovulation when taken up to five days after intercourse. Ulipristal can block ovarian rupture at or even just after the time of the LH surge, confirming that at least some of its effects are directly in the ovary. Ulipristal may also block endometrial implantation of the fertilized egg, although whether this contributes to its effects as an emergency contraceptive (see below) is not clear.

History. Around the beginning of the 20th century, a number of European scientists, including Beard, Prenant, and Loeb, developed the concept that secretions of the corpus luteum suppressed ovulation during pregnancy. The Austrian physiologist Haberlandt then produced temporary sterility in rodents in 1927 by feeding ovarian and placental extracts—a clear example of an oral contraceptive! In 1937, Makepeace and colleagues demonstrated that pure progesterone blocked ovulation in rabbits, and Astwood and Fevold found a similar effect in rats in 1939.

In the 1950s, Pincus, Garcia, and Rock found that progesterone and 19-norprogestins prevented ovulation in women. Ironically, this finding grew out of their attempts to treat infertility with progestins or estrogen-progestin combinations. The initial findings were that either treatment effectively blocked ovulation in most women. However, concern about cancer and other possible side effects of the estrogen they used (i.e., DES) led to the use of a progestin alone in their studies. One of the compounds used was norethynodrel, and early batches of this compound were contaminated with a small amount of mestranol. When mestranol was removed, it was noted that treatment with pure norethynodrel led to increased breakthrough bleeding and less consistent inhibition of ovulation. Mestranol was thus reincorporated into the preparation, and this combination was employed in the first large-scale clinical trial of combination oral contraceptives.

Clinical studies in the 1950s in Puerto Rico and Haiti established the virtually complete contraceptive success of the norethynodrel/mestranol combination. In early 1961, enovid (norethynodrel plus mestranol; no longer marketed in the U.S.) was the first "Pill" approved by the FDA for use as a contraceptive agent in the U.S.; this was followed in 1962 by approval for ortho-novum (norethindrone plus mestranol). By 1966, numerous preparations using either mestranol or ethinyl estradiol with a 19-norprogestin were available. In the 1960s, the progestin-only minipill and long-acting injectable preparations were developed and introduced.

Millions of women began using oral contraceptives, and frequent reports of untoward effects began appearing in the 1970s. The recognition that these side effects were dose-dependent and the realization that estrogens and progestins synergistically inhibited ovulation led to the reduction of doses and the development of so-called low-dose or second-generation contraceptives. The increasing use of biphasic and triphasic preparations throughout the 1980s further reduced steroid dosages; it may be that currently used doses are the lowest that will provide reliable contraception. In the 1990s, the "third-generation" oral contraceptives, containing progestins with reduced androgenic activity (e.g., norgestimate [ortho-cyclen, ortho tri-cyclen lo, others] and desogestrel [desogen, others]), became available in the U.S. after being used in Europe. A variety of contraceptive formulations are currently available, including pills, injections, skin patches, subdermal implants, vaginal rings, and IUDs that release hormones.

The estrogen content of current preparations ranges from 20 to 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. For example, monophasic pills currently available in the U.S. contain 0.4-1.5 mg of norethindrone, 0.09-0.15 mg of levonorgestrel, 0.3-0.5 mg of norgestrel, 1 mg of ethynodiol diacetate, 0.25 mg of norgestimate, or 0.15 mg of desogestrel, with slightly different dose ranges in biphasic and triphasic preparations. In contrast, most first-generation preparations (circa 1966) contained 50-100 μg of an estrogen and 2-10 mg of a progestin. These large differences in doses complicate extrapolation of data from early epidemiological studies on the side effects of "high-dose" oral contraceptives to the "low-dose" preparations now 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).

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 intrauterine device (mirena) releases levonorgestrel for up to 5 years. It inhibits ovulation in some women but is thought to act primarily by producing local effects.

Given the multiple actions of estrogens and progestins on the hypothalamic-pituitary-ovarian axis during the menstrual cycle and the extraordinary efficacy of these agents, several effects probably contribute to the blockade of ovulation.

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. In monkeys and women with normal menstrual cycles, estrogens do not affect the frequency of the pulse generator. However, in the prolonged absence of a menstrual cycle (e.g., in ovariectomized monkeys and postmenopausal women; Hotchkiss and Knobil, 1994), estrogens markedly diminish pulse-generator frequency, and progesterone enhances this effect. In theory, this hypothalamic effect of estrogens could come into play when oral contraceptives are used for extended time periods.

Multiple pituitary effects of both estrogen and progestin components are thus 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. However, it is difficult to assess quantitatively the contributions of these effects because the drugs block ovulation so effectively.

Cardiovascular Effects. The question of cardiovascular side effects has been reexamined for the newer low-dose oral contraceptives (Burkman et al., 2004; Sherif, 1999). 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). Nevertheless, the risk is significantly increased in women who smoke or have other factors that predispose to thrombosis or thromboembolism (Castelli, 1999). Of note, postmarketing epidemiologic 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. As noted previously, estrogens increase serum HDL and decrease LDL levels, and 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. These concerns were further heightened in the late 1960s by reports of endometrial changes caused by sequential oral contraceptives, which have since been removed from the market in the U.S. However, it is now clear that there is not a widespread association between oral contraceptive use and cancer (Burkman et al., 2004; Westhoff, 1999).

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 (Moodley, 2004).

There have been reports of increases in the incidence of hepatic adenoma and hepatocellular carcinoma in oral contraceptive users. Current estimates indicate there is about a doubling in the risk of liver cancer after 4-8 years of use. However, these are rare cancers, and the absolute increases are small.

The major present concern about the carcinogenic effects of oral contraceptives is focused on breast cancer. Numerous studies have dealt with this issue, and the following general picture has emerged. 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. In addition, breast cancers diagnosed in women who have ever used oral contraceptives are more likely to be localized to the breast and thus easier to treat (i.e., are less likely to have spread to other sites) (Westhoff, 1999). Thus overall there is no significant difference in the cumulative risk of breast cancer between those who have ever used oral contraceptives and those who have never used them.

Combination oral contraceptives do not increase the incidence of endometrial cancer but actually cause a 50% decrease in the incidence of this disease, which lasts 15 years after the pills are stopped. This is thought to be due to the inclusion of a progestin, which opposes estrogen-induced proliferation, throughout the entire 21-day cycle of administration. These agents also decrease the incidence of ovarian cancer, and decreased ovarian stimulation by gonadotropins provides a logical basis for this effect. There are accumulating data that oral contraceptive use decreases the risk of colorectal cancer (Fernandez et al., 2001).

Metabolic and Endocrine Effects. The effects of sex steroids on glucose metabolism and insulin sensitivity are complex (Godsland, 1996) and may differ among agents in the same class (e.g., the 19-nor progestins). Early studies with high-dose oral contraceptives generally reported impaired glucose tolerance as demonstrated by increases in fasting glucose and insulin levels and responses to glucose challenge. These effects have decreased as steroid dosages have been lowered, and current low-dose combination contraceptives may even improve insulin sensitivity. Similarly, the high-dose progestins in early oral contraceptives did raise LDL and reduce HDL levels, but modern low-dose preparations do not produce unfavorable lipid profiles (Sherif, 1999). There also have been periodic reports that oral contraceptives increase the incidence of gallbladder disease, but any such effect appears to be weak and limited to current or very long-term users (Burkman et al., 2004).

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 total plasma 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, which exerts a counter effect so that overall there is a minimal effect on hemostatic balance. In women who smoke, however, this compensatory effect is diminished, which may shift the hemostatic profile toward a hypercoagulable condition (Fruzzetti, 1999).

Miscellaneous Effects. Nausea, edema, and mild headache occur in some individuals, and more severe migraine headaches may be precipitated by oral contraceptive use in a smaller fraction of women. Some patients may experience breakthrough bleeding 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 are thought to be mediated by the androgenic activity of the 19-nor progestins.

No evidence indicates that the progestin-only minipill preparations increase thromboembolic events, which are thought to be related to the estrogenic component of combination preparations; blood pressure does not appear to be elevated, and nausea and breast tenderness do not occur. Acne may be a problem, however, because of the androgenic activity of norethindrone-containing preparations. These preparations may be attractive for nursing mothers because they do not decrease lactation as do products containing estrogens.

Aside from bleeding irregularities, headache is the most commonly reported untoward effect of depot MPA. Mood changes and weight gain also have been reported, but controlled clinical studies of these effects are not available. It is of more concern that many studies have found decreases in HDL levels and increases in LDL levels, and there have been several reports of decreased bone density. These effects may be due to reduced endogenous estrogens because depot MPA is particularly effective in lowering gonadotropin levels. Numerous human studies have not found any increases in breast, endometrial, cervical, or ovarian cancer in women receiving MPA (Westhoff, 2003). 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, and acne is seen in some patients. A number of metabolic studies have been performed in users of norplant (no longer marketed in the U.S.), and in most cases only minimal changes have been observed in lipid, carbohydrate, and protein metabolism. In women desiring pregnancy, ovulation occurs fairly soon after implant removal, reaching 50% in 3 months and almost 90% within 1 year.

Several other conditions are relative contraindications and should be considered on an individual basis. These include migraine headaches, hypertension, diabetes mellitus, obstructive jaundice of pregnancy or prior oral contraceptive use, and gallbladder disease. If elective surgery is planned, many physicians recommend discontinuation of oral contraceptives for several weeks to a month 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 pills 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.

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.

In summary, for a given individual, both the efficacy and side effects of hormonal contraceptives may vary considerably among preparations. A number of choices are available to counter the development of side effects and improve patient tolerance, both in terms of specific components and routes of administration, without decreasing contraceptive efficacy. Risks for serious side effects as enumerated earlier should be considered before initiating contraceptives in any individual patient.