Estrogens

There are three endogenous nineteen-carbon steroids in humans that have estrogenic activity. The principal ovarian estrogens are 17β-estradiol, which is the primary circulating form, and its metabolite, estrone, which the primary postmenopausal estrogen. During pregnancy the placenta synthesizes estriol. Estrogens coordinate systemic responses during the ovulatory cycle, including regulation of the reproductive tract, pituitary, breasts, and other tissues. Also, some forms of cancer are estrogen-dependent for growth. The hypothalamic-pituitary-ovarian axis and target organs for the actions of estrogens are shown in Figure 40-1. Estrogens are also responsible for mediating development of secondary sex characteristics when females enter puberty, including progressive maturation of the fallopian tubes, uterus, vagina, and external genitalia. Upon estrogenic stimulation, more fat is deposited in the breast, buttocks, and thighs, leading to the normal adult female habitus. The following are characteristics promoted by estrogens.

FIGURE 40–1 Feedback loops and target tissues. A, Negative and positive feedback action of estrogens and progesterone on the hypothalamic-pituitary-ovarian axis. B, Other target tissues for these steroid hormones.

Estrogens may play a direct role in the progression of some endometrial tumors, and lifetime exposure to estrogens is associated with the greatest risk for development of breast cancer. Exposure of the uterus to estrogen without exposure to progesterone is associated with endometrial hyperplasia, episodes of breakthrough bleeding, and an approximate sevenfold increased risk of endometrial cancer.

Progestins

The important endogenous progestin is progesterone, although 17α-, 20α-, and 20β-hydroxyprogesterones have weak progestational activities. Estrogen priming is necessary for progesterone receptor (PGR) expression in almost all progesterone-responsive tissues, including the uterus. Progesterone concentrations rise rapidly in the luteal phase of the menstrual cycle, resulting in a modulation of the action of estrogen on the uterus. Progesterone antagonizes estrogen-induced proliferation in the uterus and initiates secretory changes in preparation for embryo implantation. In the absence of pregnancy, plasma progesterone concentrations decrease, resulting in sloughing of the endometrial lining. Progesterone is responsible for causing the increased basal body temperature observed in the luteal phase. Progesterone is important in mammary glandular development and, unlike the uterus, probably stimulates breast cell proliferation. During pregnancy, progesterone can promote maintenance of pregnancy, inhibit uterine contraction, alter carbohydrate metabolism, decrease HDL, increase LDL, and increase Na⁺ and water elimination by competitive antagonism of aldosterone interaction with mineralocorticoid receptors. A variety of menstrual cycle disorders are treated with progestins, estrogens, or both.

Combined Effects

Progesterone and estrogen coordinate the events associated with the luteal phase of the ovulatory cycle and pregnancy. In females with primary ovarian failure, estrogens and progestins are administered to optimize normal development of secondary sex characteristics. An important pharmacological use of estrogens and progestins is as contraceptives. In this regard estrogens and progestins act

predominantly at the pituitary-hypothalamic axis to decrease production of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Inhibition of the mid-cycle LH surge prevents ovulation. A combination oral contraceptive formulation is also approved for the treatment of severe acne in females over age 15 years (acne vulgaris). Antiestrogens have been developed to aid in treatment of infertility by inducing an increase in circulating FSH, which leads to ovulation. Estrogen and progestin replacement therapy have been used extensively in treatment of symptoms arising at menopause.

The major therapeutic uses of estrogens, progestins, their synthetic agonists and antagonists, and inhibitors of estrogen biosynthesis are summarized in the Therapeutic Overview Box.

Biosynthesis of Estrogens and Progestins

Estrogens and progestins are produced by steroidogenesis in various tissues (see Fig. 38-1). The ovary is the predominant source of these steroids in nonpregnant, premenopausal women. A significant amount of estrogenic activity is also produced by skeletal muscle, liver, and adipose tissue through the conversion of circulating androgens to estrone. Certain brain areas in males and females may also produce estrogens through the action of aromatase on circulating androgens. Small amounts of estradiol can be produced in the male testes.

During the menstrual cycle, the pituitary gonadotropins FSH and LH regulate the synthesis and release of estrogen and progesterone from the ovary. The pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), in turn, regulates FSH and LH synthesis and release. GnRH concentrations are regulated through negative and positive feedback by the steroid hormones. Estrogens and progestins also act directly on the pituitary gonadotrophs to decrease FSH and LH concentrations. In addition, an ovarian protein, inhibin, negatively affects FSH synthesis. The pathways for the integrated control of hormone regulation are shown in Figure 40-1, A.

The ovulatory-menstrual cycle normally spans 25 to 35 days. The steps in the ovarian and endometrial cycles are shown in Figure 40-2. The ovarian cycle is divided into the follicular (preovulatory) phase, when ova maturation and estrogen release occurs, ovulation, when follicular rupture leads to ova release, and the postovulatory phase, when the corpus luteum maximally releases progesterone and stimulates growth of the endometrial lining. The follicle is the basic reproductive unit of the ovary and consists of an oocyte surrounded by granulosa cells. At the onset of a menstrual cycle, FSH accelerates maturation of several follicles. Through interactions with its receptor, FSH increases aromatase activity, which stimulates conversion of androgens to estradiol. By days 8 to 10, FSH decreases, and the dominant follicle becomes more sensitive to circulating gonadotropin because of an increased number of FSH receptors. In the late follicular phase, estradiol levels increase rapidly and initiate a mid-cycle LH surge (16 to 24 hours before ovulation). Increased LH levels promote follicular production of progesterone, prostaglandin F_2α, and proteolytic enzymes, and ultimately, follicular rupture and ovulation occur. After ovulation, the granulosa and theca cells become the corpus luteum, which produces and releases progesterone throughout the first half of the luteal phase (10 to 20 ng/mL). The suppression of FSH and LH release promotes the decline of progesterone and estrogen, luteolysis, initiation of menses, and ultimately a new cycle.

FIGURE 40–2 Ovulatory and menstrual cycle. Ovarian and uterine changes that occur with the cyclical hormonal changes during the normal human menstrual cycle. Note the increase in LH, FSH, and estradiol concentrations before ovulation during the follicular phase. Progesterone rises and peaks in the midluteal phase, concomitant with reductions in LH, FSH, and estradiol.

During pregnancy the placenta secretes chorionic gonadotropin into the maternal circulation. The chorionic gonadotropin concentration rises rapidly after implantation and peaks in approximately 6 to 8 weeks. Chorionic gonadotropin maintains the corpus luteum and stimulates progesterone production, which initially maintains placental implantation and pregnancy. Sometime after the fifth week of pregnancy, the fetal-placental unit becomes the major source of circulating progesterone and estrogens, especially estriol.

As women age, the number of follicles in the ovaries diminish, predominantly as a result of atresia. Eventually, the normal menstrual cycles cease (menopause). Without estrogen and progesterone to suppress the hypothalamic-pituitary axis, FSH and LH levels increase. Although adrenal androgens, predominantly androstenedione, can be converted to estrone by peripheral tissues with aromatase activity, circulating estrogen concentrations decrease to extremely low levels. This is associated with symptomology of estrogen deficiency, which can occur rapidly, whereas other symptoms (osteopenia) are delayed. The major acute symptoms include vasomotor instability (hot flashes and sweats) and vaginal atrophy, resulting in discomfort, dyspareunia, and urethral syndrome. Other symptoms, possibly related to decreased estrogen levels, include loss of concentration, loss of libido, weight gain, depression, thinning hair, joint discomfort, and sleep disruption.

Ligand Structure

Compounds with estrogenic activity can be classified as either steroidal or nonsteroidal. Steroidal estrogens can be subdivided into natural and synthetic forms. The structures of progesterone, the three endogenous human estrogens (β-estradiol, estrone, and estriol), and their biosynthetic pathways are shown in Figures 38-1 and 38-2. Estradiol is the most potent of the three estrogens. Synthetic hormones that are used therapeutically generally have a heterocyclic structure resembling endogenous steroids.

Endogenous human estrogens have a low potency if administered orally as a result of poor absorption and rapid inactivation by first-pass hepatic metabolism. Estrogen conjugates are formed by enzymatic addition of sulfate at C3 or glucuronidation, which confers inactivation and solubility, enhancing their renal excretion. The endogenous pool of estrogenic steroids represents a balance among the three naturally occurring estrogens and loss by conjugation and excretion. Estradiol predominates before menopause, estrone sulfate predominates in postmenopausal women, and estriol levels predominate during pregnancy.

The synthetic estrogens, ethinyl estradiol and mestranol, are used predominantly in combination oral contraceptives. These compounds have an ethinyl group at C17, which retards hepatic inactivation. Mestranol requires activation by hepatic conversion to ethinyl estradiol. More recently, attention has focused on the nonsteroidal synthetic compounds, selective estrogen receptor modulators (SERMs), that interact with estrogen receptors (ER). The first available SERM, tamoxifen, is a triphenylethylene derivative that acts as an estrogen antagonist in breast; clinical applications include treatment, and recently prevention, of breast cancer (see Chapter 55). A clinically important benefit of tamoxifen is its agonist activity in bone, which antagonizes osteopenia. A concern with tamoxifen is the significantly increased risk of endometrial cancer and venous thrombosis related to its estrogenic activity. Raloxifene is a SERM developed to delay osteoporosis in postmenopausal women who are not candidates for estrogen treatment. It has agonist activity in bone but displays little estrogen-like activity in breast or uterus. Clomiphene citrate is a racemic mixture of two stereoisomers that has both agonist and antagonist properties and is used to treat infertility by inducing ovulation. Considerable research is directed at identifying new SERMS with tissue-specific agonist and antagonist properties for each therapeutic goal.

The progestin derivatives are classified on the basis of their structure at positions C21 or C19 (19-nortestosterone). The C21 derivatives include the natural progestins, progesterone and 17α-hydroxyprogesterone, which use the same carbon backbone as pregnenolone, from which they are derived. The synthetic C21 compounds are derivatives of 17α-hydroxyprogesterone and include medroxyprogesterone acetate, megestrol acetate, and hydroxyprogesterone caproate. The presence of an acetate ester in medroxyprogesterone acetate and megestrol acetate helps protect these compounds from inactivation in the liver and allows their oral use.

The synthetic 19-nortestosterone derivatives are similar to testosterone but lack the C19 methyl group and have an ethinyl group at C17α. The ethinyl group present at C17 retards hepatic inactivation, which allows oral administration to attain effective blood levels. These compounds are divided into the estranes and gonanes. The estranes are 19-nortestosterone analogs that include norethindrone, norethindrone acetate, norethynodrel, and ethynodiol diacetate. The estranes exhibit relatively greater androgenic activity, less progestin activity than progesterone analogs, and relatively little estrogenic activity. Norethindrone acetate and norethynodrel are metabolized to the active progestin norethindrone. The gonanes are norgestrel analogs that include levonorgestrel, desogestrel, and norgestimate. These compounds are less androgenic and estrogenic than norethindrone.

Two additional important ligands of the PGR include danazol and mifepristone (formerly called RU486). Danazol is a steroid derivative that has significant agonist activity at both progesterone and androgen receptors and is used in treating endometriosis. Mifepristone is a steroid derivative that binds to both progesterone and glucocorticoid receptors and displays progestin antagonist activity in most target tissues.

Transport of Hormones in the Blood

Steroid hormones are highly hydrophobic molecules that must be transported by serum proteins to their target tissues. Circulating estrogens are specifically bound by SHBG, and progesterone by corticosteroid-binding globulin (CBG). These are relatively high-affinity, low-capacity interactions compared with those of albumin. The concentration of these binding globulins relative to hormone concentrations determines free hormone concentrations. Free hormone concentrations represents hormone availability to target tissues. The concentrations of the binding globulins are hormonally regulated, and the synthesis of both globulins increase in response to estrogen administration; serum albumin concentrations are unaffected. Synthetic ligands show variable affinities for these serum proteins.

Receptor Mechanisms

The molecular basis for hormone action, including estrogen and progesterone, is reviewed in Chapter 1. Free steroid passively diffuses into any cell but accumulates only in cells expressing the specific cytoplasmic steroid-binding proteins. Both estrogen and progesterone receptors are members of the nuclear receptor superfamily. The two distinct ER subtypes, ERα and ERβ, are products of different genes, and estrogen binds with high affinity to both receptor subtypes. ERα is expressed in the reproductive tract and breast and mediates many of the effects of estrogen on sexual development and reproductive function. ERβ is highly expressed in ovary and brain. All currently available drugs that target estrogen receptors can bind to both receptor dimers, suggesting that selectivity of action is not simply dependent on the presence of receptor subtypes. Because the ligand-binding domains of these two ER subtypes are different, specific ligands for each receptor are likely to be developed. Only one gene encodes the PGR, but two protein isoforms are produced, PGR-A and PGR-B. These proteins display some functional differences in experimental systems, and their ratio shows some variability. However, they have the same ligand-binding domain, and pharmacological effects result from activation of both isoforms.

The classical mechanism of action of nuclear steroid hormones is that the steroid-hormone complex can act as a steroid-activated transcription factor (see Chapter 1). The response of a tissue to a specific ligand is highly regulated at multiple levels:

The antihormones and SERMs competitively antagonize hormone receptor binding. These agents induce a distinct conformational change in the receptor, allowing it to bind to the HRE in target genes. Also, the effect of the multiprotein complex on gene activity depends on the ligand. These effects provide a rationale for SERMs to act either as agonist or antagonist in a tissue-specific manner.

Receptor concentrations also influence tissue responses and are strongly affected by the hormonal environment. PGRs are expressed in response to estrogen exposure, and high concentrations of progesterone decrease ER concentrations, which, in turn, leads to decreased PGR concentrations. Furthermore each hormone can directly regulate its own receptor concentration (down or up). The half-life for estrogen receptors is 2 to 4 hours, and this may be reduced by binding ligand.

Estrogens

Estrogens are rapidly absorbed from the gastrointestinal (GI) tract, skin, and mucous membranes, and after parenteral injection. Because the unconjugated natural estrogens are rapidly inactivated in the GI tract and liver, if taken orally, their delivery by other routes (transdermally, vaginally, nasally, or intramuscularly) is warranted. Micronized estradiols, steroidal estrogens that contain an ethinyl group at C17, the conjugated estrogens, and nonsteroidal estrogens are active orally. Once absorbed, they are rapidly metabolized in the liver.

Estrogens are excreted primarily as polyhydroxylated forms that are conjugated at C3 with sulfate or glucuronic acid. Free estrogens are distributed to the bile, resorbed in the GI tract, and recirculated to the liver (enterohepatic recirculation). Approximately 20% of the estrogen is excreted in feces and the rest in urine. Estradiol is rapidly cleared from the blood. Estrone is converted in the liver to estrone sulfate, which is excreted or hydrolyzed back to estrone. The serum half-life for estrone sulfate is approximately 12 hours. The common synthetic steroidal estrogens, ethinyl estradiol and mestranol, are metabolized more slowly than estradiol because of the ethinyl group at C17. Brain tissue can metabolize 17β-estradiol to form catechol estrogens, which are structurally similar to catecholamines but of unclear function. The synthetic nonsteroidal estrogens may be excreted as glucuronide or sulfate conjugates.

Progestins

Oral progesterone is almost completely inactivated in the liver; thus synthetic modifications are necessary to produce orally active progestins. Progesterone can be given parenterally but has an elimination half-life of only a few minutes. It is converted in the liver to pregnanediol and conjugated with glucuronic acid at C3, and the conjugate is excreted mainly in urine. The 19-nortestosterone derivatives are all orally active. Medroxyprogesterone acetate can be administered orally or intramuscularly (IM), whereas megestrol acetate is administered orally only. The plasma half-lives of the C21 derivatives and the 19-nortestosterone compounds are longer than those of progesterone. Most of them are metabolized in the liver and conjugated to glucuronides and excreted in the urine.

Other Estrogen and Progesterone Receptor Ligands

Clomiphene is administered orally and readily absorbed from the GI tract. It may enter the enterohepatic circulation, with approximately 50% excreted in the feces within 5 days, but its serum half-life is shorter than this. The two active isomers of clomiphene reach peak plasma concentrations within 3 to 6 hours after an oral dose. However, the trans-isomer (enclomiphene) has a shorter plasma elimination half-life (4 to 10 hours) than the cis-isomer (zuclomiphene >18 hours). Tamoxifen is administered orally, and absorption is somewhat slow with extensive metabolism. The major metabolites of tamoxifen include N-desmethyltamoxifen, which binds only weakly to estrogen receptors but is present in greater concentrations than tamoxifen itself, and 4-hydroxytamoxifen, which binds much more tightly to estrogen receptors but is present in low concentrations. The antiestrogen action of tamoxifen is likely aided by its metabolites. Conjugated metabolites of tamoxifen are primarily excreted by the biliary route into the feces. The enterohepatic recirculation of the metabolites, their binding to serum albumin, and their high affinity binding to tissues all contribute to their long half-life of 7 days. Raloxifene is administered orally and is rapidly absorbed but is extensively conjugated to glucuronides by first-pass metabolism in the liver. Raloxifene and its metabolites are interconverted with a mean plasma half-life of approximately 30 hours. Elimination is primarily in the feces. Orally administered danazol is rapidly absorbed and metabolized but takes 7 to 14 days to reach a steady-state concentration. Metabolites are excreted in both urine and feces.

Inhibitors of Steroidogenesis and Aromatase

Aminoglutethimide is rapidly absorbed after oral administration, with maximum circulating concentrations reached in 1.5 hours. A total of 20% to 35% of the drug is bound to plasma proteins, and 35% to 50% is excreted unchanged in the urine; only 4% to 15% is excreted as acetyl aminoglutethimide. None of the observed metabolites block steroidogenesis. Anastrozole is rapidly absorbed after oral administration, with maximum circulating concentrations reached in 2 hours. Approximately 40% is bound to plasma proteins. It is extensively metabolized and excreted primarily in the urine.

Fertility Control

Ovulation Induction

Approximately 20% to 30% of cases of infertility result from an anovulatory condition. Agents that induce ovulation in these patients include gonadotropins, GnRH, and clomiphene citrate. Clomiphene citrate, a SERM with both agonist and antagonist properties, is used to treat ovulatory failure in women desiring pregnancy whose mates are fertile and potent. This agent may act as an antiestrogen in the hypothalamus, relieving estrogen-induced negative feedback on GnRH release. After clomiphene administration, the pulse frequency (but not amplitude) of LH release increases significantly, possibly because of an increase in the pulse frequency of GnRH release. Clomiphene is most effective in women with normal concentrations of estrogen before therapy and is not useful in women with primary ovarian or pituitary dysfunction. This agent can cause multiple ovulations, resulting in a 6% to 12% incidence of multiple gestation.

Replacement Therapy

Other Uses of Replacement Therapy

Hormone replacement therapy is useful in treating ovarian failure (primary or premature), dysfunctional uterine bleeding, and luteal phase deficiency. Estrogen therapy initiated near the time of puberty may help stimulate normal sexual development in girls with primary ovarian failure from multiple causes. Dysfunctional uterine bleeding occurs during irregular menstrual cycles and is often characterized by prolonged bleeding. High-dose progestin therapy can be used to stop an episode of prolonged bleeding but should be followed by long-term cyclic therapy with an orally administered progestin to ensure occurrence of regular withdrawal bleeding. Luteal phase deficiency results from insufficient progesterone. Ovulation is normal, but the corpus luteum functions subnormally, with insufficient progesterone produced to maintain pregnancy. The most popular method of treating this is natural progesterone supplementation.

Cancer Chemotherapy

Approximately one third of patients with advanced breast cancer who undergo therapy that decreases estrogen production or action will exhibit tumor regression, a prolongation of disease-free survival, or both. An overall response rate of 30% to 40%, with few adverse effects, is observed in women with breast cancer receiving adjuvant treatment with tamoxifen. Tamoxifen is an SERM showing antagonist effects in the breast while being an agonist in uterus and bone. Tamoxifen acts in the breast by competing with endogenous estrogens for binding to and activating ERs. Tamoxifen has also been approved for use as a breast cancer preventative based on clinical trials with women at high risk; factors used to assess high risk include age, family history of breast cancer, and others. The studies showed a 49% decrease in the risk of developing breast cancer in women taking tamoxifen compared with those taking placebo. The results are consistent with earlier studies that showed a 50% reduction in the risk of developing a new tumor in the opposite breast in women with breast cancer who took tamoxifen. Raloxifene, another SERM, is currently in clinical trials for prevention of breast cancer.

A reduction in estrogen production in postmenopausal women as a means of preventing breast cancer recurrence can be achieved by inhibition of adrenal steroidogenesis or peripheral aromatization of adrenal androgens. Aminoglutethimide acts by inhibiting two enzymes. One is the cholesterol side-chain-cleaving enzyme, which converts cholesterol to pregnenolone, and the other is the aromatase enzyme, which converts adrenal androstenedione to estrone, and testosterone to estradiol (see Fig. 38-1). Glucocorticoid replacement therapy is needed in such patients, mainly to inhibit the compensatory rise in adrenocorticotropic hormone, which can antagonize the action of aminoglutethimide. Several drugs are now available that specifically inhibit the aromatase enzyme and not the cholesterol side-chain-cleaving enzyme. Adrenal steroidogenesis is not inhibited, avoiding the need for glucocorticoid replacement. Circulating estrogen concentrations are effectively suppressed. These compounds include anastrozole, letrozole, and exemestane. These agents are used in the adjuvant treatment of breast cancer but also as first-line treatment in advanced disease (see Chapter 55). Clinical studies have shown that the sequential use of tamoxifen for 5 years followed by an aromatase inhibitor reduced the risk of breast cancer recurrence compared with tamoxifen use alone.

Progestin therapy is used as an adjuvant and palliative treatment of advanced endometrial carcinoma. Several synthetic progestins can be used and likely act through the PGR to down regulate the ER and induce formation of 17β-hydroxysteroid dehydrogenase, which increases estradiol metabolism. In addition, progestins may have direct cellular actions, leading to decreased cell division. High PGR concentrations in endometrial tumors correlate with increased survival.

High doses of estrogens can be used as an adjuvant and palliative treatment for advanced prostate cancer by antagonizing gonadotropin formation. High-dose estrogen therapy is associated with a high incidence of adverse cardiovascular events, predominantly thromboembolism. The use of the synthetic nonsteroidal estrogen diethylstilbestrol has been replaced with newer therapies using a combination of steroidal estrogens that have a somewhat lower incidence of side effects. The benefit of high-dose estrogen is presumed to be due to its suppression of testosterone production.

Other Uses

Endometriosis results from implantation of ectopic endometrial cells outside the uterus. These cells continue to respond to steroid hormones but may show subtle differences in ER and PGR concentrations and function. Clinically, patients experience dysmenorrhea and sometimes dyspareunia. The goal of therapy in endometriosis is to induce an estrogen-poor environment to inhibit the growth of implants and thereby alleviate symptoms. The compounds used in the United States to treat endometriosis are combination oral contraceptives, danazol, progestins, and GnRH analogs. These hormone regimens may function by binding to the PGR and opposing estrogen action or inhibiting the LH-FSH surge. Danazol can interact with both androgen and progesterone receptors.

Estrogens

The more serious, long-term side effects occasionally encountered with estrogen usage include endometrial cancer, thromboembolic disorders, and gallbladder disease. The incidence of endometrial cancer is increased as much as 24-fold in those exposed to prolonged (> 5 years) unopposed estrogens, but this increased risk can be eliminated by using a progestin in combination. The risk of venous thromboembolism increases twofold to threefold with estrogens. The incidence of thromboembolic disorders is greatest among older smokers. High-dose estrogen used in prostate cancer treatment is associated with an increased risk of nonfatal myocardial infarction, stroke, pulmonary embolism, and thrombophlebitis. A twofold to fourfold increase in the risk of gallbladder disease is seen in estrogen users. A substantial increase in blood pressure reported in a small number of women appears to be an idiosyncratic or genomic-based response to estrogens not seen in large clinical trials. An increased risk of ovarian cancer has been seen in some studies but not others. Studies of estrogen-only therapy show little, if any, increased risk of breast cancer, and any increased risk was associated with prolonged use and higher doses.

Some less serious, more acute adverse effects of estrogen therapy include changes in vaginal bleeding patterns, nausea, occasional vomiting, abdominal cramps, bloating, diarrhea, appetite changes, fluid retention, dizziness, headache, breast discomfort, weight gain, mood changes, ocular changes, allergic rash, and changes in some serum proteins. Most of these effects are related to dose. High-dose therapy in men is associated with gynecomastia and impotence.

An etiological role for diethylstilbestrol, a nonsteroidal estrogen agonist, in the development of clear-cell adenocarcinoma of the vagina and cervix is based on epidemiological data from the 1950s, when this drug was used to prevent miscarriage. An increased incidence of rare cancers of these types has been noted in women exposed to diethylstilbestrol in utero, and it is no longer used in the United States.

Progestins

Progestin-only implants and oral contraception are associated with an increased incidence of ectopic pregnancy upon contraceptive failure. The occasional and less serious side effects of progestin-only therapy include breakthrough bleeding, spotting, changes in menstrual flow, amenorrhea, edema, weight changes, nausea, bloating, headache, allergic rash, mood changes, and changes in lipoprotein concentrations (HDL, decreased; LDL, increased). Glucose tolerance test results are abnormal in 4% to 16% of women receiving high-dose progestin. Plasma glucose concentrations should be monitored in diabetic women and in those with a history of glucose intolerance taking oral contraceptives. A progestin, at as low a dose and with as low a potency as possible, should be used in such women. The most common side effects of intramuscular medroxyprogesterone acetate and Norplant used for contraception are menstrual abnormalities, characterized by irregular bleeding early in the treatment, followed by amenorrhea in 50% to 70% of patients after 2 years of treatment. In addition, the surgical insertion and removal of Norplant-2 silastic rods can be associated with patient discomfort and possible infection.

Combination Oral Contraceptives

Despite more than 40 years of oral contraceptive use, some controversy remains concerning the risks. However, several factors must be considered to put this controversy into perspective. First, the hormone doses used in many of the early studies that associated the use of oral contraception with specific side effects were much higher than are used currently. Fewer adverse effects have been noted in recent studies with the use of low-dose oral contraceptives. Second, the design of several early studies was criticized because composition of the subgroups did not allow direct comparison. Finally, restricting the use of oral contraceptives in certain high-risk patient subgroups has led to a decrease in the incidence of cardiovascular side effects.

A number of clinical studies show an association between combined oral contraceptive use and thromboembolic disease in the absence of other predisposing factors. The risk of venous thromboembolism is twofold to six fold greater in those who use combined oral contraceptives than in nonusers. The increased risk is dependent on the type of progestin used. The increased risk of thromboembolic events is greater in women who smoke, in older women (over 35), and in women with higher doses of estrogen. Women who use oral contraceptives should not smoke. The risk of thromboembolic disease rapidly returns to normal after oral contraceptive use is discontinued and should be stopped at least 2 to 4 weeks before elective surgery and not restarted until at least 2 weeks after surgery. Combination oral contraceptives can cause a small increase in both systolic and diastolic blood pressure in some patients, and their use is contraindicated in patients with moderate to severe hypertension.

An increased risk of stroke and myocardial infarction are not definitively correlated with combination oral contraceptive use in women with no other risk factors. Nearly all recent studies have shown no increased risk of myocardial infarction or ischemic stroke without other major risk factors. However, compared with nonusers, there is a substantial increased risk of myocardial infarction and ischemic stroke in women who use combination oral contraceptives and have one or more of these risk factors: smoking, uncontrolled hypertension, diabetes, and hypercholesterolemia. The risks increase with age.

Multiple studies have shown no change in the incidence of breast cancer in women who take combination oral contraceptives, though a few studies showed an increased risk. Given the relatively small number of breast cancer patients in the age group of women using contraception, the number of increased cases is actually small. The association of breast cancer with oral contraceptive use continues to be an area of uncertainty. Women who are positive for human papillomavirus and use oral contraceptives may be at increased risk for cervical cancer, if they have used these drugs for more than 5 years.

Oral contraceptives are contraindicated in women with a current or past history of thrombophlebitis or thromboembolic disorders, cerebrovascular or coronary artery disease, a known or suspected pregnancy, undiagnosed abnormal genital bleeding, a known or suspected carcinoma of the breast, uterus, cervix, vagina, or other estrogen-dependent neoplasm, hepatic adenoma or carcinoma, and cholestatic jaundice of pregnancy or jaundice after previous oral contraceptive use. Oral contraceptives should be used with caution in patients with liver or renal disease, asthma, migraine headaches, diabetes, hypertension, or congestive heart failure, and in patients receiving medications that can interfere with its effectiveness. Women who smoke and use oral contraceptives should be advised to use alternative methods of birth control after 35 years of age. In addition, several drugs increase the risk of contraceptive failure by increasing the metabolism of the oral contraceptives. Examples of such drugs include barbiturates, rifampin, phenylbutazone, phenytoin, carbamazepine, oxcarbazepine, topiramate, ampicillin, and tetracyclines.

Combination Replacement Therapy

Our understanding of the risks and benefits of estrogen plus progestin replacement therapy in postmenopausal women with an intact uterus has been strongly influenced by the results of the Women’s Health Initiative randomized, placebo-controlled clinical trial published in July 2002. The strengths of this trial were its randomized design, large numbers (16,608 women enrolled), and more than 5 years of detailed follow-up. The limitations include the use of only one replacement formulation (0.625 mg/day conjugated equine estrogens, plus 2.5 mg/day medroxyprogesterone acetate), inclusion of a broad age range with many women several years past the initial cessation of menses (average age 63), and a high rate of patient withdrawal from the study. The results of this study have fueled extensive debate over the use of replacement therapy and significantly reduce its use by menopausal women.

The most serious risks observed in this study for users of estrogen plus progestin replacement therapy were an increase in venous thromboembolic disease, stroke, nonfatal myocardial infarction and fatal coronary heart disease, and breast cancer. The overall rates of cardiovascular disease were low, but up to a twofold increase in venous thromboembolism, a 41% increase in stroke, and a 29% increase in coronary heart disease were observed. Much of the increased relative risk of cardiovascular disease was seen in the first year. A 26% increase in breast cancer was observed, with the difference between the replacement and placebo groups being evident only after 4 years. A decreased risk of ovarian cancer was not observed. Rather, an increased number of ovarian cancers was observed in the replacement group, although the increase over the placebo group was not statistically significant.

Current recommendations for use of estrogen plus progestin combination therapy is for treatment of acute symptoms of menopause for the shortest duration possible. Use is contraindicated in women with abnormal genital bleeding, a history of breast cancer or other estrogen-dependent neoplasia, venous or arterial thromboembolic disease, or liver dysfunction. The treatment of patients should be governed by the particular risk profile of the individual.

Antiestrogens, SERMs, and Progesterone Receptor Ligands

The frequency and severity of the adverse effects of clomiphene citrate are dose-related and include vasomotor symptoms that resemble those in menopausal patients. Visual problems occur occasionally and have been correlated with an increase in total dose. Other high-dose side effects include ovarian enlargement or cyst formation, ovarian hyperstimulation syndrome, abdominal discomfort, nausea and vomiting, abnormal uterine bleeding, breast tenderness, headache, dizziness, depression, allergic dermatitis, and urinary frequency. There is a 6% to 12% incidence of multiple gestations, particularly twins, in women taking clomiphene, as compared with a 1% incidence in the general population. Clomiphene is contraindicated in patients with ovarian cysts, pregnancy, a history of liver disease, abnormal uterine bleeding, and thyroid or adrenal dysfunction.

The serious side effects of tamoxifen include a twofold increased risk of endometrial cancer, a threefold increased risk of pulmonary thromboembolism, a 59% increased risk of deep vein thrombosis, and a 40% increased risk of stroke. Less serious side effects seen in some women include vasomotor symptoms, nausea, and vomiting. Although the teratogenic effects of tamoxifen in humans are unknown, pregnancy should be avoided in women taking tamoxifen, because numerous defects have been demonstrated in animals. Tamoxifen is contraindicated in women using anticoagulation therapy or with a history of deep vein thrombosis or pulmonary embolus.

The serious side effects of raloxifene include an increase in the risk of pulmonary thromboembolism and deep vein thrombosis. The most common, less serious side effect seen

in some women is vasomotor symptoms. Raloxifene is contraindicated in women who are lactating, pregnant, or have a history of venous thromboembolic events.

Mifepristone is well tolerated and associated with only occasional prolonged uterine bleeding. Less serious common side effects include uterine cramping, abdominal pain, back pain, headache, and GI disturbances.

The use of danazol is fraught with multiple antiestrogen-like and androgenic side effects, including weight gain, muscle cramps, decreased breast size, deepening of the voice, edema, amenorrhea, emotional lability, flushing, sweating, acne, mild hirsutism, oily skin and hair, altered libido, nausea, headache, dizziness, insomnia, rash, increased LDL and decreased HDL concentrations, and increased hepatic enzyme activities. Most of these effects are reversed upon cessation of the drug. Danazol is contraindicated in pregnant women or in breastfeeding mothers.

The most frequent reversible side effects of aminoglutethimide include drowsiness, rash, nausea, anorexia, fever, dizziness, and ataxia, which can diminish with continued use. Reported adverse effects of anastrozole include fatigue, nausea, headache, hot flashes, pain, and back pain.