Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

65. Hormone Therapy in Women

Sophia N. Kalantaridou, Devra K. Dang, and Karim Anton Calis


KEY CONCEPTS

 Images The decision to use perimenopausal or postmenopausal hormone therapy must be individualized and based on several parameters, including menopausal symptoms, osteoporosis fracture risk, cardiovascular disease risk, breast cancer risk, and thromboembolic risk.

 Images Hormone therapy is the most effective treatment option for alleviating vasomotor and vaginal symptoms of menopause.

 Images Osteoporotic fracture prevention is an indication for use of systemic estrogen products when alternate therapies are contraindicated or cause adverse effects.

 Images Hormone therapy may improve depressive symptoms in symptomatic menopausal women.

 Images Cardiovascular disease, including coronary artery disease, stroke, and peripheral vascular disease, is the leading cause of death among women. Postmenopausal hormone therapy should not be used for reducing the risk of cardiovascular disease.

 Images Because of the increased risk of endometrial hyperplasia and endometrial cancer with estrogen monotherapy (i.e., unopposed estrogen), hormone therapy in women who have not undergone hysterectomy should include a progestogen in addition to the estrogen.

 Images Use of hormone therapy at doses lower than those prescribed historically (i.e., prior to the Women’s Health Initiative study) is effective in the management of menopausal symptoms.

 Images Results from randomized trials of hormone therapy in postmenopausal women cannot be extrapolated to premenopausal women with ovarian dysfunction. Women with primary ovarian insufficiency need exogenous sex steroids to compensate for decreased production by their ovaries.


MENOPAUSE AND PERIMENOPAUSAL AND POSTMENOPAUSAL HORMONE THERAPY

Epidemiology

Menopause is the permanent cessation of menses following the loss of ovarian follicular activity. The median age at the onset of menopause in the United States is 51 years. By definition, it is a physiologic event that occurs after 12 consecutive months of amenorrhea, so the time of the final menses is determined retrospectively. Women who have undergone hysterectomy must rely on their symptoms to estimate the actual time of menopause.

Etiology

Menopause refers to loss of ovarian function and subsequent hormonal deficiency. This can be due to the normal process of aging (i.e., natural menopause), ovarian surgery (bilateral oophorectomy), medications (e.g., cancer chemotherapy), or pelvic irradiation.

Pathophysiology

A woman is born with approximately two million primordial follicles in her ovaries. During a normal reproductive life span, she ovulates fewer than 500 times. The vast majority of follicles undergo atresia.

The hypothalamic–pituitary–ovarian axis dynamically controls reproductive physiology throughout the reproductive years. The pituitary is regulated by pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH), produced by the pituitary in response to GnRH, regulate ovarian function. These gonadotropins also are influenced by negative feedback from estradiol and progesterone. Ovarian follicular activity is reflected by the circulating concentrations of sex steroids and by peptide hormones including inhibin, activin, and anti-Mullerian hormone (AMH). AMH is a product of growing ovarian follicles, which appears to be independent of the hypothalamic–pituitary–gonadal axis. It is a principal regulator of early follicular recruitment from the primordial pool such that the concentration of AMH in blood may also reflect the nongrowing follicle population. AMH concentrations decline with age. For women without any menstrual cycle disorder, AMH levels predicted the median time to menopause.1 The sex steroids include estradiol, produced by the dominant follicle; progesterone, produced by the corpus luteum after maturation of the dominant ovarian follicle; and androgens, primarily testosterone and androstenedione, secreted by the ovarian stroma. Sex steroids are important for the healthy functioning of many organs, including the bones, brain, skin, and reproductive and urogenital tracts. They act primarily by regulating gene expression.

Pathophysiologic changes associated with menopause are caused by loss of ovarian follicular activity. Ovarian primordial follicle numbers decrease with advancing age, and at the time of the menopause, few follicles remain in the ovary. Hence, the postmenopausal ovary is no longer the primary site of estradiol or progesterone synthesis. The postmenopausal ovary secretes primarily androstenedione. In contrast to the acute fall in circulating estrogen at the time of menopause, the decline in circulating androgens commences in the decade leading up to the average age of natural menopause and closely parallels increasing age.2 Whether the ovary continues to secrete testosterone after menopause remains controversial.3 Hypertrophy of the ovarian stroma may develop after menopause, probably secondary to high LH concentrations, thereby resulting in increased ovarian testosterone production. Alternatively, the ovaries may become fibrotic and a poor source of sex steroids. No endocrine event clearly signals the time just prior to final menses.4

As women age, a progressive rise in circulating FSH and a concomitant decline in ovarian inhibin-B and AMH are observed. In women who continue to experience menstrual bleeding, FSH determinations on day 2 or 3 of the menstrual cycle are considered elevated when concentrations exceed 10 to 12 international units/L (10 to 12 IU/L), an indication of diminished ovarian reserve. Alternatively AMH measured at any time in the cycle predicts diminishing ovarian reserve.2 Clear elevations in serum FSH are seen in women approximately at age 40 years.4 When ovarian function has ceased, serum FSH concentrations are greater than 40 international units/L (40 IU/L). Menopause is characterized by a 10- to 15-fold increase in circulating FSH concentrations compared with concentrations of FSH in the follicular phase of the cycle, a fourfold to fivefold increase in LH, and a greater than 90% decrease in circulating estradiol concentrations.4 During the perimenopause, FSH concentrations may rise to the postmenopausal range during some cycles but return to premenopausal levels during subsequent cycles. Thus, high concentrations of FSH should not be used to diagnose menopause in perimenopausal women.

Clinical Presentation

The perimenopause commences with the onset of menstrual irregularity and ends 12 months after the last menstrual period.5 The menstrual cycle irregularity is caused by the increased frequency of anovulatory cycles. Women commonly experience symptoms during the perimenopause, which substantially impact their health and daily function. Research has shown that 25% of women experience severe vasomotor symptoms (e.g., hot flushes and night sweats), 30% experience severe psychological symptoms (e.g., depression, anxiety), and 50% report moderate to severe symptoms of sleep disturbance, joint pain, or headache, and at least one in four women have sexual dysfunction.6,7

Women who experience severe symptoms, either from early in the menopause transition or from their final menstrual period, are likely to continue to experience severe symptoms for several years.6 The perimenopause is associated with a higher vulnerability to depression with the risk increasing from early to late perimenopause and decreasing during postmenopause.8 Women with a history of depression are nearly five times as likely to be diagnosed with depression during the perimenopause, whereas women with no history of depression are two to four times more likely to have a diagnosis compared with premenopausal women.8

In addition to the symptoms of menopause, loss of estrogen production results in significant metabolic changes including effects on body composition, lipids, vascular function, and bone metabolism. The menopause transition is associated with a significant increase in central abdominal fat, which may occur without commensurate change in body weight.9

Symptoms in perimenopausal women may require treatment despite the presence of menstrual bleeding. Although other conditions that may cause similar symptomatology should be first excluded, there is no condition that mimics classic menopausal vasomotor symptomatology.

Dysfunctional uterine bleeding may occur during the perimenopausal years because of anovulatory cycles; however, abnormal uterine bleeding always merits investigation when it cannot be simply explained by menopausal cyclical irregularity. Treatment options for dysfunctional uterine bleeding include insertion of an intrauterine progestin-impregnated device, systemic progestogen therapy, or the combined oral contraceptive pill.

TREATMENT

Nonpharmacological options may alleviate mild symptoms but are unlikely to be effective for severely symptomatic women.

Desired Outcomes

Menopause is a natural life event, not a disease. The primary goals of therapy for menopause are to relieve symptoms and improve quality of life while minimizing adverse effects.

General Approach to Treatment

In women with mild vasomotor and/or vaginal symptoms, nonpharmacologic therapy can be considered. However, for some women these are not effective. Figure 65-1 outlines a treatment algorithm for women requiring pharmacologic therapy. In the absence of contraindications, hormone therapy is appropriate for women with hot flushes and vulvar or vaginal atrophy (Table 65-1).

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FIGURE 65-1 Algorithm for pharmacologic management of menopausal symptoms.

TABLE 65-1 FDA Indications and Contraindications for Menopausal Hormone Therapy with Estrogens and Progestins

Images

Images The decision to use hormone therapy and the type of formulation used must be individualized and based on several parameters, including the woman’s assessment of the severity of her menopausal symptoms and her wishes, the risk of osteoporosis fracture, cardiovascular disease, breast cancer, and venous thromboembolic events (VTE). The potential adverse effects of hormone therapy on breast cancer and VTE risk vary according to the need for concurrent progestogen therapy and route of administration, respectively.


CLINICAL PRESENTATION AND DIAGNOSIS Perimenopause and Menopause

Symptoms

    • Vasomotor symptoms (hot flushes and night sweats)

    • Sleep disturbances

    • Mood changes

    • Problems with concentration and memory

    • Vaginal dryness and dyspareunia

    • Arthralgia

Signs

    • Perimenopause: dysfunctional uterine bleeding as a result of anovulatory cycles (other gynecologic disorders should be excluded)

    • Menopause: signs of urogenital atrophy

Laboratory Tests

    • Perimenopause: FSH on day 2 or 3 of the menstrual cycle greater than 10–12 international units/L (10–12 IU/L)

    • Menopause: FSH greater than 40 international units/L (40 IU/L)

Other Relevant Diagnostic Tests

    • Thyroid function tests

    • Iron stores

    • Lipid profile

The duration of therapy also needs to be individualized according to severity of symptoms and the patient’s wishes. An informed patient may choose to have longer term therapy if her symptoms are persistent. Recommendations should be specific to each woman’s clinical profile and concerns. Approved indications of hormone therapy include treatment of vasomotor symptoms and urogenital atrophy and prevention of postmenopausal osteoporosis. For treatment of vasomotor symptoms, systemic hormone therapy is the most effective pharmacologic intervention (see Fig. 65-1). For symptoms of urogenital atrophy, such as vaginal dryness, intravaginal products should be considered.

Nonpharmacologic Therapy

Although it is frequently suggested that menopausal symptoms can be managed effectively with lifestyle modifications, including wearing layered clothing that can be removed or added as necessary, lowering room temperature, decreasing intake of hot spicy foods, caffeine, and hot beverages, exercise, and other good general health practices, most women with moderate to severe symptoms find these approaches inadequate. More recently, dietary supplements have been promoted as “complementary medicine” alternatives to hormone therapy. To date, little evidence supports the use of such nonprescription herbal products, which include various herbal remedies and soy-based supplements.

Pharmacologic Therapy

Pharmacologic therapy is the mainstay of management of menopausal symptoms and includes both hormonal (estrogen with or without progestogen) and nonhormonal medications.

Drug Treatment of First Choice

Images Hormone therapy is the most effective treatment option for alleviating moderate and severe vasomotor and vaginal symptoms. In women with an intact uterus, hormone therapy consists of an estrogen plus a progestogen to prevent endometrial hyperplasia. In women who have undergone hysterectomy, estrogen therapy is given unopposed by a progestogen.

Published Guidelines

A number of national and international guidelines and consensus statements on the management of menopause are available.1014 The United States Preventive Services Task Force also provides a recommendation statement on the use of hormone therapy for the prevention of chronic medical conditions in postmenopausal women.15

Hormone Therapy for Vasomotor Symptoms and Vaginal Atrophy

Hormone therapy remains the most effective treatment for moderate and severe vasomotor symptoms, impaired sleep quality, and urogenital symptoms of menopause.

Vasomotor Symptoms The major indication for postmenopausal hormone therapy is management of vasomotor symptoms. Most women with vasomotor symptoms require hormone treatment for fewer than 5 years, so the risks of therapy appear to be small.

Fewer than 25% of women experience a menopausal transition without symptoms, whereas more than 25% suffer severe menopausal symptoms, most commonly hot flushes and night sweats. Women with mild vasomotor symptoms can experience relief by lifestyle modification, and at least 25% of women in clinical trials reported significant improvement of vasomotor symptoms when taking placebo. However, no therapy has been shown to be as effective as estrogen therapy in alleviating significant vasomotor symptoms.

Vaginal Atrophy Estrogen receptors have been demonstrated in the lower genitourinary tract, and at least 50% of postmenopausal women suffer symptoms of urogenital atrophy caused by estrogen deficiency.16Atrophy of the vaginal mucosa results in vaginal dryness and dyspareunia. Lower urinary tract symptoms include urethritis, recurrent urinary tract infection, urinary urgency, and frequency. Most women with significant vaginal dryness because of vaginal atrophy require local or systemic estrogen therapy for symptom relief. Intravaginal estrogen has been shown to reduce the risk of recurrent urinary tract infections, possibly by modifying the vaginal flora.13,17 Vaginal dryness and dyspareunia can be treated with an intravaginal estrogen cream, tablet, or ring; or with the selective estrogen receptor modulator (SERM) ospemifene. In clinical trials, vaginal estrogen appears to be better than systemic estrogen for relieving these symptoms and avoids high levels of circulating estrogen. Concomitant progestogen therapy is unnecessary if women are using low-dose micronized 17β-estradiol or estriol cream. Vaginal conjugated equine estrogens (CEE) creams are not recommended, as they require intermittent progestogen challenges (i.e., for 10 days every 12 weeks). This is an important caveat because vaginal atrophy requires long-term estrogen treatment.17

Urinary stress incontinence is not improved by estrogen therapy, whereas urge incontinence and overactive bladder, which become more prevalent with increasing age, may improve with vaginal estrogen therapy.18 Combined oral CEE and medroxyprogesterone acetate (MPA) therapy may increase stress incontinence.19

Osteoporosis Prevention and Treatment Postmenopausal osteoporosis is a serious age-related disease that affects millions of women throughout the world. Menopause is accompanied by accelerated bone loss, and the central role of estrogen deficiency in postmenopausal osteoporosis is well established. Osteoporosis is characterized by reduced bone mass associated with architectural deterioration of the skeleton and increased risk for fracture. Estrogen deficiency results in bone loss through its actions in accelerating bone turnover and uncoupling bone formation from resorption. It is important to recognize that bone loss commences 2 years before the final menstrual period.20Throughout menopause, the average loss of bone mineral density (BMD) is around 6.4% at the lumbar spine and 4% to 5% at the femoral neck, with obese women experiencing less bone loss than nonobese women.20 An observational study of more than 9,000 postmenopausal women examined the relationship between endogenous estrogens and BMD, bone loss, fractures, and breast cancer.2124 Women with detectable serum estradiol concentrations (5 to 25 pg/mL [18 to 92 pmol/L]) had a 6% to 7% higher BMD at the total hip and spine compared with women with undetectable levels (less than 5 pg/mL [18 pmol/L]).23 They also had significantly less bone loss at the hip than women with undetectable levels.22 Women with undetectable serum estradiol concentrations had a relative risk of 2.5 for subsequent hip and vertebral fractures.24 However, women with the highest estradiol serum concentrations had the greatest risk of developing breast cancer.21

The Women’s Health Initiative (WHI), a landmark controlled clinical trial evaluating the benefits and risks of postmenopausal hormone therapy, was the first randomized trial to demonstrate that hormone therapy reduces the risk of fractures at the hip, spine, and wrist.25,26 These findings are in agreement with observational data and several meta-analyses of the efficacy of hormone therapy for reducing fractures in postmenopausal women.27 Estrogen therapy reduces bone turnover and increases bone density in postmenopausal women of all ages. The protective effect persists as long as the treatment is maintained. With cessation of therapy, postmenopausal bone loss resumes at the same rate as in untreated women.28,29 The standard bone-sparing daily estrogen dose is equivalent to 0.625 mg CEE.30 However, lower doses of estrogen have been shown to increase bone mass to the same extent as standard-dose estrogen therapy.31

Images Systemic estrogen therapy is indicated for the prevention of osteoporotic fracture in postmenopausal women younger than 60 years of age who are at increased fracture risk when alternate therapies are contraindicated or cause adverse effects. Indeed estrogen is one of the few treatments shown to prevent fragility fractures in osteopenic women.

General protective measures, such as regular weight-bearing exercise and avoidance of detrimental lifestyle habits such as smoking and alcohol abuse, are appropriate for all women. Some women require calcium supplementation to their dietary intake. Adequate vitamin D intake and/or supplementation is also needed. See Chapter 73 for a full discussion of osteoporosis prevention and treatment.

Colon Cancer Risk Reduction

Colorectal cancer is the fourth most common cancer and the second leading cause of cancer death in the United States (see Chap. 107). The estrogen–progestogen arm of the WHI study showed that combined estrogen–progestogen therapy may reduce colon cancer risk.25 In the postintervention follow-up period, the reduction in colorectal cancer risk disappeared.28

Quality of Life, Mood, Cognition, and Dementia

Images Hormone therapy improves depressive symptoms in symptomatic menopausal women, most probably by relieving flushing and improving sleep.32 Women with vasomotor symptoms receiving hormone therapy have improved mental health and fewer depressive symptoms compared with women receiving placebo; however, hormone therapy may worsen quality of life in women without flushes.33

There is no evidence that hormone therapy improves quality of life or cognition in older, asymptomatic women.3236


Clinical Controversy…

Some clinicians believe that hormone therapy can improve well-being and quality of life of early menopausal women, whereas others believe that hormone therapy, at best, has no effect in this population.

More than 33% of women 65 years and older will develop dementia during their lifetime.37 Several observational studies have suggested that estrogen therapy may be protective against Alzheimer’s disease (see Chap. 38). The WHI Memory Study (WHIMS, an ancillary study of the WHI trial) evaluated the effect of combined hormone therapy on dementia and cognition in 4,532 women 65 to 79 years old.35 The study found that postmenopausal women 65 years and older taking estrogen plus progestogen therapy had twice the rate of dementia, including Alzheimer’s disease, than women taking placebo (HR 2.05, 95% CI: 1.21 to 3.48).35 In addition, estrogen plus progestogen therapy in these women did not prevent mild cognitive impairment, a cognitive and functional state between normal aging and dementia that frequently progresses to dementia.35 The estrogen alone arm of the WHI trial showed similar findings.38,39

In contrast, the Women’s Health Initiative Memory Study of Younger Women (WHIMSY) found that neither estrogen plus progestogen or estrogen therapy alone confer any risk or benefit to cognitive function when taken by postmenopausal women aged 50 to 55 years old.40

Other Potential Effects

Diabetes In healthy postmenopausal women, hormone therapy appears to have a beneficial effect on fasting glucose levels in women with elevated fasting insulin concentrations.41 Also, in women with coronary artery disease, hormone therapy reduces the incidence of diabetes by 35%.42 These findings provide important insights into the metabolic effects of hormone therapy but are insufficient to recommend the long-term use of hormone therapy in women with diabetes.

Body Weight A meta-analysis of randomized controlled trials showed that unopposed estrogen or estrogen combined with a progestogen has no effect on body weight, suggesting that hormone therapy does not cause weight gain in excess of that normally observed at the time of menopause.43

Risks of Hormone Therapy

The potential risks of hormone therapy include ovarian cancer, endometrial cancer, breast cancer, venous thromboembolism, gallbladder disease, and possibly cardiovascular disease and lung cancer in older women. The level of risk may depend on the hormonal regimen used (estrogen only vs. estrogen plus progestogen), the route of administration, dose, duration of therapy, age at treatment initiation, and the patient’s other risk factors. Data on potential risks of hormone therapy remain limited.

Cardiovascular Disease

Images Cardiovascular disease, including coronary artery disease, stroke, and peripheral vascular disease, is the leading cause of death among women. Menopause is associated with the development of a more adverse lipid profile, increasing the risk for cardiovascular disease.44

In the decade prior to the publication of the WHI results in 2002, an expectation of coronary benefit had been a major reason for use of postmenopausal hormones because observational studies indicated that women who use hormone therapy have a 35% to 50% lower risk of coronary heart disease (CHD) than nonusers.45 In addition, previous studies have shown that estrogen exerts protective effects on the cardiovascular system, including lipid-lowering,46 antioxidant,47 and vasodilating effects.47 However, in the 2000s, published results of several randomized clinical trials provided no evidence of cardiovascular disease protection and even some evidence of harm with hormone therapy.25,4851

The primary findings of the estrogen plus progestogen arm of the WHI trial showed an overall increase in the risk of CHD (HR 1.29, 95% CI 1.02–1.63) among healthy postmenopausal women 50 to 79 years old receiving combined estrogen–progestogen hormone therapy compared with those receiving placebo.25 The primary findings of the estrogen-only arm of the WHI trial show no effect (either increase or decrease) on the risk of coronary heart disease in women taking estrogen alone.52 Subgroup analyses performed in the years after the WHI was first published in 2002 revealed that women who initiated hormone therapy 10 or more years after the time of menopause tended to have increased CHD risk compared with women who initiated therapy within 10 years of menopause.53,54 Neither estrogen alone nor estrogen plus progestogen was associated with a statistically significant effect on CHD in women aged 50–59 years, and hormone therapy was associated with reduced overall mortality, although this decrease was not statistically significant.53 More recently, subgroup analyses from the WHI that included only adherent study participants found that the risk of CHD with estrogen plus progestogen use is increased in the first 2 years of treatment, even in women aged 50–59 years at study entry. However, the risk of CHD in women who initiated therapy within 10 years of menopause appears to decrease after 6 years of treatment.54 Most women who commence estrogen or estrogen plus progestogen therapy do so within the first few years of becoming menopausal.

A randomized controlled study of 1,006 recently menopausal women revealed that 10-year hormone therapy was associated with a significantly reduced risk of cardiovascular disease.55 In addition, studies of recently menopausal women showed that the presence and severity of hot flushes are associated with vascular endothelial dysfunction and vascular inflammation (markers of increased risk for CHD); hormone therapy improved both parameters.5658Randomized controlled studies of low-dose hormone therapy started around the time of menopause are awaited.


Clinical Controversy…

Although some clinicians believe that early menopausal women using hormone therapy are at increased risk for cardiovascular disease, others believe that hormone therapy use early in menopause may be associated with a reduced cardiovascular disease risk.

Hormone therapy should not be initiated or continued solely for the prevention of cardiovascular disease. Adherence to a healthful lifestyle (cessation of smoking, regular exercise, healthy diet, and body mass index less than 25 kg/m2) may prevent the onset of cardiovascular disease in postmenopausal women.

In the estrogen plus progestogen arm of the WHI study, the increased risk for stroke and venous thromboembolism continued throughout the 5 years of therapy.25 Increased risk was observed only for ischemic stroke and not for hemorrhagic stroke.59 In the estrogen-alone arm of the study, a similar increased risk for stroke was observed.52 After the cessation of treatment, there is no increased risk for stroke.28,29

Breast Cancer

The WHI trial found that combined estrogen plus progestogen oral therapy has an increased risk of invasive breast cancer (HR 1.26, 95% CI: 1.0 to 1.59) and a trend toward increasing risk with increasing duration of therapy.25 This risk does not persist after discontinuation of hormone treatment.28 The estrogen-only arm of the WHI trial found a decreased risk for breast cancer during the 7-year follow-up period,52 which persisted after discontinuation of treatment.29

In the estrogen plus progestogen arm, the increased breast cancer risk did not appear until after 3 years of study participation.25 The risk was seen only in women who initiated therapy within 5 years of the start of menopause but not in those who started therapy more than 5 years after menopause.60 The breast cancers diagnosed in women in the hormone therapy group had similar histology and grade but were more likely to be in an advanced stage compared with women in the placebo group.61 The risk of breast cancer returns to baseline rapidly after discontinuation of hormone therapy.28,62 In an unselected postmenopausal population, the Million Women Study found that current use of hormone therapy increased breast cancer risk and breast cancer mortality (relative risk 1.66 and 1.22, respectively). Increased incidence was observed for estrogen-only use (relative risk 1.30), for estrogen plus progestogen (relative risk 2), and for tibolone (relative risk 1.45).63 The risk for estrogen only and estrogen plus progestin therapy were higher for those who initiated treatment within 5 years of menopause compared to those who started therapy 5 or more years after menopause.64

For women in the United States, the lifetime risk of developing breast cancer is approximately one in eight,65 and the greatest incidence occurs in women older than 60 years (see Chap. 105). In a collaborative re-analysis of data from 51 studies evaluating 52,705 women with breast cancer and 108,411 controls, less than 5 years of combined estrogen–progestogen therapy was associated with a 15% increase in breast cancer risk, and the risk increased with longer duration (relative risk 1.35 with 5 or more years of use).66 However, 5 years after discontinuation of hormone therapy, the risk of breast cancer was no longer increased.66

Addition of progestogens to estrogen may increase breast cancer risk beyond that observed with estrogen alone.67

Sex-steroid deficiency during the menopause results in lipomatous involution of the breast, which is seen as decreased mammographic breast density and markedly improved radiotransparency of breast tissue. Thus, mammographic changes indicating breast cancer can be recognized more easily and earlier after the menopause. Conversely, combination hormone therapy results in increased mammographic breast density, and increased density on mammography has been associated with higher breast cancer risk.6870

Endometrial Cancer

The WHI trial suggests that combined oral hormone therapy does not increase endometrial cancer risk compared with placebo (HR 0.81, 95% CI: 0.48 to 1.36).71 However, estrogen alone given to women with an intact uterus significantly increases uterine cancer risk.72 The excess risk increases with dose and duration of estrogen (10 years of unopposed estrogen increases the risk 10-fold), is apparent within 2 years of the start of treatment, and persists for many years after estrogen replacement is discontinued.72 Estrogen-induced endometrial cancer usually is of a low stage and grade at the time of diagnosis,55 and it can be prevented almost entirely by progestogen coadministration. The sequential addition of progestogen to estrogen for at least 10 days of the treatment cycle or continuous combined estrogen–progestogen does not increase the risk of endometrial cancer.73

Lower doses of estrogen may be associated with a lower risk of endometrial hyperplasia.74 SERMs do not result in endometrial hyperplasia.75 A 4-year trial of raloxifene in women with osteoporosis showed no increased risk of endometrial cancer.76

Ovarian Cancer

Lifetime risk of ovarian cancer is low (1.7%). The WHI trial suggested that orally administered combined hormone therapy does not increase the risk of ovarian cancer (HR 1.58, 95% CI: 0.77 to 3.24).71 An observational study reported an increased risk of ovarian cancer in women taking postmenopausal estrogen-only therapy for more than 10 years (relative risk 1.8, 95% CI: 1.1 to 3.0 and 3.2, 95% CI: 1.7 to 5.7 for 10 to 19 years and 20 or more years, respectively), but no increased risk of ovarian cancer among women receiving combination estrogen–progestogen therapy.77

Lung Cancer

The WHI trial found that combined oral estrogen–progestogen therapy did not increase lung cancer incidence, but significantly increased deaths from lung cancer, mainly from nonsmall cell lung cancers (HR 1.87, 95% CI: 1.22–2.88).78 The estrogen-only arm of the WHI trial found no increased risk for lung cancer death.79 It should be noted that the WHI was not designed to assess lung cancer.13

Venous Thromboembolism

Venous thromboembolism, including thrombosis of the deep veins of the legs and embolism to the pulmonary arteries, is uncommon in the general population. Women taking oral estrogen therapy have a twofold increased risk for thromboembolic events, with the highest risk occurring in the first year of use.25,52 However, women with certain risk factors for venous thromboembolism including those with a Factor V Leiden mutation, obesity, and history of previous thromboembolic events, are at increased risk with hormone therapy.13 Lower doses of estrogen are associated with a decreased risk for thromboembolism as compared with higher doses.80 Oral administration of estrogen increases the risk of venous thromboembolism compared to the transdermal route.81 In addition, the norpregnane progestogens, unlike micronized progesterone, appear to be thrombogenic.

Currently, there is no indication for thrombophilia screening before initiating hormone therapy. However, hormone therapy should be avoided in women at high risk for thromboembolic events.

Gallbladder Disease

Gallbladder disease is a commonly cited complication of oral estrogen use. The WHI studies reported an increased risk for cholecystitis, cholelithiasis, and cholecystectomy among women taking oral estrogen or estrogen–progestogen therapy.82 Transdermal estrogen is an alternative to oral therapy for women at high risk for cholelithiasis.

Estrogens

Estrogens are naturally occurring hormones or synthetic steroidal or nonsteroidal compounds with estrogenic activity. The primary indication for systemic estrogen-based hormone therapy is the relief of moderate and severe vasomotor symptoms, and the initial dose should be the lowest effective dose for symptom control.

Adverse Effects Common adverse effects of estrogen include nausea, headache, breast tenderness, and heavy bleeding. More serious adverse effects include increased risk for CHD, stroke, venous thromboembolism, breast cancer, and gallbladder disease. Transdermal estradiol is associated with a lower incidence of breast tenderness and deep vein thrombosis than is oral estrogen.55,83,84

Dose and Administration Various systemically administered estrogens (typically oral and transdermal) are suitable for replacement therapy (Table 65-2). Estrogens can be administered orally, percutaneously (transdermal patches and topical products), intravaginally (creams, tablets, or rings), intramuscularly, and even subcutaneously in the form of implanted pellets. The choice of estrogen delivery (product, route, and method) should be determined in consultation with the patient to ensure acceptability and enhance adherence. In general, the oral and transdermal routes are used most frequently. No evidence indicates that one estrogen compound is more effective than another in relieving menopausal symptoms or preventing osteoporosis.

TABLE 65-2 Estrogen Products for Hormone Therapy

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Oral Estrogen Oral CEE has been available for more than 50 years. CEE is prepared from the urine of pregnant mares and is composed of estrone sulfate (50% to 60%) and multiple other equine estrogens such as equilin and 17α-dihydroequilin.85

Estradiol is the predominant and most active form of endogenous estrogens. A micronized form of estradiol (produced by a technique that yields extremely small particles of the pure hormone) is readily absorbed from the small intestines.85 When given orally, estradiol is metabolized by the intestinal mucosa and the liver during the first hepatic passage, and only 10% reaches circulation as free estradiol. Metabolism of estrogen is partly mediated by the cytochrome P450 3A4 isoenzyme. Gut and liver metabolism converts a large proportion of estradiol to the less potent estrone. Thus, measurement of serum estradiol is not useful for monitoring oral estrogen replacement. The principal metabolites of micronized estradiol are estrone and estrone sulfate. Administration of estradiol via the oral route results in estrone concentrations that are three to six times those of estradiol. Ethinyl estradiol is a highly potent semisynthetic estrogen that has similar activity following administration by the oral or nonoral route.

Orally administered estrogens stimulate the synthesis of hepatic proteins and increase the circulating concentrations of sex hormone-binding globulin, which, in turn, may compromise the bioavailability of androgens and estrogens.

Other Routes Nonoral forms of estrogens bypass the GI tract and thereby avoid first-pass liver metabolism. These routes of estradiol delivery result in a more physiologic estradiol-to-estrone ratio (estradiol concentrations greater than estrone concentrations), as seen in the normal premenopausal state. Transdermal estrogen therapy also is less likely to affect sex hormone-binding globulin compared with oral therapy. These regimens produce little or no change in circulating lipids, coagulation parameters, or C-reactive protein levels.86

Transdermal estrogen patches share the advantages of other nonoral estrogen routes and have the added advantage of delivering estradiol to the general venous circulation at a continuous rate. The matrix transdermal systems (estrogen in adhesive) generally are well tolerated, and fewer than 5% of women experience skin reactions.87 The incidence of skin irritation diminishes when the application site is rotated. Topical antiinflammatory products (e.g., hydrocortisone cream) can be applied for managing the rashes, and switching to another transdermal patch is often a viable option.

Topical gels, sprays, and emulsions are convenient, but variability in drug absorption has been noted with some formulations. These forms of estrogen are also used for systemic therapy.

Estradiol pellets (implants) containing pure crystalline 17β-estradiol have been available for more than 50 years. They are inserted subcutaneously into the anterior abdominal wall or buttock. Pellets are difficult to remove and may continue to release estradiol for a long time after insertion. Implantation should not be repeated until serum estradiol concentrations have fallen to values similar to those at the midfollicular phase of the menstrual cycle. Estradiol pellets are not available in the United States.

Intravaginal creams, tablets, and rings are used for treatment of urogenital (vulvar and vaginal) atrophy. However, this route of administration can have more than just a local effect. Systemic estrogen absorption is lower with vaginal tablets and rings (specifically Estring) compared with vaginal creams. Nonetheless, local application of the cream at low doses can reverse atrophic vaginal changes and avoid significant systemic exposure. Nonestrogen vaginal moisturizers and lubricants also may provide local symptom relief. These products can be used alone or in combination with locally acting intravaginal estrogens. Intravaginal rings are a sustained-release delivery system composed of a biologically inert liquid polymer matrix with pure crystalline estradiol that can maintain adequate estradiol concentrations. One such intravaginal ring product (Femring) is designed to achieve systemic concentrations of estrogen and is indicated for treatment of moderate to severe vasomotor symptoms.

Progestogens

Images Because of the increased risk of endometrial hyperplasia and endometrial cancer with estrogen monotherapy (unopposed estrogen), women who have not undergone hysterectomy should be treated concurrently with a progestogen in addition to the estrogen.88

Progestogens reduce nuclear estradiol receptor concentrations, suppress DNA synthesis, and decrease estrogen bioavailability by increasing the activity of endometrial 17-hydroxysteroid dehydrogenase, an enzyme responsible for converting estradiol to estrone.72

The first generation of progestogens included the C-19 androgenic progestogens norethindrone (also known as norethisterone), norgestrel, and levonorgestrel. More recent preparations have included the C-21 progestogens dydrogesterone and MPA, which are less androgenic. Drospirenone, a synthetic progestogen analog of the potassium-sparing diuretic spironolactone, has both antiandrogenic and antialdosterone properties. Micronized progesterone also has become available for use in postmenopausal women. The most commonly used oral progestogens are MPA, micronized progesterone, and norethindrone acetate. The latter can be administered transdermally in the form of a combined estrogen–progestogen patch.

Adverse Effects Common adverse effects of progestogens include irritability, weight gain, bloating, and headache. Changing from a cyclic to a continuous-combined regimen or changing from one progestogen to another may decrease the incidence or severity of untoward effects. Adverse effects of progestogens are difficult to evaluate and can vary with the agent administered. Some women experience “premenstrual-like” symptoms, such as mood swings, bloating, fluid retention, and sleep disturbance. Newer methods and routes of progestogen delivery (e.g., locally by an intrauterine device that releases levonorgestrel or a progesterone-containing bioadhesive vaginal gel) may be associated with fewer adverse effects.

Dose and Administration Several progestogen regimens designed to prevent endometrial hyperplasia are available (Table 65-3). Progestogens must be taken for a sufficient period of time during each cycle. A minimum of 12 to 14 days of progestogen therapy each month is required for complete protection against estrogen-induced endometrial hyperplasia.89 Of note, use of even low-dose estrogen, including some intravaginal preparations, requires progestogen coadministration for endometrial protection in women with an intact uterus.90 However, rarely is progestogen administration needed in women who have undergone hysterectomy (i.e., women with hysterectomy and a past history of endometriosis).

TABLE 65-3 Progestogen Doses for Endometrial Protection (Oral Cyclic Administration)

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Methods of Combined Estrogen and Progestogen Administration

Four combination estrogen and progestogen regimens currently in use are continuous cyclic (sequential), continuous combined, continuous long-cycle (or cyclic withdrawal), and intermittent combined (or continuous-pulsed) hormone therapy.91 Various hormone therapy regimens that combine an estrogen and a progestogen are available (Table 65-4).

TABLE 65-4 Common Combination Postmenopausal Hormone Therapy Regimens

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Continuous Cyclic Estrogen–Progestogen (Sequential) Treatment Estrogen typically is administered continuously (daily). A progestogen is coadministered with the estrogen for at least 12 to 14 days of a 28-day cycle.89 The progestogen causes scheduled withdrawal bleeding in approximately 90% of women. With this regimen, bleeding usually begins 1 to 2 days after the last progestogen dose. Occasionally, bleeding begins during the latter phase of progestogen administration.

Continuous Combined Estrogen–Progestogen Treatment Continuous combined estrogen–progestogen administration results in endometrial atrophy and the absence of vaginal bleeding. Continuous combined hormone therapy is more acceptable than traditional cyclic therapy. This method of treatment can be achieved by using either commercially available oral and transdermal preparations or by administering systemic oral or nonoral estrogen along with the use of the levonorgestrel-releasing intrauterine system.

Continuous Long-Cycle Estrogen–Progestogen Treatment This modified sequential regimen was developed to decrease the incidence of uterine bleeding.91 In the continuous long-cycle (or cyclic withdrawal) estrogen–progestogen regimen, estrogen is given daily, and progestogen is given six times per year, every other month for 12 to 14 days, resulting in six periods per year. Bleeding episodes may be heavier and last for more days than withdrawal bleeding with continuous cyclic regimens. The effect of continuous long-cycle estrogen–progestogen treatment on endometrial protection is unclear.

Intermittent Combined Estrogen–Progestogen Treatment The intermittent combined estrogen–progestogen regimen, also called continuous-pulsed estrogen–progestogen or pulsed-progestogen, consists of 3 days of estrogen therapy alone, followed by 3 days of combined estrogen and progestogen, which is then repeated without interruption.91 This regimen is designed to lower the incidence of uterine bleeding. It is based on the assumption that pulsed-progestogen administration will prevent downregulation of progesterone receptors that can be produced by continuous combined regimens. The lower progestogen dose induces fewer side effects and can be better tolerated. The long-term effect of intermittent combined regimens in endometrial protection is undetermined.

Low-Dose Hormone Therapy

Images Increasingly, it has become recognized that use of hormone therapy at doses lower than those prescribed historically (i.e., prior to the WHI study) may be effective in the management of menopausal symptoms (Table 65-2). Low-dose estrogen regimens include 0.3 to 0.45 mg conjugated estrogens, 0.5 mg micronized 17β-estradiol, and 0.014 to 0.0375 mg transdermal 17β-estradiol patch.13 The standard dose of estrogen previously believed to be effective in alleviating vasomotor symptoms is equivalent to 0.625 mg CEE,30 but new evidence indicates that lower doses of estrogen also are effective in controlling postmenopausal symptoms and reducing bone loss.9295 The Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial demonstrated equivalent symptom relief and bone density preservation without an increase in endometrial hyperplasia using lower doses of hormone therapy (CEE 0.45 mg/day and MPA 1.5 mg/day).9395 Even ultralow doses of 17β-estradiol delivered by a vaginal ring (Estring) improved serum lipid profiles and prevented bone loss in elderly women.96 Whether lower doses of estrogen will be safer (lower incidence of venous thromboembolism and breast cancer) remains to be proven.

Compounded Hormones Compounded “bioidentical” hormone therapy has received much attention by patients, health care professionals, and the media since the initial publication of the WHI results. Advocates of this practice tout the benefits of natural rather than synthetic formulations of sex hormones. Often, these hormones are compounded in pharmacies to make a variety of formulations, in theory, to individualize hormone therapy based on each patient’s specific physiologic hormone milieu as measured via salivary hormone concentrations. This strategy is thought to reduce the risk of adverse effects. However, there is a paucity of evidence regarding both their efficacy and safety.97Bioidentical hormones appear to carry the same risks as traditional hormone therapy. Several major medical organizations, along with the FDA, have released statements that dissuade against the use of this treatment approach.98,99

Other Treatments

In women who have contraindications to estrogen and progestogen use, prefer not to take estrogen and/or progestogen, or cannot tolerate estrogen and/or progestogen administration, a number of other medications may be considered, depending on the goals of therapy. These include the prescription medications testosterone, SERMs (only raloxifene is currently available in the United States), and tibolone (not currently available in the United States) as well as nonhormonal prescription medications (e.g., selective serotonin reuptake inhibitors). Some women prefer to use herbals and other natural therapies, but the efficacy and safety of these methods have not been definitively established.

Alternatives to estrogen for treatment of hot flushes include tibolone, selective serotonin reuptake inhibitors (e.g., paroxetine, fluoxetine), dual serotonin and norepinephrine reuptake inhibitors (e.g., venlafaxine), MPA, megestrol acetate, clonidine, and gabapentin (Table 65-5).100 Progestogens alone may be an option for some women (e.g., those with a history of venous thrombosis), but weight gain, vaginal bleeding, and other adverse effects often limit their use. Tibolone and progestogens cannot be considered non-hormonal agents for treatment of hot flushes in women for whom hormone therapy is contraindicated. For this group of patients, selective serotonin reuptake inhibitors and venlafaxine are considered by some to be a first-line therapy.100,101 However, the efficacy of venlafaxine for treatment of hot flushes has not been shown to extend beyond 12 weeks.102 Furthermore, in breast cancer patients, evidence suggests that selective serotonin reuptake inhibitors could interfere with metabolism of endocrine therapies, such as tamoxifen via cytochrome P450 2D6 inhibition.103 Clonidine is often effective for symptom control, but its side effects (e.g., sedation, dry mouth, hypotension) are not always well tolerated by women.

TABLE 65-5 Alternatives to Estrogen for Treatment of Hot Flushesa

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Androgens

Pathophysiologic states affecting ovarian and adrenal function, along with aging, have been associated with androgen deficiency in women.104 The therapeutic use of testosterone in women, although controversial, is becoming more widespread despite the lack of accurate clinical or biochemical findings of androgen deficiency.104 Androgens have important biologic effects in women, acting both directly via androgen receptors in tissues, such as bone, skin fibroblasts, hair follicles, and sebaceous glands, and indirectly via the aromatization of testosterone to estrogen in the ovaries, bone, brain, adipose tissue, and other tissues.

Efficacy A cluster of symptoms that characterizes androgen insufficiency in women, manifested as diminished sense of well-being, persistent or unexplained fatigue, and sexual function changes such as decreased libido, decreased sexual receptivity, and decreased pleasure has been reported.104 However, studies designed to evaluate this have shown no relationships between serum total and free testosterone levels and either sexual function105 or well-being106in women. Thus, as data supporting an androgen deficiency syndrome are lacking, in 2006 the American Endocrine Society recommended against making a diagnosis of androgen deficiency in women at the present time.105 Several large randomized placebo-controlled clinical trials involving naturally107,108 and surgically109 postmenopausal women presenting with low libido demonstrate that testosterone therapy, with and without concurrent estrogen therapy, improves the quality of the sexual experience, with preliminary data that this may also apply to premenopausal women.110

Adverse Effects Absolute contraindications to androgen therapy include pregnancy or lactation and known or suspected androgen-dependent neoplasia. Relative contraindications include concurrent use of CEEs (for systemic testosterone therapy), low sex hormone-binding globulin level (below the normal range for women) moderate to severe acne, clinical hirsutism, and androgenic alopecia.

Adverse effects from excessive dosage include virilization, fluid retention, and potentially adverse lipoprotein lipid effects, which are more likely with oral administration. There is no evidence that systemic transdermal testosterone is associated with increased cardiovascular morbidity or mortality111 or of a significant change in the risk of invasive breast cancer.112,113 However, further studies are required to determine the long-term safety of testosterone in women.

Dose and Administration Testosterone is available as oral methyltestosterone in the United States. Methyltestosterone in combination with esterified estrogen (either 0.625 mg esterified estrogen plus 1.25 mg methyltestosterone or 1.25 mg esterified estrogen plus 2.5 mg methyltestosterone) is the most widely studied.

Testosterone replacement for women is available in a variety of formulations (Table 65-6). Most of the earlier studies showing clinical improvement with testosterone therapy reported supraphysiologic levels. More recent studies using transdermal patch therapy have shown efficacy with free testosterone levels in the upper normal range for young women. The availability of testosterone regimens specifically designed for women has the potential to maintain testosterone levels within the normal range and help to clarify whether the apparent beneficial effects of testosterone therapy are physiologic or pharmacologic.109,114 In general, testosterone treatment can be administered to postmenopausal women with and without concurrent estrogen therapy. At present, generalized use of testosterone is not recommended because the indications are inadequate, and evidence from long-term studies evaluating safety is lacking.115

TABLE 65-6 Androgen Regimens Used for Women

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Selective Estrogen Receptor Modulators

SERMs are a group of nonsteroidal compounds that are chemically distinct from estradiol. They act as estrogen agonists in some tissues, such as bone, and as estrogen antagonists in other tissues, such as breast, through specific, high-affinity binding to the estrogen receptor.

Efficacy The ideal SERM would protect against osteoporosis and decrease the incidence of breast, endometrial, and colorectal cancer and CHD without exacerbating menopausal symptoms or increasing the risk of venous thromboembolism or gallbladder disease. To date, no SERM meets these ideals. Tamoxifen, the first-generation SERM (a nonsteroidal triphenylethylene derivative), has estrogen antagonist activity on the breast and estrogen-like agonist activity on bone and endometrium. The second-generation SERM raloxifene, a nonsteroidal benzothiophene derivative, is used to reduce the risk of postmenopausal osteoporosis and invasive breast cancer, and also for treatment of postmenopausal osteoporosis. The third generation of SERMs, bazedoxifene and lasofoxifene, have similar efficacy and adverse effect profile compared to raloxifene.75 These new SERMs are approved only in Europe. SERMs do not alleviate, or may even exacerbate, vasomotor symptoms, and increase the risk for venous thromboembolism.75

Raloxifene increases BMD in the spine and femoral neck and reduces the risk of vertebral fractures.116 It has not been shown to decrease the risk of hip fractures. Raloxifene decreases bone loss in recently menopausal women without affecting the endometrium and has estrogen-like actions on lipid metabolism.116 Lasofoxifene and bazedoxifene have shown similar effects.117,118 Raloxifene use is associated with a significantly lower incidence of breast cancer compared with placebo.76,119 This benefit is primarily due to a reduced risk of estrogen receptor-positive invasive breast cancers.76,119 A prospective randomized double-blinded trial of 19,747 women at high risk for breast cancer (Study of Tamoxifen and Raloxifene [STAR]) showed that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events.120 The tissue-selective estrogen complex (TSEC), a novel regimen pairing a SERM with one estrogen, is currently under investigation aiming to treat both menopausal symptoms and bone loss.

Ospemifene is an orally administered SERM approved by the FDA in the first quarter of 2013 for the treatment of moderate-to-severe dyspareunia from menopausal vulvar and vaginal atrophy. Ospemifene’s labeling carries a boxed warning about its estrogenic effect on the endometrium: there is an increased risk of endometrial hyperplasia and endometrial cancer in a woman with a uterus who takes unopposed estrogen therapy. Ospemifene also has a boxed warning about the possible risk of stroke and venous thromboembolism. At the time of writing, safety data longer than 1 year have not been published.

Adverse Effects SERMs are commonly associated with hot flushes and less often with leg cramps. SERMs increase the risk of venous thromboembolism76,116–118 and fatal stroke76 to a degree similar to that of oral estrogen.

Dose and Administration Raloxifene is FDA-approved for the treatment and prevention of postmenopausal osteoporosis and for the reduction of the risk of invasive breast cancer in postmenopausal women with osteoporosis as well as postmenopausal women at high risk for invasive breast cancer. The dose is 60 mg orally once daily.

Tibolone

Tibolone is a gonadomimetic synthetic steroid in the norpregnane family with combined estrogenic, progestogenic, and androgenic activity.121 Tibolone has been used for three decades in Europe for treatment of menopausal symptoms and prevention of osteoporosis but is currently not available in the United States. The hormonal effects of this synthetic steroid depend on its metabolism and activation in peripheral tissues. The parent compound has been described as a prodrug that is metabolized quickly in the GI tract. It has several active metabolites, including a Δ4-isomer and 3α-OH and 3β-OH compounds.121 The Δ4-isomer metabolite confers significant progestogenic and androgenic properties.

Efficacy Tibolone has beneficial effects on mood and libido and improves menopausal symptoms and vaginal atrophy. Tibolone protects against bone loss and significantly reduces the risk of vertebral fractures in postmenopausal women with osteoporosis.122 It has also been shown to decrease the risk of breast cancer and colon cancer in healthy women aged 60 to 85 years.122 It is also more effective than conventional hormone therapy for management of sexual dysfunction.123

Adverse Effects Tibolone use in elderly women has been reported to be associated with an increased risk of stroke.122 Tibolone use is associated with breast cancer recurrence in breast cancer patients with vasomotor symptoms.124Tibolone lowers concentrations of total cholesterol, triglycerides, and lipoprotein (a) but may decrease high-density lipoprotein (HDL) cholesterol.85 The Million Women Study, an observational cohort study, found a greater risk of endometrial cancer (adjusted relative risk 1.79, 95% CI: 1.43 to 2.25).125 However, other randomized placebo-controlled studies have not shown an increased risk of endometrial cancer with tibolone and suggest that tibolone has an endometrial safety profile similar to continuous combined CEE and MPA.126

The most commonly reported adverse effects of tibolone include weight gain and bloating.

Complementary and Alternative Medicine

Some women prefer to use natural remedies due to a belief that they are safer. Randomized, placebo-controlled trials of complementary and alternative therapies have been equivocal and have not established the safety and efficacy of herbal remedies, homeopathic treatments, or acupuncture for the prevention or treatment of hot flushes.

Phytoestrogens Phytoestrogens have physiologic effects in humans.127 They are plant compounds with estrogen-like biologic activity and relatively weak estrogen receptor-binding properties. Epidemiologic studies suggest that consumption of a phytoestrogen-rich diet, which is common in traditional Asian societies, is associated with a lower risk of breast cancer.127

The biologic potencies of phytoestrogens vary. Most of these compounds are nonsteroidal and are less potent than synthetic estrogens. The three main classes of phytoestrogens are isoflavones, lignans, and coumestans, all of which are found in plants or their seeds.127 The most commonly studied phytoestrogen is the isoflavone class. Genistein and daidzein are the most abundant active components of isoflavones. The concentration of isoflavones per gram of soy protein varies considerably among preparations. Also, a single plant often contains more than one class of phytoestrogen. Common food sources of phytoestrogens include soybeans (isoflavones), cereals, oilseeds such as flaxseed (lignans), and alfalfa sprouts (coumestans).

Mild estrogenic effects have been seen in postmenopausal women,127 but current data suggest that phytoestrogen supplementation is no more effective than placebo in relieving hot flushes or other symptoms of menopause in postmenopausal women.128

Phytoestrogens decrease low-density lipoprotein (LDL) cholesterol and triglyceride concentrations with no significant change in HDL cholesterol concentrations.129 Furthermore, phytoestrogens have the ability to inhibit LDL oxidation and normalize vascular reactivity in estrogen-deprived primates.129 In addition, BMD may be improved by phytoestrogens.127 Common adverse effects include constipation, bloating, and nausea.130

A recent meta-analysis reported that phytoestrogen use is not associated with increased rates of endometrial cancer, vaginal bleeding, and breast cancer.130 Large, long-term studies are needed to further document the effects of phytoestrogens on the breast, bone, and endometrium. Furthermore, differences among classes of phytoestrogens must be identified clearly, including dosing and biologic activity, before phytoestrogens can be considered an alternative to conventional hormone therapy in postmenopausal women.

Other Herbal Products Black cohosh (Cimicifuga racemosa or Actaea racemosa), a widely used herbal supplement, may not offer substantial benefits for relief of vasomotor symptoms as suggested by earlier trials.131 This substance does not appear to have strong intrinsic estrogenic properties but may act through the serotonergic system. Black cohosh appears to be generally well tolerated, although hepatotoxicity has been reported. It is unclear if this is due to the herb itself or adulterations of commercially available products.132 The long-term effects of black cohosh are unknown. Other herbals and alternative treatments that may be used by women include dong quai, red clover leaf (contains phytoestrogens), kava, and dehydroepiandrosterone. These have not been shown to be effective in the treatment of menopausal symptoms and may carry the risk of adverse events.133 Complementary and alternative therapies should not be recommended to treat menopausal symptoms.

Personalized Pharmacotherapy

The severity of menopausal symptoms varies widely from woman to woman. The decision to use menopausal hormone therapy must be individualized and based on several parameters, including vasomotor and urogenital symptoms, osteoporosis risk, cardiovascular disease risk, breast cancer risk, and thromboembolism risk. Hormone therapy is not indicated for prevention of chronic diseases of aging.

Moderate and severe menopausal symptoms likely require pharmacologic therapy, after the exclusion of possible contraindications for hormone therapy (Table 65-1). Estrogen therapy is the most effective treatment for moderate and severe vasomotor symptoms, impaired sleep quality, and urogenital symptoms of menopause (Fig. 65-1). A thorough discussion of the risks and benefits of hormone therapy should be completed with the patient so that she can weigh the risks and benefits versus alternatives and make a rational decision about whether to use hormone therapy. For a healthy recently menopausal woman who has vasomotor symptoms, the benefits of hormonal therapy outweigh the risks. The risk primary involves the venous thromboembolism risk. The benefits include the control of vasomotor symptoms, treatment of urogenital atrophy, and prevention of postmenopausal bone loss.

Hormone therapy should be tailored for optimal formulation, dose, route of delivery, and counseling should be based on age, years since menopause, and hysterectomy status. Women who have undergone hysterectomy use hormone therapy more frequently than do women with an intact uterus (58.7% vs. 19.6%).134

Estrogens diminish hot flushes in most women, and all types and routes of administration of estrogen are equally effective.13 A dose-dependent relationship between estrogen administration and suppression of hot flushes is well established. Some women, especially younger women, may require a higher than average dose of estrogen to suppress symptoms. On the other hand, many women with hot flushes at the time of menopause require lower doses of estrogen.135 Initiating therapy with low doses of estrogen often will minimize adverse effects, such as breast tenderness and unscheduled bleeding. Transdermal estradiol is less likely than oral estrogen to cause nausea and headache. In many cases changing from one estrogen regimen to another can alleviate certain adverse effects.

Prior to initiating pharmacologic therapy, a complete medical history and physical examination should be performed. Medical history should include a personal and family history of cardiovascular disease and thrombotic problems. The physical examination should include a complete cardiovascular examination, clinical assessment of thyroid status, and breast and pelvic examinations. Papanicolaou cervical cytologic examination and screening mammography negative for malignancy are required before initiating hormone therapy. Thyroid function tests and lipoprotein lipid profile also are performed at the discretion of the clinician. Oral estrogen should be avoided in women with hypertriglyceridemia, liver disease, and gallbladder disease. For these women, transdermal administration is a safer approach. Sequential estrogen/progestogen therapy results in scheduled vaginal withdrawal bleeding but often is scant or completely absent in older women. For many women, scheduled withdrawal bleeding is one of the main reasons for avoiding or discontinuing hormone therapy. Because there is no physiologic need for bleeding, new hormone therapy regimens that reduce monthly bleeding (e.g., continuous long-cycle regimens) or prevent monthly bleeding (e.g., continuous combined and intermittent combined regimens) were developed. Continuous combined estrogen–progestogen administration results in endometrial atrophy and the absence of vaginal bleeding. Initially, it causes unpredictable spotting or bleeding, which usually resolves within 6 to 12 months. Decreasing the estrogen dose or increasing the progestogen dose usually decreases or stops the spotting. Occasionally, a drug-free period of 1 or 2 weeks is useful to stop the bleeding. Women who recently have undergone menopause have a higher risk for excessive, unpredictable bleeding while receiving continuous therapy; thus, this regimen is best reserved for women who are at least 2 years postmenopause.

If hormone therapy is to be initiated, the selection of the drug should also take into account the potential for drug interactions, including those involving the cytochrome P450 (CYP450) microsomal enzyme system. Estrogen is metabolized partly by the CYP 450 isoenzymes 1A2 and 3A4, and the progestin medroxyprogesterone is metabolized by CYP450 3A4. Inducers or inhibitors of these enzymes may either decrease or increase, respectively, the therapeutic effects or result in side effects. Similarly, selection of nonhormonal drug therapy options should take into account the potential for interactions with other prescription and nonprescription medications the patient may be taking. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors can have major interactions with other drugs also affecting CYP450 2D6 and 3A4 (Chap. 51). Patients using vaginal estrogen creams or nonestrogen vaginal moisturizers should be warned that products with oil-based lubricants or vehicles can weaken latex condoms, which can decrease protection against sexually transmitted infections. Pharmacodynamic drug interactions (e.g., additive side effects) should also be considered.

Evaluation of Therapeutic Outcomes

Even before publication of the WHI trial findings, only a fraction of women filled their hormone therapy prescriptions, and only 25% to 40% continued to take postmenopausal hormone therapy for more than 1 year.136 Hormone therapy use in the United States declined substantially after dissemination of the WHI trial results.137

The main reasons for discontinuing hormone therapy are side effects such as bleeding, breast tenderness, bloating, and “premenstrual-like symptoms.” Reducing the dose or changing the regimen or the route of administration can minimize these effects. Alternatively, if vasomotor symptoms are not controlled adequately with a lower-dose regimen, increasing the estrogen dose may be a reasonable option. Therefore, after the menopausal woman begins hormone therapy, a brief follow-up visit 6 weeks later may be useful to discuss patient concerns about hormone therapy and to evaluate the patient for symptom relief, adverse effects, and patterns of withdrawal bleeding (Table 65-7). Women receiving hormone therapy should be seen by the clinician for annual monitoring (Table 65-7).

TABLE 65-7 Monitoring Patients Taking Hormone Therapy Regimens

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The main indication for hormone therapy is relief of menopausal symptoms. If combined estrogen/progestogen treatment is stopped within 5 years, no evidence of increased risk of breast cancer is observed.25Estrogen-only treatment is not associated with an increased risk of breast cancer.52

Many women have no difficulty abruptly stopping hormone therapy; others develop vasomotor symptoms after discontinuation. Although these symptoms may be mild and resolve over a few months, in some women the symptoms are severe and intolerable. There is no evidence that gradual discontinuation of hormone therapy reduces the recurrence of hot flushes compared with sudden discontinuation.138

Conclusions

Menopause is a natural life event, not a disease. Therefore, the decision to use hormone therapy must be individualized based on the severity of menopausal symptoms, risk of osteoporosis fracture, and consideration of factors such as cardiovascular disease, breast cancer, and thromboembolism (Table 65-8).

TABLE 65-8 Evidence-Based Hormone Therapy Guidelines for Menopausal Symptom Management

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The WHI trial reported increased risk of cardiovascular disease, breast cancer, stroke, and thromboembolic disease among women using continuous combined therapy with CEE plus MPA compared with placebo. In the estrogen-alone arm of the study, CEE had no effect on cardiovascular disease or breast cancer risk compared to placebo, but an increased risk of stroke and thromboembolic disease was noted in those who received estrogen. The WHI trial also demonstrated that quality of life and cognition were no better in the group receiving hormone therapy than in the placebo group, and that hormone therapy increases dementia risk in women 65 years or older.

In the absence of contraindications, hormone therapy is the most effective treatment for managing postmenopausal symptoms, such as hot flushes, night sweats, and vaginal dryness. For short-term use of hormone therapy for relief of menopausal symptoms, the benefits for many women outweigh the risks. For symptoms of genital atrophy alone, local estrogen, nonhormonal lubricants, or ospemifene should be considered.

Long-term use of hormone therapy cannot be recommended routinely for osteoporosis prevention given the availability of alternative therapies, such as bisphosphonates and raloxifene. For long-term hormone therapy use, the potential harm (cardiovascular disease, breast cancer, and thromboembolism) outweighs the potential benefits. Hormone therapy should not be used for prevention of CHD. Women with cardiovascular risk factors (e.g., hypertension, lipid abnormalities) can benefit from reduction of these risk factors through interventions such as weight loss, lipid-lowering therapy, use of aspirin, and physical activity.

PRIMARY OVARIAN INSUFFICIENCY AND PREMENOPAUSAL HORMONE REPLACEMENT THERAPY

Primary ovarian insufficiency is a condition characterized by sex-steroid deficiency, amenorrhea, and infertility in women younger than 40 years.139 Primary ovarian insufficiency was once considered irreversible and was described as “premature menopause,” and the condition is still referred to as premature ovarian failure. However, primary ovarian insufficiency is not an early, natural menopause. Normal menopause results from ovarian follicle depletion, whereas primary ovarian insufficiency is characterized by intermittent ovarian function in half of affected women.139 These women produce estrogen intermittently and may ovulate despite the presence of high gonadotropin concentrations. Pregnancies have occurred in 5% to 10% of women after the diagnosis of premature ovarian failure, even in women with no follicles observed on ovarian biopsy.

Epidemiology

The prevalence of primary ovarian insufficiency increases with increasing age, reaching approximately 1% of women by age 40 years.140

Etiology

A number of physiologic or metabolic abnormalities can lead to primary ovarian insufficiency (Table 65-9). In most cases, the etiology cannot be identified.

TABLE 65-9 Etiology of Primary Ovarian Insufficiency

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Pathophysiology

Primary ovarian insufficiency may occur as a result of ovarian follicle dysfunction or ovarian follicle depletion and may present as either primary amenorrhea (absence of menses in a girl who has reached age 16 years) or secondary amenorrhea (cessation of menses in a woman previously menstruating for at least 6 months). Approximately 50% of women with primary ovarian insufficiency have documented ovarian follicle function.139

Clinical Presentation

No characteristic menstrual pattern or history precedes primary ovarian insufficiency. Approximately 50% of patients with this condition have a history of oligomenorrhea or dysfunctional uterine bleeding (prodromal premature ovarian failure), and approximately 25% develop amenorrhea acutely. Some patients develop amenorrhea postpartum, whereas others experience amenorrhea after discontinuing oral contraceptives. Primary amenorrhea is not associated with symptoms of estrogen deficiency. In cases of secondary amenorrhea, symptoms may include hot flushes, night sweats, fatigue, and mood changes. Prodromal primary ovarian insufficiency may present with hot flushes even in women who menstruate regularly. Incomplete development of secondary sex characteristics may occur in women with primary amenorrhea, whereas these characteristics typically are normal in women with secondary amenorrhea. In general, women with primary ovarian insufficiency have normal fertility before the disorder develops.


CLINICAL PRESENTATION AND DIAGNOSIS Primary Ovarian Insufficiency

Symptoms

    • Primary amenorrhea: no symptoms of estrogen deficiency

    • Secondary amenorrhea: vasomotor symptoms (hot flushes and night sweats), sleep disturbances, mood changes, sexual dysfunction, problems with concentration and memory, vaginal dryness, and dyspareunia

Signs

    • Primary amenorrhea: incomplete development of secondary sex characteristics

    • Secondary amenorrhea: normal development of secondary sex characteristics, signs of urogenital atrophy

Laboratory Tests

    • FSH greater than 40 international units/L (40 IU/L)

    • Other relevant diagnostic tests (e.g., bone mineral density, ultrasound of the ovaries)

    • Thyroid function tests, fasting glucose level, and adrenocorticotropic hormone stimulation test

Primary ovarian insufficiency is defined by the presence of at least 4 months of amenorrhea and at least two serum FSH concentrations measuring greater than 40 international units/L (40 IU/L) (obtained at least 1 month apart) in women younger than 40 years. A complete history should be taken, considering other factors that can affect ovarian function such as prior ovarian surgery, chemotherapy, radiation, and autoimmune disorders. In patients with primary amenorrhea, particular attention should be paid to breast and pubic hair development according to Tanner stages. Short stature, stigmata of Turner syndrome, and other dysmorphic features of gonadal dysgenesis should be considered. Ideally, a pelvic examination is performed but is not always clinically appropriate. Alternatively, transabdominal ultrasonography can be performed in patients with primary amenorrhea to confirm the presence of normal anatomic structures. In the majority of cases, physical examination is completely normal. A karyotype should be performed in all patients experiencing primary ovarian insufficiency. Women with ovarian insufficiency and a karyotype containing a Y chromosome should undergo bilateral gonadectomy because of substantial risk for gonadal germ cell neoplasia.139 Ovarian biopsy and antiovarian antibody testing are investigational procedures with no proven clinical benefit in primary ovarian insufficiency. As clinically indicated, the workup should include tests for the diagnosis of other possible associated autoimmune disorders, such as hypothyroidism, diabetes mellitus, and Addison’s disease.

In the majority of patients, ovarian insufficiency develops after the establishment of regular menses. Young women with primary ovarian insufficiency who develop ovarian dysfunction before they achieve peak adult bone mass sustain sex steroid deficiency for more years than do naturally menopausal women. This deficiency can result in a significantly higher risk for osteoporosis141 and cardiovascular disease.142,143 Importantly, a survey of more than 19,000 women between the ages of 25 and 100 years suggests that ovarian insufficiency occurring before age 40 years is associated with significantly increased mortality, with an age-adjusted odds ratio for all-cause mortality of 2.14 (95% CI: 1.15 to 3.99).144

Young women find the diagnosis of primary ovarian insufficiency particularly traumatic and frequently need extensive emotional and psychological support. Although most of these women will, in fact, be infertile, it is important to emphasize that primary ovarian insufficiency can be transient and that spontaneous pregnancies have occurred even years after diagnosis.

TREATMENT

Images Results from randomized trials of hormone therapy in postmenopausal women cannot be extrapolated to premenopausal women with ovarian dysfunction. Postmenopausal women who take hormone therapy prolong their exposure to estrogen beyond the average age of completion of their reproductive phase. In contrast, women with primary ovarian insufficiency need exogenous sex steroids to compensate for the decreased production by their ovaries. Importantly, 47% of young women with primary ovarian insufficiency have significantly reduced BMD within 1.5 years of their diagnosis despite taking standard hormone therapy.141

Desired Outcome

The goal of therapy in young women with primary ovarian insufficiency is to provide a hormone replacement regimen that maintains sex steroid status as effectively as the normal, functioning ovary.

General Approach to Treatment

Hormone therapy with estrogen, progestogen, and testosterone is used and generally should be continued until the average age of natural menopause.

Personalized Pharmacotherapy

Optimal hormone therapy depends on whether the patient has primary or secondary amenorrhea. Young women with primary amenorrhea in whom secondary sex characteristics have failed to develop initially should be given very low doses of estrogen in an attempt to mimic the gradual pubertal maturation process. A typical regimen is 0.3 mg CEE unopposed (i.e., no progestogen) daily for 6 months, with incremental dose increases at 6-month intervals until the required maintenance dose is achieved. Gradual dose escalation often results in optimal breast development and allows time for the young woman to adjust psychologically to her physical maturation. Cyclic progestogen therapy, given 12 to 14 days per month, should be instituted toward the end of the second year of treatment.

Women with secondary amenorrhea who have been estrogen deficient for 12 months or longer also should be given low-dose estrogen replacement initially to avoid adverse effects such as mastalgia and nausea. However, the dose can be titrated up to maintenance levels over a 6-month period, and progestogen therapy can be instituted with the initiation of estrogen therapy. Women with a brief history of secondary amenorrhea are less likely to experience undesired effects from hormone therapy if they are given a reduced dose for the first month of therapy, followed by a full dose from the second month onward.

An estrogen dose equivalent to at least 1.25 mg CEE (or 100 mcg transdermal estradiol) is needed to achieve adequate estrogen replacement in young women. A progestogen should be given for 12 to 14 days per calendar month to prevent endometrial hyperplasia (Table 65-10). Estrogens given in usual replacement doses do not suppress spontaneous follicular activity or ovulation. Because women with primary ovarian insufficiency can have spontaneous pregnancies, hormone therapy should produce regular, predictable menstrual flow patterns (i.e., only cyclic regimens should be used). Patients who miss an expected menses should be tested for pregnancy and should discontinue hormone therapy. Because most young women negatively associate hormone therapy with menopause in older women, some clinicians prefer to prescribe oral contraceptives for hormone replacement in premenopausal women with hypogonadism. However, oral contraceptives may not inhibit ovulation or effectively prevent pregnancy in young women with elevated gonadotropin levels.

TABLE 65-10 Premenopausal Hormone Replacement Therapy for Young Women with Primary Ovarian Insufficiency (Continuous Sequential Therapy)

Images

Women with primary ovarian insufficiency have testosterone deficiency.145 In these young women, testosterone replacement, in addition to estrogen, may be important.114 However, preliminary analysis of a prospective study at the National Institutes of Health suggests that long-term “physiologic” testosterone supplementation (150 mcg/day), in addition to standard hormone replacement, did not significantly improve BMD and sexual function in these young women.146,147

Importantly, all women with primary ovarian insufficiency should understand that hormone therapy generally should be continued until the average age of natural menopause and that long-term follow-up is necessary.

Evaluation of Therapeutic Outcomes

Similar to the treatment of menopause, an assessment of the efficacy of hormone therapy, and its accompanying risks, should be performed on a regular basis. Young women with primary ovarian insufficiency should be monitored annually for their response to treatment, and their adherence with hormone therapy should be assessed regularly. Patients should be evaluated continuously for the presence of signs and symptoms of associated autoimmune endocrine disorders, such as hypothyroidism, adrenal insufficiency, and diabetes mellitus. Baseline BMD testing should be performed in all women with primary ovarian insufficiency. Mammography should be performed annually after age 40 years in accordance with accepted guidelines. Additional mammography screening in premenopausal women younger than 40 years who are receiving physiologic hormone therapy is not warranted. Other tests should be performed as clinically indicated.

Conclusions

Approximately 1% of women spontaneously develop ovarian insufficiency before age 40 years. Primary ovarian insufficiency is not an early natural menopause. Most affected women produce estrogen intermittently and may ovulate despite the presence of high gonadotropin concentrations. However, these women sustain sex steroid deficiency for more years than do naturally menopausal women, resulting in a significantly higher risk for osteoporosis and cardiovascular disease.

Women with primary ovarian insufficiency need exogenous sex steroids to compensate for the decreased production by their ovaries. Thus, premenopausal hormone therapy is required at least until these women reach the age of natural menopause.

The goal of therapy is to provide a hormone replacement regimen that maintains sex steroid status as effectively as the normal, functioning ovary. This usually requires the administration of estrogen at a dose greater than the standard dose given to older women experiencing natural menopause.

Because women with primary ovarian insufficiency can have spontaneous pregnancies, hormone therapy should produce regular, predictable menstrual flow patterns. Patients who miss an expected menses should be tested for pregnancy and, if positive, the hormone therapy should be promptly discontinued.

Annual follow-up should include assessment of adherence with the prescribed hormone therapy regimen and evaluation for signs and symptoms of associated endocrine disorders.

ACKNOWLEDGMENT

This research was supported in part by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health.

ABBREVIATIONS

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