Menopause and Hormone Replacement Therapy

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Menopause and Hormone Replacement Therapy

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Amanda Vincent and Henry Burger

MAJOR CONTROVERSIES ● ● ● ● ● ● ●

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What are the indications for the use of hormone therapy? What are the adverse effects associated with hormone therapy use? Which hormone therapy regimen should be used? When should treatment be instituted? What is the role of estrogen in the etiology of gynecologic cancer? Can hormone therapy be used in women with a history of gynecologic cancer? What is the role of androgen therapy in postmenopausal women with a history of gynecologic cancer? What is the role of selective estrogen receptor modulators? What is the role of phytoestrogens? What nonestrogenic therapies are available for the relief of menopausal symptoms? What is the role of herbal therapies? What alternative therapies are available for management of osteoporosis?

MENOPAUSE Consideration of the short-term and long-term consequences of the menopause has become an increasingly important issue for women with gynecologic cancer and their treating clinicians due to advances in diagnosis and therapy as well as demographic trends. Increased life expectancy and aging of the “baby boomers” have resulted in a greater proportion of women entering the menopause and therefore an increase in potential cases of gynecologic cancer. In addition, improved disease-free survival rate (the 5-year disease-free survival rate of women with breast cancer or endometrial cancer is now greater than 85% in the United States)1 and increased use of adjuvant chemotherapy has resulted in more women undergoing premature menopause, creating a larger number of

postmenopausal women with a history of gynecologic cancer than previously. Definition Menopause, defined by the World Health Organization (WHO) as the final spontaneous menses, is diagnosed retrospectively after 12 months of amenorrhea. The perimenopause delineates the period that begins with the first symptoms of the approaching menopause and ends 12 months after the final menstrual period. Longitudinal studies,2,3 using a clinical definition of the perimenopause as the period of irregular menses, have documented a median age at onset of 45.5 to 47.5 years (range, 41 to 59 years) and average duration of 4 to 4.8 years (range, 0 to 11 years). Currently, there is no biochemical, hormonal, or symptom cluster marker 795

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for the onset of the perimenopause. Premature menopause, defined as menopause that occurs before the age of 40 years, may occur spontaneously, as in premature ovarian failure (POF), or as a result of therapeutic intervention. Spontaneous menopause occurs as a result of the failure of ovarian function. Loss of ovarian follicular activity results in the cessation of ovulation and the characteristic decline in production of ovarian hormones, including estradiol, progesterone, and inhibin, with reciprocal elevation of gonadotrophins (Fig. 60-1). Steroid secretion by the postmenopausal ovary is minimal; estrone (predominantly formed by the aromatization in peripheral tissues of adrenal gland–derived androstenedione) is the main circulating estrogen. Low levels of estradiol may be produced by aromatization of testosterone in adipose tissue. Extragonadal synthesis of estrogens increases with increasing age and body mass index (BMI); however, the mechanisms that regulate estrogen production in postmenopausal women remain unclear.4 Although the probability of being menopausal increases with the duration of amenorrhea and increasing age,5 there are no specific predictors of menopause. Population-based studies in Western industrialized societies have determined the average age of spontaneous menopause to be approximately 50 years.3,6,7 Smoking, single or nulliparous status, low socioeconomic status, and shorter premenopausal cycle

length appear to be associated with an earlier onset of menopause.6,8 Causes of Menopause in this Patient Population Spontaneous physiologic menopause has already occurred in the majority of women at the time of diagnosis of gynecologic malignancy. For example, two thirds of women diagnosed with breast cancer in the United States are postmenopausal.9 However, in many women diagnosed with gynecologic malignancy, menopause may be a consequence of oophorectomy (surgical menopause), chemotherapy, or may spontaneous occurrence at an earlier age.10,11 Women younger than 50 years of age who have primary breast cancer derive the greatest benefit from adjuvant chemotherapy12; they therefore represent a significant population at risk for chemotherapy-induced premature menopause. The risk of chemotherapy- or radiotherapyinduced POF is increased with age greater than 40 years, use of alkylating agents such as cyclophosphamide, greater cumulative dose of cytotoxic drug, and more extensive irradiation (below the pelvic brim).11,13,14 The question as to whether conservative hysterectomy (in which one or both ovaries are conserved) is associated with an increased risk of early menopause remains unresolved, but it appears probable15;

Figure 60–1. Hormonal changes that occur during the transition from premenopause to postmenopause. Mean serum levels of (A) follicle-stimulating hormone (FSH) and estradiol and (B) inhibin A (InhA) and inhibin B (InhB), in relation to the final menstrual period (denoted on the horizontal axis as time 0, with negative and positive numbers indicating years before and after the final menses, respectively). Parentheses above the time scale indicate the percentage of measured InhA or InhB at or below assay sensitivity. (Reproduced with permission of The Endocrine Society from Burger HG, Dudley EC, Hopper JL, et al: Prospectively measured levels of serum follicle-stimulating hormone, estradiol and the dimeric inhibins during the menopausal transition in a population-based cohort of women. J Clin Endocrinol Metab 1999;4025-4030.)

M e n o pa u s e a n d H o r m o n e R e p l a c e m e n t Th e r a p y 797 39% of women younger than 39 years develop menopausal symptoms after hysterectomy.16 Parker and coworkers17 reported that 20% of women developed ovarian failure after radical hysterectomy for cervical carcinoma. Clinical Features of Menopause Consequences of menopausal estrogen deficiency include short-term physical and psychological symptomatology as well as long-term health issues, such as increased risks for osteoporosis, cardiovascular disease, and cognitive decline. The pathophysiologic changes and clinical manifestations associated with androgen and progesterone deficiency are less well defined (Table 60-1). Women with premature menopause may experience more severe symptoms, and their risks for osteoporosis,18,19 coronary heart disease (CHD),20-22 and stroke23 are greater. However, the association between these long-term consequences and menopause induced by chemotherapy or radiotherapy remains unclear. Women with early or premature menopause must also

confront issues such as the loss of fertility, altered body image, and “being out of step with their peers.”24,25 Symptoms associated with menopause. Characteristic

symptoms of estrogen deficiency are vasomotor instability and urogenital atrophy. A number of other physical and psychological symptoms are commonly reported in association with menopause (see Table 60-1); however, their relation to hormonal deficiency, psychosocial factors, and environmental influences is less clear. Hot flushes occur in up to 75% of menopausal women, more frequently after surgical menopause; frequent, severe episodes are reported by 10% to 15% of women. The frequency and severity of climacteric symptoms is also greater in hysterectomized women with ovarian conservation.26 The pathophysiologic cause of hot flushes remains unclear. The onset of symptoms may occur during the perimenopause or within 4 to 6 days after oophorectomy. Variation in the frequency, type, severity, onset, and duration of symptoms occurs between individuals and between ethnic groups.27 Osteoporosis. Osteoporosis is a major public health

Table 60–1. Clinical Features of Menopause Symptoms of estrogen deficiency Vasomotor instability Hot flashes/flushes Night sweats Urogenital atrophy Vaginal dryness and irritation Dyspareunia Micturition disorders Irritability Mood disturbance/mood swings Depression Insomnia Arthralgia and myalgia Memory and concentration disturbance Formication Dry eyes Palpitations Mastalgia Headache Paresthesia Long-term consequences of estrogen deficiency Osteoporosis Cardiovascular disease Altered lipid metabolism Altered vascular reactivity Cancer Colorectal Cognitive decline Symptoms of androgen deficiency (?) Altered sexual function Decreased libido Decreased well-being/energy levels Long-term consequences of androgen deficiency Unknown Symptoms of progesterone deficiency Unknown Long-term consequences of progesterone deficiency Unknown

problem associated with significant morbidity, mortality, and financial burden.28 Although osteoporotic fractures are observed worldwide, geographic variation is demonstrated. The highest incidence occurs in Western countries, where 30% to 40% of women over 50 years of age will suffer an osteoporotic fracture during the remainder of their lifetime.29 Postmenopausal osteoporosis is characterized by low bone mass, bone fragility resulting from deterioration of bone microarchitecture, and increased risk of fracture.30 Coexistent independent factors, including inadequate calcium intake, smoking, and concurrent medical problems such as hyperthyroidism or Cushing’s syndrome, may further increase the rapidity of bone loss.

Clinical Management of Menopause A comprehensive evaluation of the patient includes a detailed history, thorough physical examination, and relevant investigations (Table 60-2), including determination of serum lipids for cardiovascular risk assessment, bone densitometry to assess osteoporosis risk, and other measures as indicated by the history (e.g., thyroid function tests, serum iron and coagulation screen). Reproductive hormonal assessment is of little diagnostic value. Discussion with the woman is essential to explore her comprehension, attitude, perceptions, cultural beliefs, and concerns regarding menopause and the potential therapies available, thereby enabling the practitioner to “individualize” management and promote compliance with clinical recommendations. Management of the menopause includes the following approaches: 1. Dietary advice and lifestyle advice (see later discussion)

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Table 60–2. Clinical Evaluation History Menopausal symptoms Chronologic reproductive history, including age at menarche and menstrual history, gravidity and parity, gynecologic surgical history, date and cause of menopause History of hormonal treatment, both contraceptive and hormone replacement therapy (HRT) Sexual history, including frequency of intercourse, ease of arousal, libido, orgasm, dyspareunia Urogenital symptoms, including bladder dysfunction and prolapse Bone or joint pain, arthritis, fractures, osteoporosis, bone density measurement Loss of height General current and past medical history Gastrointestinal symptoms, including esophageal reflux, and history of achlorhydria, lactose intolerance History of weight fluctuations, physical activity, exercise tolerance Psychiatric history, including premenstrual symptoms and cognitive functioning Family history, especially of early menopause, cardiovascular disease, osteoporosis, cancer, and dementia Social history Dietary history, particularly vitamins, calcium, sodium, alcohol, caffeine, and fiber intake History of smoking Medications, both prescribed and nonprescribed (herbal, “natural therapies”) Allergies, including sensitivities to adhesive tapes

Examination

Laboratory Investigations

General physical examination with particular reference to the following: Posture (signs related to the presence of osteoporotic compression fractures), gait, muscle tone, coordination Height, body mass index, waist circumference, and body composition Heart rate and rhythm, blood pressure Breast examination Cardiovascular examination Pelvic examination, including size and shape of uterus and adnexal structures, estrogenic state of the vagina mucosa and vulva, elasticity of the vaginal wall (discharge, atrophy), integrity of the pelvic floor (cystocele, rectocele) Eyesight and hearing acuity (in terms of fracture risk and quality of life)

Follicle-stimulating hormone (FSH), estradiol (of limited diagnostic use) Serum androgens, including testosterone, free testosterone (or free androgen index), dehydroepiandrosterone sulfate Thyrotropin (TSH) Prolactin if indicated Fasting lipids, glucose Baseline chemistry, including electrolytes and liver function tests Mammogram Papanicolaou (Pap) smear Bone mineral density determination Calcium, phosphate, vitamin D, and parathyroid hormone estimation Vaginal ultrasound and endometrial sampling if indicated Evaluation of clotting profile if indicated

Adapted from American Association of Clinical Endocrinologists: AACE medical guidelines for clinical practice for management of menopause. Endocr Pract 1999; 5:354-366.

2. Use of hormone therapy (HT) and nonhormonal treatments in the management of menopausal symptoms and in prevention and treatment of the long-term complications of menopause (see later discussion) 3. Education of the patient with reference to her previous understanding of menopausal issues, enabling her to make an informed decision regarding the use of various treatments and, particularly, the risk and benefits of HT 4. Exploration and evaluation of relevant psychological issues and the institution of appropriate therapeutic measures (psychosocial distress, mood disorders, anxiety, cognitive impairment, and the complaint of fatigue are commonly experienced by cancer survivors); a multidisciplinary approach involving psychiatrists, psychologists, nurse practitioners, and support groups can be invaluable Dietary and lifestyle management. Modification of

dietary and lifestyle factors assists in control of

menopausal symptoms and psychological symptomatology, in addition to reducing the risks of cardiovascular disease and osteoporosis. However, the impact of these modifications on cancer recurrence or mortality is unknown. Evidence from laboratory investigations, epidemiologic studies, and randomized controlled trials (RCTs) supports the following recommendations: 1. Dietary modification incorporating a low transsaturated fat and low glycemic load, high cereal fiber, and high n-3 fatty acid content with a high ratio of polyunsaturated to saturated fat31 2. Calcium, 1000 to 1500 mg/day, with supplemental vitamin D, 400 to 800 U/day32 3. Limited caffeine intake 4. Less than 10 g/day of alcohol 5. Cessation of smoking 6. Regular exercise (including aerobic exercise, resistance training, and walking) 7. Maintenance of ideal weight The use of dietary phytoestrogens is discussed later.

M e n o pa u s e a n d H o r m o n e R e p l a c e m e n t Th e r a p y 799 HORMONE THERAPY The term hormone therapy (preferred to the term “hormone replacement therapy”), as discussed here, refers to the use of exogenous estrogen, either alone or in combination with a progestin. Newer agents that exhibit some estrogen-like effects (e.g., tibolone, raloxifene) are discussed separately. What are the indications for the use of hormone therapy? Although there is general consensus regarding the shortterm use of HT in the management of vasomotor symptoms, controversy exists regarding long-term use, with evidence regarding the benefits of long-term HT counterbalanced by data documenting the risks. Uncertainty also exists regarding the appropriate time at which to initiate long-term therapy and the duration of therapy. Information about the benefits and risks of HT has been derived from studies involving the use of predominately unopposed oral estrogens, mainly conjugated equine estrogens (CEE), in the majority of subjects, with a minority using combined estrogen/progestin therapy (EPT). How the findings

of these studies relate to the use of other estrogen preparations is unclear. This issue is further complicated by the exclusion of women with premature menopause or gynecologic cancer from recruitment into the RCTs conducted to evaluate HT use, which reduces the relevance of the study findings to this patient population. The continuing controversy regarding the risks and benefits of HT emphasizes the need to individualize therapy to the particular woman, involving her in the decision-making process. The indications for use of HT and assessment of the adverse effects is discussed in the following sections and summarized in Table 60-3. Menopausal symptoms. A multitude of studies, both

epidemiologic investigations and RCTs, attest to the benefits of estrogen therapy (ET), both alone and in combination with a progestin, in the treatment of vasomotor and urogenital symptoms associated with estrogen deficiency (see Table 60-3).33 Evidence regarding the benefit of ET in the management of other menopausal-related symptoms, especially psychological symptoms, is less clear.34 Younger women often require higher doses of estrogen, compared with older postmenopausal women, for relief of their symptoms.35

Table 60–3. Benefits and Risks of Hormone Replacement Therapy* Outcome Vasomotor symptom control Fracture Hip Vertebral Total Colorectal cancer Dementia Breast cancer >5 yr use (all HT) >5 yr use (EPT) Endometrial cancer Unopposed estrogen EPT Coronary heart disease Observational studies EPT HERS Stroke (nonhemorrhagic) Thromboembolic events Current HT use <1 Yr use Gallbladder disease <5 Yr use >5 Yr use (all HT) HERS Total mortality Current use >5 Yr

Relative Risk (95% CI) from Meta-analysis and Systematic Review

Hazard Ratio (nominal 95% CI) from Women’s Health Initiative with 5.2 Yr Follow-up (EPT)

77% reduction (58.2-87.5%)

Not measured

Current use, 0.64 (0.32-1.04) Ever use, 0.76 (1.56-1.01) Ever use, 0.60 (0.36-0.99)

0.66 (0.45-0.98)

Current use, 0.66 (0.59-0.74) Ever use, 0.80 (0.74-0.86) 0.66 (0.53-0.82)

0.66 (0.44-0.98) 0.76 (0.69-0.85) 0.63 (0.43-0.92) —

1.35 (1.21-1.49) 1.53

— 1.26 (1.00-1.59)

2.3 (2.1-2.5) 0.8 (0.6-1.2)

— 0.83 (0.47-1.47)

0.55-0.97 0.66 (0.53-0.84) 0.99 (0.80-1.22) 1.20 (1.01-1.40)

— 1.29 (1.02-1.63) — 1.41 (1.07-1.85)

2.14 (1.64-2.81) 3.49 (2.33-5.59)

2.11 (1.58-2.82) —

1.8 (1.6-2.0) 2.5 (2.0-2.9) 1.44 (1.10-1.90)

— — —

0.54 (0.45-0.63)

0.98 (0.82-1.18)

CI, confidence interval; EPT, combined estrogen and progestin therapy; HT, hormone therapy; HERS, Heart and Estrogen/Progestin Replacement Study. *Controversy exists as to whether nominal or adjusted CI should be used in relation to each of the study outcomes. If adjusted 95% CI is used, statistical significance is achieved only for decreased risk of total fractures (0.63-0.92) and increased risk of thromboembolic events (1.26-3.55). Adapted from Nelson HD, Humphrey LL, Nygren P, et al: Postmenopausal hormone replacement therapy: Scientific review. JAMA 2002;288:872-881.

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Prevention of osteoporosis. Numerous studies have reported a positive effect of estrogen in regard to maintenance of calcium balance, decreased bone resorption, and increased bone mineral density (reviewed by Compston32). The antiresorptive effect appears to be independent of the estrogen formulation used (oral, transdermal, or parenteral) or the addition of a progestin. Although conventional doses of estrogen are considered bone-sparing, the minimal effective dose is undetermined.36-38 A higher estrogen dose may be required in women with premature menopause.35 Positive effects are observed regardless of the age at which ET is begun, although the effect may be attenuated if treatment is commenced at a later age.39 Data from epidemiologic studies40 and results of small RCTs39,41 demonstrate a reduction of approximately 25% in hip fractures and nonvertebral fractures and a 50% decrease in vertebral fractures among ET users (see Table 60-3). Consistent with these earlier studies are data from the Women’s Health Initiative (WHI) study,42 an RCT in which 16,608 women were enrolled in the EPT arm (0.625 mg CEE with continuous 2.5 mg medroxyprogesterone acetate [MPA]) compared with placebo. The WHI results indicated a 34% reduction in hip fracture risk (hazard ratio [HR], 0.66; nominal 95% confidence interval [CI], 0.45 to 0.98) among HT-treated women, with an absolute benefit of 5 fewer fractures per 10,000 women per year (Fig. 60-2; Table 60-4). Reductions in risks of vertebral fractures (HR, 0.66; 95% CI, 0.44 to 0.98) and other osteoporotic fractures (HR, 0.77; 95% CI, 0.69 to 0.86) was also documented (see Table 60-3). The positive skeletal effects of estrogen decrease rapidly once therapy ceases; therefore, long-term HT use is required for the treatment of osteopenia/osteoporosis. Because most vertebral fractures occur in women who are older than 60 years of age and most hip fractures in those older than 70 years, controversy exists as to when ET should be instituted (i.e., at menopause or at 60 years, when the absolute risk of fracture increases significantly). This question is further complicated by data from the WHI study, which indicate a significantly increased risk of breast cancer, cardiovascular disease, and thromboembolic events in women treated with combined continuous HT, results which precipitated the early cessation of this arm of the trial (see Fig. 60-2 and Table 60-4). These results suggest that the risk/benefit analysis is not supportive of long-term use of this form of HT. Whether such risks and benefits are present with other types of HT (including various EPT preparations), with ET alone (the estrogen-only versus placebo arm of the WHI study continues) or with low-dose HT is unknown. Prevention of cardiovascular disease. Cardiovascular disease is the leading cause of death among postmenopausal women in industrialized countries.40 Laboratory studies in animals and humans have documented multiple mechanisms by which estrogens modify cardiovascular risk factors,43 including improved lipid profile and metabolism, altered vasoreactivity, hemostatic effects, and inflammatory effects. However,

as demonstrated in both animal studies and clinical trials, the addition of a progestin appears to attenuate the beneficial effects of estrogen, an effect that varies with the type of progestin used. The Postmenopausal Estrogen/Progestins Intervention (PEPI) trial documented that treatment with CEE plus MPA (continuous or sequential) raised blood glucose levels and reduced the magnitude of the potentially beneficial rise in high-density lipoprotein, compared with treatment with CEE alone or with CEE plus micronized progesterone.44 Previous meta-analyses of observational studies have reported a 35% to 50% decrease in the relative risk (RR) of CHD among women using HT (predominately unopposed estrogen), compared with nonusers.40,45 However, a recent meta-analysis46 reported no significant reduction in CHD among current users of estrogen (summary RR, 0.97; 95% CI, 0.82 to 1.16) after excluding poor quality studies and adjusting for socioeconomic status (see Table 60-3). The benefit of ET appeared to be confined to current use of estrogen rather than past use, and the effect of the addition of a progestin on CHD risk was variable.46 Despite the positive effect noted in many observational studies, the results of RCTs raise questions regarding the use of HT in either secondary or, more recently, primary prevention of cardiovascular events. The Heart and Estrogen/Progestin Replacement Study (HERS), a large, placebo-controlled RCT, assessed the effect of HT (0.625 mg CEE plus 2.5 mg MPA), compared with placebo, in women with known CHD.47 Although no significant effect of HT on CHD recurrence was observed over the mean 4-year follow-up period (log rank P = .91),47 or during the subsequently reported 6.8-year follow-up period,48 an increased RR of CHD was apparent during the first 4 months of the treatment period, with decreased risk present in the final 2 years of the study. The RRs for each individual year were not significantly different, although the trend was (P = .009). The Estrogen Replacement and Atherosclerosis trial also noted no significant difference in progression of angiographically verified coronary atherosclerosis in women with preexisting CHD treated with CEE alone versus combined CEE/MPA versus placebo during a 3-year follow-up period.49 The recently published results from the WHI study described earlier also cast doubt regarding the efficacy of HT in primary prevention of CHD. An increase of 29% (nominal 95% CI, 1.02 to 1.63) in CHD events (predominately nonfatal myocardial infarction rather Figure 60–2. Kaplan-Meier estimates of cumulative hazards for selected clinical outcomes of the Women’s Health Initiative (WHI) study. Differences between the treatment and placebo groups became apparent after approximately 4 years and 3 years of follow-up, respectively, for invasive breast cancer and colorectal cancer. Divergence between treatment groups was observed shortly after randomization for coronary heart disease, stroke, and pulmonary embolism. aCI, adjusted confidence interval; HR, hazard ratio; nCI, nominal confidence interval. (Reproduced with permission from Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-333.)

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Gynecologic Cancer: Controversies in Management Table 60–4. Outcomes of the Women’s Health Initiative Study (Events per 1000 Women during a 5.2-Yr Follow-up Period)* Treatment Outcome Coronary heart disease Stroke Venous thromboembolism Pulmonary embolus Invasive breast cancer Colorectal cancer Total fractures Hip fracture Total deaths Global index

Significance

Active

Placebo

Excess/Deficiency

Nominal CI

Adjusted CI

19.3 14.9 17.8 8.2 19.5 5.3 79 5.2 27 88.3

15.1 10.5 8.3 3.8 15.3 8.3 97 7.7 27 76.9

+4.2 +4.4 +9.5 +4.4 +4.2 −3.0 −21 −2.5 — 11.4

Yes Yes Yes Yes Yes Yes Yes Yes No Yes

No No Yes No No No Yes No No No

CI, 95% confidence interval. *The active treatment group received conjugated equine estrogen plus medroxyprogesterone acetate (versus a placebo group). The global index summarizes the balance of risks and benefits and includes stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. Controversy exists as to whether nominal or adjusted CI should be considered in relation to the study outcomes. If the adjusted 95% CI is used, statistical significance is achieved only for decreased risk of total fractures (0.63-0.92) and increased risk of thromboembolic events. Adapted from Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-333.

than fatal myocardial infarction or revascularization procedures) was observed in women treated with EPT, compared with placebo (see Fig. 60-2 and Table 60-3).42 This corresponds to an absolute risk of 7 more CHD events per 10,000 person-years (see Table 60-4). As noted in the HERS study, the difference between the two treatment groups developed within the first year after randomization (see Fig. 60-2). The authors reported that this effect was independent of age, race, BMI, prior hormone use, smoking status, blood pressure, diabetes, statin use, or aspirin use. The discrepancy between the findings of epidemiologic studies and those of RCTs remains speculative but may relate to bias in the observational studies, RCT design regarding the choice of HT regimen, age at initiation of HT, and subject characteristics. Potential biases present in the observational studies include the selection bias “healthy user effect,”50-52 compliance bias, diagnostic detection bias, and prevalence-incidence bias.52 In regard to the WHI study, significant cardiovascular disease risk factors were present in the study population at baseline, including a mean age greater than 60 years, past or current smoking status in 50% of subjects, and BMI greater than 25 in most subjects (with one third obese). It is therefore reasonable to conclude that the evidence from RCTs does not support the use of combined oral CEE/MPA for secondary prevention of CHD or primary prevention with initiation of therapy in older women with known risk factors such as obesity and smoking. However, the relevance of these clinical trial findings in relation to younger, nonobese women and the use of other EPT preparations remains unclear. Results from the estrogen-only arm of the WHI study (scheduled to conclude in 2005) are awaited with interest. Evidence from observational studies suggests that cardiovascular mortality is reduced in ever-users of estrogen (RR, 0.63; 95% CI, 0.55 to 72).40 Epidemiologic studies have also documented improved survival in

women with established CHD.53-56 Mortality due to CHD was neither increased nor decreased in women treated with HT compared with placebo in the HERS47 or in the WHI study.42 Cancer prevention. Epidemiologic evidence suggests a reduced risk of colorectal cancer among women taking HT (see Table 60-3).57,58 A meta-analysis57 of 18 eligible studies published to September 1998 reported a 20% decrease (summary RR, 0.80; 95% CI, 0.74 to 0.86) in the risk of colon cancer and a 19% reduction (summary RR, 0.81; 95% CI, 0.72 to 0.92) in the risk of rectal cancer for women who had ever used HT compared with never-users. Current use of HT was associated with an apparently greater protection from colorectal cancer compared with ever-use (summary RR, 0.66; 95% CI, 0.59 to 0.74). Although a limited number of studies were available for analysis, similar results were observed regardless of the duration of current use, the use of CEE or estradiol compounds, or the use of combined EPT. The association between hormone use and colorectal adenomas (which tend to arise 10 to 15 years before the development of cancer) is ill defined. Consistent with the data from observational studies, WHI study investigators reported a reduction of 37% (95% CI, 0.43 to 0.92) in colorectal cancer risk in the group treated with CEE plus MPA, compared with the placebo group (see Fig. 60-2 and Table 60-3); there was an absolute risk reduction of 6 cancers per 10,000 person-years (see Table 60-4).42 Biologic mechanisms by which estrogen could exert a protective effect include alteration in bile acid metabolism, direct effects on colonic epithelium, potential tumor suppressor effect of the estrogen receptor, and estrogen-induced suppression of the mitogen designated insulin-like growth factor-1.57 Data from epidemiologic studies regarding the association between HT and the prevention of other

M e n o pa u s e a n d H o r m o n e R e p l a c e m e n t Th e r a p y 803 neoplasms are limited and inconsistent. HT treatment was not associated with reduced cancer risk for any other neoplasm in the WHI study.42 No reduction in cancer risk or mortality was observed among HT users in HERS.47 Prevention of cognitive decline and dementia.

Numerous in vitro and in vivo studies have demonstrated biologic mechanisms by which estrogen may influence brain function. These include neurotrophic and neuroprotective effects, alteration of neurotransmitter systems, antioxidant effects, beneficial alteration of proteins associated with Alzheimer’s disease (AD), and indirect favorable changes in cerebral circulation and immune function.59 Evidence from epidemiologic studies59,60 indicates a reduction in the risk of AD among postmenopausal estrogen users (summary odds ratio [OR], 0.66; 95% CI, 0.53 to 0.82); this result was reported in a meta-analysis of 12 studies (see Table 60-3).60 Two meta-analyses, one of combined cohort studies and RCTs60 and the other a later review of nine RCTs,46 concluded that HT use was associated with improvement in certain areas of cognitive function (e.g., verbal memory, vigilance, reasoning, motor speed) in symptomatic, but not in asymptomatic, nondemented postmenopausal women. The hypothesis that the estrogen-induced reduction in menopausal symptoms (e.g., alleviation of depression and sleep disturbance) is responsible for cognitive improvement remains controversial.60 The authors of Cochrane reviews of RCTs investigating the effects of HT on cognitive function in postmenopausal women with61 and without dementia62 concluded that there was no overall positive effect of HT. As with the observational studies, methodologic problems limit the interpretation of the RCTs, and the effect of age, type of menopause, type and dose of estrogen, addition of a progestin, and duration of therapy remain unresolved. In regard to the risk of dementia when HT is initiated in women who are many years postmenopausal (in contrast to the data described above obtained in women receiving HT at around the time of menopause), recent results from the Women’s Health Initiative Memory Study (WHIMS)62a suggest an adverse effect of HT in the risk of dementia. This ancillary study of the WHI involving 4532 postmenopausal women, aged 65 years or older (53% women aged >70 years) and free of probable dementia at the time of recruitment, reported a doubling of the risk probable dementia (HR 2.05; 95% CI 1.21-3.48); with an excess of 23 cases/10000 personyear (45 vs 22 cases/10000 person-year in the EPT and placebo groups respectively; p = 0.01) (see Table 60-3). AD was the most common dementia classification although the authors note that microvascular infarcts may coexist/contribute to AD. No effect of HT on mild cognitive impairment was observed. These data are compatible with the interpretation that delaying of HT until old age is no longer associated with protective effects that may occur when HT is started at the time of declining estrogen levels—the “critical window” of exposure (Victor Henderson 2002, personal communication).

Reduction in mortality. Analysis of data from the Nurse’s Health Study,63 a prospective cohort study, indicated reduced all-cause mortality among current users of HT (mainly CEE), compared with never-users (RR, 0.63; 95% CI, 0.56 to 0.70) (see Table 60-3). This effect appeared to be secondary to a reduction in CHD-associated death (RR, 0.47; 95% CI, 0.25 to 0.49) and, to a lesser extent, in death due to cancer (RR, 0.47; 95% CI, 0.25 to 0.49). Importantly, this study provided information regarding the temporal association of HT use. The protective effect of HT appeared to be lost 5 years after cessation of use, and attenuation of the benefit of HT was observed after 10 years of use. Stratification of risk revealed that women with the lowest risk of CHD derived the least benefit from HT use. The methodologic limitations of this and other observational studies relate to the potential “healthy user” effect50,51 and the definition of use, raising questions as to whether the observed reduction in mortality actually results from HT use or from characteristics of the user. In contrast to the results of the Nurses Health Study, no differences in mortality or cause of death were observed between women treated with EPT and those treated with placebo in either HERS47 or the WHI42 (despite the reported increased risk of cardiovascular and thromboembolic events or breast cancer) (see Table 60-4). The results of the estrogenonly arm of the WHI study may help to further clarify this issue. What are the adverse effects associated with hormone therapy use? Endometrial cancer. A causal relationship between

unopposed ET and endometrial hyperplasia and carcinoma has been recognized for more than 25 years.40,64 The risk of endometrial hyperplasia/carcinoma appears to depend on estrogen preparation, dose, and duration. Meta-analyses of 29 observational studies65 reported a twofold increased risk of endometrial cancer among users of unopposed ET, compared with nonusers (95% CI, 2.1 to 2.5); cancer risk increased to 9.5-fold (95% CI, 7.4 to 12.3) with 10 or more years of use (see Table 60-3). Endometrial cancer risk was greater in users of CEE compared with users of synthetic estrogens (RR, 2.5 versus 1.3, respectively). The elevated risk persisted after cessation of ET for at least 5 years (RR. 2.3; 95% CI, 1.8 to 3.1). A Cochrane review66 of 18 RCTs reported a significantly increased rate of endometrial hyperplasia among women treated with moderate-dose ET (OR, 8.3; 95% CI, 4.2 to 16.2) or with high-dose ET (OR, 10.7; 95% CI, 4.6 to 25.1), compared with placebo, after 12 months of therapy. However, the risk of endometrial hyperplasia with low-dose ET remains unclear. Longer duration of ET was associated with a further increase in the rate of hyperplasia, with a reported OR of 16.0 (95% CI, 9.3 to 27.5) after 36 months of moderate-dose ET. No increase in endometrial cancer was observed in these RCTs; however, these studies were of limited duration and of insufficient sample size to assess this outcome adequately.66 Irregular bleeding, nonadherence to therapy, and surgical intervention were more likely with

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Gynecologic Cancer: Controversies in Management

unopposed ET. Despite the increased risk of endometrial cancer associated with unopposed ET, no significant increase in mortality has been observed (RR, 2.7; 95% CI, 0.9 to 8.0).65 Use of EPT does not appear to be associated with an elevated risk of endometrial cancer (summary RR, 0.8; 95% CI, 0.6 to 1.2) (see Table 60-3).65 Although of limited duration (maximum, 5 years), data from RCTs are consistent with the findings of the observational studies, with no demonstrated difference in the rate of endometrial hyperplasia/cancer among women using EPT, compared with placebo.42,47,66 However, questions remain regarding the long-term protective effect of sequential progestin therapy. Lethaby and coreviewers65 concluded that, with longer duration, continuous progestin therapy appeared to be more protective than sequential therapy (OR, 0.3; 95% CI, 0.1 to 0.97). At present, the optimal progestin preparation, dose, duration, and regimen for the prevention of endometrial hyperplasia/carcinoma and minimization of side effects are unknown. Breast cancer. Concern regarding a possible increased

risk of breast cancer is a major reason why women choose not to use or continue HT. This issue is complicated by lack of consensus among the many published observational studies. A meta-analysis involving a comprehensive reanalysis of the data from 51 observational studies (incorporating 52,705 women with invasive breast cancer and 108,411 control women) found no significant increased risk of breast cancer with short-term use (less than 5 years) of HT.67 However, an increased risk of breast cancer was observed with a duration of 5 or more years of ET use (RR, 1.35; 95% CI, 1.21 to 1.49) (see Table 60-3). This increased risk was inversely proportional to weight or BMI and persisted for at least 5 years after cessation of use. Although the data were limited regarding the effects of various hormone preparations, 5 or more years use of EPT was associated with an RR of 1.53 (see Table 60-3). Recently, the Million Women study,66a an observational study involving 1,084,110 United Kingdom women aged 50-64 years (average age 55.9 years) who were classified according to their HT use at baseline and with an average follow-up of 2.6 years (breast cancer incidence) and 4.1 years (breast cancer mortality), reported a significant increase in the incidence of breast cancer in current users of ET (RR 1.30, 95% CI, 1.21-1.41; p < 0.0001), EPT (RR 2.00, 95% CI, 1.88-2.12; p < 0.0001) and tibolone (RR 1.45, 95% CI, 1.25-1.68; p < 0.0001). An increased risk of breast cancer was observed regardless of the formulation of ET (oral, transdermal or subcutaneous implant) or EPT (progestin constituent or type of regiman). In contrast to the previous meta-analysis,67 an increased risk of breast cancer was observed in current HT users who had used HT for less than 5 years (ET RR 1.25, 95% CI, 1.101.41 and EPT RR 1.74, 95% CI, 1.60-1.89). However, it is important to note that data regarding duration of hormone use was obstained only at recruitment (several years prior to breast cancer diagnosis). Thus no

reliable estimate is really possible of the relationship between duration of HT and cancer risk for this study as actual duration of use could necessarily have been greater than at recruitment for most women. The results of the WHI are consistent with these data. This RCT was halted prematurely because the test statistic for invasive breast cancer exceeded the predetermined adverse effect boundary. It is noteworthy that 74% of the subjects in the study had not previously used HT while 26% reported varying duration of prior use. After an average of 5.2 years of follow-up, those women without prior HT use had no significant increase in breast cancer risk (HR 1.06; 95% CI, 1.00 to 1.59) compared with placebo (see Fig. 60-2, Table 6-3 and Table 60-4).42 This difference between the treatment and placebo groups was apparent after approximately 4 years (see Fig. 60-2).42 Interestingly, no interaction with age, BMI, family history, or age at first birth was observed. The absolute increased risk of breast cancer was therefore calculated as 8 more invasive breast cancers per 10,000 women per year (see Table 60-4).42 Combined HT appears to be associated with a higher risk of breast cancer compared with estrogen alone, as was demonstrated by evidence derived from observational studies58, 66a, 67 and RCTs, including the WHI (the estrogen-only arm of the WHI study currently continues) and the PEPI study (which assessed the effect of combined EPT on mammographic density, a surrogate marker for breast cancer).68 Despite a potential increase in the risk of breast cancer with HT use the effect on breast cancer mortality remains unclear; conflicting evidence is provided by the observational studies, some of which show evidence of a reduction in cancer mortality.69,70 The Million Women study66a reported a marginally significant increased risk of fatal breast cancer with current (RR 1.22, 95% CI, 1.00-1.48; p = 0.05) but not past HT use, although the total number of deaths (517) in the follow-up period was small and the authors themselves cautioned regarding the reliability of this section of the data. Mortality due to breast cancer was not assessed in the WHI. Bias present in the observational studies35 and biologic differences among tumors have been proposed to account for these findings. Thromboembolic events. Despite methodologic limitations, data from observational studies and RCTs support the association between an increased risk of venous thromboembolism and postmenopausal estrogen use (see Table 60-3). A recent meta-analysis71 of 12 studies reported an overall RR of 2.14 (95% CI, 1.64 to 2.81) for venous thromboembolic events (VTE) among current estrogen users (see Table 60-3). Significantly, the highest risk was observed during the first year of use (RR, 3.49; 95% CI, 2.23 to 5.59). Limited data also suggest that the risk of VTE is greater with higher estrogen doses and greater with the addition of a progestin (EPT). Consistent with these previous investigations, the WHI42 demonstrated that women treated with EPT experienced a twofold increase in VTE (HR, 2.11; nominal 95% CI, 1.58 to 2.82), including deep venous

M e n o pa u s e a n d H o r m o n e R e p l a c e m e n t Th e r a p y 805 thrombosis (HR, 2.07; nominal 95% CI, 1.49 to 2.87) and pulmonary embolism (HR, 2.13; nominal 95% CI, 1.39 to 3.25), compared with the placebo-treated group (see Fig. 60-2, Table 60-3, and Table 60-4). This corresponded to an absolute excess risk of 8 additional pulmonary emboli per 10,000 person-years. As noted in previous studies, the risk of VTE appears to decrease with time.42 Identified risk factors for VTE in HERS72 included hip or lower-extremity fracture, cancer, hospitalization, surgery, and later onset of menopause. Interestingly, no interaction was found between the risk of VTE and BMI, smoking status, or blood pressure in either HERS72 or the WHI.42 Although aspirin and statin use appeared to be protective in HERS,47 this effect was not observed in the WHI study.42 Additional information from the WHI regarding risk factors for VTE is awaited. The risk of VTE is multiplied in the presence of preexisting thrombophilias or past history of VTE.73,74 Therefore, the use of HT in women with a known genetic thrombophilia or prior history of VTE is not advocated. Routine coagulation profile screening of women who have no family or personal history of VTE before commencing HT remains controversial. Further investigation is required to delineate risk factors and those who would benefit from screening. The majority of clinical studies have involved the use of oral estrogens. The risk of VTE with transdermal estrogen is unknown, although theoretical and limited clinical data suggest a less procoagulant effect.75 The efficacy of aspirin or temporary cessation of HT to prevent VTE in the setting of short-term acquired risk factors (e.g., lower-limb fracture, surgery) is unknown. Use of HT with anticoagulation has been reported anecdotally in women at risk for VTE. The pathophysiology of HT-induced venous thrombosis remains ill defined but appears to involve early activation of coagulation, reduction in circulating anticoagulants, and potential effects on vascular endothelium.71,76,77 Stroke. Conflicting results have emerged from epidemiologic research regarding an association between HT and stroke. However, evidence from a recent metaanalysis of epidemiologic studies and from the WHI study suggests that HT is associated with an increased risk of nonhemorrhagic stroke. Nelson and coworkers46 conducted a meta-analysis of nine observational studies and reported a significantly elevated risk of thromboembolic stroke among ever-users of estrogen (RR, 1.20; 95% CI, 1.01 to 1.40); but this effect was not observed for subarachnoid or intracerebral stroke (see Table 60-3). In addition, overall stroke mortality was slightly reduced (RR, 0.81; 95% CI, 0.71 to 0.92). These findings are consistent with those of the WHI study, which reported an increased rate of nonfatal stroke (but not fatal stroke) among women treated with EPT, compared with placebo (HR, 1.41; nominal 95% CI, 1.07 to 1.85) (see Fig. 60-2, Table 60-3, and Table 60-4). The excess risk of stroke occurred after the first year of HT use and appeared to be independent of age, BMI,

smoking status, prior stroke history, and presence of hypertension.42 In contrast, two secondary prevention RCTs compared the risk of stroke among women with previous CHD treated with combined CEE plus MPA (HERS)98 and among women with previous stroke treated with unopposed estradiol (Women’s Estrogen and Stroke Trial)79 with that among placebo-treated women and reported no statistical difference. In those studies, increasing age, atrial fibrillation, hypertension, diabetes mellitus, and smoking status were independent risk factors for stroke events. Therefore, HT does not appear to confer any benefit regarding stroke prevention and may indeed be associated with an increased risk of stroke, particularly in women with vascular risk factors. Gallbladder disease. With a few exceptions, observa-

tional studies have documented an increased risk of gallstones or cholecystectomy in postmenopausal women taking exogenous estrogen. Data from the Nurses’ Health Study80 revealed an increased ageadjusted RR for cholelithiasis of 1.8 (95% CI, 1.6 to 2.0) among current estrogen users, compared with neverusers, with a further elevation in risk occurring after 5 years of use (RR, 2.5; 95% CI, 2.0 to 2.0) (see Table 60-3). Past estrogen users continued to demonstrate an increased risk of cholelithiasis. Consistent with the epidemiologic studies, women treated with combined CEE plus MPA in the HERS had a marginally significant increase of 38% (95% CI, 1.00 to 1.92) in the RR of gallbladder disease (89% undergoing biliary tract surgery), compared with the placebo group.47,81 Information from the WHI regarding gallbladder disease is awaited. The risk of gallbladder disease with nonoral estrogen preparations is unknown. Experimental studies in animals and humans indicate that estrogen increases bile lithogenicity, leading to cholelithiasis via mechanisms including alteration in hepatic lipoprotein uptake, inhibition of biliary acid synthesis, increased biliary cholesterol, and reduction of cholesterol nucleation time.82 Limited clinical data suggest that transdermal and oral estrogens exert similar effects.83 Ovarian cancer. Data regarding an association between HT and ovarian cancer are inconclusive. Evidence from earlier epidemiologic studies is conflicting58; however, results from a cohort study involving 44,241 women suggest an increased risk of ovarian cancer with long-term (>10 years) use of ET (RR, 1.8; 95% CI, 1.1 to 3.0) but not with short-term use of EPT (mean duration, 5.6 years).84 No increase in ovarian cancer was observed among women using EPT in the WHI study42 or HERS,47 compared with placebo. Other disorders. Observational evidence indicating an association between HT use and systemic lupus erythematosus or Raynaud’s disease is inconclusive. Limited, inconclusive data exist regarding an association between HT and other cancers.

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Gynecologic Cancer: Controversies in Management

Which hormone therapy regimen should be used? Since the advent of the use of exogenous hormones in the management of menopause, there has been evolution in the preparations available and patterns of use. The most important introduction was the use of EPT after the realization of an increased risk for endometrial malignancy in women with an intact uterus who received ET alone. Administration of estrogen may be via the oral or parenteral route; different preparations demonstrate different degrees of potency, pharmacokinetics, and biologic effects. For example, transdermal estrogen is considered to cause less mastalgia, nausea, and deep vein thrombosis than oral preparations do.35 Recent research36-38, 84a, 90 assessing the use of low-dose estrogen regimens (equivalent to 0.3 mg CEE) indicates a positive response in regard to menopausal symptoms, bone mineral density (BMD), lipid profile, and reduction of adverse effects. However, further studies are required to clarify the long-term risks and benefits of these HT regimens. Use of vaginal estrogens has been considered to be associated with minimal systemic absorption. However, variation in serum estrogen levels above pretreatment levels is observed with different vaginal estrogen preparations. Direct comparisons among different preparations are scarce, and long-term safety data are lacking. The dose and type of estrogen used should be individualized depending on the age of the patient, cause of menopause (surgical or nonsurgical), types of menopausal symptoms or conditions requiring therapy, smoking status, presence of concurrent disease (e.g., hepatic disease), and patient acceptance. The oral progestin preparations that are currently available for use in combined HT include the progesterone-like C21-steroid derivatives, the testosterone-like C19-nortestosterone derivatives, and the antiandrogen, cyproterone acetate. Other modes of delivery include natural progesterone as a vaginal suppository, norethisterone combined with estradiol in a transdermal patch, and the levonorgestrel-releasing intrauterine system. Current evidence indicates that progestincontaining creams (either progesterone or plant-derived “yam” cream) do not provide effective endometrial protection.85,86 Variation in progestin preparations and sequential regimens is observed among countries. Limited data suggest that the type of progestin may be important in regard to endometrial protection,87 in addition to duration and dose of progestin therapy. Progestin administration during sequential therapy should continue for at least 10 to 12 days each month88; evidence suggests that long-cycle sequential therapy (progestin administered every 3 months) is associated with a higher incidence of endometrial hyperplasia.66 The long-term protective effect of sequential progestin administration remains in doubt (see earlier discussion). The choice of cyclic or continuous progestin administration depends on the stage of the climacteric; studies suggest that continuous progestin use should be instituted at least 1 year after menopause (reviewed by Marsh and Whitehead89). Progestin-related side

effects, including both physical and psychological complaints, vary according to the agent used and are a major cause of noncompliance with HT.89 Irregular bleeding is more likely with continuous combined HT than with sequential combined HT (OR, 2.3; 95% CI, 2.1 to 2.5),66 although the lower-dose regimens are associated with less bleeding.90 Evidence from human and animal studies also indicates that progestins may attenuate the beneficial effects of estrogen, particularly in regard to vascular function. The combined oral contraceptive pill, either conventional dose or low-dose, is a potential therapeutic option particularly for perimenopausal women who require contraception and for women with premature menopause. When should treatment be instituted? There is general consensus that treatment should be instituted early for management of menopausal symptoms, particularly in the case of women with surgical menopause or premature menopause. However, for those women without symptoms who are at risk for osteoporosis, the possibility of delayed treatment (low-dose HT beginning at approximately 60 years of age) exists. Potential advantages include reduction in the duration of therapy, facilitation of identification of women at high risk of fracture, and, because most fractures occur in women older than 65 years of age, need to treat fewer women to have a positive outcome.35 The advantages of delayed or any HT use would need to be evaluated in regard to the adverse effects documented in the WHI. Tibolone Tibolone, a synthetic steroid whose metabolites have estrogenic, progestogenic, and androgenic properties, is an alternative to conventional HT. The lack of approval from the Food and Drug Administration (FDA) has restricted its use in the United States, although it is widely used in the rest of the world. After administration, the parent compound is rapidly metabolized to three active compounds: 3α-hydroxytibolone, 3β-hydroxytibolone, and a Δ4-isomer (Fig. 60-3). These metabolites exhibit differences in steroid receptor affinity, tissue specific metabolism, and concentration. The hydroxytibolone metabolites, binding to the estrogen receptor only, demonstrate estrogenic effects in regard to vasomotor symptoms, bone, and vagina, whereas the Δ4-isomer, binding to the androgen and progesterone receptors, functions as a progestogen in the endometrium but has androgenic effects in the brain and liver.91 Interestingly, 3αhydroxytibolone–induced inhibition of sulphatase activity in breast tissue prevents conversion of estrone to estradiol. Data from in vitro and in vivo studies suggests that tibolone may have antiestrogen and tamoxifen-like effects on the breast.92 A recent review of RCTs91 concluded that tibolone significantly reduces

M e n o pa u s e a n d H o r m o n e R e p l a c e m e n t Th e r a p y 807 Figure 60–3. Metabolites of tibolone. Tibolone is metabolized into three compounds that exhibit tissue-specific effects. The effects of tibolone can be characterized as stimulatory effects on the receptor (+), suppressive effect on the receptor (−), and unknown effects (?) on postmenopausal women. (Reproduced with permission of The Endocrine Society from Modelska K, Cummings S: Tibolone for postmenopausal women: Systematic review of randomised trials. J Clin Endocrinol Metab 2002;87: 16-23.

Tibolone is metabolized into:

3α-OH-tibolone

Δ4-isomer

3β-OH-tibolone

Estrogen receptors • Bone Decreases bone turnover (+) Improves bone density (+) • Vagina Improves vaginal dryness (+) Reduces dyspaurenia (+)

Progesterone receptors • Endometrium (–) Endometrial effects (?) Inhibition of enzymatic activity • Breast Effect on risk of breast cancer (?)

vasomotor symptoms and increases BMD in postmenopausal women. Use of tibolone is also associated with a reduction in abnormal uterine bleeding, compared with conventional continuous EPT, although bleeding rates were higher with a higher dose (5 versus 2.5 mg) and in women with recent onset of menopause. No evidence of endometrial stimulation has been observed in short-term studies. The data also suggest potential beneficial effects on sexual function, hemostasis, and lipid metabolism, but further clarification is required.91 No increase in the rate of mastalgia or mammographic density with tibolone treatment has been noted in small RCTs.4,93 However, the long-term effects of tibolone on reduction of fracture, cognitive function, breast cancer risk, and cardiovascular disease remains unclear. The Million Women study66a reported that the risk of breast cancer associated with the current use of tiblone lay between ET and EPT (see earlier discussion). However, the total number of incident cases was small (184) including only 88 women who had used tibolone as the sole form of HT. As this was an abservationl study, the possibility of bias (or example, tibolone has been advocated as a preferred therapy for women at risk of breast cancer) cannot be excluded. Several RCTs are in progress to address these questions. What is the role of estrogen in the etiology of gynecologic cancer? Data regarding a role for estrogen in the etiology of gynecologic cancer are complex and often conflicting. A putative role is suggested by the observed association between increased levels or prolonged exposure to endogenous estrogen and risk of cancer. Earlier

Androgen receptors • Brain Improves libido (?) • Liver HDL (–) SHBG (–) Fibrinolitic factors (+)

onset of menarche, later onset of menopause, nulliparity, delayed childbearing, increased BMI, higher BMD, and chronic anovulation are known risk factors for breast, endometrial, and ovarian cancer. The results of observational studies and RCTs also indicate an association between exogenous estrogen and gynecologic cancer (discussed earlier). Finally, extensive research has been directed at unraveling the biologic basis for this association. Steroid hormone receptors are present in all of these tissues. In vitro studies have reported variable dose-dependent effects of estrogen on cancer cell proliferation, as well as independent local regulation of estradiol levels by breast tumors. Two mechanisms of estrogen-induced carcinogenesis have been proposed (reviewed by Santen94): (1) estradiol stimulation of cell proliferation increases the chances of a genetic mutation with subsequent neoplastic transformation, initiation of tumor formation, and promotion of tumor growth; and (2) reactive estradiol metabolites cause depurination, leading to faulty DNA repair, genetic mutations, and tumor initiation. As with estrogen, clinical and laboratory evidence is conflicting regarding an association between progesterone and breast cancer. Can hormone therapy be used in women with a history of gynecologic cancer? For many years, the prevailing wisdom has been that HT is contraindicated in women with a history of gynecologic cancer, because of the perceived potential adverse effect of estrogen on disease recurrence or progression and patient survival. However, the large number of postmenopausal gynecologic cancer survivors has

64 120 24

Case-control

Cohort Cohort

O’Meara et al.97 (2001) HABITS

RCT in progress

Case-control

174/695

125/362

39

Cohort

Case-control

56

Cohort

21/42

61 41/82

Cohort Case-control

Decker135 (1996) DiSaia et al.136 (1996) Peters & Jones137 (1996) Vassilopoulou-Sellin et al.138 (1997) Beckman et al.139 (1998) Espie et al.140 (1999) Guidozzi141 (1999)

Case-control

90/180

Case-control

Eden et al.100 (1995)

Ursic-Vrscaj & Bebar142 (1999) DiSaia et al.143 (2000)

51

25

Range 35-74

52

47

45 48

NS

45

42

52 50

47

51

Mean Age (Yr)

35

Study Design

A. History of Breast Cancer Powles et al.133 Retrospective (1993) Wile et al.100 (1993) Cohort

Reference and Year

No. of Subjects (Cases/Controls)

>50% Stage I or II

>60% Stage T0-T2 15 Stage I 8 Stage II 66% Disease limited to breast 42% Stage I 22% Stage II

56 Stage T1-T2

—

12 Stage T1 14 Stage T2 52% Stage I 28% Stage II 80% Disease limited to breast 39 Stage T1 or less 56% Stage I 22% Stage II 40 Stage 0-II

Tumor Stage

Table 60–5. Use of Hormone Therapy in Women with a History of Gynecologic Cancer

Range 12- > 96

Mean 46

Mean 62

Mean 96 Mean 34

0

Median 84

Mean 57

44.4 NS

Median 60

Mean 26

Mean 31

Interval to Treatment after Surgery* (Mo)

Median 15

Median 22

Mean 28

Mean 28.8 Mean 32

Mean 15

Mean 40

Mean 37

26.4 NS

Median 18

Mean 35.2

Mean 14.6

Duration of HT (Mo)

Median 44

180

4/5 19%/11% Risk of all-cause mortality odds ratio, 0.28 (95% confidence interval, 0.1-0.71) 16/101 9%/15%

5 0

Mean 28.8† Mean 68

1

0

5 6/7

6

Mean 108

No. of Recurrences (Cases/Controls)

7%/17%

3

2

Mean 32

Mean 40

Mean 37

26.4† 48

Median 36

Mean 25.2

Mean 14.6

Duration of Follow-up (Mo)

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Gynecologic Cancer: Controversies in Management

Case-control

Retrospective Retrospective case-control

RCT

Lee et al.147 (1990)

Gitsch et al.148 (1995) Chapman et al.149 (1996)

Gynecologic Oncology Group

59 ERT 66 No ERT 24/4

78/295

Projected 1054/1054

8‡ 62/61

HT, hormone therapy; NS, not stated; RCT, randomized controlled trial. * For breast cancer patients, interval after diagnosis/primary therapy. † Assumed to be equal to the duration of HT use. ‡ Eight of 15 patients accepted HT.

C. History of Ovarian Cancer Eeles et al.103 (1991) Retrospective case-control Guidozzi & Daponte105 Nonblinded (1999) RCT Ursic-Vrscaj et al.104 Case-control (2001)

31 20

Cohort Cohort

Baker145 (1990) Bryant146 (1990) 44/99

47/174

B. History of Endometrial Cancer Creasman et al.144 Case-control (1986)

41/43

Cases younger than controls Range 27-59

—

40 Mean 57.6/69.3

—

Range 29-69 NS

—

50% Stage I-II 65-70% Stage III Stage IV excluded

30 Stage Ia 17 Stage Ib 0 Stage II NS 19 Stage Ia 1 Stage II 24 Stage Ia 20 Stage Ib 0 Stage II NS 54 Stage Ia + Ib 6 Stage Ic 2 Stage II All

1-25

6-8 weeks

40

<3

NS Median 8

Median (1 > 60)

Range 0-120 Range 18-24

Median 26

NS (minimum 48?) —

28

—

Range 12-78 NS

—

NS Range 12-132

—

1-70

Minimum 48

42

60

Range 12-78† Median 39.5

Range 24-84

Up to 16 years Range 42-168

Range 25-150

ERT: 32 (54%) Non-ERT: 41 (62%) 5 (21%)/15 (31%)

17/147 deaths

Pending

0 26 3.2%/9.8%

0/8 0%/8%

0 0

1/26 2.1%/14.9%

M e n o pa u s e a n d H o r m o n e R e p l a c e m e n t Th e r a p y 809

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Gynecologic Cancer: Controversies in Management

necessitated a reevaluation of this dictum. Responses to questionnaires indicate that menopausal symptoms are common among breast cancer survivors; symptom intensity rather than long-term health risks influence a woman’s decision to use HT.95 The advent of effective nonhormonal therapies for the management of certain menopausal symptoms, osteoporosis, and cardiovascular disease in postmenopausal women, in addition to concerns regarding the risks associated with HT use, has meant that HT may be considered as “secondline” therapy in some instances. Before any treatment is instituted, consideration should be given to cancer prognosis, patient age, premenopausal or postmenopausal status, clinical symptoms, and patient concerns and wishes. Hormone therapy use in women with a history of breast cancer. A number of observational studies have

attempted to address the question of HT use in women with previous breast cancer (Table 60-5A). However, methodologic limitations, including retrospective design, lack of randomization, small sample size, lack of a control group, selection bias, short duration of follow-up, concurrent tamoxifen use, and differing estrogen doses or preparations (vaginal or oral predominantly) mean that cautious interpretation of the results is required. Col and coinvestigators96 conducted a review and meta-analysis of 11 eligible studies from among 28 published reports to 1999. They reported no significant increase in the risk of recurrence among breast cancer survivors using HT (RR, 0.82; 95% CI, 0.58 to 1.15) (Fig. 60-4). They concluded that their findings “may be limited to women who have been disease free for several years and who take HT for 2 years or less.”96 A subsequent case-control study97 reported a decreased risk of recurrence (RR, 0.5; 95% CI, 0.3 to 0.85) and mortality (RR, 0.48; 95% CI, 0.29 to 0.78) among women with previous breast cancer using HT. No difference was observed between oral and vaginal estrogen use, or with unopposed versus combined therapy. Data from biologic studies suggests that

continuous progestin may be preferable to sequential progestin use.98 Vasomotor symptom control, efficacy in the treatment of advanced breast cancer, and in vitro antiproliferative effects99 provided the basis for the decision to use a moderate-dose (equivalent to 50 mg MPA) continuous progestin regimen as described in the Australian cohort.100,101 However, the optimal HT regimen for this patient population remains unknown. Further clarification will be obtained from the Hormones After Breast Cancer: Is It Safe (HABITS) RCT. Hormone therapy use in women with a history of endometrial cancer. The few studies that have investi-

gated the question of HT use in women with a history of endometrial cancer have failed to demonstrate any increase in recurrence or in death rate among HT users (see Table 60-5, part B). However, these studies were limited by a number of methodologic flaws, including small sample size, retrospective design, selection bias, and variations in HT preparation used, time before institution of HT, cancer diagnosis, and disease severity. Therefore the data, although encouraging, do not provide definitive support for the use of HT in women with a history of gynecologic cancer. The patients treated with HT were often younger and included those with significant estrogen deficiency symptoms, earlier-stage disease, and fewer intercurrent illnesses (where assessed). Oral or vaginal estrogens (or both) were the predominant preparations used, and 30% to 50% of patients were treated with additional progestin. The results of the prospective Gynecologic Oncology Group study, a double-blind, placebo-controlled RCT investigating the effects of CEE treatment on recurrencefree and overall survival in women with a history of stage I or II endometrial cancer, will help to clarify this issue. The American College of Obstetrics and Gynecologists102 concluded that there is insufficient evidence to support specific recommendations regarding the use of HT in women with a history of endometrial cancer. They commented that, although the indications for use of HT in this population are similar

Figure 60–4. Relative risks (RR) of recurrent breast cancer associated with hormone replacement therapy. The left side of the figure represents each study individually, whereas the right side represents a cumulative meta-analysis. (This analysis appeared before the publication of the report by O’Meara and coworkers.97) The RR of recurrent breast cancer is denoted by the ● symbol, and the 95% confidence interval by the solid lines. Studies that included a control group are indicated by an asterisk. (Reproduced with permission from Col NF, Hirota LK, Orr RK, et al: Hormone replacement therapy after breast cancer: A systematic review and quantitative assessment of risk. J Clin Oncol 2001;19:2357-2363.)

M e n o pa u s e a n d H o r m o n e R e p l a c e m e n t Th e r a p y 811 to those for other women, candidates should be selected on the basis of prognostic indicators such as depth of invasion, degree of differentiation and cell type, and the risk the patient is willing to assume.102 Despite theoretical advantages, whether the addition of continuous progestin to ET or the use of tibolone provides any advantage over the use of unopposed estrogen in these women who have undergone previous hysterectomy is unknown. Hormone therapy use in women with a history of ovarian cancer. The two observational studies and one

RCT (see Table 60-5, part C) that have investigated the use of HT in women with a history of epithelial ovarian carcinoma reported no adverse effect on recurrence or survival rate. The retrospective study of Eeles and coworkers103 was limited by small sample size, selection bias to patients with earlier-stage disease, and short follow-up. The small case-control study104 compared 24 women with significant menopausal symptoms who were treated with oral estrogen (combined with a progestin in 30% of subjects) with 48 control women matched for age, disease stage, cancer treatment, and follow-up. HT was initiated at an average of 21 months after diagnosis and continued for approximately 2 years. The RCT of ovarian cancer survivors,105 in which women were randomly assigned to CEE treatment or no ET, was also limited by small sample size. Within each group, recurrence was more likely among those with poorly differentiated tumors, more advanced disease, and suboptimal primary surgery. The use of transdermal estrogens or tibolone has not been investigated in this patient population. Hormone therapy use in women with a history of cervical cancer. Limited evidence from observational

studies suggests that noncontraceptive hormone use is associated with a decreased risk of carcinoma of the cervix.106,107 In addition, HT was not associated with increased risk of virus carriage or replication in a study of human papilloma virus (HPV) infection in postmenopausal women.108 No published studies specifically addressing the question of HT use in women with previous cervical cancer could be found.

What is the role of androgen therapy in postmenopausal women with a history of gynecologic cancer? Androgen deficiency, as a clinical entity, has been recognized mainly in women with hypopituitarism, adrenal insufficiency, or ovarian failure (premature menopause or therapeutic intervention including oophorectomy).109 The occurrence of clinical androgen insufficiency (and the perceived benefits of testosterone therapy) in women who have undergone spontaneous physiologic menopause remains controversial. The presence of characteristic symptoms, including diminished well-being, decreased sexual function, dysphoric mood, and fatigue, in the setting

of a low serum testosterone concentration is required for the diagnosis of female androgen deficiency.110 Improvement in sexual function, well-being, and energy levels with maintenance of BMD has been reported in small studies of postmenopausal women treated with pharmacologic doses of testosterone plus estrogen, compared with placebo or estrogen-only therapy.109 The largest study111 investigated 75 women who had undergone oophorectomy and hysterectomy before menopause and were receiving conventional ET; they were randomly assigned to treatment with either transdermal testosterone patches (150 or 300 μg/day) or placebo for 12 weeks. A significant increase in wellbeing and parameters of sexual function was observed in women treated with the higher testosterone dose, compared with placebo. The lack of specific androgen formulations for women has necessitated the adaption and use of testosterone preparations designed for men.109 Recognized side effects of androgen therapy include virilization (which is minimized if testosterone levels approximate the physiologic range) and unfavorable lipid changes (associated with oral androgen use). There are no data regarding the use of androgen therapy in postmenopausal women with a history of gynecologic cancer. Potential disadvantages of androgen therapy in this clinical setting include the requirement for concurrent ET with testosterone therapy to avoid virilization and the potential for aromatization of testosterone to estradiol. However, there is abundant clinical evidence that androgens normally inhibit mammary epithelial proliferation,80 and clinical trials to assess the effects of combined estrogen/androgen therapy on breast cancer risk and recurrence are needed. Tibolone, with its reported beneficial effects on libido and well-being, is a potential alternative to testosterone therapy, although its efficacy in the treatment of androgen deficiency has not been studied.

USE OF OTHER THERAPIES IN POSTMENOPAUSAL WOMEN WITH A HISTORY OF GYNECOLOGIC CANCER What is the role of selective estrogen receptor modulators? Raloxifene, a serum estrogen receptor modulator (SERM) (Fig. 60-5), displays estrogen agonist effects on bone, brain, and lipids and antagonist effects on the uterus and breast. The Multiple Outcomes of Raloxifene (MORE) study, a double-blind, placebocontrolled RCT involving 7705 postmenopausal women with osteoporosis (based on dual-energy x-ray absorptiometry [DEXA] or fracture criteria), reported a 39% decrease (95% CI, 0.43 to 0.88) in new vertebral fracture risk among women treated with 60 mg raloxifene after 4 years of follow-up.112 Although an increase in BMD was observed, nonvertebral fracture risk was not significantly reduced. Importantly, use of raloxifene was associated with a significant decrease in the risk of estrogen receptor–positive breast cancer

812

Gynecologic Cancer: Controversies in Management Figure 60–5. A comparison of the chemical structures of estrogen, phytoestrogens and the selective estrogen receptor modulators (SERMs). Structural similarities to 17β-estradiol can be observed in the phytoestrogens (isoflavones and lignans) and in the SERM, raloxifene. (Adapted from Warren M, Shortle B, Dominguez J: Use of alternative therapies in menopause. Best Prac Res Clin Obstet Gynecol 2002;16:411-448.)

(RR, 0.24; 95% CI, 0.13 to 0.44), corresponding to an absolute risk reduction of 7.9 cases per 1000 women over the 40-month follow-up period.113 No effect of raloxifene on endometrial cancer risk113 or on overall cognitive scores was demonstrated in the MORE study after 3 years.114 Beneficial effects of raloxifene treatment on surrogate markers for cardiovascular disease have been reported,115,116 including altered lipid profile (reduction in low-density lipoprotein, increased highdensity lipoprotein, no increase in triglycerides), reduction in lipoprotein(a), decrease in serum homocysteine, and reduction in fibrinogen. In addition, secondary analysis revealed that the risk of cardiovascular events (coronary and cerebrovascular events) was significantly reduced in the subset of women with high cardiovascular risk (RR, 0.60; 95% CI, 0.38 to 0.95), although no significant effect was observed in the overall MORE cohort.117 The effect of raloxifene on primary and secondary prevention of cardiovascular disease is being investigated in the ongoing Raloxifene Use in the Heart (RUTH) RCT. Raloxifene does not relieve menopausal symptoms and may induce or exacerbate vasomotor symptoms. Other adverse effects of raloxifene include an increase

in the risk of VTE (similar to that with HT) and leg cramps. Studies investigating tamoxifen, the first-generation SERM used in the management of breast cancer, have demonstrated favorable effects on lipid profile and BMD but increased risks for endometrial cancer, VTE, and vasomotor and urogenital symptoms.118 Information regarding the combined use of estrogen and tamoxifen is obtained from the tamoxifen prevention studies, in which approximately 25% of subjects were receiving ET and tamoxifen. Beneficial effects on vasomotor symptoms and BMD without detrimental effects on coagulation parameters were observed.119 In addition, subgroup analysis of the Italian Tamoxifen Prevention Study revealed a significant decrease in breast cancer incidence among women using ET who were treated with tamoxifen, compared with those using ET who were treated with placebo (HR, 0.36; 95% CI, 0.14 to 0.91).118 The Study of Tamoxifen and Raloxifene (STAR) trial is an ongoing RCT designed to compare the efficacy of tamoxifen or raloxifene in prevention of primary breast cancer in highrisk postmenopausal women. Preliminary evidence suggests that a new SERM, arzoxifene, is active in

M e n o pa u s e a n d H o r m o n e R e p l a c e m e n t Th e r a p y 813 the treatment of advanced endometrial and breast cancer.120 What is the role of phytoestrogens? Phytoestrogens are plant-derived, estrogen-like compounds that exhibit both agonist and antagonist properties and have been the subject of several recent reviews.121,122 There are three main classes of phytoestrogens: isoflavones, lignans, and coumestans (see Fig. 60-5). Genistein and diadzein, found in soybeans, possess the greatest estrogenic activity. Laboratory research indicates that phytoestrogens exhibit both estrogen receptor–dependent and independent effects on multiple biologic systems. Despite observational studies indicating potential benefits of phytoestrogens in regard to cardiovascular risk factors, vasomotor symptoms, and urogenital atrophy, data from interventional studies are inconclusive.122 Evidence regarding phytoestrogen effects on bone and cognition is limited and inconsistent. Epidemiologic evidence suggests an inverse association between phytoestrogen intake and the risk of breast or endometrial cancer, but human and animal interventional studies have demonstrated conflicting results with respect to breast cancer.121,122 More research is required to establish the efficacy and safety of phytoestrogens before recommendations can be made for their use in the management of menopause in women with previous gynecologic cancer. What nonestrogenic therapies are available for the relief of menopausal symptoms? The existence of effective nonestrogenic therapies increases the therapeutic options available to clinicians for the management of mild to moderate vasomotor symptoms in women with a history of gynecologic cancer. Loprinzi and coworkers123 reported a significant reduction in vasomotor symptoms among postmenopausal breast cancer survivors randomly assigned to treatment with the selective serotonin- and noradrenaline-reuptake inhibitor, venlafaxine, compared with placebo. Low-dose therapy (37.5 and 75 mg) was as effective as the higher 150 mg dose and was associated with a lower rate of side effects. Fluoexetine124 and paroxetine,125 selective serotonin reuptake inhibitors, also appear to decrease hot flush frequency and severity. High-dose progestins including megestrol acetate, MPA, and norethisterone are effective in relieving vasomotor symptoms in approximately 60% of patients. Limited clinical evidence suggests that high-dose progestin therapy is associated with a reduction in the risks of secondary breast cancer and spread of endometrial cancer.99 A significant reduction in hot flush frequency was observed with the administration of clonidine; however, use of this medication is limited by adverse effects, including dry mouth, constipation, and drowsiness.

Nonhormonal therapy for urogenital atrophy consists of vaginal moisturizers, used chronically to improve symptoms, and lubricants, used before sexual intercourse. Use of a vaginal moisturizer decreases vaginal pH, improves vaginal elasticity, and reverses vaginal atrophy, albeit to a lesser extent than vaginal estrogen cream.126 What is the role of herbal therapies? Considerable interest has been expressed by women regarding the use of herbal therapies. This may relate in part to their availability without prescription and also the misconception that these compounds are “natural” and therefore safe. However, these remedies exhibit medicinal properties and there is increasing recognition of adverse effects, including interaction with conventional pharmaceuticals. As denoted by Germany’s Commission E, specific herbs that are purported to be efficacious for particular menopausal symptoms (e.g., vasomotor instability, urogenital atrophy, psychological symptoms, sexual functioning) include ginseng, passion flower, St. John’s wort, valerian, balm, black cohosh, chaste tree, and ginkgo (reviewed by Warren and colleagues122). Although estrogen-like effects have been observed with the use of black cohosh,122 a short-term RCT conducted to assess the efficacy this herb on vasomotor symptoms in women with breast cancer demonstrated no difference from placebo.127 The safety of these therapies in women with previous gynecologic cancer is unknown. However, a recent in vitro study demonstrated that ginseng and dong quai (but not black cohosh) increased the growth of a human breast cancer cell line.128 What alternative therapies are available for management of osteoporosis? Drugs that act to inhibit bone resorption include the bisphosphonates, synthetic analogs of pyrophosphate, and calcitonin. In RCTs, oral bisphosphonates, including cyclic etidronate, alendronate, and risedronate, were demonstrated to increase BMD; a significant reduction in hip, spine, and nonvertebral fractures was observed among postmenopausal women with osteoporosis treated with the latter two agents (reviewed by Compston32). More recently, an RCT involving the intravenously administered bisphosphonate, zoledronic acid, also demonstrated antifracture efficacy in postmenopausal women with osteopenia/osteoporosis.129 Inhibition of bony metastases and treatment of malignancy associated hypercalcemia are additional relevant clinical effects of bisphosphonates. Antifracture efficacy has also been demonstrated for intranasal calcitonin. Subcutaneous parathyroid hormone therapy stimulates bone formation; significant increases in BMD and reductions in vertebral and nonvertebral fractures were demonstrated in short-term RCTs

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involving postmenopausal women (reviewed by Rosen and Bilezikian130). Summary Demographic trends combined with therapeutic interventions have meant that a greater number of women with a history of gynecologic cancer are experiencing menopause. Although the evidence is encouraging, definitive data regarding HT use and disease recurrence or mortality are lacking. Recent studies also raise questions regarding the long-term use of HT. For most women, climacteric symptom control, rather than long-term disease prevention, is the primary concern and reason for considering HT. A prudent approach would advocate risk factor management through dietary and lifestyle changes and the initial use of nonhormonal therapies for the control of vasomotor symptoms, cardiovascular disease, and osteoporosis. If such agents are ineffective, and after informed patient consent, a trial of HT could be instituted. Introduction of the lowest effective estrogen dose and use of drugs, such as tibolone, that have theoretical advantages over conventional HT are reasonable choices. However, there are no data on the safety of tibolone in women with gynecologic cancer. The SERMS offer future promise in regard to osteoporosis, cardiovascular disease, and breast cancer prevention. The efficacy and safety of phytoestrogens, herbal therapies, and homeopathic preparations have yet to be determined. The 1998 Consensus Statement9 regarding breast cancer patients is applicable to women with gynecologic cancer: “We should seek other established symptomatic or health promoting interventions before considering the use of estrogens. When estrogen is used as a last resort, it should be used in the lowest dose for the shortest duration of time and only after full discussion of concerns regarding potential risks with respect to breast cancer outcomes. When estrogen is being considered, the role of the informed woman as the final decision maker should be accepted by the health care practitioner.”

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