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The conditions promoting the need for hormone replacement therapy for women and men differ substantially. In women, the decrease in reproductive hormones is surgically induced, is due to premature ovarian failure (also known as idiopathic ovarian failure), or is a normal function/consequence of aging. In these cases, hormone replacement therapy is offered to manage symptoms of menopause and to help prevent osteoporosis. While there is some normal decrease in male reproductive hormones with age, in men the need for replacement of reproductive hormones often is linked to pathology—that is, hypogonadism or disease. These differences in causation also create unique challenges for clinicians as they work with patients, as some conditions will require lifetime therapy.
Hormone Replacement Therapy for Women
The uses of hormones for menopause symptom management and osteoporosis prevention are the only indications discussed for women in this chapter. A variety of estrogen and progestogen formulations are available. New products frequently enter the market as hormones are reformulated, combined, and recombined. Similarly, a variety of new delivery methods are now available (e.g., creams, gels, and sprays). There are also formulations known as bioidentical hormones, which are the same in molecular structure as the endogenous hormones produced in a woman’s body. These hormones are made or synthesized from plant chemicals extracted from yams and soy. The term bioidentical hormones is often used for compounded preparations, but several bioidentical formulations are available that are manufactured by pharmaceutical companies in consistent doses and strengths and are approved by the Food and Drug Administration.
Estrogen and progestogen are FDA approved for the treatment of moderate to severe menopause-related symptoms, including hot flashes and vulvovaginal atrophy, and for the prevention of postmenopausal osteoporosis. Many women anecdotally report improved quality of life (QOL) with hormone therapy (HT) use. These anecdotal reports are supported by findings of several research studies undertaken to evaluate QOL effects, and they are refuted by the findings of others.
The Women’s Health Initiative (WHI) was a research study designed to evaluate the effectiveness of estrogen and estrogen plus progestogen on preventing coronary heart disease (CHD) in women. The study also evaluated several secondary outcomes, including hip fracture, colon cancer, stroke, venous thromboembolic events, breast cancer, and mortality. There were five arms of the study: one evaluated estrogen alone, one evaluated estrogen plus progestogen, and the others evaluated lifestyle factors such as diet and exercise.
The WHI’s results, released in 2002, changed the approach used to prescribe estrogen and progestogen. The estrogen plus progestogen (E-P) arm of the WHI randomized controlled trial was halted early because women who were taking estrogen plus progestogen (conjugated equine estrogens [CEEs] 0.625 mg and medroxyprogesterone [MPA] 2.5 mg) had an increased incidence of CHD, stroke, venous thromboembolic events (VTEs), and invasive breast cancer. The E-P arm also showed a reduced risk for colorectal cancer and a reduction in osteoporotic fracture. The estrogen-only arm of the WHI was also halted early in 2004 because of increased risk of stroke. It is interesting to note that the estrogen-only arm of the study also showed a trend toward a reduced risk of breast cancer and no change in CHD. QOL was not changed in women taking HT vs. placebo in the WHI study.
Additionally, results from the Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI, suggested that postmenopausal women 65 years of age or older treated with CEE 0.625 mg combined with MPA 2.5 mg for 4 years and with CEE 0.625 mg alone for 5.2 years had an increased relative risk of developing probable dementia when compared with taking placebo.
Absolute risk in the WHI was greatest in the oldest group studied (women aged 75 and older). Several important limitations of the WHI have been identified: (1) The women in this study were approximately 10 years postmenopausal (average age was 63.3 years), (2) participants were not symptomatic (symptomatic women were excluded because they would have known whether they were taking active drug or placebo), (3) many participants were overweight, and (4) many had established heart disease (e.g., hypertension). However, data from the Women’s HOPE (Health, Osteoporosis, Progestin, Estrogen) study suggest that lower doses of estrogen and progestogen effectively decreased vasomotor symptoms, yet did not raise the risk of CHD. A more recent meta-analysis of several observational studies and a reanalysis of data from the WHI that focused on age cohorts indicate that heart disease is reduced in women who initiate HT at the time of menopause, supporting a hypothesis that the time of initiation of HT is critical. Additional research is required to further elucidate the relationship between HT and cardiovascular health. Women who took estrogen plus progestin in the WHI trial were found to remain at a higher risk of breast cancer 3 years after the trial was stopped compared with those who took placebo. Higher risks of cardiovascular events seen in those taking the active preparation abated in the follow-up period, however, as did the beneficial effects of HT on bone strength.
Many national organizations, such as the North American Menopause Society (NAMS), the Endocrine Society, the American College/Congress of Obstetricians and Gynecologists (ACOG), the American Association of Clinical Endocrinologists (AACE), the National Association of Nurse Practitioners in Women’s Health (NPWH), the American Society of Reproductive Medicine (ASRM), and the U.S. Preventive Services Task Force (USPSTF), along with the FDA, support the use of HT for moderate to severe vasomotor symptoms and vaginal atrophy associated with menopause. Most of these organizations and the FDA recommend against the use of HT for prevention of chronic disease (e.g., cardiovascular disease), with the exception of osteoporosis. However, they note that other options are also available for osteoporosis prevention and should be considered in women who do not experience moderate to severe vasomotor symptoms (see Chapter 39). Additionally, current recommendations for HT use advocate using the lowest effective dose and, in most cases, for the shortest length of time. Women who use HT should regularly review their symptoms with their clinicians to consider the need for continued use. The WHI results indicate that HT use for 3 to 5 years is reasonably safe. The risks vs. benefits for use, especially for longer periods, must be determined on an individual basis. The NAMS states that there is no clear data regarding length of therapy, and the International Menopause Society (IMA) notes that there is no reason to place a specified limit on the length of therapy.
Most clinicians review use of HT with their patients annually and attempt slow weaning to determine whether therapy is still necessary or to determine if the woman may be able to manage her symptoms effectively at a lower dose. Therapy decisions should be individualized for each patient, with consideration of her personal and family history, symptom severity, and personal preferences. Clinicians must recognize that many women use OTC and herbal remedies to manage their menopausal symptoms. It is essential to elicit information about use of these products because they have the potential to produce adverse side effects or drug interactions. Research regarding HT use is ongoing; it is recommended that the reader consult up-to-date resources for the latest information on this topic.
The answer to the question of when to initiate HT is evolving. Reanalyses of the WHI results, some meta-analyses, and the British Million Women study (a prospective observational study of over 1.1 million women) have given rise to two distinct hypotheses: the timing hypothesis regarding heart disease, which supports initiating HT at the time of menopause, and the gap hypothesis regarding breast cancer, which supports initiating HT 5 years or more after menopause. The timing hypothesis is derived from data that have shown that women who start HT at the time of menopause are less likely to develop CHD and may have some beneficial effects against developing CHD. In contrast, the gap hypothesis is derived from the reanalysis data and the Million Women study data that showed there was no or very little increase in risk for breast cancer when women initiated HT 5 years or more after menopause. When HT was discontinued, any increased risk in breast cancer quickly returned to baseline.
Therapeutic Overview of Hormone Therapy
See Chapter 54 for a discussion of hormone use during the reproductive years.
The menopausal transition is a natural biologic process that all women who live long enough will experience. This transition consists of three distinct stages: perimenopause, menopause, and postmenopause. Perimenopause is the period that spans the 8 to 10 years prior to menopause, during which symptoms associated with changing levels of estrogen and progesterone often occur. The perimenopausal years usually occur between the ages of 42 and 55. For several years before menopause, the frequency of ovulation decreases and may be erratic. Hot flashes may occur and premenstrual syndrome (PMS) symptoms may intensify. Menstrual bleeding frequently becomes irregular. Unplanned pregnancy is a risk because of the irregularity of ovulation. Menopause is defined as a point in time that occurs after the natural cessation of menses for 12 consecutive months. The average age of menopause in North America is 51 years. Postmenopause, the 5-year period following menopause, is commonly associated with symptoms such as hot flashes, sleep interruptions, and vulvovaginal changes, as well as later processes related to reduced hormone levels. Menopause is not a disease process; rather, it is a normal transition. However, the symptoms experienced as hormone levels fluctuate and decline prior to and following menopause may require intervention.
Menses completely terminate 12 months preceding menopause, and ovarian production of estrogen ceases. The low plasma estradiol concentration that remains is the result of peripheral conversion of androgen precursors that are secreted predominantly by the adrenal glands. The precursors found in plasma become estrone rather than estradiol. The conversion of androgen precursors to estrone occurs in adipose tissue, and the adrenals provide a very small amount of progesterone.
During the perimenopausal period, as ovarian sensitivity to follicular stimulating hormone (FSH) stimulation decreases, plasma levels of FSH and luteinizing hormone (LH) increase. Following menopause, the lack of negative feedback from ovarian production of estradiol in the hypothalamic-pituitary-ovarian axis allows FSH and LH levels to increase to about 4 to 10 times the levels seen during the premenopausal follicular phase. Pulsatile secretion may persist, and the high levels of circulating FSH and LH stimulate the ovarian corticostromal and hilar cells to continue to produce significant levels of androstenedione and testosterone. Circulating levels of androstenedione are lower in postmenopausal women; circulating testosterone levels are similar to those found in premenopausal women.
Disease Process
Some symptoms develop while estrogen levels are changing. Vasomotor symptoms are most problematic in the first 7 years following menopause. However, they can persist for many more years. Vaginal atrophy starts early and persists throughout postmenopause, causing dryness, dyspareunia, and increased vaginal pH.
Vasomotor Tone Instability: Short-term vasomotor changes resulting from hormonal variations can cause hot flashes during perimenopause and postmenopause. When hot flashes are accompanied by flushing, usually at the face, neck, and upper chest, they are called hot flushes. Core body temperature rises, peripheral blood vessels dilate, skin conductance increases, and heart rate increases. Many women experience a prodrome before a hot flash occurs. Hot flashes or flushes also may be accompanied by dizziness, nausea, headache, palpitations, or sweating. They vary in duration and intensity, lasting from 1 to 4 minutes. The exact origin of hot flashes is poorly understood; however, they are associated with a surge in LH and declining estrogen and progesterone levels. During postmenopause, the thermoneutral zone narrows for many women, leading to sweating when the core body temperature rises above the upper limit or shivering when the core temperature dips below the lower limit. Hot flashes can be triggered by emotional stress, excitement, fear, anxiety, alcohol, caffeine, or environmental temperatures that raise the core temperature too high. Hot flashes or flushes that occur during the night are referred to as night sweats and often interrupt sleep. Sleep interruptions frequently lead to reduced cognitive functioning and difficulty with remembering.
Vaginal Atrophy: In the postmenopausal woman, vaginal pH increases from about 5.0 to 7.0, making the tissue more susceptible to infection. Definitive changes take place at the cellular level: the cervix atrophies, the cervical os decreases in size, the superficial vaginal epithelium atrophies, the labia majora and minora shrink, and urethral tone decreases. Muscle tone throughout the pelvic area decreases, which may lead to urinary tract infection and incontinence. The ovaries and uterus decrease in size. The vagina shortens, narrows, and loses some of its elasticity. Time for vaginal lubrication is increased, and vaginal secretions are reduced. This predisposes the woman to urinary tract infection, prolapse, dyspareunia, vaginitis, irritation, bleeding, burning, pruritus, and urinary symptoms such as frequency, urgency, and dysuria.
Long-Term Effects
Several effects related to reduced hormone levels are not significant or identifiable until a woman is several years into postmenopause.
Cardiovascular: Women begin to develop atherosclerosis immediately following menopause; within 5 to 10 years, the incidence of cardiovascular disease in women surpasses that reported in men. Estrogen stimulates enzyme production that affects cholesterol metabolism. Without estrogen, breakdown of LDL cholesterol and production of HDL cholesterol are reduced, producing a lipid profile that contributes to the development of atherosclerosis. Estrogen also plays an important role in maintaining vascular elasticity, contributing to the increased incidence of hypertension present in postmenopausal women. Mortality rates from cardiovascular disease in women are higher than those in men; approximately 50% of all women will die from heart disease.
Breast: Breast tissue mass decreases during postmenopause. Glandular breast tissue is replaced by fat deposits and connective tissue. Breast tissue decreases both in size and in density. However, breast cancer risk increases with age.
Bone Density: Loss of bone mass is associated with postmenopause. Bone density peaks in the early to mid 30s and then begins to decline slowly over time. Loss accelerates following menopause at a rate of 1% to 5% per year for the first 4 to 8 years after menopause; it then slows again to a rate of about 1% per year. This loss of bone mass can lead to osteopenia and osteoporosis, which predispose women to fracture; it is a major cause of morbidity and mortality in the elderly. See Chapter 39 for further discussion.
Brain: Estrogen and progesterone have biochemical, neurophysiologic, and structural effects on the brain. For example, progesterone affects the regulation of GABA (gamma-aminobutyric acid, an important inhibitory neurotransmitter) receptor sites. Estrogen affects cognitive function and memory, and both estrogen and progesterone aid the thermoregulatory center in maintaining normal body temperature.
Other: Menopause is associated with many additional symptoms, such as dry skin, fatigue, insomnia, paresthesias, poor sleep quality, increased sleep latency, constipation, mood changes, muscle and joint pain, and decreased QOL. Now that estrogen and progesterone receptors have been identified throughout the body, systemic symptoms are beginning to be better understood.
Assessment
Monitoring FSH levels for the purpose of diagnosing menopause is not recommended. Identification of menopause is based on symptom patterns, menstrual changes, and age. Most clinicians do some laboratory testing to rule out other conditions that can mimic menopausal symptoms, such as thyroid abnormalities (see Chapter 52) or diabetes (see Chapter 53). If the woman is perimenopausal, FSH levels are especially unreliable because of the irregularity of hormone levels during this phase. FSH levels may be high when tested and then may fall low enough to allow for ovulation and pregnancy.
Mechanism of Action
Three classes of estrogen formulations have been identified: conjugated, synthetic, and bioidentical. Conjugated and synthetic estrogens stimulate hepatic globulins and the renin-angiotensin system to a greater extent than do bioidentical estrogens. Studies have demonstrated no clinical differences between classes. For drug action, see the section “Anatomy and Physiology.”
Estrogen exists in the body in three main forms: estrone (E1), estradiol (E2), and estriol (E3). The active form of the most prevalent estrogen, 17β-estradiol, is not well absorbed when taken by mouth. The liver rapidly metabolizes much of the absorbed drug into inactive substances before it enters the bloodstream (first-pass phenomenon). Thus, different methods of delivery have been devised. Oral estrogens are metabolized into estrone in the liver. Transdermal estrogens (e.g., creams, gels, patches, sprays) do not undergo the same liver first-pass effect and can be dosed at lower levels.
In 1970, conjugated estrogens were officially defined as a mixture of sodium estrone sulfate and sodium equilin sulfate. The oldest form of estrogen used for menopause HT is the conjugated equine estrogen (CEE), Premarin. Premarin is derived from the urine of pregnant mares and contains nine different estrogens, including sodium estrone sulfate (50% to 65%), sodium equilin sulfate (20% to 35%), and others. It received FDA approval for use in postmenopausal women in 1942 and has been included in many research studies. Multiple other estrogen formulations are also available.
Progestogens include bioidentically manufactured progesterone and a number of other synthesized manufactured progestogens and synthesized compounded progestogens. Common major classes of synthetic progestogens are the 17 acetoxyl-progestin derivatives (21-carbon atoms; e.g., medroxyprogesterone), which are very similar to the endogenous hormone (e.g., micronized progesterone); micronized progesterone; and the 19-nortestosterone compounds (e.g., norethindrone), which have both progestogen effects and a variety of androgenic effects. Progestogens are lipophilic and bind to progesterone receptors throughout the body. See Chapter 53 for more information on progestogens.
Some androgens have predominantly androgenic properties, whereas others have primarily anabolic characteristics. Those androgens with highly androgenic properties are used for the treatment of patients with conditions that are hormonal in nature. Methyltestosterone is highly androgenic. Androgens with mainly anabolic effects are used to promote weight gain, increase muscle mass, or stimulate red blood cell production in certain forms of anemia.
Drug Effects in Menopause
The effects of estrogens and progestogens must be clearly separated. Estrogen, both individually and in combination with progestogens, has been studied most extensively. Progestogens most often have been studied in conjunction with estrogen for use in the management of menopause-related symptoms and prevention of endometrial cancer in women using estrogen who have an intact uterus.
Vasomotor Effects
Estrogen effectively treats those with hot flashes, decreasing frequency and severity. Progestogens have been used for hot flash management as well. However, because of their side effect profile, progestogens are not commonly used for this purpose alone.
Vaginal Atrophy
Use of estrogen in oral, vaginal, and transdermal forms has been shown to decrease atrophic vaginitis. Local vaginal estrogen provides relief more rapidly than the systemic alternatives.
Cardiovascular
Findings from the WHI study reveal a higher incidence of CHD, stroke, and pulmonary emboli risk in women taking estrogen plus progestogen. CHD was not found to be increased in women taking estrogen only. Earlier studies and more recent reports evaluating effects on women close to the age of menopause describe cardiovascular benefits. Estrogen is known to increase the risk of thromboembolic disease. This risk may be dose related. Estrogen doses in HT are much lower than those in oral contraceptives (OCs). Emerging data based on recent research and reanalyses of the WHI studies have given rise to a timing hypothesis, which suggests that initiating HT at or very near to the time of menopause reduces CHD in postmenopausal women.
Breast Cancer
Data regarding estrogen and progestogen effects on breast cancer are controversial. Estrogen therapy (ET) may increase the risk of breast cancer. However, no change in mortality has been observed, and several studies have shown that women given a diagnosis of breast cancer while taking HT have a greater likelihood of survival. Evidence suggests that progestogen also may increase the risk of breast cancer. It is interesting to note that Megace (a progestogen) sometimes is used for breast cancer treatment. Some postulate that HT or ET speeds the development of breast cancer in patients who would have developed cancer at a later date. Estrogen also preserves or increases breast tissue density, making mammographic interpretation difficult in some instances. Emerging data from the Million Women study and reanalysis of the WHI studies have given rise to the gap hypothesis, which suggests that waiting about 5 years after menopause to initiate HT may reduce the risk for developing breast cancer.
Bone Density
HT slows or halts the progression of bone loss and osteoporosis. It decreases the risk of osteoporosis-related fracture by helping to maintain bone mineral density.
Brain
The effect of HT on brain function and Alzheimer’s disease is another area of controversy. Some studies demonstrate reduced Alzheimer’s incidence, and others show an increased incidence of probable dementia. Two such studies were the Harvard-based Nurses’ Health Study (NHS) and the Kaiser-Permanente–based Cache County Memory Study. The NHS included over 120,000 women, and it showed declines in several cognitive domains that were associated with long-term hormone use. The Cache County Memory Study, which included approximately 1300 women, used pharmacy records to track participants’ prescription histories. That study reported a slight increase in total dementia among long-term users of both estrogen alone and of estrogen/progestin. Further research is needed in these areas to provide evidence of the effects of HT on brain function.
Endometrial Cancer
Unopposed estrogen in postmenopausal women with an intact uterus increases the risks of endometrial hyperplasia and cancer. Progestogens change the endometrium from a constant proliferative state to a secretory state, preventing endometrial hyperplasia associated with unopposed estrogen and reducing the risk of endometrial cancer.
Gastrointestinal
HT predisposes users to cholecystitis. Data from the WHI study indicate that HT decreases the risk of developing colorectal cancer.
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