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.

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.

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.