Hormone therapy has been riding the roller coaster of public opinion since 1966 when Robert Wilson published Feminine Forever (Wilson, 1966). Touted as the fountain of youth, estrogen used in uncontrolled amounts was thought to revitalize and rejuvenate menopausal women. The tidal wave of interest in estrogen replacement therapy came to an abrupt halt 12–15 years later after the publication of an article that provided the first clinical evidence that estrogen therapy may increase a woman’s risk of endometrial cancer (Mack et al., 1976).

Estrogen regained some of its luster 10 years later, with the support of clinical data that demonstrated its efficacy and safety when used in a combined regimen with progesterone. Retrospective analyses demonstrated the protective effects of hormone therapy on the development of osteoporosis, heart disease, Alzheimer’s disease and, potentially, colon cancer. These results strengthened support for hormone therapy among clinicians and patients alike (McMichael & Potter, 1980; Colditz et al., 1987). However, this short-lived respite once again came to a grinding halt in July 2002 when the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) released the unblinded first arm of the first prospective study into the effects of hormone replacement therapy on postmenopausal women (Petitti, 2002).

The Women’s Health Initiative (WHI) studied almost 50 000 women receiving hormone replacement therapy after menopause. The women were divided into two groups: those with an intact uterus receiving a combination of estrogen and progesterone and those, post hysterectomy, receiving estrogen alone. The estrogen and progesterone arm was stopped in July 2002 because the apparent risks of hormone replacement therapy outweighed any evident benefits. The estrogen-only arm of the study continued for another 2 years before it, too, was prematurely discontinued: it failed to show the protective cardiovascular benefit that the study was designed to demonstrate. In total, 7 of the 8 projected years of the study had elapsed and, although with estrogen alone there was no increase in the risk of breast cancer, a significant increase in the risk of heart disease, blood clots and stroke became evident for women receiving hormone replacement therapy (Anderson & Limacher, 2004). This information was a wake-up call to physicians to carefully analyze what women need in the menopausal years to maintain health and reduce risk.

The WHI was designed to look at the effects of hormone replacement therapy on the risks of breast cancer, heart disease, stroke, blood clotting, osteoporosis and fractures, and colorectal cancers. It did not initially assess the symptoms of menopause, including hot flashes, insomnia, mood changes and genital dryness and atrophy. However, further analysis looked at menopausal quality of life and found that, although women receiving hormone replacement therapy had significant improvements in sleep, physical functioning, body pain, hot flashes and mood swings, overall, there was no significant difference in sexual wellbeing, mental health or vitality. What the study did show was an increased risk of breast cancer that began after 4 years of clinical use and that raised the relative risk by almost 25% in women receiving estrogen plus progesterone. This extrapolated to eight additional breast cancers per year per 10 000 women receiving hormone replacement therapy. In the women receiving estrogen alone, no such increased risk was evident. Concurrent studies published in the Journal of the American Medical Association reported that breast cancers that developed after hormone replacement therapy were more aggressive and larger than other breast cancers, and that women with a previous history of breast cancer had a higher rate of recurrence when receiving hormone therapy (Anderson & Limacher, 2004).

Heart disease was also a major factor in the discontinuation of the WHI (Anderson & Limacher, 2004). An increased risk of heart disease was noted in the first year of the study and the relative risk for the development of heart disease rose by 29%, extrapolating to seven more heart attacks per 10 000 women using hormone replacement therapy each year. This seemed to hold true for both women receiving estrogen alone and women receiving estrogen and progesterone in combination. Multiple etiologies for these phenomena have been postulated, including an increase in the levels of C-reactive protein and insulin-like growth factor in women receiving oral estrogen. However, this has yet to be proven definitively (Ridker et al., 2003).

The study also found an increased risk of stroke, with an increased relative risk of 41%, which extrapolated to eight more cerebrovascular accidents per 10 000 women taking hormone replacement therapy per year. This risk seemed to hold true for all age groups, regardless of any baseline stroke risk such as hypertension, diabetes, previous coronary disease or use of aspirin or lipid-lowering drugs. For women less than 60 years of age, the absolute risk of stroke from standard-dose hormone therapy is rare, about two additional strokes per 10 000 person-years of use; the absolute risk is considerably greater for older women (Henderson & Lobo, 2012). A similar and parallel risk was demonstrated for the development of other blood clots: there were approximately 18 more clots per 10 000 women per year. The risk for the development of blood clots was greatest in the first 2 years of therapy and decreased, but was still elevated even after 4 years of use.

The Women’s Health Initiative Memory Study (WHIMS) was published in May 2003 (Hays et al., 2003) and, contrary to previous beliefs supported by the Nurses Health Study, which identified hormone replacement therapy as a major prevention strategy for dementia, demonstrated an increase in dementia among women using hormone replacement therapy over the age of 65. There were an additional 23 cases of dementia per 10 000 women, with no statistical difference in risk regardless of socioeconomic status, educational attainment or use of aspirin. In addition, no protection was afforded for mild cognitive impairment, a less severe form of dementia (Shumaker et al., 1998). Subsequent analyses seem to infer a protective effect for younger women initiating therapy at the onset of menopause (Ryan et al., 2008).

There was some good news in the WHI: osteoporotic fracture risk was reduced by 34%, resulting in five fewer fractures per 10 000 women per year. This was the first trial to document a decreased risk of fractures with hormone replacement therapy and not just an improvement in bone density (WHI, 2006). A similar reduction in the risk of colon cancer was demonstrated; after 3 years of hormone replacement therapy, the relative risk of the development of colon cancer was reduced by 37%, resulting in six fewer cancers per 10 000 women per year.

No other menopausal treatment or regimen has undergone this degree of scrutiny. The assumption that alternative treatments for menopause and their effects are safe is unwise (North American Menopause Society, 2004). We are therefore faced with an aging population of women who are living more of their life in menopause, and a population of patients who are more educated and more consumer-savvy about healthcare. It is up to clinicians to educate themselves about the management of menopause, to talk to patients and allow them to contribute to decision-making with regard to menopausal therapies and to continually reassess the risk of adverse outcomes for patients over their lifetime (Moyer, 2012).

The WHI has provided physicians with a unique opportunity to join with patients to create a designer approach to their menopause management. No two women have the same experiences, risks and needs. The goal of this partnership is to create a fluid approach that continually evaluates risks, symptoms and comorbidities and addresses the specific needs of women as they enter menopause. Special attention must be given to the prevention of heart disease, osteoporosis, memory loss and sexual dysfunction and the development of menopausal symptoms (Moyer, 2012).

The modification of heart disease risk requires lifestyle changes. Risk can be reduced by dietary reduction of saturated fats, exercise, smoking cessation, assumption of ideal body weight and reduction of alcohol consumption. Preexisting conditions such as hypertension, diabetes and hyperlipidemia should be optimally controlled to prevent the development of heart disease. The recognition of the gender differences between men and women in the presentation of heart disease is essential for optimal risk reduction (Mosca et al., 2011).

The prevention of osteoporosis goes beyond hormone replacement therapy. Lifestyle changes such as increasing exercise, smoking cessation, maintenance of an ideal body weight and adequate calcium and vitamin D intake will help to prevent osteoporosis. Other therapeutic devices, such as selective estrogen receptor modulators (SERMs) that mimic the effects of estrogen in bone without affecting the cardiovascular system or breasts, have been proven to prevent osteoporosis. Bisphosphonates have been shown to build damaged bone. Calcitonin, approved since the 1980s in the United States of America, has recently had reports of increased risks of cancer and the efficacy for fracture reduction has not been clearly established. Thus, the European Medicines Agency and others recommend that calcitonin not be used for osteoporosis and fracture prevention (Overman et al., 2013). Unfortunately, natural estrogen analogs have not been found to be as helpful in osteoporosis prevention.

The reduction of menopausal symptoms relies on lifestyle changes such as limiting alcohol and caffeine intake and stress reduction; the wearing of light clothing may also be helpful. Soy supplementation has been shown to reduce mild hot flashes when six to eight servings are taken per day. Selective serotonin reuptake inhibitors (SSRIs), a type of antidepressant, offer moderate relief for women with menopausal symptoms. Estrogen remains the only proven treatment for severe hot flashes and the NIH now recommend short-term use at the lowest effective dose as the ideal treatment for the vasomotor symptoms of menopause (Marjoribanks et al., 2012).

Urogenital atrophy (vaginal dryness) can be treated with lubricants and feminine moisture replacements. The topical use of estrogen in small doses at infrequent intervals is helpful and may limit systemic exposure and therefore risk. Newer delivery systems, such as the vaginal ring with estrogen, have also proven to be quite successful in the reduction of symptomatology.

The WHIMS demonstrated no benefit of hormone replacement therapy in the prevention of Alzheimer’s disease in older women. The improvement of memory as women enter menopause relies upon an active lifestyle and the early recognition and treatment of depression and other forms of pseudodementia that may mimic Alzheimer’s dementia (Shumaker et al., 1998).