Balancing Act: The Health Advantages of Naturally-Occurring Hormone Replacement Therapy

Testimony excerpt

By: Barbara Alving, M. D.

Date: July 22, 2004

Source: United States House of Representatives. "Test-imony Before the Subcommittee on Human Rights and Wellness Committee on Government Reform." 〈http://reform.house.gov/UploadedFiles/HHS%20alving.pdf〉 (January 16, 2006).

About the Author: Barbara M. Alving is a physician who has specialized in hematology. Through the course of her professional career, she has served as investigator in the blood and blood products division of the Food and Drug Administration, served as Chief of the Department of Hematology at the Walter Reed Army Medical Center, directed the hematology and oncology unit at Washington Hospital Center before accepting a position at the National Heart, Lung, and Blood Institute (NHLBI). She served as Acting Director of NHLBI for approximately four years before joining the National Center for Research Resources, as Director, in 2005. She is a part holder of two patents, has edited several scholarly books, and has authored more than one hundred academic and scholarly works.

INTRODUCTION

Historically, menopause has been defined as the time in a woman's life when she ceases to menstruate monthly. The age at which this is occurs varies a great deal by individual, but it typically happens somewhere between the mid-forties and early fifties for most women. For several years prior to actual cessation of menses (typically defined as a period of at least twelve months without menstruation), many women experience cycle changes, with erratic or missed menses.

There are three primary circumstances in which menopause occurs: naturally, when hormone levels decrease over time and menstruation gradually ceases according to the rhythms of the body, surgically, when the uterus and one or both ovaries are removed, and medically, when the ovaries are damaged or chemically destroyed (also called chemical ablation) by radiation or chemotherapy for the treatment of cancer.

In the past, it was called the change of life, referring to the shift in lifestyle that happens when women can no longer bear children. The myriad of associated symptoms experienced by many (although certainly not all) women were considered highly subjective and therefore prone to distortion—particularly by male physicians—and quite unavoidable. The conventional wisdom suggested that menopausal discomfort, as a purely natural component of the aging process, was simply a phase of life to "suffer through and endure."

Symptoms associated with hormonal reductions (estrogen and progesterone) associated with menopause have included: irregular or missed menses; night sweats; hot flashes; emotional lability and mood swings; depression or mood disorder; headaches; weight gain; fluid retention (sometimes accompanied by swelling in the joints or in the extremities); markedly decreased libido (loss of interest in sex); sore or tender breasts—sometimes accompanied by an increase in cystic masses of the breasts, ovaries, or uterus; irritability or moodiness; fatigue or diminished energy level; confusion or difficulty making decisions; temporary thinking or memory changes; vaginal dryness; urinary incontinence; insomnia or sleep pattern changes; muscle or joint pain or stiffness; and other physical, emotional, or psychosocial signs and symptoms. More recently, concerns began to be raised regarding the possibility of a temporal association between menopause and onset of osteoporosis or loss of bone density and the development of heart disease (no implication of association between osteoporosis and heart disease is herein implied).

In the mid-1920s, a form of estrogen synthesized from the urine of pregnant women was first used as a treatment for the symptoms of menopause. By the 1940s, it had been determined that a biosimilar substance could be made from the urine of pregnant mares (adult female horses), a much more plentiful and less costly supply. The patented formulation resulting from this discovery became very widely prescribed for the treatment of menopausal symptoms, beginning in 1943. By the mid-1970s, Premarin was one of the most frequently prescribed pharmaceuticals in the United States. Things began to change in 1975, when the first report linking synthetic estrogens (Premarin and similar drugs) to an increase in the development of uterine cancer (also called endometrial cancer). In the 1980s, progesterone was added to the former estrogen-only hormone replacement therapies, in an effort to prevent endometrial cancers.

During the latter half of the twentieth century, the burgeoning women's movement began to focus the attention of the medical and biomedical research establishment in America (and elsewhere in the developed world) on a large number of women's health issues. For the first time, close scrutiny concerning etiology was focused on breast, cervical, uterine, and ovarian cancers; on osteoporosis; on the incidence and prevalence of heart disease; on arthritis and connective tissue diseases; and on memory changes first evidenced at midlife. The following testimony was provided to Congress by a scientist participating in the Women's Health Initiative, a long-term study examining the benefits and risks of hormone replacement therapy for women.

PRIMARY SOURCE

Testimony Before the Subcommittee on Human Rights and Wellness

Committee on Government Reform

United States House of Representatives Balancing Act: The Health Advantages of Naturally Occurring Hormones in Hormone Replacement Therapy

Statement of Barbara Alving, M.D., MACP Acting Director National Heart, Lung, and Blood Institute National Institutes of Health, U.S. Department of Health and Human Services

I am pleased to appear before this Committee in my capacity as Acting Director of the National Heart, Lung, and Blood Institute (NHLBI) and director of the NIH Women's Health Initiative (WHI), which has been administered by the NHLBI since 1997. I am here, first, to tell you what we learned from the WHI with regard to hormone therapy using conjugated equine estrogen and, second, to comment on alternative therapies that are now receiving attention.

The WHI began in 1991 to investigate approaches that might be helpful to older women in preventing common chronic diseases—coronary heart disease, breast and colorectal cancers, and osteoporosis. Estrogen "replacement" therapy is one such approach. For much of the twentieth century, popular thinking was that restoring levels of estrogen, which ebb during middle age, would enable women to remain "forever young." Although estrogen was initially prescribed to alleviate troublesome menopausal symptoms, a number of epidemiological studies provided evidence that women who took estrogen experienced a lower incidence of disease, particularly cardiovascular disease (CVD), and enjoyed better health overall than women who did not. Data from many basic science investigations provided plausible explanations for the observed CVD benefit, and an NHLBI-supported clinical trial documented improvements in CVD risk factors (e.g., cholesterol levels) that might account for such a benefit.

But, the observation that women who took estrogen tended to enjoy better health did not prove causality, and important questions remained. Does estrogen make women healthy? Or … does being healthy (or, at least, health-conscious) make women take estrogen? The WHI hormone trial was designed to address these questions. It recruited about 27,000 healthy postmenopausal women, 50-79 years of age, and divided them into one of two groups according to whether they had still had a uterus. Those who had a uterus were assigned to take either a pill containing estrogen and progestin (0.625 mg of conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate—Prempro) or a placebo; those who had undergone a hysterectomy took an estrogen pill (0.625 mg of conjugated equine estrogen—Premarin) or a placebo.

It is worth noting that at the outset of the WHI trial, many interested parties believed that an outcome favoring estrogen was a foregone conclusion. Indeed, some doctors and researchers argued that such a trial was unethical because it would require half of the participating women to take placebos and thereby deny them the presumed benefits of hormones. Nonetheless, arguments in favor of randomized, placebo-controlled, clinical trials prevailed—and, as we now know, they were justified.

The WHI trial of estrogen plus progestin was halted in 2002 after an average follow-up of 5.2 years. Compared with women who took a placebo pill, women taking the hormones experienced an excess risk of breast cancer and more episodes of heart attack, stroke, and blood clots. Although the hormone-treated women had lower rates of colorectal cancer and fractures, and overall death rates were equal, it was concluded that the hormone combination should not be recommended as a health-promoting regimen. Moreover, the WHI Memory Study (WHIMS), which focused on women aged 65 years and older, found an increased risk of dementia and no effect on cognitive impairment among recipients of estrogen plus progestin.

Subsequently, in the spring of 2004, the WHI estrogen-alone trial also was halted upon determination that the hormone therapy had no effect on coronary heart disease risk but increased the risk of stroke. The study also found that estrogen-alone therapy significantly increased the risk of deep vein thrombosis, had no significant effect on the risk of breast or colorectal cancer, and reduced the risk of hip and other fractures. Findings from the WHIMS, published just last month, indicated that estrogen therapy did not reduce incidence of dementia and had an adverse effect on cognitive function.

In light of the WHI and WHIMS findings, the Food and Drug Administration (FDA) offers the following recommendations (updated April 19, 2004):

• Estrogens and progestins should not be used to prevent memory loss, heart disease, heart attacks, or strokes.
• Estrogens provide valuable therapy for many women, but carry serious risks, and therefore postmenopausal women who use or are considering using estrogen or estrogen with progestin treatments should discuss with their physicians whether the benefits outweigh the risks.
• For hot flashes and significant symptoms of vulvar and vaginal atrophy, these products are the most effective approved therapies. These products are also options for women whose significant risk of osteoporosis outweighs the risks of treatment; other treatments for prevention of postmenopausal osteoporosis are available.
• Estrogens and progestins should be used at the lowest doses for the shortest duration to reach treatment goals, although it is not known at what dose there may be less risk of serious side effects. Women are encouraged to talk to their health care provider regularly about whether treatment is still needed.
• There is a higher incidence of abnormal mammograms which require medical attention.
• Each woman's individual medical situation needs to be carefully discussed with her health care provider to make the best decision for her.

For prescription hormone formulations other than those studied in the WHI, the FDA advises the following: "Although … other estrogens and progestins were not studied, it is important to warn postmenopausal women who take estrogens and progestins about the potential risks, which must be presumed to be the same."

In the aftermath of the WHI findings, increased attention has been focused on the use of complementary and alternative medicine (CAM) to manage symptoms associated with the menopausal transition. Dietary supplements, including botanicals, are the most commonly used CAM modality for menopausal symptoms.

The National Center for Complementary and Alternative Medicine (NCCAM) supports basic and clinical research on the safety and efficacy of botanicals such as soy, black cohosh, and red clover in alleviating hot flashes, osteoporosis, and cognitive and affective problems. Other studies are generating laboratory data that are vital to understanding mechanism of action, characterizing the botanicals, identifying active constituents, and preparing standardized supplements. For example, two ongoing basic studies are looking at the effect of black cohosh extract on human breast tissue and its role as a serotonin modulator, and other research is looking at the effect of soy on breast and endometrial tissue as well as bone. In addition to individual research project grants, the NCCAM supports several research centers on women's health.

The National Institute on Aging (NIA) is supporting a 4-year, randomized, controlled trial to evaluate the efficacy and safety of phytoestrogen-based approaches (black cohosh, and a multibotanical preparation given with and without soy diet counseling) for treating vasomotor symptoms in perimenopausal and postmenopausal women.

Toxicity of black cohosh and other herbals and phytoestrogens is being evaluated by the National Institute of Environmental Health Sciences as part of an overall effort to establish the safety of herbal medicines.

The scientific literature on CAM therapies for menopause is equivocal, due to problems with small trials, short duration of treatment, large placebo effects, and imprecise measures for critical outcomes such as hot flashes. Investigations of the efficacy of soy to prevent cognitive changes, for example, have produced conflicting results, with the latest study (published in the July 7, 2004, issue of the Journal of the American Medical Association) finding no effect. The NCCAM has contracted with the Agency for Healthcare Research and Quality to conduct a review and assessment of the literature to provide a clearer picture of what is known about soy.

Clearly, additional research will be needed to provide safety and efficacy information on the range of CAM modalities being used by women to manage menopausal symptoms. The NIH is working to improve the rigor of future studies in this area. In collaboration with eight other NIH components, the NCCAM convened a working group of scientists to assess the quality of hot flash measurements currently in use and to make recommendations for research needed to improve these measurements. In addition the NCCAM, the NIA, and others at the NIH will co-sponsor a state-of-the-science meeting in March 2005 on the management of menopause-related symptoms.

Women are eagerly awaiting the outcome of federal efforts to uncover new approaches to address menopausal symptoms. Moreover, in discussions with gynecologists in the community, we have learned that women are seeking natural (biologically identical) hormone therapies via entities such as the Women's International Pharmacy (http://www.womensinternational.com/about.html).

Thank you for the opportunity to address these issues of great importance to women. I would be pleased to answer any questions the committee may have.

SIGNIFICANCE

The boom of perimenopausal, menopausal, and postmenopausal women taking estrogen-only replacement abruptly reversed after the publication of the 1975 scientific research report linking markedly increased risk of uterine cancer associated with synthetic estrogen use. In the 1980s, progesterone was combined with the estrogens, in order to more closely approximate the human body's natural hormonal activity. It was assumed, both among the medical and the lay communities, that hormone replacement therapy not only relieved the myriad symptoms associated with menopause, but afforded some protection or decreased the incidence of osteoporosis. Traditional hormone replacement therapy for a women who had undergone surgical removal of the uterus (and were therefore not at risk for uterine cancer) was estrogen alone; for women with an intact uterus, it was a combination of estrogen and progesterone, either in a single administration, or taken cyclically (to mimic the body's natural hormonal fluctuations).

The Women's Health Initiative (WHI) a large-scale long-term study initially anticipated finding that there was substantial benefit to be derived, for post-menopausal women, in utilizing conventional hormone replacement therapy (HRT). A summary of the findings published by WHI and the FDA is as follows: study participants who were given combination hormone therapy, when compared to study participants given placebo, were found to be at greater risk for stroke, breast cancer, heart attack, and the development of blood clots. Contrary to prior hypotheses, HRT was not found to diminish cognitive changes sometimes associated with menopause; it was found to increase the risk for early onset of dementia. The two significant benefits of combination HRT were a reduction in fractures, suggesting some protective benefit against osteoporosis, and decreased likelihood of developing rectal or colon cancer. For study participants who were given estrogen-only HRT: when compared with those receiving placebo, they were at greater risk of stroke or for developing blood clots; no between groups difference was found for heart attack risk or for the development of colon or rectal cancers. The effect on incidence of breast cancer was considered uncertain, and there was a definite protective effect against fractures associated with osteoporosis. While still evaluating the study results, and continuing some aspects of the project, it is the overall recommendation of WHI that synthetic HRT not be a treatment of first resort, that it be used only in the event of severe and life-impacting symptoms not amenable to any other treatment, and the used for the briefest possible duration.

Rather than immediately utilizing synthetic HRT, there is benefit in adopting healthy lifestyle and dietary habits long before the onset of menopause. If menopausal symptoms are severe or life impacting, some physicians advise considering bio-identical (sometimes called natural hormone therapy) hormones created from plant-based phytoestrogens and progesterones. They are extracted from plant products and combined with hydrocarbons in a laboratory setting, in order to render them identical to hormones occurring naturally in the human body. These preparations can be tailored to the individual biochemistry of the person for whom they are prescribed, by a health care professional working in concert with a compounding pharmacist. Considerable research is currently in progress in this area, as well as in other areas of complementary and alternative treatments for the symptoms of menopause.

FURTHER RESOURCES

Books

Lee, John R., and Virginia Hopkins. What Your Doctor May Not Tell You About Menopause: The Breakthrough Book on Natural Hormone Balance. New York: Time Warner Book Group, 2004.

Wiley, T. S., and Julia Taguchi. Sex, Lies and Menopause: The Shocking Truth About Synthetic Hormones and the Benefits of Natural Alternatives. New York: HarperCollins, 2004.

Web sites

Holistic online.com. "Menopause and HRT." 〈http://www.ncrr.nih.gov/about_ncrr/ncrr_director.asp〉 (accessed January 16, 2006).

National Center for Research Resources. "The Director's Page." 〈http://www.ncrr.nih.gov/about_ncrr/ncrr_director.asp〉 (accessed January 16, 2006).

Women's Health Initiative. "Questions and Answers About the WHI Postmenopausal Hormone Therapy Trials." 〈http://www.nhlbi.nih.gov/whi/whi_faq.htm〉 (accessed January 16, 2006).