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The 50-Something Woman: What We Know, What We Think We Know, and What We Need to Know

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Introduction

In an environment in which data are rapidly generated, published, and arrive at the office of the clinician in the form of questions as to how to apply the new information, this symposium served as a bridge. “What we know, what we think we know, and what we need to know” aptly summarized this program’s goal of offering evidence-based data helpful to individualize hormone-replacement therapy (HRT) for “The 50-something woman” who is menopausal. Moderated by Valerie Montgomery Rice, MD, from the University of Kansas Medical Center, the symposium was conducted in question-and-answer format. Responding to pointed questions on osteoporosis prevention, cardiovascular disease, cancer and quality of life issues in relation to hormone replacement therapy and its alternatives were David J. Portman, MD, Ohio State University College of Medicine; Roger S. Blumenthal, MD, The Johns Hopkins Hospital; and Judi Chervenak, MD, Albert Einstein College of Medicine.

Highlights of the symposium, which was scientifically timely and clinically relevant, are presented in their interrogative format. Dr. Montgomery Rice posed questions to her colleagues on the panel, beginning with Dr. David Portman.


What is the greatest health risk facing postmenopausal women?
“Osteoporosis, a silent disease, may be one of the greatest health risks facing postmenopausal women,” said Dr. David Portman, who added that 50% of all women will have an osteoporosis-related fracture in their lifetimes. These fractures can be lethal. Women who are hospitalized for a hip fracture have a 30% chance of dying within one year (National Institute of Arthritis and Musculoskeletal and Skin Diseases. Osteoporosis: Progress and Promise.  http://www.nih.gov/hiams/healthinfo/opbkgr.htm.). Healthcare costs due to fractures are estimated to be $13.8 billion per year (American College of Obstetricians and Gynecologists. Hormone Replacement Therapy. ACOG Educational Bulletin 247. Washington, D.C., May 1998;1-10).

Is HRT still the standard for the prevention of osteoporosis? 
The utility of HRT has recently been called into question in many areas, said Dr. Portman. But since estrogen loss in menopause is the cause of postmenopausal osteoporosis in the vast majority of women, replacing estrogen is a rational, physiologic strategy. Studies with ERT/HRT have shown a dramatic effect on vertebral and hip fracture reduction and have substantiated its preventive effect—especially on hip fracture (Lufkin EG et al. Ann Intern Med.1992; 117:1-9. Cummings SR et al. New Engl J Med 1998;339:733-8). Case controlled studies have shown approximately 60% reductions in hip and wrist fractures when estrogen replacement is started within a few years of menopause (Lufkin EG et al. Ann Intern Med.1992; 117:1-9). While hormones are not the only option, Dr. Portman reasoned that hormone replacement early in menopause, when bone loss is dramatic and rapid, may help women to arrive at later menopause with better bone mass. At this point, bone-specific drugs may be used.

Is there reason to believe that there may be differences among various estrogens, other progestins, or other combinations? 
“What we are learning today is that one size does not fit all in terms of both estrogen and progestins.” In the past, it was typical for all postmenopausal women to be prescribed a standard 0.625 mg dose of conjugated equine estrogen. Today it is known that patient responses are typically inconsistent; some women are managed well with low doses of estrogen, while others taking higher doses don’t respond with the expected effects on bone mineral density. 

Progestin-specific differences have also been seen in the bone. For example, norethindrone acetate (NA) seems to have some independent bone-sparing properties. In a study by Abdalla (Abdalla H et al. Obstet Gynecol 1985; 66:789), postmenopausal patients treated with 5-10 milligrams of norethindrone had a maintenance of bone marrow content, compared with a significant bone loss in patients taking placebo (Figure 1). “This effect is not seen nearly to this extent with other progestins, and in fact, there seems to be some trabecular bone loss with high users of medroxy-progesterone (MPA), according to studies done by Gallagher several years ago” (Gallagher JC. In: Osteoporosis. Academic Press. 1990. Chapter 63). Dr. Portman referred to the CHART study whose findings included a possible synergy between estrogens and 1 mg norethindrone acetate, but not 0.5 mg (Speroff L. JAMA 1996;276: 1397-1403).

How do you decide whether to use HRT or a SERM or bisphosphonates or calcitonin or some combination in a given patient? 
“Data, including that from the international EPIC Trial, suggest that combined hormone replacement therapy, especially with norethindrone acetate versus MPA, offers great bone effects” (Ravn P. Ann Intern Med 1999;131(12):935-42). Especially for early menopausal intervention, Dr. Portman reiterated that the gold standard of continuous combined therapy offers wonderful ancillary benefits and will take women into mid- and later menopause with excellent peak bone mass. 

He acknowledged ongoing fertile areas of research involving selective estrogen receptor modulators (SERMs), bone specific drugs and even anabolic drugs, such as parathyroid hormones. Data from the large MORE Trial, for example, enrolling women with osteoporosis with or without vertebral fracturing, proved that selective estrogens were capable of preventing vertebral osteoporotic fracture in both groups of women (those with and without existing fractures) (Ettinger B, et al. JAMA 1999;282:637-46). 

What has research shown us regarding the relationship between HRT or ERT and cancer?
The data are mixed, according to Dr. Portman, but contain some strong evidence for protection from some forms of cancer. For example, combined oral contraceptive use is associated with a 50-80% relative risk reduction of ovarian and endometrial cancer, in both current and past users (Cash. N Engl J Med 1987;316:650-55). In addition, current and past users of ERT/HRT enjoy a 30-40% relative risk reduction of colon cancer, based on robust epidemiological data from the Nurses Health Study (Calle EE et al. J Natl Cancer Inst 1995; 87:517). 

The breast cancer picture is confusing. “Some studies show a slight increased risk, others show a deceased risk and other study results are inconclusive or showed the same risk as with an unexposed population” (Bush T et al. Obstet Gynecol 2001;198:498-508). However, it appears from several studies that risk of breast cancer increases after five years of use (Ross et al. J Natl Cancer Inst 2000;923:328-332). Dr. Portman noted, however, in relation to one of the studies, that when data are broken down by treatment group, “…it appears that the ERT (estrogen alone) group had no statistically significant short-term increase, and minimal increase even up to 15 years of use.” (Ross et al. J Natl Cancer Inst 2000;923:328-332). When a progestin was added, the association with the diagnosis of breast cancer became more apparent, but it was related to mostly sequential HRT and not continuous combined users. Interestingly, users of a continuous combined hormone regimen seemed to have the same insignificant risk of estrogen alone (Ross et al. J Natl Cancer Inst 2000;923:328-332).

A similar benefit to continuous combined regimens versus sequential use concerns the endometrium. Citing a European study in which women using 10 days of sequential progestins still had a three-fold increase in uterine cancers with greater than five years of use, Dr. Portman suggested that a sequential regimen or suboptimal duration of progestins is not enough to protect the endometrium (Weiderpass E. J Natl Cancer Inst 1999;91:1131-7). 

What do we know or think we know about the effects of tamoxifen or raloxifene on breast cancer and breast cancer risk? 
“We learned from the very large breast cancer prevention project involving 13,000 women, that it is possible to achieve a 50% reduction in the incidence of breast cancer,” said Dr. Portman, who added that tamoxifen is currently the gold standard for breast chemoprevention (Fisher WE et al. J Natl Cancer Inst 1998;90:1371-88). He said that the ongoing STAR trial will help to determine whether raloxifene has the same effects at the breast as tamoxifen. “The MORE trial did show a decrease in the diagnosis of ER+ tumors in raloxifene-treated women. The question remains as to whether this is tumor suppression or just masking a tumor that will eventually develop.” (Cummings SR et al. JAMA 1999;281:2189-97).

Should a patient with a family history for breast cancer, or a history of any type of other hormone-related cancer, take HRT? 
Hormone exposure in the form of exogenous hormones are not the sole factors implicated in the risk of cancer, (Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1997; 360:1047) and, in fact there is no greater relative risk with use in patients with a family history of breast cancer, said Dr. Portman. “The best data we have regarding HRT and family history are from the Iowa Women’s Health Study showing no significant relationship with exposure in women who were hormone users with a family history of breast cancer compared to matched, similar controls” (Sellers TA et al. Ann Intern Med 1997;127:973). When counseled appropriately, even breast cancer survivors may indeed be legitimate candidates for HRT, Dr. Portman suggested, adding that further trials are needed to strengthen this conclusion. 

If I am diagnosed with breast cancer while taking HRT, do I have a different prognosis from other women diagnosed with breast cancer? 
Women who are unfortunate enough to be diagnosed with breast cancer are represented among the largest number of cancer survivors in this country and elsewhere, Dr. Portman responded. Women diagnosed with cancer while on HRT appear to have earlier stage disease, better differentiated tumors, and tumors of a more favorable histologic type (Gapstur et al. JAMA 1997;277:1140-7). Survivors of breast cancer may even benefit from treatment, and have no greater risk of recurrence than non-users he repeated. (O’Meara et al. JNCI 2001;93:754-762). 

What is it that we need to know about osteoporosis?
“Large scale trials are needed to confirm what we all think we know intuitively, which is that hypoestrogenism causes bone loss in women and that giving physiologic replacement may prevent it and its consequence of fracture.” Additional questions in need of answers include:

• Who are appropriate candidates for HRT (versus alternative therapies)? Which women are going to respond and at what doses? 
• As we move to lower and lower effective doses, what are the optimal doses? 
• Who are candidates for bone-specific agents and drugs like calcitonin?
• Might norethindrone acetate have additive benefit, with estrogen, versus other progestins, for bone and fractures, as well as for long-term use? 

Dr. Montgomery Rice turned to Dr. Blumenthal for a perspective on cardiovascular disease and HRT, asking for a reading on what is known, what is thought but not known with certainty, and what remains to be learned. In considering these questions, Dr. Blumenthal invited the audience to keep in mind that cardiovascular disease is the leading killer of both men and women over the age of 50. Death rates due to coronary heart disease and stroke are much greater for both white women and black women than death rates for lung cancer and breast cancer (American Heart Association. Accessed at americanheart.org/ statistics/biostats/). 

He added that it is known that hormone replacement therapy can have favorable effects on most lipids. These data were among findings from the large PEPI trial, which showed that, among HRT regimens, estrogen alone raises the HDL the most (Writing Group for the PEPI Trial. JAMA 1995;273:199). Estrogen plus MPA, medroxyprogesterone acetate, induces a blunted increase in the rise in HDL compared with estrogen alone. In terms of lowering [bad] LDL cholesterol, Dr. Blumenthal said that whether or not a progestin is included in the regimen there is still a 10-13% decrease with HRT. All ERT/HRT preparations raise triglycerides modestly (Speroff L et al. JAMA 1996;276:1397-1403). 

Are there other hemodynamic and vascular factors that come into play?
“There is some evidence that ethinyl estradiol increases coronary artery diameter,” said Dr. Blumenthal. A study conducted within his own laboratory led to the first published report demonstrating that ethinyl estradiol can increase the blood flow in human females (Reis et al. Circulation 1994;89:52). 

A number of other issues pertain to the risk of cardiovascular disease with hormone replacement therapy, and a collection of factors can influence the risk of vascular complications (Clarkson et al. Estrogens and Antiestrogens. Lippincott Press, 1997 Chapter 8). In fact, some experts believe that if there is an overall cardioprotective benefit [from ERT/ HRT], 30% of the benefit derives from lipid effects, while 70% of the benefit arises from other potential beneficial effects of HRT. These include improvements in endothelial function, increases in vascular dilatation, decreases in LDL uptake (Korylkowski M, Kelley D. Women’s Health in Primary Care. 1998;8:691-9). 

Is there any reason to believe that there may be differences among the progestins used today in hormone replacement therapy [in terms of CVD]?
“Data from a rabbit model, looking at cholesterol deposition in the aorta, suggest that the addition of the androgenic progestin norethindrone acetate may lead to a slowing of atherosclerosis progression. A paper by Seeger published in Menopause earlier this year suggested that there may be less smooth muscle cell proliferation with higher dosages of norethindrone acetate, compared to medroxyprogesterone acetate (Seeger H et al. Menopause 2001;8:5-9). 

Acknowledging that these data are preliminary, Dr. Blumenthal nevertheless asserted their strong suggestion that progestins may differ in their effect on atherosclerosis. 

The relationship between hormone replacement therapy and hemostatic factors has been investigated. In a study with Factor VII, data suggest that the HRT, femhrt® (1 mg NA/5 mcg EE), may have a modest beneficial effect, resulting in a decrease of Factor VII levels (Figure 2). Dr. Blumenthal added as well that femhrt® and Prempro™ (0.625 mg CEE/2.5 mg MPA), based upon findings from a recent study, may be associated with salutary alterations in PAI (plasminogen activator inhibitor) levels and Lp(a) (lipoprotein (a)) (Data on file. Pfizer Pharmaceutical Research. Ann Arbor, MI. 2001). 

The results of several recent trials have questioned the role of HRT in primary prevention versus secondary prevention. Can you summarize what we know or what we think we know about this issue of primary and secondary CHD prevention related to ERT and HRT?
“There are excellent observational data suggesting hormone replacement therapy may be very helpful in primary CVD prevention—the prevention of an initial heart attack,” Dr. Blumenthal stated. Some of the most compelling observational data comes from the Nurses Health Study, data from which were recently published by Grodstein, with a follow-up from 1976 to 1996 (Grodstein F et al. Ann Intern Med 2001;135:1-8;Grodstein F et al. Ann Intern Med. 2001;133:933-41). Its results, according to Dr. Blumenthal, “made very clear the that the risk for major coronary events were considerably lower with either the standard 0.625 or its equivalent, or even the lower 0.3 milligrams of estrogen per day” (Grodstein F et al. Ann Intern Med. 2001;133:933-41) . 

According to the American Heart Association (AHA) Recommendations, there are not sufficient data to state that HRT may provide primary prevention of coronary artery disease, and HRT should not be prescribed for secondary prevention in women with heart disease (Mosca L et al. Circulation 2001;104: 499-503. Herrington D et al. NEJM 2000;343:522-9) 
HRT regimens affect coronary risk differently. Among questions that remain to be answered is how progestins differ and either attenuate or interact with estrogen.

Quality of life issues concern every woman considering or choosing hormone replacement therapy, and the physicians who care for them. Dr. Montgomery Rice addressed a number of these issues with Dr. Judi Chervenak, from Albert Einstein in New York. She began with bleeding, which emerges as a critical issue in regimen selection and patient compliance with HRT.

Are there differences among the combination HRT products that may account for differences in bleeding?
“There are differences in cumulative amenorrhea with different hormone replacement therapy regimens,” Dr. Chervenak began. In this regard, she said, norethindrone acetate is different from other types of progestins. It is thought that norethindrone acetate causes more endometrial atrophy than other forms of progestin, leading to a lowered bleeding incidence (Simon JA et al. Menopause 2001;8:321-7). 

Unscheduled bleeding was examined in a 12-month direct comparison between norethindrone acetate (NA) and ethinyl estradiol (EE) and medroxyprogesterone acetate (MPA) and conjugated equine estrogens (CEE), both taken in a continuous combined regimen (Simon JA et al. Menopause 2001;8:321-7). According to results of this study, significantly more women achieved amenorrhea with the NA/EE combination, compared to CEE-MPA. 

What do we need to know about optimum care and counseling our patients? 
“We need to know how to best customize hormone replacement therapy, and to [take into account] differences in regimens that affect mood, sleep, waking, and prevention of Alzheimer’s disease. Some agents have better skin effects, effects on macular degeneration, genital health effects and side effects such as breast tenderness. “Breast tenderness is a big problem for many women. We want to know how we can minimize side effects and improve the tolerance of these product for the patients who use them.” 
 

 

 

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