Health Briefs

July 12, 2002

A Cancer Surgeon’s Perspective on Hormone Replacement Therapy
This week’s Women’s Health Initiative (WHI) report on hormone replacement therapy (HRT), published by the Journal of the American Medical Association, has created a furor among women and many of their doctors.  The study evaluated 16,608 postmenopausal women who were taking either hormone replacement pills or placebo pills (sugar pills).  A total of 8,506 women took tablets containing estrogen and progestin, the two female “sex hormones,” while 8,102 women took the placebo pills (progestin is added to HRT in women who still have their uterus, as estrogen is known to increase the risk of uterine cancer).  The study was originally designed to last 8.5 years, but was stopped following an average patient follow-up duration of 5.2 years after the trial’s data and safety monitoring board determined that the risks of receiving the hormone replacement pills were excessively high.  The study was originally designed to evaluate HRT in terms of its potential effects on the incidence of coronary artery disease, breast cancer, stroke, blood clots in the lungs, uterine cancer, colorectal cancer, hip fracture, and death due to any cause.

After full analysis of the data, the study found that the combined use of estrogen and progestin increased the risk of breast cancer by 26%, and that this increased risk begins to develop after only 4 years of HRT (earlier studies have shown an increased risk of breast cancer developing after 7-10 years of HRT).  Unfortunately, there is more potential bad news about HRT.  For decades, physicians have been telling their patients that estrogen protects women’s hearts against coronary heart disease.  Next to HRT’s ability to alleviate the often vexing symptoms of menopause, this supposed “heart protective” benefit of HRT has been the most compelling reason cited, by physicians and patients, for taking estrogen.  The ancillary benefits of estrogen, including the reversal of vaginal dryness and improvements in skin quality, are also well-known, and are common reasons for HRT use.  The data supporting this supposition has been largely anecdotal (based largely upon inferences drawn from the favorable blood cholesterol profiles of women using HRT).  Indeed, the relatively low incidence of early heart disease in women, when compared to men, has often been cited as clinical proof of this hypothesis.  However, recent large scale studies, including the Heart and Estrogen/progestin Replacement Study (HERS), have not shown any reduction in the incidence of cardiovascular disease associated with prolonged HRT.  Not only does the new WHI report confirm that HRT, at least with combined estrogen and progestin, not protect the heart, but the patients receiving HRT actually experienced a 29% increase in the incidence of coronary heart disease when compared to the placebo group.  Moreover, the increased risk of heart disease began to show up almost immediately after the study began, suggesting that the effects of HRT on the heart begin to occur very soon after patients begin taking estrogen/progestin pills.  The bad news doesn’t stop here, either.  Strokes increased by 41%, while blood clots in the lung increased more than two-fold, or by 113%.  There was, however, a bit of good news as well.  The incidence of uterine cancer was reduced by 17% (probably due to the protective effects of progestin), colorectal cancer was reduced by 37%, and hip fractures were reduced by 24% (a known beneficial “side effect” of estrogen).  The apparent reduction in colorectal cancer cases is an interesting finding, but breast cancer occurs far more commonly in women than colorectal cancer.  More than 200,000 women will develop breast cancer this year, and 40,000 will die of the disease.  On the other hand, 75,000 women will be diagnosed with colorectal cancer, and 28,000 will succumb to the disease.  When all adverse and beneficial effects of HRT were tallied up in this study, however, the harmful effects were judged to be more frequent and more serious than the beneficial effects.

While most of the debate currently swirling around this study relates to the increased risk of breast cancer among the HRT group of women, it actually comes as no surprise to physicians who treat breast cancer or the symptoms of menopause, as long term estrogen use has been shown by multiple other studies to increase the risk of breast cancer by 20-40%.  (Estrogen, whether derived from a woman’s own ovaries or HRT pills, has also long been known to stimulate normal breast duct cells to divide more rapidly, and to cause breast cancer cells to grow and divide more vigorously.)  Rather, it is the rapid and significant increase in the incidence of coronary heart disease that is especially stunning.  At most, prior HRT studies have found either a modest cardiac health benefit from HRT, or no benefit at all.  This new large scale study, however, reveals the convincing appearance of a significantly increased coronary artery disease risk among women taking combined estrogen/progestin HRT.  At the same time, the increases observed in stroke and blood clot rates are not particularly surprising, as estrogen revs up the blood’s clotting system (an effect that is further accelerated in smokers).  Thus, now stripped of its previous reputation as a protector of coronary arteries, and as a drug with minimal impact on the risk of breast cancer, it is time to reconsider the indications for HRT.  Essentially, one is left with a therapy that alleviates the symptoms of menopause and, perhaps, makes the skin appear more youthful, whilst simultaneously increasing the risk of some quite serious diseases.  This paradigm shift in the risk-to-benefit equation for HRT will necessarily demand a careful reassessment of the indications for estrogen/progestin HRT in virtually all women who are taking these medications.

What does the information reported in this study really mean in practical terms?  Does it mean that HRT should be forever abolished for all women?  Are there any women who might still benefit, overall, from HRT despite its apparent risks?  Upon first analysis of this study, most prudent physicians and patients would probably conclude that HRT should no longer be prescribed to anyone.  While I too find the results of this study sobering, I have long been accustomed, as a cancer physician, to weighing the relative risks and benefits of estrogen replacement therapy to patients with either a personal or a family history of breast cancer.  There is certainly cause for concern here, though perhaps not for the degree of alarm that this study has generated since it was released early this week.  Consider, first, the actual impact of HRT in terms of the increased incidence of the diseases that it now appears to be firmly linked with.  The increased risk percentages are relative risks, and not absolute risks.  That is to say, the HRT-associated increase in the risk of heart disease or breast cancer is relative to the risk that already exists for everyone in the population at large.  According to this study’s findings, if 10,000 women took estrogen/progestin for 5 years, there would be 7 more cases of coronary artery disease, 8 more strokes, 8 more blood clots in the lungs, 8 more breast cancers, 6 fewer colorectal cancer cases, and 5 fewer hip fractures.  Of course, when you extrapolate these numbers to the 143,368,343 females in the United States, the numbers become more substantial over the course of their lifetimes. 

Another consideration is that this study measured outcomes associated with a combined HRT regimen containing estrogen and progestin.  Another part of the same study is evaluating the effects of estrogen alone in 10,739 women who have had a hysterectomy.  This second group of patients entered the study at the same time as the estrogen/progestin group and, so far anyway, the estrogen-only group’s incidence of coronary heart disease and breast cancer has not reached sufficiently high levels to compel researchers to halt this arm of the WHI study.  At the same time, previous studies linking high levels of naturally occurring estrogen in the blood, and estrogen-only HRT, with increased rates of breast cancer have also been published over the past 5 years.  Even before any convincing data about HRT’s effects became available, a woman’s lifetime exposure to her own body’s estrogen was known to appreciably affect her risk of developing breast cancer. 

Getting back to the previous questions that this study necessarily engenders, it is clear that HRT, and estrogen/progestin combinations in particular, should not be prescribed to reduce the risk of cardiovascular disease.  It also seems prudent for women with preexisting risk factors for breast cancer to generally avoid HRT.  Such risk factors include a prior history of breast cancer, atypical ductal or lobular hyperplasia discovered on prior breast biopsies, multiple prior breast biopsies, early onset of menstrual periods, late onset of menopause, late age at first live birth, and a family history of breast cancer among first or second degree relatives.  Women with significant cardiovascular disease risk factors may also want to avoid HRT.  Fortunately, there are a number of non-hormonal medications that can significantly ameliorate the symptoms and health risks of menopause in most women.  Clonidine and the SSRI antidepressants (for hot flashes), the bisphosphonates (anti-osteoporosis drugs), aspirin (an anti-clotting drug), and vaginal estrogen cream for dryness (which is not significantly absorbed into the bloodstream) are a few examples.  Vitamin E and oil of primrose also can reduce the severity of hot flashes in many women. 

At the other extreme, perhaps, are women with a relatively low risk of breast cancer and cardiovascular disease, and who are severely debilitated by hot flashes, mood instability and depression, or memory loss associated with menopause.  Fortunately, most women will adjust to the lack of natural estrogen following menopause, and their symptoms will abate over time, with or without treatment.  For those few women who remain genuinely debilitated by their menopausal symptoms despite non-hormonal treatment, and who have minimal cardiovascular or breast cancer risk factors, small doses of estrogen (below the 0.625 mg daily dose used in this study) may be considered.  Otherwise low risk women with a strong family history of Alzheimer’s Disease might also at least be considered for reduced dose HRT.  However, all patients considering HRT must be thoroughly appraised of the potential risks of even low dose HRT, and they must be followed very closely for early signs of coronary artery disease, stroke, blood clots and, of course, breast cancer.  While it is possible that low dose estrogen regimens, and possibly continuous release estrogen skin patches, may reduce the potentially deleterious effects of HRT, one cannot assume that these risks will be completely eliminated.  Therefore, the indications for HRT, following the publication of the WHI study, would appear to have narrowed considerably, although they have not been altogether excluded.  Each patient, and their physician, must carefully weigh both the potential benefits and risks of HRT in view of this study, as well as other related studies published over the past 5 years.  Meanwhile, additional research is urgently required to develop more effective and safer treatments for the symptoms of menopause, and especially those symptoms that cause some women to experience such a dramatic decline in the quality of their lives.

Dr. Robert A. Wascher