A Fresh Look at Post-Menopausal Hormone Therapy:  Benefits and Risks

Research by: Marie Manteuffel, Pharm D, MPH
Health Policy Analyst, SWHR
January 2010 (Updated April 28, 2010)

One of the biggest health stories of the past decade was the announcement and subsequent debate over the results of the Women’s Health Initiative (WHI) study, published in 2002.   This multi-million dollar National Institutes of Health study reported that post-menopausal women taking hormone therapy (either estrogen alone or estrogen/progesterone combinations) were at an increased risk of invasive breast cancer, myocardial infarction (heart attack), stroke, pulmonary emboli (lung clot), deep vein thrombosis (blood clot) and dementia.¹  Given the number of women using hormone therapy, and the many women looking for control over menopausal symptoms, patient information and evidence supported recommendations by the medical community are essential. 

Since 2002, a number of studies have been published that re-examine and call into question many of the WHI findings.  These newer findings have been published in various scientific papers and journals, but, due to the quieter nature of these discoveries, women and many physicians continue to refer to the 2002 WHI findings exclusively to guide hormone therapy decisions.  Regrettably, doing so means that women and doctors are choosing therapies—or avoiding them—based on results that are no longer entirely accurate.  

Science is rarely definitive.  Information is constantly emerging and being revised.  Women and health care providers need to know that many of the initial results were inappropriately over-generalized, distorted (either in interpretation or by the media), or, in some cases, proven flat out wrong by newer and more specific studies. 

Nearly a decade after its initial publication, it is again time to explore the latest medical information available on HRT, so that women can have information and access to the most accurate personalized medical care available.

Recent Findings

When the Women’s Health Initiative results were published in 2002, the size and scope of the study made it one of the most complete investigations into the effects of HRT at that time.  Studies on hormone therapy date back many decades and the results continue to range from health enhancing to life threatening. 

Since 2002, one area where there is a growing body of evidence contradicting the WHI results is the impact of HRT on developing coronary heart disease (CHD).  In 2003, following the release of the WHI, the Food and Drug Administration mandated the inclusion of a Black Box warning on all estrogen and estrogen/progesterone therapies, warning that these medications should not be used for the prevention of cardiovascular disease.  There are risks for women who begin taking HRT in their sixties and later, particularly during the first year of use, especially if there is any pre-existing artery disease.²    However, newer studies are showing that certain groups of women, perhaps large numbers, may experience cardiovascular benefits from appropriately timed HRT use.

In 2007, investigators in a secondary analysis of the WHI suggested that women who start short-term HRT closer to menopause may actually reduce their risk of CHD, compared to the increased risk seen in women starting HRT farther out from menopause.³  While these secondary WHI findings, like those in 2002, did not reach statistical significance, it did introduce the “timing hypothesis”, an increasingly popular suggestion that proximity to menopause may be the key factor in determining when HRT transitions from being helpful to being harmful, at least in the case of CHD.  Additional research on the timing hypothesis, HRT use and duration, and cardiovascular health continues:

-Animal studies suggest that continuous estrogen keeps blood vessels healthy, but that estrogen replacement after a hormone-free interval after menopause cannot reverse vascular damage done.⁴

-The Nurses Health Study, an ongoing observational study of 121,000 nurses dating back to 1976, reported a 40% decrease in heart attacks in hormone users.⁵  A 2006 review of the Nurses Health Study data found a significantly lower risk for developing coronary heart disease among women starting HRT near menopause, in both the estrogen-alone and estrogen/progesterone groups.  In women starting either form of HRT more than 10 years after menopause (similar to women in the WHI), no significant relationship was found between use and CHD development.⁶

-In 2003, a case-controlled study of 864 women in the United Kingdom reported a significantly reduced risk of acute myocardial infarction in women, only if they had been on HRT (estrogen alone or combined estrogen/progesterone therapy) for longer than 60 months.⁷ 

One area where the science is less clear and where confusion remains is on the ultimate risk of developing breast cancer after using HRT.  Timing, dose, and duration of HRT all play a role in determining when the medicines are protective and when they may be harmful. In 2007, Wyeth introduced a 0.3 mg form of Premarin, less than half of the standard 0.625 mg dose used in the WHI.  Guidelines established after the 2002 WHI results advised taking the lowest HRT dose necessary for the shortest amount of time necessary.  Today, this recommendation continues to be analyzed.  Until more is known, results may continue to vary:

-A review article published in The Cancer Journal in 2009 states that many of the 2002 WHI reported increases in risk either did not reach statistical significance, or did not report data sufficiently so as to calculate whether a rise was significant.⁸

-An estrogen-alone study reported in 2006 found no increased risk of breast cancer, even after eight years of use.⁹ Also in 2006, the WHI reported that not only was there no observed increase in risk of developing breast cancer after estrogen use, but that the risk is lower than in non-HRT users.¹⁰  This same year, the International Menopause Society went on the record, stating that newer studies sent a “very clear message that ET [estrogen therapy] for postmenopausal women does not increase the risk of breast cancer”, and for some users might even prove protective.¹¹

-A 2008 report in the Journal of the National Cancer Institute reported that in trials where estrogen was given to high-risk women with the implicated BRCA1 gene mutation they did not find an increased risk of breast cancer.¹²

However, recent studies have not exclusively ruled out an association for some women between HRT use and breast cancer:

-A 2009 report in Cancer Epidemiology, Biomarkers & Prevention reported a link between HRT and atypical ductal hyperplasia, with over 50% fewer cases in 2005 versus 1999, detected upon reviewing 2.5 million mammographies from the Breast Cancer Surveillance Consortium.  This condition, marked by abnormal cells in the milk ducts of the breast, increases a woman’s risk for breast cancer three to five times.¹³ 

-At a 2009 meeting of the American Association for Cancer Research, it was reported that between 2002 and 2003 there was a 7 percent drop in breast cancer incidence for American women.  A decline of 3 percent is attributable to changes in hormone therapy use, leaving other pathways and influences responsible for a 4 percent decrease.¹⁴

-A 2008 report at the San Antonio Breast Cancer Symposium suggested that using hormones in excess of 5 years can double the risk for breast cancer.¹⁵ 

-A 2007 Kaiser Permanente study reviewed records over 25 years and found breast cancer rates moving in tandem with hormone use since 1990. Their study of 7,386 women revealed a 26 percent increase in breast cancer incidence from the early 1980s to early 1990s, an additional 15 percent rise through 2001 (despite level rates of mammography), then a decrease of 18 percent 2003-2006.¹⁶

Another component related to vascular health and hormonal impact on vessels involves the risk of stroke and blood clot development.  The proposed risk has been studied extensively, going back decades.  Many of the currently available hormonal contraceptives (birth control pills) carry warnings of increased risk of blood clot, including deep vein thrombosis and pulmonary embolism, though contraceptives typically contain estrogen and/or progestins in much higher concentrations than those used in hormone therapies for menopausal symptoms. 

-The 2007 re-analysis of the WHI by its investigators reconfirmed a link between HRT and risk of stroke, unaffected by proximity to menopause.¹⁷  In 2008, a similar increase in risk of stroke due to HRT was reported from the ongoing Nurses’ Health Study, also regardless of length of time since menopause.¹⁸

-A 2007 review article in Menopause: The Journal of The North American Menopause Society found that stroke and venous thromboembolism (a form of blood clot) in women using HRT are rare, and even rarer when hormone therapy is initiated in women less than 60 years old and in close proximity to menopause.¹⁹  The lead author in second 2008 piece in the Cleveland Clinic Journal of Medicine reported that the new data has changed recommendations, with the benefits of HRT exceeding risks when initiated in menopausal women younger than 60 years.²⁰  

-When the estrogen-only arm of the WHI was ended in 2004 due to an increased stroke risk, women were already being exposed to warnings of the risks of HRT.  The potential for women over-reporting subtle neurological deficits, fitting into the WHI’s broad definition of “stroke”, may have artificially raised the numbers reported.²¹ 

Other Areas of HRT Benefit, Promise

With most of the attention in print focusing on the negative effects of HRT, it is worth re-examining the number of benefits realized by women using HRT.  

First, HRT has unmatched effectiveness in reducing the classical vasomotor symptoms of menopause.  Hot flashes and night sweats are reported to affect anywhere from 35 percent to 80 percent of women, for an average of 3 to 4 years.^{22, 23}  Vaginally delivered estrogen therapies (cream, tablet or ring) are also very effective for treating vaginal dryness after menopause, though there are not long term studies on the risks of treatment.²⁴   

Maintaining estrogen levels through HRT may prevent or delay the precipitous bone loss that accompanies estrogen decreases at menopause.  A study of 9,704 women over 65 years old found a lower relative risk of wrist fractures (0.39), non-spinal fractures (0.66), and hip fractures (0.60) among current estrogen users.  An even lower relative risk for wrist (0.29), non-spinal (0.50), and hip fractures (0.29), was seen when looking at current estrogen users who started therapy within 5 years of menopause. ²⁵ 

A lesser known finding of the WHI was a reported 21 percent decrease in the risk of new-onset diabetes observed in the women randomized to estrogen/progesterone therapies versus placebo.²⁶  The effect may possibly be the result of a decrease in insulin resistance, though further study is required.  A study in 2006 reported the combination of conjugated equine estrogen and medroxyprogesterone may protect against new incidence of type 2 diabetes, though the effect of estrogen alone in protecting against diabetes is stronger than that of combined estrogen and progestins.²⁷  At this time it is not recommended that hormone therapies be used to prevent diabetes.

Despite the concerns over risk of cancer development, researchers at Washington University have found some breast cancer tumors that go into submission when given estrogen.²⁸  High dose estrogen therapy was used by some doctors to treat breast cancer prior to the availability of tamoxifen, a breast cancer treatment that also is bound by estrogen receptors.  Also relating to cancer, estrogen therapy with continuous progesterone levels have been shown to decrease risk for endometrial cancer, though estrogen-alone or estrogen plus cyclic progesterone use therapies can increase risk.²⁹  Combined estrogen/progesterone use is also reported to decrease risk of colon cancer, with the greatest reduction in risk seen among current users and women on the therapies over 10 years.³⁰      

Conclusion

The science of hormone therapy is complex.  It is essential to carefully assess each new study to see what can be learned and what specifically it adds to the pool of information surrounding HRT.  Patients and practitioners must be cautious to not over reach when trying to apply in real life what research data from a controlled study may show.  Looking singularly at the role of HRT on a woman's health does not account for the differences in diet, lifestyle, environmental exposures, and genetic make up that all contribute to ultimate well-being. A number of studies are on going, looking at estrogen’s long term protective benefits and also potential risks. 

It is worth noting that not all HRT therapies are the same, and the impact different hormones have on a woman’s health should not be generalized to all formulations.  Drastic differences can be seen in estrogen/progesterone combinations versus estrogen alone, as well as different chemical formulations of single therapy estrogens.  Synthetic, conjugated, equine, bioidentical and personalized compounded therapies all have different benefit/risk profiles, and what is appropriate for one woman may not be for another. 

As medicines transition to be more personalized, it will require individual patients, practitioners and the general public to outgrow the desire for sweeping guidelines and one size fits all recommendations.  Instead, health care in this decade and for decades to come will demand a focus that narrows, all the way to the level of an individual patient, then further yet—down to the DNA, genes, and gender that make each person who they are.    

Updates since initial posting (in January 2010)

Studies continue to be published looking at the area of possible risks and possible benefits relating to HRT use and exploring past studies.

-A gradual increase in body mass index during adulthood has reported links to post-menopausal breast cancer. Estrogen is produced by body fat, called adipose tissue, and this estrogen is thought to promote breast cell proliferation. Of the 72,007 women studied, those who had an increase in BMI of 5 kg/m2 (equivalent to gaining 30 pounds for a woman 5’4’’) between age 20 and 50 were at an 88 percent increased risk of developing breast cancer after menopause. A smaller but still significant 56 percent increased risk was noted in women with a BMI increase of 5 kg/m2 after age 50.³¹ Critics of the Women’s Health Initiative cite the health and weight of the study subjects as a possible confounder of the 2002 published results.

-Elevated epidermal growth factor receptor (EGFR) levels in the blood may be a clinical marker of breast cancer development. In a study of 420 women with estrogen receptor positive (ER+) breast cancer, the type thought to be influenced most by HRT use, EGFR levels were significantly elevated 17 month prior to their cancer diagnosis when compared to cancer-free control patients. Those with the highest EGFR levels were found to be at a 2.9-fold increased risk of cancer versus those with the lowest EGFR levels. For women using HRT (current users of estrogen plus progestin therapy) a 9-fold risk of developing breast cancer was seen.³²

[1] Rossouw JE, Anderson GL, Prentice RL, et al. Writing Group for the Women’s Health Initiative investigators. Risks and benefits of estrogen plus progestin in healthy post menopausal women: principal results from the Women’s Health Initiative Randomized Controlled Trial. JAMA. 2002;288:321–333.

[2] Bluming AZ and Tavris C.  Hormone replacement therapy:  Real concerns and false alarms.  The Cancer Journal.  2009;15(2):93-104.

[3] Rossouw JE, et al.  Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.  Journal of the American Medical Association.  2007;297(13):1465-1477.

[4] Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res. 2002;53:605– 619.

[5] Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, and Stampfer MJ.  A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease.  Ann Internal Med.  2000 Dec;113:933-941.

[6] Grodstein F, Manson JE, and Stampfer MJ.  Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation.  J Womens Health.  2006 Jan-Feb;15(1):35-44.

[7] Chilvers CED, Knibb RC, Armstrong SJ, Woods KL, and Logan RFA.  Post menopausal hormone replacement therapy and risk of acute myocardial infarction – a case control study of women in the East Midlands, UK.  European Heart Journal.  2003;24(24):2197-2205. 

[8] Bluming AZ and Tavris C. Hormone replacement therapy: Real concerns and false alarms The Cancer Journal.  2009; 15(2):93-104.

[9] Zhang SM, Manson JE, Rexrode KM, et al. Use of oral conjugated estrogen alone and risk of breast cancer. Am J Epidemiol. 2007;165:524 –529.

[10] Stefanick ML, Anderson GL, Margolis KL, et al; for the WHI Investigators.  Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy.  JAMA. 2006;295:1647–1657.

[11] WHI and breast cancer.  International Menopause Society.  April 2006.  http://www.j-menopause.com/images/IMS_20060411.pdf  Accessed January 12, 2010.

[12] Eisen A, et al.  Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst. 2008 Oct 1;100(19):1361-7. Epub 2008 Sep 23.

[13] Menes TS, Kerlikowske K, Jaffer S, Seger D, and Miglioretti DL.  Rates of atypical ductal hyperplasia have declined with less use of postmenopausal hormone treatment: findings from the Breast Cancer Surveillance Consortium.  Cancer Epidemiology, Biomarkers & Prevention.  November 2009;18:2822.

[14] American Association for Cancer Research.  Decline in breast cancer: not just because of hormone therapy.  AACR Press Release.  December 7, 2009.  http://www.aacr.org/home/public--media/aacr-press-releases.aspx?d=1682  Accessed January 13, 2010.

[15] Marchione M.  New study firmly ties hormone use to breast cancer.  Washington Post.  December 13, 2008.

[16] New Study Confirms Link Between Breast Cancer and Hormone Therapy. Kaiser Permanente News release: National. July 24, 2007. Available at: http://ckp.kp.org/newsroom/national/archive/nat_072407_hrtandcancer.html

[17] Rossouw JE, et al.  Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.  Journal of the American Medical Association.  2007;297(13):1465-1477.

[18] Grodstein F, Manson JE, Stampfer MJ, Rexrode K. Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy. Arch Intern Med 2008;168:861-868.

[19] Hodis HN and Mack WJ.  Postmenopausal hormone therapy in clinical perspective.  Menopause.  2007;14(5):1-14.

[20] Hodis HN.  Assessing benefits and risks of hormone therapy in 2008:  New evidence, especially with regard to the heart.  Cleveland Clinic Journal of Medicine. 2008;75 (supplement 4): S3-S12. 

[21] Bluming AZ and Tavris C. Hormone replacement therapy: Real concerns and false alarms. The Cancer Journal. 2009; 15(2):93-104.

[22] NIH State-of-the-Science Panel. National Institutes of Health State-of-the-Science Conference Statement: Management of Menopause-Related Symptoms. Annals of Internal Medicine 2005;142(12): 1003-13.

[23] Avis NE, Crawford SL and McKinlay SM. Psychosocial, behavioral, and health factors related to menopause symptomatology," Women's Health. 1997;3(3):103-120.

[24] Patient information: vaginal dryness.  UpToDate.  September 2009.  http://www.uptodate.com/patients/content/topic.do?topicKey=~7xsnLcKzzgHQ_Oi  Accessed January 13, 2010. 

[25] Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, and Cummings SR.  Estrogen replacement therapy and fractures in older women.  Study of Osteoporotic Fractures Research Group.  Ann Intern Med.  1995 Jan 1;122(1):9-16.

[26] Margolis KL, et al.  Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women:  results from the Women’s Health Initiative Hormone Trial.  Diabetologia.  2004 Jul;47(7):1175-1187.  Epub 2004 Jul 14. 

[27] Bonds DE, et al.  The effect of conjugated equine oestrogen on diabetes incidence:  the Women’s Health Initiative randomised trial.  Diabetologia.  2006 Mar;49(3):459-468.  Epub 2006 Jan 27. 

[28] Bernhard B.  Estrogen therapy, once considered taboo, may again be effective in breast cancer treatment.  St. Louis Post-Dispatch.  December 12, 2008. 

[29] Weiderpass E, et al.  Risk of endometrial cancer following estrogen replacement with and without progestins.  J Natl Cancer Inst.  1999 Jul 7;91(13):1131-1137.

[30] Johnson JR, et al.  Menopausal hormone therapy and risk of colorectal cancer.  Cancer Epidemiology, Biomarkers & Prevention.  2009 Jan;18:196. 

[31] Body Mass Index Gain Throughout Adulthood May Increase Risk of Postmenopausal Breast Cancer. American Association for Cancer Research Press Release. April 20, 2010. Available at: http://www.aacr.org/home/public--media/aacr-press-releases.aspx?d=1853

[32] Increased EGFR Levels May be an Early Marker of Breast Cancer. American Association for Cancer Research Press Release. April 20, 2010. Available at: http://www.aacr.org/home/public--media/aacr-press-releases.aspx?d=1850