Experts discuss hormone therapy use 10 years after WHI

Ten years have passed since the publication of the first results of the Women’s Health Initiative, which demonstrated that estrogen plus progestin increased the risk for cardiovascular complications, deep vein thrombosis and breast cancer, and estrogen alone increased the risk for stroke and deep vein thrombosis, but not coronary heart disease or cancer. Both, however, prevented fractures.

The data produced widespread uncertainty for patients and their physicians regarding the safety of hormone therapy (HT) use. Within months of the release of the results, prescribing trends decreased and have continued to decline in the United States. However, some of the dust has settled and experts have reached a consensus on the key points of HT. Additionally, recent data from the Kronos Early Estrogen Prevention Study (KEEPS) help substantiate the role of low-dose HT in the treatment of menopausal symptoms. Although some experts said it is too early to make any concrete conclusions, there is a feeling of reassurance associated with the early results of KEEPS.

“The pendulum has swung from chronic disease prevention to the more appropriate place of HT reserved for the treatment of menopausal symptoms,” JoAnn Manson, MD,DrPH, NCMP, one of the principal investigators of the Women’s Health Initiative (WHI) and KEEPS, told Endocrine Today of the progress made in the 10 years after the WHI. “There’s an improved understanding of the different balance of benefits and risks when HT is used for short-term symptom management vs. long-term disease prevention.”

Endocrine Today spoke with experts about this deeper understanding and its effect on prescribing practices during the past 10 years and to determine whether recent data have helped allay doubts about HT.

Shift to a new paradigm

“The WHI was a landmark study and will never be replicated again in the way that it was,” Martha Gulati, MD, MS, FACC, FAHA, associate professor of medicine, division of cardiology at Ohio State University, told Endocrine Today. “It answered, for me as a cardiologist, an important question about the safety of HT. When the results came out in 2002, they changed practice; they changed the way that we viewed HT, and they changed women’s lives.”

In the mid- to late-1990s, researchers estimated that more than one-third of postmenopausal women aged 50 to 74 years were taking HT.

“Hormones were used long-term for many years, as they were thought to be beneficial both for bones and the heart, but physicians weren’t starting patients on HT the way they were used in the WHI, that is, among much older women.”

However, once the estrogen and progestin trial was stopped early in July 2002 and the estrogen alone trial in March 2004, HT prescribing rates began to decrease.

In a study published in Menopause in June 2012, Bruce Ettinger, MD, emeritus clinical professor of medicine at the University of California Medical Center in San Francisco, and colleagues reported that the rate of HT utilization in the United States decreased 30% within the first year after the results of the WHI trial were released. That number continued to progressively decline, reaching a nadir of 70% reduction by 2007 and showing no change over the years 2007-2009.

“Our study found that women are voting with their feet, and by and large, they have left the use of HT,” Ettinger told Endocrine Today. “However, prescribers still have — especially OB/GYNs — a strong connection to the use of HT and have looked for reasons to prescribe it or to fight the trend of not using HT.”

By analyzing nationwide HT prescription claims between 2002 and 2009, Ettinger and colleagues found that OB/GYNs prescribed transdermal HT nearly twice as often as all other provider types.

Based on the risks discovered in the WHI, however, the decrease in HT’s popularity as a long-term preventive therapy seems to have been a good result, according to Manson, who is president of the North American Menopause Society (NAMS); professor of medicine and the Michael and Lee Bell professor of women’s health at Harvard Medical School; and chief of preventive medicine at Brigham and Women’s Hospital.

“The WHI deserves credit for stopping the increasingly common practice of prescribing HT to older women at high risk for CVD,” she said in an interview. “I think that’s forgotten, or some of the younger physicians may not even be aware of the trend that developed in the 1980s and 1990s. It’s also important to consider that if the WHI had been limited to younger, newly menopausal women and did show a favorable balance of benefits and risks of HT when used for prevention, those results may have been extrapolated to older women and those at high risk for CVD, and that would have been detrimental.”

Early results of KEEPS

Now, long-awaited KEEPS data suggest that HT has several benefits when administered for short-term symptomatic relief, a practice that many experts have been following for the past 10 years.

At the NAMS 23rd Annual Meeting in October, Manson and colleagues presented findings from KEEPS. Early evidence from the 4-year study suggests that estrogen and progesterone administered shortly after menopause appeared to be safe, relieved various symptoms, and improved mood, sexual function and biomarkers for CV risk.

The double blind, placebo-controlled, randomized study tested low-dose oral or transdermal estrogen and cyclic monthly progesterone in healthy women aged 42 to 58 years who were within 3 years of their final menses at the time of randomization.

Participants (n=727) were categorized into three arms, besides cyclical micronized progesterone (Prometrium, Abbott) at 200 mg per day for 12 days per month:

Researchers found that oral conjugated equine estrogens (o-CEE) and transdermal estradiol (t-E2) did not significantly affect systolic or diastolic blood pressure, in contrast to the increased BP observed with the higher dose of CEE in the WHI. Also, o-CEE was linked to an increase in HDL, a decrease in LDL and an increase in triglyceride levels. According to researchers, the t-E2 had neutral effects on HDL, LDL and triglycerides. Additional data indicate that t-E2 improved insulin sensitivity.

Additionally, menopausal symptoms such as hot flashes and night sweats were relieved, and the HT had beneficial effects on bone mineral density compared with placebo-treated patients.

One of the most interesting findings, according to Manson, was the effect both oral and transdermal HT had on sexual function. Treatment with either o-CEE or t-E2 resulted in decreased dyspareunia and increased lubrication compared with placebo. Additionally, t-E2 was associated with improved libido-related aspects of sexual function, including desire, arousal and orgasm, Manson said.

During the presentation at NAMS, S. Mitchell Harman, MD, PhD, director and president of the Kronos Longevity Research Institute and chief of the endocrinology division at Phoenix VA Health Care System in Arizona, said the KEEPS results also show no significant risks or benefits of HT regarding the rates of breast cancer, endometrial cancer, myocardial infarction, stroke or venous thromboembolic events. However, the study was not large enough to provide conclusive evidence on the risk of clinical events. HT also showed no significant effect on atherosclerosis progression assessed by noninvasive imaging.

“This is nothing that’s going to change women’s minds about HT,” Ettinger said of the results. “It shows that, sure you might feel better, especially if you’re symptomatic, but this isn’t going to prevent you from getting heart disease, which is the way it was sold back in the 1980s and 1990s. So, the revolution is that HT is not being prescribed or recommended for the prevention of disease or to make you healthier, but rather just for short-term symptomatic relief.”

The publication of the results of KEEPS is expected in late 2012 or early 2013.

Cognition and KEEPS

In the KEEPS Cognitive Study, Sanjay Asthana, MD, the Duncan G. and Lottie H. Ballantine chair in geriatrics and head of the division of geriatrics and gerontology at the University of Wisconsin School of Medicine, said there were significant improvements in the mood of women taking oral estrogen. Upon enrollment, the 662 women in the study were free of depression, dementia or memory problems.

“The cognitive study evaluated the relationship between vascular risk factors and cognition,” Asthana said during the presentation.

According to data, 22% of the women had at least one apolipoprotein E4 allele, a known risk factor for Alzheimer’s disease.

Asthana and colleagues conducted a confirmatory factor analysis using four independent factors, consisting of nine cognitive tests and a global cognitive measure. These factors included verbal learning and memory; auditory attention and working memory; visual attention and executive function; and speeded language and flexibility.

Upon analyzing baseline, researchers found an inverse link between testosterone and verbal memory and reported that increased systolic BP was related to negative performance on working memory and attention.

Based on CV risk markers, including BMI, Framingham risk score, carotid intima-media thickness, systolic BP, LDL, HDL, triglycerides and fasting glucose, the researchers categorized patients into two groups: patients at high risk for CVD, and patients at low risk for CVD. Ultimately, patients at low risk for CVD had better performance scores on global cognition and language and flexibility. Patients in the high-risk group were aged older and had a higher prevalence for the apolipoprotein E4 allele.

Although HT had no significant positive or negative effects regarding general measures of cognition in the overall cohort, the women at low baseline risk of CVD appeared to have benefits for memory and verbal learning, explained Asthana.

“There were no adverse effects and also there was no benefit of this test,” Asthana said.

One dose, formulation does not fit all

Many experts said the results of the KEEPS are reassuring because they demonstrate no adverse events associated with therapy, and the data have confirmed the importance of individualized treatment.

“Overall, the findings underscore the importance of individualized care for women and personalized decision making about HT based on a woman’s symptoms, her underlying risk factor status, her personal preferences and her priorities for treatment,” Manson said.

Stephen A. Brietzke, MD, an Endocrine Today Editorial Board member and associate professor of medicine at the University of Missouri School of Medicine, said: “KEEPS offers a valuable lesson: We should not shun short-term estrogen therapy in women who have severe menopausal hot flashes and are miserable in those early years of menopause and who, as a group, are likely to be at low risk for CVD and breast cancer. Obviously, we have to individualize our care and screen patients for CV risk factors and personal risk of breast cancer, but for a woman at average risk with severe symptoms, we should not withhold short-term estrogen therapy for 3 years or so post-menopause.”

This belief is shared by experts from NAMS, the American Society for Reproductive Medicine and The Endocrine Society in a paper published in the August issue of Menopause. In their statement, Manson and colleagues said the lowest dose of HT should be used for the shortest amount of time needed for the management of menopausal symptoms. Although less than 5 years of therapy is recommended for estrogen plus progestin, they said duration should be individualized.

The statement also says the use of HT or estrogen therapy is not associated with an increased CVD risk if started early in menopause and is considered safe in women under 60 (or within 10 years of menopause).This was specifically stated in the combined statement released by a consortium of societies

However, some women are still uncertain about undergoing treatment with HT. Endocrine Today Editorial Board member Michelle P. Warren, MD, medical director, Center for Menopause, Hormonal Disorders and Women’s Health; professor of medicine and obstetrics and gynecology; Wyeth Professor of Women’s Health, College of Physicians and Surgeons, New York Presbyterian Hospital/Columbia University Medical Center, said some women are still scared.

“The initial impression makes the most significant impression, and the initial impression (of HT) was fear after the results (of the WHI) came out in 2002,” she said. “That (fear) hasn’t completely gone away.”

But it is not just patients who are scared. According to Warren, some women who enter her practice said they have seen physicians who refuse to prescribe hormones. “The fact is that the medical community is still anxious about giving these medications. (But what we’ve learned is) you have to individualize therapy. There are a lot of different preparations out there, and not everyone reacts the same way to the hormones available. So, there’s a skill involved in individualized care, and if you’re not interested and you’re not going to prescribe HT, the skill doesn’t develop,” she said.

More data expected, needed

Manson told Endocrine Today that she and colleagues are hoping to receive a renewal of funding for KEEPS to continue follow-up for another 4 or 5 years and examine the changes in atherosclerosis progression and cognitive function outcomes. Additionally, an ancillary breast density study is under way to determine whether there is a difference in mammographic density or a need for repeat testing with different formulations or doses.

According to Gulati, a decade after the WHI, experts should still have a sense of reserve about HT, but it is important to be open-minded about the future and the need for additional trials. With different formulations of estrogen available, questions surrounding their efficacy and safety need answering.

“I’m open to the idea that there might be some form of estrogen that will at least not increase CV events. We need data, and we need to not be foolish. What we did to women prior to the WHI was experimenting on them; we didn’t have studies and we didn’t follow things appropriately,” she said. “We’re always taught in medicine that we need a randomized controlled trial before we make decisions, and we didn’t listen to that prior to the WHI, when HT was the No. 1 drug without any randomized trials at all.”

More data are emerging, although not from placebo-controlled randomized trials. In an October issue of the British Medical Journal, researchers from Denmark demonstrated that after 10 years of treatment with triphasic estradiol and norethisterone acetate, recently postmenopausal women (or those with perimenopausal symptoms) had a significantly reduced risk for mortality, heart failure and MI with no increase in the risk for cancer, venous thromboembolism or stroke.

Additionally, the United States Preventive Services Task Force (USPSTF) issued a statement on Oct. 22, 2012, addressing the use of HT for the primary prevention of chronic conditions in menopause. It recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women.

“The USPSTF concludes with high certainty that the chronic disease prevention benefits of combined estrogen and progestin do not outweigh the harms in most postmenopausal women,” the task force wrote.

According to the statement, more data are needed regarding the balance of benefits and risks based on age at initiation, duration of use and dose or delivery mechanism, as those available were limited by lack of power or were post hoc exploratory analyses.

“Additional research to better understand the apparently contradictory finding that combined hormone therapy increases the risk for invasive breast cancer incidence and possibly breast cancer death, whereas estrogen alone exerts a small but statistically significant protective effect on these outcomes, is also warranted,” they wrote.

“It’s interesting how there’s a forward wave of enthusiasm and a backwash of recoil from a therapy once negative studies come out. The fact is that there’s probably some current in between those extremes: a very focused target group who will benefit from estrogen treatment, with low risk for disease. At the same time, estrogen therapy is not a panacea,” Brietzke said. – by Stacey L. Fisher and Samantha Costa

For more information:

For more information:

• Stephen A. Brietzke, MD, can be reached at University of Missouri, Columbia School of Medicine Diabetes Center, D110A, Columbia, Missouri 65212; brietzkes@health.missouri.edu.
• Bruce Ettinger, MD, can be reached at doc.ettinger@gmail.com
• Martha Gulati, MD, MS, FACC, FAHA, can be reached at The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Suite 200, Columbus, OH 43210; martha.gulati@osumc.edu.
• JoAnn Manson, MD, DrPH, NCMP, can be reached at Harvard Medical School, 900 Commonwealth Avenue, 3rd fl, Boston, Massachusetts 02215; jmanson@rics.bwh.harvard.edu.
• Michelle P. Warren, MD, can be reached at New York Presbyterian Hospital, 622 West 168th St., New York, NY 10032; mpw1@columbia.edu.

• Disclosure: Brietzke, Ettinger, Gulati and Manson report no relevant financial disclosures. Warren is on the advisory board or review panel and has received consultancy fees from: Agile Therapeutics, Ferring Pharmaceuticals, Pfizer and Yoplait.

Should HT be used for chronic disease prevention?

Postmenopausal hormone replacement therapy remains FDA approved for osteoporosis prevention and is the only therapy proven (by WHI) to reduce bone fractures in an unselected high-risk population (ie, low T-score, previous fractures)

HRT (when initiated in young postmenopausal women) is the only effective primary prevention therapy for cardiovascular disease (CVD) and the only therapy that reduces total mortality and extends life in women (Hodis H.Climacteric. 2012;15:217-228).

The totality of evidenced-based data collected over the last 5 decades is the largest and most consistent for any prevention therapy. Confirming this immense body of data are recent data from the only long-term prospective longitudinal randomized trial designed to examine clinical outcomes among women who were specifically a-priori randomized (for 10 years) to HRT (estradiol with/without sequential progestin) in the perimenopausal/early postmenopausal period (average, 50 years old and 7 months-since-menopause). CVD, stroke, breast cancer and total mortality were reduced by 52%, 27%, 42% and 43%, respectively. These effects were maintained after 16 years of total follow-up (Schierbeck LL. BMJ. 2012; 345:e6409).

These data confirm the post-hoc analyses conducted in WHI for young postmenopausal women as well as the reduction in breast cancer reported from WHI for conjugated estrogen therapy.

In sum, the totality of evidence-based data shows that when initiated in young postmenopausal women at or near menopause and continued long-term, HRT significantly reduces morbidity and mortality while substantially increasing quality-adjusted life years (QALYs) and it does so safely and cost-effectively (approximately $2,400/QALY). Unquestionably, the consistency of evidenced-based data showing the reduction of morbidity and mortality with long-term use of HRT is unparalleled by any prevention therapy used in women’s health, as is the data supporting the safety of HRT, the risks of which are rare and similar to risks associated with other medications used in women’s health. For example, the absolute risk for breast cancer associated with continuous combined conjugated estrogen plus medroxyprogesterone acetate therapy as reported from WHI is no different than the risk of breast cancer reported with the use of statin therapy (Hodis H. Climacteric. 2012;15:217-228).

Howard N. Hodis, MD, is Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology; Professor of Medicine and Preventive Medicine; Professor of Molecular Pharmacology and Toxicology; Director, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Keck School of Medicine at the University of Southern California. He can be reached at 2250 Alcazar Street, CSC 132, Los Angeles, CA 90033; athero@usc.edu. Disclosure: Hodis reports no relevant financial disclosures.

Preventive measures should be effective with minimal risk

Preventive benefits for heart and brain have not been documented in properly randomized, controlled trials. On the other hand, serious risks of hormone therapy (HT) have been documented (breast cancer, stroke and thrombosis) along with less serious side effects, potentially requiring surgery (uterine bleeding, gallstones, renal stones, urinary incontinence and pelvic organ prolapse).

Early postmenopausal use of HT is necessary if any cardiac benefit is to be seen. However, early initiation of HT is more likely to increase the risk for breast cancer, compared with delayed initiation. Both estrogen and progestogen therapy and estrogen alone appear to result in an increased risk for breast cancer when initiated near menopause and followed long enough. There is a conflict with the different timing considerations for maximizing cardiovascular and breast health.

HT is approved by the FDA for prevention of osteoporosis. However, guidelines from major medical societies recommend calcium and vitamin D for prevention. Pharmacologic therapy is recommended only when a woman is assessed to be at high risk of fracture by specific criteria. Using HT for prevention of osteoporosis in early postmenopausal women who are not at significant risk of fracture is not consistent with osteoporosis guidelines. Use in older women will result in more adverse events.

Preliminary results from KEEPS failed to demonstrate cardiovascular benefit as measured by coronary artery calcification and CIMT in healthy early menopausal women. Neither the measurements nor the trends were statistically significant.

Results from the Danish Osteoporosis Prevention Study appeared favorable for HT but are weakened by study design issues.

This month, the US Preventive Services Task Force concluded that HT should not be used for prevention of chronic conditions.

Margery Gass, MD, NCMP, is executive director of The North American Menopause Society; Editor, of the Menopause: The Journal of The North American Menopause Society; consultant at Cleveland Clinic Center for Specialized Women’s Health; and clinical professor at Case Western Reserve University School of Medicine. She can be reached at 5900 Landerbrook Drive, Suite 390, Mayfield Heights, OH 44124; info@menopause.org. Disclosure: Gass reports no relevant financial disclosures.