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After the Women’s Health Initiative: Where are we now?

Elyse J. Watkins, DHSc, PA-C; Sheri Lim, DO

Fifteen years have passed since the preliminary results of the Women’s Health Initiative (WHI) upended the hormone replacement recommendations for menopausal symptom management. PAs in primary care and women’s health are at the forefront of recognizing and providing care for women with both vasomotor and vaginal complaints attributed to either natural or surgical menopause. Understanding the history and continued challenges with hormone replacement therapy is important.

In 1991, the National Institutes of Health (NIH) launched the landmark WHI to assess quality of life and major causes of death and disability in postmenopausal women.1 The study was designed to specifically address cardiovascular disease, osteoporosis, colorectal and breast cancer, and the role of hormone therapy in the prevention of these diseases. The three key components were a double-blind, placebo-controlled randomized controlled clinical trial, a community prevention study, and an observational study.

The clinical trial, which enrolled more than 68,000 women ages 50 to 79 years, had three arms: hormone therapy with conjugated equine estrogen and/or medroxyprogesterone acetate, dietary modifications, and calcium/vitamin D supplementation. Women had the option of enrolling in one or all three study arms.1

The community prevention study specifically addressed community-based healthful behavior modification strategies at 11 CDC-funded university-based prevention research centers across the country. It was designed to assess behavior change and disease prevention predominantly among black women.1

The observational study was offered to women who were ineligible for the clinical trial. This study included almost 94,000 women and sought to identify risk factors and biologic markers for disease. The study gave the researchers a population to compare with the clinical trial findings and let them further stratify the population by sociodemographics.1

The clinical trial
Women without a uterus were given either conjugated equine estrogen 0.625 mg every day or a placebo. Women with a uterus were given the same estrogen plus medroxyprogesterone acetate 2.5 mg every day or a placebo. In 2002, the NIH stopped the estrogen plus progestin arm of the study due to concerns about safety. Women taking conjugated equine estrogen and medroxyprogesterone acetate had an increased risk of myocardial events, cerebrovascular events, peripheral thrombotic events, breast cancer, and dementia. In early 2004, the NIH stopped the estrogen without progestin arm of the study due to safety concerns. Women taking conjugated equine estrogens had significantly higher rates of cerebrovascular events and peripheral thrombotic events. However, women taking estrogen had a decreased risk of fracture, but a negligible effect on colorectal or breast cancer.

The fallout
When the findings of the study were released to the public, many PAs and physicians were met with angry and confused patients. Many women abruptly stopped their hormone therapy. Some of us who were working in women’s health asked our office staff to identify all patients on hormone therapy and requested that they come in for an appointment to discuss stopping therapy. The pharmaceutical salespeople representing the estrogen used in the clinical trial were scrambling to maintain a sense of order and actively engaging in damage control. The effects of this pivotal moment in women’s health are still being felt by many prescribers and patients today with continued confusion of the treatment of menopausal symptoms and the role of hormone therapy.

Jewitt and colleagues quantified prescribing patterns after the WHI.2 They analyzed data regarding estrogen plus progestin use from the National Health and Nutrition Examination Survey and the National Prescription Audit 1970-2003. The authors found that estrogen and progestin use tripled in the 1980s compared with the 1970s. Hormone therapy use among women ages 45 to 64 years peaked in 1999 at almost 14%. However, after the WHI, use of hormone therapy in this age group declined to 2.7%. These statistics illustrate the effect of the WHI on hormone therapy prescribing practices across the United States.

Where are we now?
In 2016, deVilliers and colleagues summarized updated guidelines from a 2013 Global Consensus on Menopausal Hormone Therapy paper written by several international menopause and osteoporosis professional organizations.3 This new guideline summarizes the current state of the evidence and offers prescribers a concise guide to hormone therapy. It also allows providers to relay current, evidence-based information to their patients so that they can make informed decisions about whether to use hormone therapy.

Summary of the evidence
The consensus is that the benefits of estrogen therapy are likely to outweigh risks if estrogen therapy is initiated within 10 years of menopause or by age 60 years.4-6 However, the addition of a progestin to an estrogen regimen reveals a less robust benefit.3 A progestin is required in a women with an intact uterus if she is to take oral or transdermal estrogens to decrease the risk of endometrial hyperplasia. Data indicate that women who take estrogen and progestin in a combined hormone regimen have a statistically significant increased risk for breast cancer and thromboembolic events. Use of estrogen alone does not increase the overall risk for breast cancer, but the addition of medroxyprogesterone (the progestin used in the WHI), increases the overall risk, independent of age at initiation of hormone therapy. An increased risk for the development of cardiovascular disease in combined regimens was not statistically significant.7 Women with a lower baseline risk of cardiovascular disease also appear to benefit more from hormone therapy.5 Women who have risk factors for heart disease, thrombotic events, and breast cancer must be assessed individually with careful attention paid to modifiable risk factors and patient expectations.

Treatment strategies
Healthcare providers are advised to use the lowest dose to achieve maximal effectiveness in patients opting to use hormone therapy, and to use FDA-approved products that have undergone rigorous safety and efficacy testing. As such, individually compounded hormone regimens, including those that use micronized progesterone and/or estradiol, are not recommended due to concerns about potency, purity, and variability in bioavailability.4 The current recommendation based upon the most recent evidence about treatment duration is to use estrogen with progestin for no more than 5 years, and estrogen alone for no more than 10 years.3 Transdermal hormone therapy may offer a lower risk of thromboembolic events, including stroke.3 Women with symptomatic vulvovaginal atrophy with little or no vasomotor symptoms should be treated with nonhormonal lubricants first. If this therapy fails to ameliorate symptoms, patients should be offered treatment with topical vaginal estrogen.7 Available vaginal agents include creams, gels, rings, and pellets. Women with a uterus who use vaginal estrogens do not require progestin therapy. Systemic estrogen for women with vulvovaginal symptoms should only be considered if vasomotor symptoms occur as well.
    

Overall quality of life, such as mood, sleep, and sexual function, may improve with hormone therapy. Estrogen may provide a benefit for early postmenopausal women experiencing depression and anxiety but antidepressant therapy is still first-line treatment for mood disorders.4-6 The antidepressants most often used are selective serotonin reuptake inhibitors and norepinephrine-serotonin reuptake inhibitors. In a study by Yaday and Volkar, gabapentin reduced menopausal hot flashes and nighttime awakenings.8

Menopausal hormone therapy is the only intervention that reduces post-menopausal hip and vertebral fractures, including in women with preexisting osteopenia. In women age 60 years and older, hormone therapy is considered second-line therapy for fracture prevention. Bisphosphonates are still first-line pharmacologic options for the prevention of osteoporotic fractures in postmenopausal women considered to be at high risk for a fracture per the National Osteoporosis Foundation guidelines.9

Cardioprotection may occur when estrogen alone is used within 10 years of menopause and among women younger than age 60 years. Data suggest that estrogen use in this population may decrease the risk of myocardial infarction and all-cause mortality but the US Preventive Services Task Force advises against using hormone therapy for cardiovascular disease prevention.3,6,10 Estrogen plus progestin in women within 10 years of menopause and younger than age 60 years reveals less compelling evidence of benefit.

Premature ovarian failure and surgical menopause
Women who undergo premature ovarian failure and surgical menopause before age 40 years have an increased risk of adverse cardiovascular events and osteoporosis.4-6 The addition of estrogen for these women has been shown to mitigate these risks. However, women with premature ovarian failure who still have a uterus will need treatment with a progestin in addition to estrogen to help prevent endometrial hyperplasia. Use of estrogen in women with premature ovarian failure has not shown an overall reduction in risk of dementia, but further studies may help elucidate this relationship. Hormone therapy for these women should be prescribed until about age 50 years, the average age of menopause. Longer duration of therapy requires individualized assessment not only of risks, but symptom severity. Patient preference and expectations must also be taken into account.

Alternatives for menopausal symptoms
Level A recommendations for prescription alternatives to hormone therapy include selective serotonin reuptake inhibitors and norepinephrine inhibitors, gabapentin, and ospemifene. Paroxetine is the only FDA-approved nonhormonal intervention indicated for relief of vasomotor symptoms. Ospemifene, an oral selective estrogen receptor modulator, is approved for postmenopausal moderate-to-severe dyspareunia but not vasomotor symptoms.4 In late 2016, the FDA approved the use of a dehydroepiandrosterone (DHEA) vaginal suppository for menopausal dyspareunia due to vaginal and/or vulvar atrophy.11

All women should be counseled with respect to achieving or maintaining a healthful weight, obtaining adequate exercise, stopping tobacco use, minimizing alcohol consumption, and preserving a positive quality of life. Some women may ask about complementary and alternative therapies, such as acupuncture and nutriceuticals, but there is no clear evidence to recommend for or against the use of these therapies.

Conclusion
Women younger than age 60 years who are within 10 years of menopause and are experiencing moderate to severe symptoms of menopause, such as hot flashes, may benefit from hormone therapy. Women desiring hormone therapy should use the lowest effective dose for the shortest duration of time to relieve symptoms. Women experiencing only vaginal symptoms should receive topical vaginal estrogen if lubricants fail to relieve symptoms.

Therapy should be individualized and consideration given to individual risk factors and expectations for quality of life. The route of administration and duration of treatment should align with the patients baseline risk assessment after a careful analysis of risk and benefit as well as patient preference. Lastly, hormone therapy should not be used solely for the prevention of chronic diseases, such as cardiovascular disease or osteoporosis.

REFERENCES

1. National Institutes of Health. Women’s health initiative.

2. Jewitt PI, Gangnon RE, Trentham-Dietz A, Sprague BL. Trends of postmenopausal estrogen plus progestin prevalence in the United States between 1970 and 2010. Obstet and Gynecol. 2014;124(4): 727-733.

3. de Villiers TJ, Hall JE, Pinkerton JV, et al. Revised global consensus statement on menopausal hormone therapy. Climacteric. 2016;19(4):313-315.
     

4. American College of Obstetricians and Gynecologists. Practice Bulletin: Management of menopausal symptoms. Obstet Gynecol. 2014;123(1), 202-216.

5. Kaunitz AM, Manson JE. Management of menopausal symptoms. Obstet Gynecol. 2015;126(4): 859댴.

6. Moyer VA. US Preventive Services Task Force. Menopausal hormone therapy for the primary prevention of chronic conditions: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2013158:47-54.

7. Boardman LA. What is new in hormonal management and menopause? Best articles from the past year. Obstet Gynecol. 2014;123(3):661-663.

8. Yaday M, Volkar J. Potential role of gabapentin and extended-release gabapentin in the management of menopausal hot flashes. Int J Gen Med. 2013;6:657-664.
     

9. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014;25(10):2359-2381.

10. Nabel EG. The Women’s Health Initiative—a victory for women and their health. JAMA. 2013;310:1349-1250.

11. US Food and Drug Administration. FDA approves Intrarosa for postmenopausal women experiencing pain during sex.


Elyse J. Watkins and Sheri Lim are assistant professors at High Point (N.C.) University. The views expressed in this blog post are those of the authors and may not reflect AAPA policies.

Published: 9/18/2017 8:02:00 AM

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