The Evolving Use of Estrogen and Hormone Therapy: Practical Advice for the Practicing Clinician

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November 2011 · Vol. 23, No. 11

The Evolving Use of Estrogen and Hormone Therapy: Practical Advice for the Practicing Clinician

MODERATOR

James A. Simon, MD, CCD, NCMP, FACOG
Clinical Professor, Obstetrics and Gynecology
George Washington University
Washington, D. C.

PANELISTS

David F. Archer, MD
Director of the CONRAD Clinical Research Center
Director of the Reproductive Endocrinology and Infertility
Fellowship Program at Eastern Virginia Medical School
Norfolk, Virginia

Richard J. Santen, MD
Professor of Medicine,
Endocrinology, and Metabolism
University of Virginia
Charlottesville, Virginia

Wulf H. Utian, MD, PhD, DSc(Med), NCMP
Arthur H. Bill Professor Emeritus of Reproductive Biology
Case Western Reserve University School of Medicine Cleveland, Ohio
Chairman, Advisory Board
Rapid Medical Research
Beachwood, Ohio

Susan Wysocki, WHNP-BC, FAANP
President and CEO
National Association of Nurse Practitioners in Women’s Health
Washington, D.C.

The use of estrogen and hormone therapy (estrogen plus progestin [E + P]) in clinical practice continues to evolve as scientific findings accumulate and are disseminated through society position statements and recommendations. A group of leading women’s health-care professionals, each an expert in hormonal therapy of the menopausal woman, met to discuss how clinical practice recommendations are evolving and are applicable to everyday clinical practice.

Disseminating and Adopting Practice Recommendations

What is the value of position statements to the clinician? How do they help clinicians make treatment decisions regarding estrogen and E + P therapy? How can they be made more useful?

Position statements fail to elicit change because they are not easily interpreted or patient-specific. “We’ve been putting out scholarly documents people don’t have time to read,” said Dr Utian. “There is too much minutiae for the average practitioner to successfully integrate recommendations into their practice,” added Dr Archer.

“It’s all about the clinical pearl. The guidelines contain a lot of information. Perhaps the recommendations should be packaged in a way that is simple, focused, and can be pulled together to make treatment decisions,” suggested Ms Wysocki. “Also, simple methods of assessing patient risk of heart disease, breast cancer, and bone loss are needed,” said Dr Archer.

The sensitivity of current quality of life instruments substantiates a definite improvement in quality of life with use of hormone therapy. —David F. Archer, MD

Impact of the Women’s Health Initiative (WHI) on Practice Patterns

Prior to the 2002 early termination of the E + P treatment arm of the WHI,¹ physicians in the United States prescribed hormone therapy for the prevention of osteoporosis, and to a lesser degree, the prevention of heart disease, in addition to prescribing it as first-line treatment for common menopausal symptoms. However, following the preliminary WHI results, guidelines were amended to recommend against E + P therapy for prevention of chronic conditions and intense media attention caused many women to discontinue treatment without counseling by a knowledgeable healthcare professional.

Analysis of survey data from the IMS Health National Disease and Therapeutic Index from 2001 to 2009 found that systemic hormone therapy declined each year from 2002 to 2009. While use of lower-dose and vaginal products showed modest increases, standard-dose (equivalent to ≥0.625 mg conjugated equine estrogen [CEE]) oral hormone therapy remained the dominant formulation. Overall, use of oral E + P declined 76% from 2001 to 2009 and oral estrogen-only therapy decreased 62%. Compared with physicians in other specialties, obstetrician/gynecologists changed their practice patterns to a lesser degree by having a smaller decline in reported hormone therapy visits.²

What bothered me most about how practice changed after the WHI is that we took something we knew a lot about—the prevention of bone loss in early menopause with estrogen—to something we knew very little about: using bisphosphonates in a 55-year-old woman. —Susan Wysocki, WHNP-BC, FAANP

In a 2006 survey of obstetrician/gynecologists (n=286), 84.7% reported their patients were apprehensive about hormone therapy and 63.6% reported many of their patients were choosing to stop hormone therapy.³ In a similar 2003 survey (n=644), about one-third (29.6%) reported they would be “somewhat less likely” and 9.5x% reported they would be “dramatically less likely” to prescribe hormone therapy as a result of the WHI findings. More than half of physicians (53.3%) reported they were unlikely to change their prescribing practices. Physicians who had been practicing longer were more positive about the benefits of hormone therapy and more skeptical about the WHI findings.⁴

In a small Canadian study of practice patterns following surgical menopause (hysterectomy and bilateral salpingo-oophorectomy) from December 1, 2006, to November 30, 2007 (n=70; mean age, 44.3 [± 5.2] years), only 40% of the women were started on estrogen therapy immediately after surgery and only 33% were still taking estrogen at the time of the interview (mean time since surgery, 10.2 [±3.8] months). Of those taking estrogen, 52% were on transdermal estrogen and 70% were on a dose equivalent to 0.625 mg CEE.⁵ In studies completed before the WHI, estrogen-use rates of nearly 90% were reported in women after bilateral oophorectomy.^6,7 Following bilateral oophorectomy in premenopausal women, the onset of menopausal symptoms is immediate and the symptoms are severe—hence the need for a prompt decision on the use of estrogen therapy.⁸ Women going through early menopause, due either to surgery or to natural causes, also face an increased risk for long-term health consequences such as osteoporosis, cardiovascular disease, Parkinson’s disease, and dementia.^5,9,10 Because of the association of early menopause with severe symptoms and with long-term adverse health consequences, patient education prior to surgery or at discharge may help to improve estrogen use and symptom management.⁵ It is important to note that practice patterns for estrogen-alone therapy changed even though the 2002 WHI findings were for estrogen plus progestin therapy and not applicable to women who were taking only estrogen or who had premature menopause.

WHI OVERVIEW^1,11,12,13

The randomized portion of the WHI evaluated the effects of postmenopausal hormone therapy on coronary heart disease, hip fracture, breast cancer, colorectal cancer, endometrial cancer, stroke, pulmonary embolism, and death from other causes. Interventions included E + P for women with a uterus and estrogen-alone for women without a uterus. Treatment was daily CEE (0.625 mg) with or without medroxyprogesterone (2.5 mg) or placebo. Subjects were recruited between September 1993 and December 1998. Although the planned study duration was 8.5 years, the E + P study arm was terminated approximately 3 years early because of increased risks of breast cancer, myocardial infarction, stroke, and deep vein thrombosis (DVT); the estrogen-only trial was stopped 1 year early because of increased risk of stroke and lack of effect on incidence of coronary heart disease.

SAMPLE CHARACTERISTICS^1,11,13

Mean age at enrollment: 63.3 years; range: 50 to 79 years

Only 10% of subjects were 50 to 54 years old
Only 16% of subjects were less than 5 years past the onset of menopause

36% had hypertension
49% were current or past smokers
34% had a body mass index ≥30

Subjects did not have severe postmenopausal symptoms

Practice Recommendations

Professional society clinical practice position statements aim to deliver a translation of science into clinical conclusions and recommendations.

History of Recent Recommendations

The first North American Menopause Society position statement was crafted as a rapid response to the 2002 WHI findings. Although one organization and one clinical study should not define clinical practice, the WHI had a major impact on position statements due to its study design (randomized clinical trial), large sample size, and the publicity around the release of the initial findings. The subsequent publications from the WHI continue to influence practice. “As the position statements evolve, WHI results are still important, but not the [overriding] factor—and certainly, because it was never really a study about menopausal symptoms,” said Dr Utian. Because the WHI was designed to evaluate hormone therapy in an older population (mean age 63.3 years; range 50 to 79 years), its findings cannot be generalized to symptomatic women in early menopause.¹¹

We’re really talking about treating symptomatic women who are going through menopause. We don’t have a lot of randomized control trial data on that. Women between the ages of 50 and 55 are the group the practitioner is going to see and figure out whether to treat with hormone therapy or not. —Richard J. Santen, MD

Treating Symptoms of Menopause

The debate is not about hot flashes and vaginal atrophy. Hormone therapy continues to be recommended for short-term use in the relief of menopausal symptoms. “If we look at the current clinical evidence, including the latest papers out of the WHI, there’s very little contraindication to treating otherwise healthy women with menopausal symptoms,” commented Dr Utian.

Hormone Therapy as Prevention

Clinicians responsible for the care of postmenopausal women must also manage the many chronic illnesses associated with menopause, including cardiovascular disease, dementia, osteoporosis-related fractures, and cancer. The use of estrogen has been associated with disease prevention only when therapy has been initiated during early menopause. Primary benefits include prevention of vaginal atrophy, fractures, and diabetes.^14,15 Because data from the WHI involved older women, the benefits of hormone therapy in women starting shortly after menopause are based on lower levels of evidence.¹⁴

If a patient has risk factors for DVT or cardiovascular disease, you might be better off starting them on transdermal estrogen. For patients who have no significant risk factors, it makes no difference—it’s patient preference. —Wulf H. Utian, MD

Starting Therapy Regimens

The average estrogen (CEE) dose prescribed is 0.625 mg; however, it used to be higher. So what should the starting dose be? “The safest way to go, without question, is to start with the lowest available dose [0.3 mg for oral preparations],” recommended Dr Utian. “But many physicians aren’t doing it—mainly because they have been trained in the past and are comfortable prescribing 0.625 mg,” noted Dr Archer.

Premenopausal women who have had a hysterectomy and oophorectomy are a separate population requiring a completely different set of guidelines. —Wulf H. Utian, MD

Current guidelines suggest use of hormone therapy with the lowest effective dose and for the shortest possible duration.¹⁴ What is the shortest period of time? “My problem with shortest period of time is I have a tremendous number of patients with premature ovarian failure who have hot flashes and night sweats. For them, the shortest period of time and the lowest dose are not the same as if we were talking about a 50-year-old patient,” said Dr Simon. Treatment needs to be individualized. “And the decision needs to go back to risk factors,” added Dr Utian.

When patients are asked “Would you like me to make the decision for you, or would you like me to present the data in a very objective way so that you can make the decision?” I find that most prefer to make their own decisions. —Richard J. Santen, MD

What are the deal-breakers for the patient/clinician interaction as it relates to choosing a therapeutic regimen for hormone therapy? “If the patient has a close relative with breast cancer, that’s often a deal-breaker—even if a family history of breast cancer in not a contraindication,” said Dr Santen. However, every patient is different, and clinical recommendations have to be taken in context.

“Likewise many women with an aging parent or relative with Alzheimer’s disease or another form of dementia are often predisposed to the use of hormone therapy because they perceive a benefit for prevention of such catastrophic illnesses,” said Dr Simon.

Class Effect

According to a position statement from the International Menopause Society, “…the term ‘class effect’ is confusing and inappropriate.”¹⁶ “I agree completely with the [Society] statement ‘[Hormone therapy] includes a wide range of hormonal products and routes of administration, with potentially different risks and benefits,”¹⁶ said Dr Utian. However, in the absence of head-to-head, randomized controlled trials of various estrogens and progestogens, clinicians have little choice but to generalize trial results. On a theoretical basis, there are likely to be differences within each hormonal family such as relative compound potency, androgenicity, glucocorticoid effects, and bioavailability.¹⁷

Breast Cancer Risks

The risk of breast cancer observed in the WHI differed between the E + P study and the estrogen-only study. For E + P compared with placebo, E + P was associated with greater breast cancer incidence, node-positive cancers, and breast cancer mortality (mean follow-up 11 [SD, 2.7] years).¹⁸ “There were 24% lymph nodes involved [with E + P] vs 16% [with placebo]; that’s a worrisome finding,” commented Dr Santen. Because de novo tumors require several years to reach the threshold of detection, the effect of estrogen plus a progestin in the WHI study was likely to stimulate the more rapid growth of pre-existing tumors than cause new tumors.¹⁹ [Santen, 2008]

Many women want to know if their clinician would prescribe hormone therapy to a significant woman in their life or, if the clinician is a woman, whether she takes it herself. The decision is made on so many factors. However, knowing the clinician believes that the therapy is safe for a loved one often helps allay some fear. —Susan Wysocki, WHNP-BC, FAANP

Health outcomes were more favorable in the WHI estrogen-only study. A statistically significant lower cumulative breast cancer incidence with estrogen-only therapy compared to placebo (0.27% vs 0.35%, respectively) was observed among postmenopausal women with prior hysterectomy (HR 0.77; P=.02). Median duration of estrogen use was 5.9 years; mean follow-up was 10.7 years.²⁰

Cardiovascular Disease Risks

For cardiovascular disease in the estrogen-only study, the overall hazard ratios (HR) were lower for women aged 50 to 59 years (HR 0.59) compared with those aged 60 to 69 years (HR 1.00) and aged 70 to 79 years (HR 1.06); P=.05 for interaction.²⁰

Quality of Life

Professional society recommendations state that hormone therapy produces an improvement in health-related quality of life (HRQoL) through decreased symptoms and sleep enhancement.^14,17 A survey completed by US and European clinicians (n=600) found that 98% agreed menopause significantly affects quality of life, 97% felt the majority/all of their patients experienced positive benefits from hormone therapy, 90% believed the benefits of hormone therapy outweigh the risks in suitable patients, and 92% would prescribe hormone therapy for themselves or their spouses and families.²¹

I think the caveat is with the current instruments that are used and their sensitivity, there is an improvement in quality of life. —David F. Archer, MD

While the WHI concluded there was no meaningful advantage of hormone therapy over placebo, the WHI did not measure the impact of hormone therapy on quality of life using validated instruments.²² For example, Brunner et al concluded there was no improvement in sexual satisfaction, yet only 1 question on this subject was asked—at baseline and 1 year.²³ In addition, women with severe menopausal symptoms were discouraged from participating in the study.²² Of the 12% of subjects who reported moderate-to-severe hot flashes, about three-quarters (76.7%) of those who took E + P had fewer hot flashes after 1 year, but so did more than half (51.7%) of the women taking placebo. “You’re treating a symptom that has a high placebo response,” commented Dr Archer. In an analysis restricted to women aged 50 to 54 years who reported moderate-to-severe vasomotor symptoms at baseline, positive effects of E + P on sleep disturbance were seen (P=.02).²³

Randomization to estrogen-only in the WHI was associated with a statistically significant but small reduction in sleep disturbance at 1 year compared with baseline. Among women aged 50 to 54 years with moderate-to-severe vasomotor symptoms reported at baseline, estrogen-only did not improve HRQoL variables at 1 year.²⁴

A physician’s practice activities are imprinted when he or she is a resident. Physicians very rarely deviate from their early training. —David F. Archer, MD

Conclusions

Professional societies issued position statements to aid clinicians in the use of hormone therapy following the release of the 2002 WHI results. However, gaps exist between practice recommendations and clinical practice. Extracting and publicizing “clinical pearls” taken from position statements may help adoption of recommendations by healthcare providers. Special attention should focus on practice habits involving dose, route of administration, and analysis of patient risk, perhaps through the use of case-based prescribing examples. Beyond treatment decisions, the foremost challenge is patient counseling, given the limited time healthcare providers have with patients. Reliable patient education may bridge the gap between popular misconceptions (eg, bioidentical hormones) and evidence-based decisions. Women with surgical menopause may be grossly undertreated as a result of misconceptions surrounding the WHI and estrogen therapy. Due to the rapid onset and severity of symptoms following surgery, treatment decisions need to be made prior to surgery or at discharge. Practice recommendations focusing on this specific population are also needed.

Disclosures

Dr Simon has served as a consultant or on the advisory boards of the following: Abbott Laboratories, Agile Therapeutics, Inc., Amgen Inc., Ascend Therapeutics, Azur Pharma, Inc., BioSante, Boehringer Ingelheim, Depomed, Inc., Fabre-Kramer, Laboratoire HRA Pharma, Meditrina Pharmaceuticals, Merck, Merrion Pharmaceuticals, NDA Partners LLC, Novo Nordisk, Novogyne, Pfizer Inc., Shionogi Inc., Slate Pharmaceuticals Inc., Teva Pharmaceutical Industries Ltd, Trovis Pharmaceuticals, LLC, Warner Chilcott, and Watson Pharmaceutical Inc. He has received grant/ research support from BioSante, Boehringer Ingelheim, EndoCeutics Inc., Novo Nordisk, Novogyne, Palatin Technologies, Teva Pharmaceutical Industries Ltd, Warner Chilcott, and Watson Pharmaceutical Inc. He has also served on the speakers bureaus of the following: Amgen Inc., Ascend Therapeutics, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, Novogyne, Teva Pharmaceutical Industries Ltd, and Warner Chilcott. Dr Archer is an industry consultant for Abbott Laboratories, Agile Therapeutics, Bayer HealthCare, CHEMO, Corcept, Merck (previously Schering-Plough/Organon) and Wyeth Laboratories (now Pfizer). He has also provided industry research support for Bayer HealthCare, Duramed, Warner Chilcott, Watson Pharmaceutical Inc., and Wyeth Laboratories (now Pfizer). Additionally, he has received direct industry lecture fees from Bayer Health-Care and Wyeth Laboratories (now Pfizer). Dr Santen is a consultant for Teva Women’s Health Inc. and on the advisory boards for Pfizer and Novo Nordisk. Dr Utian has served on advisory boards and/or as a consultant for the following: Bene Therapeutics, Hygeia (formerly Orcas Therapeutics) (chair, advisory board), Bionovo, Cleveland Clinic Foundation Innovations Center, Pharmavite (chair, menopausal health advisory board), Merck Sharp & Dohme (Merck subsidiary), Novogyne, Bayer (FSD advisory board), Lupin Pharmaceuticals, Teva Women’s Health Inc., and Pfizer Inc. Dr Wysocki has served on advisory boards for Bayer HealthCare, Teva Women’s Health Inc., Upsher-Smith, Novo Nordisk, GSK, Church and Dwight, Watson, and Azur. She has also served on the speakers bureau for Bayer HealthCare, Teva Women’s Health Inc., and Novo Nordisk.

References

1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333.