Rolnick, Sharon J PhD, MPH1; Kopher, Richard A MD2; DeFor, Terese A MS1; Kelley, Mary E BA1

From ¹HealthPartners Research Foundation, Minneapolis, MN; and ²HealthPartners, St. Paul Clinic, OB/Gyn Department, St. Paul, MN.

Received August 5, 2004; revised and accepted September 30, 2004.

This study was funded by HealthPartners Research Foundation and MERCK; HealthPartners Research Foundation initially provided funding for the study at the time of its conception and design of the questionnaire and MERCK provided monies to increase the study population and to do a more extensive follow-up.

Address correspondence to: Sharon J. Rolnick, PhD, MPH, Associate Director of Research, HealthPartners Research Foundation, P.O. Box 1524, MS 21111R, Minneapolis, MN 55440-1524. E-mail: cheri.j.rolnick@healthpartners.com

Abstract

Objective: To assess behaviors and concerns related to hormone therapy after the findings of the Women's Health Initiative (WHI).

Design: A survey was mailed to a random sample of 1,200 women identified through the pharmacy database as taking one of two estrogen + progestogen therapies (EPT) during the 6-month period before the publication of WHI findings. Questions included hormone use history, changes in usage, an assessment of symptoms, symptom changes, health behavior changes, use of alternative therapies, and demographics.

Results: The response rate was 70%, with women in their 60s and those receiving hormone therapy for 5 or more years were more likely to respond (P < 0.05). The majority had started hormones for symptom relief (69%) and expected to continue use. Many reported discontinuation (63%) or modifying their medication (18%). Half of these women stopped then restarted, the other half changed products. Women in their 50s were more likely to remain on hormones than older women (P < 0.01), and those taking ethinyl estradiol and norethindrone acetate were more likely to remain on their medication than those on conjugated estrogens (43% vs 29%, P < 0.01). Little change was reported in exercise and 19% increased their calcium intake. Patient concerns fell into five major categories: long-term effects, symptom control, breast cancer risk, bone health, and cognitive function.

Conclusions: Women seem to be heeding the warnings about hormones but remain concerned about the potential long-term sequelae and symptom control. More research is needed to identify safer approaches to symptom relief and to address the concerns expressed.

Before the highly publicized findings of the Women's Health Initiative (WHI), it was thought that estrogen + progestogen therapy (EPT) provided numerous health benefits to women. Several observational studies supported its benefits in reducing symptoms and cardiovascular health based on findings of lowered low-density lipoproteins, cholesterol, and increased levels of high density lipoproteins.1-3 In addition, EPT was found to maintain bone density 4,5 and decrease the incidence of colon cancer,6 and there was some support for the improvement of cognitive function.7,8 As a result, many providers encouraged women without contraindications to consider using hormone therapy with the onset of menopause. The focus of many providers was on issues of compliance.9-11 For the benefits to be maintained, sustained use was necessary. More recent clinical trials, however, have not confirmed the findings of the earlier observational studies. In fact, they have raised considerable doubt about the assumptions that had been used to guide health care recommendations.

Initially, researchers from the Heart and Estrogen/Progestin Replacement Study (HERS), whose participants all had a history of heart disease, found an excess of early cardiovascular events in women on EPT compared with those taking a placebo.12 Other studies also found negative outcomes for women with existing atherosclerosis.13,14 As a result of these trials, women with a history of coronary heart disease were dissuaded from starting EPT. For healthy women, however, it was believed that the benefits of hormones outweighed the risks.

The findings of the WHI trial raised new concerns for women with no history of cardiac conditions when the EPT arm of the study was stopped due to increased cardiac events and breast cancer compared with women taking the placebo.15 More recently, the ET arm was terminated, with further evidence of increased risk of stroke and no cardiac benefit.16,17 In the United States, where approximately 38% of postmenopausal women took hormones before the findings of randomized trials were available, there was considerable confusion and concern about what Fletcher and Colditz 18 called the “disquieting results.” Many articles recommended that physicians stop prescribing EPT for long-term use and not begin it for prevention of chronic conditions. Women who had started taking hormone therapy, assuming that this would be for the long-term, began reconsidering their options.

The lay press also provided wide coverage on this issue. Time magazine, in its July 2002 issue, ran a cover story revealing the “Truth about Hormones.” The article claimed that women were confused with the new, unexpected information.18 The purpose of this study, therefore, was to better understand what women had been thinking and doing in light of the new study findings and accompanying publicity. Specifically, the study surveyed women in a managed care organization about their EPT usage (maintenance or change), health behaviors, symptom control, and overall concerns.

METHODS

Subjects

Women who had been taking either ethinyl estradiol and norethindrone acetate or 0.625 mg of conjugated estrogens plus medroxyprogesterone acetate (MPA) were identified from administrative pharmacy records of a large Midwestern health maintenance organization. These agents were selected because one was used in the WHI study and the other was the second combination EPT most frequently used by women in this health plan. To be eligible for the study, women had to be aged 48 to 74 years, have received at least one dispensing for one of these two medications from January 1, 2002 through June 30, 2002, and be a current member of the health plan.

The women identified were stratified by medication based on the most recent prescription between January and June of 2002 and by duration of any hormone use. The goal was to target a stratified random sample of women considered recent users (up to 1 year), women with 1 to 5 years usage, and longer-term users (5 or more years). After stratifying on duration of use within medications, we selected a random sample of 10% using each of the medications of interest for a total of 1,200 women (1,000 women on conjugated estrogens plus MPA divided equally by strata and 200 women on ethinyl estradiol and norethindrone acetate, with 83 women in each of the 1-year and 1- to 5-year strata, and 34 who had been on any hormone for 5 or more years but were most recently taking this agent).

Patient survey

To assess health behaviors, symptom control, and overall concerns, we mailed a survey to each woman targeted for the study. The survey contained questions on hormone use history, awareness of the WHI findings, changes in medication use or health behaviors as a result of WHI findings, what influenced any changes, an assessment of symptoms or symptom changes, use of alternative therapies, and demographics.

First, a mailing was sent to 100 women to ensure that questions were clear and the answer options met the intent of the question. We modified the survey slightly, reordering some questions before sending out the remaining surveys. For both the pilot and the larger mailing, the initial survey was followed by a reminder postcard (after 2 weeks) and a replacement survey after 2 additional weeks. The study protocol and all materials were approved by the health plan Institutional Review Board.

Analysis

The Student's t test (for continuous measures) and [chi]² test (for categorical data) were used to examine whether cessation rates differed by medication, duration of use, and age in decades. We also examined changes in exercise, calcium intake, and bone mineral density testing. All analyses were performed using SAS 8.2 with P values of less than 0.05 indicating significance.

RESULTS

Response rate

Of the 1,100 women included in the large mailing, 10 had moved and we were unable to locate their new address, 2 had died, and 1 did not speak English. Of the remaining 1,087 eligible surveys, 757 were completed, for a response rate of 70%. Table 1 presents the characteristics of women who participated in the survey. There was no difference in response rate by product (69% vs 75%). However, a statistically significant difference was found based on age and duration of hormone use. Women in their 60s were more likely to respond than women in their 50s or 70s (78% vs 67%, P < 0.05) and women who had been taking hormone therapy more than 5 years were more likely to respond than shorter-term users (77% vs 67%, P < 0.01).

TABLE 1. Demographics of responders

History of hormone use

When asked why they started hormones, the single-most noted response was for symptom relief, which was cited by 69% of the women. Bone health was mentioned by 46%, followed by heart protection (31%) and general well-being (26%). The use of hormones was not a short-term expectation. Only 11% of the women claimed to expect to use it in the short-term (less than 2 years). The vast majority assumed they would continue with the medication. Over 40% claimed they initially planned to use hormones as long as they “felt okay,” 13% planned to continue until advised by their physician to stop, and another 35% did not give much thought to length of use, giving the impression they did not have a stop date in mind.

Changes in hormone use

Despite these stated expectations, based on publicity regarding the WHI findings, the majority of women reported modifying their EPT use. Only 19% reported making no changes. Sixty-three percent reported discontinuing EPT, and 18% made modifications but continued on medication. Among those who modified their use, half discontinued their regimen and then restarted, whereas the other half changed products, trying either a different oral combination or the patch. For the women who discontinued, there was a fairly even split between those who stopped immediately and totally (cold-turkey approach) and those who chose to wean off their hormones. The weaning process varied widely. Variation was found in regimens determined by both the providers and by the women themselves, with weaning taking anywhere from a few weeks to 10 months.

Younger women (less than 60 years) were more likely to remain on EPT than older women (P < 0.01), and those on conjugated estrogens plus MPA (the medication used in WHI study) were less likely to remain on hormones (29% vs 43%; P < 0.01).

When asked how they learned about the study findings, popular media surpassed both the medical community and friends and family as the source of this information. Television and magazines were cited by 70% of the women, compared with the 30% who cited learning about the risks from doctors, nurses, family, or friends.

Changes in health behaviors

There were no differences in frequency of exercise by age, duration of use, or by product. Approximately one third of the women reported to exercise (for at least 20 minutes) four or more times per week, 36% exercised two to three times per week, and 15% exercised once weekly. Of these women, 11% reported an increase in exercise after the WHI study, 75% reported taking calcium, of whom 19% reported to have initiated or increased their calcium intake after reading study findings, 3% reported sporadic calcium use, and 19% reported use of 10 or more years. When asked about use of alternative therapies, 11% reported initiation after the WHI. Nearly all products mentioned were taken to alleviate menopausal symptoms. Of those reporting use of alternative products, 26% listed soy products, 20% herbal supplements, 18% black cohosh (Cimicifuga racemosa), 17% Estroven, and 10% vitamins (most often vitamin E). Few of the women reported much symptom relief from the products tried. Table 2 presents an overview of reported symptoms and severity.

TABLE 2. Patient reported symptoms and severity since terminating Hormone therapy

Bone density testing

We also inquired about bone density testing to ascertain how many had been tested and if they knew the results of the testing; Table 3 offers a breakdown. Forty-three percent of the women had been tested with normal results; however, 17% reported results of osteopenia and 4% osteoporosis.

TABLE 3. Bone mineral density testing

We also had an open-ended question about the concerns of patients. There were numerous responses that fell into five primary topic areas: long-term effects of being on EPT, concerns about symptom control, breast cancer, bone health, and concerns about cognitive function.

DISCUSSION

The health implications surrounding hormones changed dramatically with the results of WHI. Before the results of this randomized trial were available, the observational findings had been strong and consistent. Estrogen alone and in combination with progesterone had a positive impact on a number of risk factors for heart disease including artherogenesis,19,20 lipid metabolism,2,21 vascular activity,22 and abnormal carbohydrate metabolism.23 In addition, hormones showed great benefit for maintaining bone health.24,25 More recently the benefits of bone health have been reiterated.26-28 Furthermore, whereas evidence was inconclusive, some encouraging information was noted in studies on Alzheimer's disease.29-31

With the evidence from randomized trials, most prior beliefs have been challenged. The protective aspects for heart health were nullified. The HERS study found a 50% increase in cardiac events in the first year of hormone therapy use among women with established coronary heart disease.12 This same trend was duplicated in WHI with increased risk found for coronary heart disease (relative risk [RR] 1.29, 95% confidence interval [CI] 1.02-1.63), breast cancer (RR 1.26, 95% CI 1.00-1.59), stroke (RR 1.41, 95% CI 1.07-1.85), and pulmonary embolism (RR 2.13, 95% CI 1.30-3.25). Although there were protective effects against hip fracture (RR 0.66, 95% CI 0.45-0.98) and colorectal cancer (RR 0.63, 95% CI 0.43-0.92), these overall risks were considered to outweigh the benefits.15

Additional research has even been more damaging to the promotion of hormone use. More recent work on cognitive function has shown no benefit,32-38 there has been a reiteration of lack of evidence of cardiac protection,44-47 reports of increased risk of stroke,43 and links to urinary incontinence,48 and the results on quality of life have been mixed.39-42 Thus, the new recommendations encourage women not to use hormones. For those with severe symptoms, women are encouraged to take the lowest dose possible for the shortest duration possible.36,49,50

Although some question the “solid, definitive and unequivocal” adjectives attributed to the results of WHI,51 rates of hormone use in the United States have been reported to have declined.52,53 The women in this study also seem to be heeding the warnings. Over half of the women discontinued their hormone usage, and for the additional 9% who remain on medication, the dose and delivery method have been modified. Only 19% reported to have remained on their initial regimen. These women tended to be younger (less than 60 years, P < 0.01) and taking ethinyl estradiol and norethindrone acetate (P < 0.01), the medication not used in WHI. Although less likely to make changes in lifestyle behaviors other than medication usage, all reported change was in the desired direction, ie, of increased exercise and calcium intake.

This study has several limitations. First, the women in this survey are from only one health plan and may not be totally representative of all former EPT users. However, the use of a survey, rather than only automated data on patterns of discontinuation, enabled us to obtain more information from the respondents and the concerns expressed resonate beyond this singular population. In addition, those who responded were more likely to be women in their 60s and those with longer durations of use (more than 5 years); thus, they may have been more likely to mention their concerns about long-term use. Because younger women were also more likely to remain on hormone therapy (P = 0.01), the 63% quit rate reported may have been lower, had more younger women responded. Still, women remain concerned about the long-term effects on health and about maintaining bone health, having valued the protective nature of EPT. Many are also struggling with symptom control. Although symptoms resolve in many women, this is not true for all.54 Hot flashes are inconvenient and often embarrassing, and sleep disturbance can be debilitating. To date, no alternative therapy has been cited in the literature or reported by the women surveyed to be as successful as estrogen for symptom relief.55,56 In a recent article on decision analysis regarding hormone use, Kim and Kwok 57 conclude that for women with menopause-related symptoms, the benefits in quality of life may exceed the risks.

CONCLUSIONS

Women seem to be heeding the warnings about hormone therapy, but remain concerned about the potential long-term sequelae and symptom control. More research is needed to identify safer approaches to symptom relief and to address the concerns expressed.

REFERENCES

1. Jneid H, Thacker HL. Coronary artery disease in women: different, often undertreated. Cleve Clin J Med 2001;68:441-448. Bibliographic Links Document Delivery Library Holdings [Context Link]

2. Binder EF, Williams DB, Schechtman KB, Jeffe DB, Kohrt WM. Effects of hormone replacement therapy on serum lipids in elderly women. a randomized, placebo-controlled trial. Ann Intern Med 2001;134(9 Pt 1):754-760. [Context Link]

3. Davidson MH, Maki KC, Marx P, et al. Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women. Arch Intern Med 2000;160:3315-3325. Bibliographic Links Document Delivery Library Holdings [Context Link]

4. Kamel HK, Perry HM III, Morley JE. Hormone replacement therapy and fractures in older adults. J Am Geriatr Soc 2001;49:179-187. Bibliographic Links Document Delivery Library Holdings [Context Link]

5. Torgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA 2001;285:2891-2897. Bibliographic Links Document Delivery Library Holdings [Context Link]

6. Grodstein F, Newcomb PA, Stampfer MJ. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 1999;106:574-582. Bibliographic Links Document Delivery Library Holdings [Context Link]

7. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 2001;285:1489-1499. Bibliographic Links Document Delivery Library Holdings [Context Link]

8. Shaywitz SE, Shaywitz BA, Pugh KR, et al. Effect of estrogen on brain activation patterns in postmenopausal women during working memory tasks. JAMA 1999;281:1197-1202. Bibliographic Links Document Delivery Library Holdings [Context Link]

9. Eiken P, Kolthoff N. Compliance with long-term oral hormonal replacement therapy. Maturitas 1995;22:97-103. Bibliographic Links Document Delivery Library Holdings [Context Link]

10. Jeffe DB, Freiman M, Fisher EB Jr. Women's reasons for using postmenopausal hormone replacement therapy: preventive medicine or therapeutic aid? Menopause 1996;3:106-116. Bibliographic Links Document Delivery Library Holdings [Context Link]

11. Andrews WC. Keynote Address: The North American Menopause Society Annual Meeting 1994. Menopause 1995;2:59-65. Bibliographic Links Document Delivery Library Holdings [Context Link]

12. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-613. Bibliographic Links Document Delivery Library Holdings [Context Link]

13. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-529. Full Text Bibliographic Links Document Delivery Library Holdings [Context Link]

14. Mosca L, Collins P, Herrington DM, et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104:499-503. Ovid Full Text Bibliographic Links Document Delivery Library Holdings [Context Link]

15. 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;288:321-333. Bibliographic Links Document Delivery Library Holdings [Context Link]

16. Women's Health Initiative. Questions and answers about the Estrogen-Alone Study. Available at: http://www.nhlbi.nih.gov /whi/e-a_faq.htm. Accessed March 9, 2004. [Context Link]

17. Alving B. NIH asks participants in Women's Health Initiative Estrogen-Alone Study to stop study pills, begin follow-up phase. NIH Available at: http://www.nhlbi.nih.gov /new/press/04-03-02.htm. Accessed March 9, 2004. [Context Link]

18. Gorman C, Park A. The truth about hormones. Time. July 22, 2002;Health and medicine section. [Context Link]

19. Adams MR, Kaplan JR, Manuck SB, et al. Inhibition of coronary artery atherosclerosis by 17ß-estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis 1990;10:1051-1057. Bibliographic Links Document Delivery Library Holdings [Context Link]

20. Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:217-221. Ovid Full Text Bibliographic Links Document Delivery Library Holdings [Context Link]

21. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1995;273:199-208. Document Delivery Library Holdings [Context Link]

22. Williams JK, Honore EK, Washburn SA, Clarkson TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24:1757-1761. Bibliographic Links Document Delivery Library Holdings [Context Link]

23. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses' health study. N Engl J Med 1991;325:756-762. Bibliographic Links Document Delivery Library Holdings [Context Link]

24. Paganini-Hill A, Ross RK, Gerkins VR, Henderson BE, Arthur M, Mack TM. Menopausal estrogen therapy and hip fractures. Ann Intern Med 1981;95:28-31. Bibliographic Links Document Delivery Library Holdings [Context Link]

25. Ettinger B, Genant HK, Cann CE. Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med 1985;102:319-324. Bibliographic Links Document Delivery Library Holdings [Context Link]

26. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003;290:1729-1738. Bibliographic Links Document Delivery Library Holdings [Context Link]

27. Greenspan SL, Resnick NM, Parker RA. Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial. JAMA 2003;289:2525-2533. Bibliographic Links Document Delivery Library Holdings [Context Link]

28. Barrett-Connor E, Wehren LE, Siris ES, et al. Recency and duration of postmenopausal hormone therapy: effects on bone mineral density and fracture risk in the National Osteoporosis Risk Assessment (NORA) study. Menopause 2003;10:412-419. Ovid Full Text Bibliographic Links Document Delivery Library Holdings [Context Link]

29. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med 1996;156:2213-2217. Bibliographic Links Document Delivery Library Holdings [Context Link]

30. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 1997;48:1517-1521. Ovid Full Text Bibliographic Links Document Delivery Library Holdings [Context Link]

31. Ohkura T, Isse K, Akazawa K, Hamamoto M, Yaoi Y, Hagino N. Low-dose estrogen replacement therapy for Alzheimer disease in women. Menopause 1994;1:125-130. Bibliographic Links Document Delivery Library Holdings [Context Link]

32. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-2662. Bibliographic Links Document Delivery Library Holdings [Context Link]

33. Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2663-2672. Bibliographic Links Document Delivery Library Holdings [Context Link]

34. Mitchell JL, Cruickshanks KJ, Klein BE, Palta M, Nondahl DM. Postmenopausal hormone therapy and its association with cognitive impairment. Arch Intern Med 2003;163:2485-2490. Bibliographic Links Document Delivery Library Holdings [Context Link]

35. Galen Buckwalter J, Crooks VC, Robins SB, Petitti DB. Hormone use and cognitive performance in women of advanced age. J Am Geriatr Soc 2004;52:182-186. Bibliographic Links Document Delivery Library Holdings