Hormone therapy for menopausal symptoms: Putting benefits and risks into perspective

,

Applied Evidence

Hormone therapy for menopausal symptoms: Putting benefits and risks into perspective

J Fam Pract. 2010 December;59(12):E1-E7

By

Michelle P. Warren, MD

Too many patients have needlessly foregone the relief provided by hormone therapy; timing of treatment can make all the difference.

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References

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3. Hoffmann M, Hammar M, Kjellgren KI, et al. Changes in women’s attitudes towards and use of hormone therapy after HERS and WHI. Maturitas. 2005;52:11-17.

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6. Maclennan AH, Broadbent JL, Lester S, et al. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 2004;(4):CD002978.-

7. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause. 2004;11:11-33.

8. Grady D, Sawaya GF. Discontinuation of postmenopausal hormone therapy. Am J Med. 2005;118:163-165.

9. Vestergaard P, Hermann AP, Stilgren L, et al. Effects of 5 years of hormonal replacement therapy on menopausal symptoms and blood pressure—a randomised controlled study. Maturitas. 2003;46:123-132.

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18. Lindsay R, Gallagher JC, Kleerekoper M, et al. Bone response to treatment with lower doses of conjugated estrogens with and without medroxyprogesterone acetate in early postmenopausal women. Osteoporos Int. 2005;16:372-379.

19. 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.

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21. Naessen T, Lindmark B, Lagerstrom C, et al. Early postmenopausal hormone therapy improves postural balance. Menopause. 2007;14:14-19.

22. Jenkins MR, Sikon AL. Update on nonhormonal approaches to menopausal management. Cleve Clin J Med. 2008;75(suppl 4):S17-S24.

23. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17:25-54.

24. Ferrara A, Quesenberry CP, Karter AJ, et al. Current use of unopposed estrogen and estrogen plus progestin and the risk of acute myocardial infarction among women with diabetes: the Northern California Kaiser Permanente Diabetes Registry, 1995-1998. Circulation. 2003;107:43-48.

25. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933-941.

26. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med. 2006;166:357-365.

27. Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation. 2006;113:2425-2434.

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

29. Hernán MA, Alonso A, Logan R, et al. Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Epidemiology. 2008;19:766-779.

30. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477.

31. Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591-2602.

32. Vickers MR, Maclennan AH, Lawton B, et al. Main morbidities recorded in the women’s international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ. 2007;335:239.-

33. Mares P, Chevallier T, Micheletti MC, et al. Coronary heart disease and HRT in France: MISSION study prospective phase results. Gynecol Endocrinol. 2008;24:696-700.

34. Salpeter SR, Walsh JM, Greyber E, et al. Brief report: coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med. 2006;21:363-366.

35. Brownley KA, Hinderliter AL, West SG, et al. Cardiovascular effects of 6 months of hormone replacement therapy versus placebo: differences associated with years since menopause. Am J Obstet Gynecol. 2004;190:1052-1058.

36. Tannen RL, Weiner MG, Xie D, et al. Estrogen affects postmenopausal women differently than estrogen plus progestin replacement therapy. Hum Reprod. 2007;22:1769-1777.

37. Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med. 2006;166:772-780.

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39. McLaren J, Barnhart K. Hormone therapy and venous thromboembolism in menopausal women. Menopausal Med. 2008;16(4):S1-S7.

40. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;288:49-57.

41. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115:840-845.

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43. 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.

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PRACTICE RECOMMENDATION

• After assessing an individual’s benefit-risk profile, consider prescribing estrogen therapy (ET) or combined estrogen/progestin therapy (EPT) for management of vasomotor and vaginal symptoms of menopause (vaginal ET for local symptoms only). A

• Use the lowest effective doses of ET and EPT, as they may be better tolerated and have a more favorable benefit–risk ratio compared with standard doses. A

• Do not use hormone therapy for coronary protection A, although initiation by women ages 50 to 59 years or by those within 10 years of menopause may reduce cardiovascular risk. B

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

Findings from the Women’s Health Initiative (WHI) and the Heart and Estrogen/progestin Replacement Study^1,2 have left physicians and patients confused about the risks and benefits of hormone therapy (HT) and have dramatically affected prescription patterns.³ After the WHI trial findings were published in 2002,¹ use of HT declined dramatically; many women discontinued therapy or switched to lower doses, while others turned to alternate therapies.⁴ This, despite long-standing evidence that HT administered as estrogen alone (ET; for hysterectomized women) or in combination with progestin (EPT; for nonhysterectomized women) effectively controls menopausal symptoms—hot flashes, vaginal atrophy, insomnia, and sexual problems.⁵

When interpreting results of recent clinical trials, it is important to consider how closely the trial subjects resemble patients in your practice. Patients in HT clinical studies may range from younger women who are newly menopausal to older women who experienced menopause decades ago. Women also have differing risk factors that determine whether HT is appropriate treatment.

Recent reanalyses of WHI data and other studies, as well as new guidelines from the North American Menopause Society (NAMS), have helped to clarify the benefit–risk profile of HT according to patient characteristics. This article places clinical trial evidence in perspective and explains how you can evaluate the benefit–risk profile of HT for individuals.

What are the benefits of HT?

The primary indication for HT is treatment of vasomotor symptoms, which are common at the time of menopause and can diminish quality of life.⁵ The efficacy of HT in alleviating these symptoms is well established.⁶ Hot flash rates are highest in women during the first 2 years postmenopause,⁷ and most women use HT for up to 2 years.⁸ A study of women who had recently become postmenopausal (45-58 years of age) showed a significant reduction in vasomotor symptoms over 5 years with ET/EPT.⁹

Both oral and vaginal ET effectively relieve vaginal dryness.^5,10 A meta-analysis of 10 clinical trials showed that low-dose vaginal ET was as effective as systemic ET in providing relief of the signs and symptoms of urogenital atrophy.¹¹

Nonhormonal treatments are also sometimes prescribed off label to treat vasomotor symptoms for women who cannot or choose not to use estrogens. Such agents include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, clonidine, and gabapentin.

A meta-analysis found that these treatments were more effective than placebo in reducing hot flashes in postmenopausal women, but the magnitude of symptom relief with these drugs has been less than that observed with estrogens.¹² In another study, off-label use of antidepressants greatly attenuated hot flashes for some patients.¹³

NAMS recommends that women with moderate-to-severe menopause-related hot flashes who have concerns with, or contraindications to, estrogen-containing treatments, consider other treatments, such as SSRIs or gabapentin;⁷ however, high-quality studies evaluating these therapies in women with moderate-to-severe hot flashes are lacking.¹²

Phytoestrogens such as soy compounds and black cohosh may be helpful, although results have been variable in clinical trials.¹⁴ Common adverse events associated with black cohosh treatment include gastrointestinal complaints and rashes. There have been rare reports of liver toxicity, suggesting the need for further investigation.¹⁵

Protecting bone mass density and reducing risk of fractures
Estrogen therapy. In the WHI study, ET reduced the rates of hip fractures (P=.01), clinical vertebral fractures (P=.02), and total osteoporotic fractures (P<.001).¹⁶ The reduced risk was not affected by patient age.¹⁷ The randomized Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) study showed protection against early bone loss with ET vs placebo. After 2 years of follow-up, 55% of placebo-treated patients exhibited >2% loss of spine bone-mass density, compared with just 7% of women using ET (0.625 mg/d).¹⁸

FAST TRACK

A meta-analysis found that hormone therapy’s fracture prevention benefits were particularly marked in women younger than 60 years.

Estrogen-progestin therapy. The WHI study^1,19 confirmed the reduced risk of osteoporotic fractures with EPT seen in previous clinical studies, and the Women’s HOPE study¹⁸ confirmed EPT’s protective effect against bone loss. In a meta-analysis of HT studies (most of which used EPT), the benefits associated with HT in fracture prevention were particularly marked in women younger than 60 years,²⁰ although no effect of age or time since menopause was observed in the WHI study.¹⁹ Initiation of EPT soon after menopause has been shown to improve postural balance to levels seen in premenopausal women, which may contribute to protection against fracture.²¹