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

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Applied Evidence

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

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

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References

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10. North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause. 2007;14:357-369.

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12. Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295:2057-2071.

13. Cheema D, Coomarasamy A, El-Toukhy T. Non-hormonal therapy of post-menopausal vasomotor symptoms: a structured evidence-based review. Arch Gynecol Obstet. 2007;276:463-469.

14. Whelan AM, Jurgens TM, Bowles SK. Natural health products in the prevention and treatment of osteoporosis: systematic review of randomized controlled trials. Ann Pharmacother. 2006;40:836-849.

15. Borrelli F, Ernst E. Black cohosh (Cimicifuga racemosa): a systematic review of adverse events. Am J Obstet Gynecol. 2008;199:455-466.

16. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.

17. Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women’s health initiative randomized trial. J Bone Miner Res. 2006;21:817-828.

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.

20. Torgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA. 2001;285:2891-2897.

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.

38. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.

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.

42. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419-427.

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.

44. Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med. 1991;151:67-72.

45. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295:1647-1657.

46. Ross RK, Paganini-Hill A, Wan PC, et al. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92:328-332.

47. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006;55:103-115.

48. Goodman N, Goldzieher J, Ayala C. Critique of the report from the Writing Group of the WHI. Menopausal Med. 2003;10(4):1-4.

49. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670-1674.

50. Chlebowski RT, Anderson GL, Gass M, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304:1684-1692.

51. Collins JA, Blake JM, Crosignani PG. Breast cancer risk with postmenopausal hormonal treatment. Hum Reprod Update. 2005;11:545-560.

52. Singletary SE. Rating the risk factors for breast cancer. Ann Surg. 2003;237:474-482.

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57. Warren MP. A comparative review of the risks and benefits of hormone replacement therapy regimens. Am J Obstet Gynecol. 2004;190:1141-1167.

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Thromboembolism: Patient age makes a difference
Estrogen therapy. Observational data from the UK General Practice Research Database, which included women ages 55 to 79 years, demonstrated a reduced risk of deep vein thrombosis (P=.008) and a trend toward reduced risk of venous thromboembolism (VTE; P=.057) among users of ET.³⁶ However, the ET arm of the WHI showed an early increased risk of venous thrombosis, particularly within the first 2 years of use.³⁷ The absolute incidence of VTE (including deep vein thrombosis and pulmonary embolism) was relatively low in the study, and risk of pulmonary embolism alone was not significantly different from that seen with placebo; however, the use of conjugated estrogens did increase the relative risk of VTE in postmenopausal women without a uterus. Risk also increased with obesity.³⁷

Estrogen-progestin therapy. The WHI study demonstrated an increased risk of VTE with EPT compared with placebo, the risk increasing with advancing age and obesity.³⁸ In addition, the risk of VTE was significantly greater with EPT than with ET in the same study.³⁷ In women younger than 60 years, the projected 5-year risk associated with EPT was 1.4% in obese women, compared with less than 0.5% in women of normal weight. In the WISDOM study, which involved women older than 65 years, there was a significant increase in VTE incidence with EPT vs placebo (hazard ratio [HR], 7.36; 95% CI, 2.20-24.60).³²

FAST TRACK

For otherwise healthy newly menopausal women age <60 years, the risk of thromboembolism from ET or EPT is negligible.

Thrombotic risk in perspective. The risk of VTE is an important determinant of the benefit–risk profile when prescribing HT. Data from observational and randomized trials have shown an increased risk of VTE with oral HT.^5,39 In women with preexisting cardiovascular disease, the use of statins appeared to negate the increased risk of thromboembolism with EPT.⁴⁰ In the WHI trials, the absolute VTE risk associated with either EPT (7 per 10,000 women per year of use) or ET (4 per 10,000 women per year of use) in women younger than 60 years was lower than in older women³⁷—and considered rare by NAMS consensus. Thus, for otherwise healthy newly menopausal women younger than 60 years, carefully consider the benefits of ET or EPT against the negligible risk of thromboembolism.

Limited observational data suggest lower risks of VTE with transdermal ET compared with oral ET,⁴¹ but there is no conclusive evidence from randomized controlled trials on this subject.⁵ Low-dose oral and transdermal formulations may provide promising routes of administration, pending further studies. Evidence suggests that women with a history of VTE or women who have factor V Leiden are at increased risk for VTE with HT use.³⁹ Use caution, therefore, when considering HT in women at higher risk of VTE, such as those with prior VTE or thrombogenic mutations, those undergoing surgery, or those who are immobilized.³⁹

FAST TRACK

A meta-analysis of studies showed no increase in breast cancer risk from estrogen therapy given at a daily dose of up to 0.625 mg.

Estrogen therapy. Observational studies have suggested an increased incidence of breast cancer among women using ET for more than 1 year, with the risk increasing as use continues.36,42 In contrast, results of the WHI study showed that invasive breast cancer was diagnosed at a 23% lower rate in the ET group than in the placebo group, although this difference did not reach statistical significance (P=.06).16 The Women’s Health Study showed no association between current use of ET and the risk of total breast cancer or invasive breast cancer.43 The degree of breast cancer risk may depend on dose, as a meta-analysis of studies showed no increase in breast cancer risk with use of ET at ≤0.625 mg/d.44 In addition, the incidence of breast cancer has been shown to be lower in women who do not have benign breast disease or first-degree relatives with breast cancer.45

Estrogen-progestin therapy. Observational studies have shown an increased risk of breast cancer with EPT.^42,46 In the WHI study, there was a significantly increased relative risk of invasive breast cancer in women receiving EPT over a follow-up of 5.6 years (HR, 1.24; 95% CI, 1.02-1.50).⁴⁷ However, some have noted that the observed increase in the incidence of invasive breast cancer in the EPT arm vs placebo was not statistically significant and could have resulted from chance alone.⁴⁸ A recent analysis of breast cancer incidence in the United States found a sharp decrease from 2002 to 2003,⁴⁹ suggesting that breast cancer risk diminished soon after discontinuation of EPT for many women following the publication of the WHI results.