Clinical Review

Postmenopausal HRT: What is fact, what is fiction?

OBG Manag. 2006 June;18(6):76-85

David F. Archer, MD

What the evidence to date does and does not confirm

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IN THIS ARTICLE

Stroke vs VTE vs breast cancer risk
Extra cases of breast cancer, by risk factor

References

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14. Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med. 1999;131:935-942.

15. Recker RR, Davies KM, Dowd RM, Heaney RP. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Ann Intern Med. 1999;130:897-904.

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. 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.

18. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause. 2001;8:245-251.

19. Lacey JV, Jr, Brinton LA, Lubin JH, Sherman ME, Schatzkin A, Schairer C. Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2005;14:1724-1731.

20. Archer DF, Furst K, Tipping D, Dain MP, Vandepol C. A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group. Obstet Gynecol. 1999;94:498-503.

21. Bouchard P, De Cicco-Nardone F, Spielmann D, Garcea N. Bleeding profile and endometrial safety of continuous combined regimens 1mg 17beta-estradiol/trimegestone versus 1or 2 mg 17beta-estradiol/norethisterone acetate in postmenopausal women. Gynecol Endocrinol. 2005;21:142-148.

22. Kurman RJ, Felix JC, Archer DF, Nanavati N, Arce J, Moyer DL. Norethindrone acetate and estradiol-induced endometrial hyperplasia. Obstet Gynecol. 2000;96:373-379.

23. Speroff L, Rowan J, Symons J, Genant H, Wilborn W. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized controlled trial. JAMA. 1996;276:1397-1403.

24. Sturdee DW, Ulrich LG, Barlow DH, et al. The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy. BJOG. 2000;107:1392-1400.

25. Ylikorkala O, Wahlstrom T, Caubel P, Lane R. Intermittent progestin administration as part of hormone replacement therapy: long-term comparison between estradiol 1mg combined with intermittent norgestimate and estradiol 2 mg combined with constant norethisterone acetate. Acta Obstet Gynecol Scand. 2002;81:654-660.

26. Espeland MA, Bush TL, Mebane-Sims I, et al. Rationale, design, and conduct of the PEPI Trial. Postmenopausal Estrogen/Progestin Interventions. Control Clin Trials. 1995;16(suppl):3S-19S.

27. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996;335:453-461.

28. 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.

29. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933-941.

30. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the nurses’ health study. a prospective, observational study. Ann Intern Med. 2001;135:1-8.

31. Bush TL, Cowan LD, Barrett-Connor E, et al. Estrogen use and all-cause mortality. Preliminary results from the Lipid Research Clinics Program Follow-Up Study. JAMA. 1983;249:903-906.

32. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health. 1998;19:55-72.

33. 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.

34. 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.

35. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.

36. 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.

37. Naftolin F, Taylor HS, Karas R, et al. The Women’s Health Initiative could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertil Steril. 2004;81:1498-1501.

38. 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.

39. Clarkson TB, Appt SE. Controversies about HRT-lessons from monkey models. Maturitas. 2005;51:64-74.

40. Wagner JD, Clarkson TB. The applicability of hormonal effects on atherosclerosis in animals to heart disease in postmenopausal women. Semin Reprod Med. 2005;23:149-156.

41. Barrett-Connor E, Laughlin GA. Hormone therapy and coronary artery calcification in symptomatic postmenopausal women: the Rancho Bernardo Study. Menopause. 2005;12:40-48.

42. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135:939-953.

43. 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.

44. Harman SM, Brinton EA, Cedars M, et al. KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric. 2005;8:3-12.

45. Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344:276-285.

46. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354:270-282.

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48. Morimoto LM, White E, Chen Z, et al. Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United States). Cancer Causes Control. 2002;13:741-751.

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

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Fast Track

Women who began HRT within 5 years of menopause had less heart disease than women who started HRT more than 5 years after menopause

In the Women’s Health Initiative, the risk of VTE increased by 1.8 cases per 1,000 women using HRT

Autopsies done on women in their 40s who died from other diseases found that 39% had breast cancer—but the clinical rate was only 1%

Top 3 risk factors for breast cancer:

Obesity
No daily exercise
More than 2 alcoholic drinks daily

Undifferentiated stem cells in the breast may become dysfunctional and result in cancer

Now that the dust is settling from the Women’s Health Initiative (WHI), our patients are again asking reasonable questions about hormone replacement therapy (HRT). I remind them of estrogen’s proven advantages in menopause, as well as its risks. Although most women are generally aware of these risks and benefits, considerable misunderstanding persists. This article reviews what the evidence to date does and does not confirm, particularly regarding breast cancer and coronary heart disease, where most of the uncertainty remains.

HRT stops vaginal atrophy, hot flashes, and bone loss

Three applications form the basis for HRT in postmenopausal women:

Hot flashes subside. Hot flashes occur with varying intensity in about 85% of women, and are effectively treated with estrogen, whether given orally, transdermally, or vaginally.^1,2 As long as an appropriate blood level of the hormone is reached, hot flashes diminish.^3-5 This reduction is dose-related.
Measurable improvements in vaginal atrophy. Estrogen’s efficacy in relieving dryness, itching, burning, and dyspareunia is well demonstrated, regardless of the route of administration.^3,6,7 A fall in vaginal pH from 6.0 to 5.0 after estrogen administration has been documented,⁸ as has the increase in the number of superficial cells of the vagina with exogenous estrogen.⁹
HRT maintains or increases bone mineral density (BMD). Most estrogen preparations on the US market have been shown to improve BMD.^10-15 “Improvement” means no significant loss, or an increase, in BMD. In the WHI, both vertebral and nonvertebral fractures diminished unequivocally in women using estrogen—alone or with a progestin.^16,17 Other clinical trials also have shown increased BMD, as well as decreased urinary and serum markers of bone turnover.

Do new data link progestin to cancer?

Although compelling evidence supports the use of progestational agents in addition to estrogen to prevent endometrial hyperplasia and endometrial cancer,¹⁸ a 2005 report¹⁹ suggests that chronic, long-term use of estrogen with a progestin may increase the risk of endometrial carcinoma. Because this is the only study in which this risk has been found, corroboration is required.

Until then, give progestin at a sufficient dose and duration to inhibit endometrial hyperplasia.^20-25

Effects on heart disease may be age-related

With notable exceptions, the overall conclusion of clinical trials and observational studies to date is that estrogen helps prevent coronary heart disease (CHD).^26-30 This finding was first observed in the late 1980s with evidence that estrogen increases high-density lipoprotein (HDL) cholesterol and reduces total and low-density lipoprotein (LDL) cholesterol.³¹

Some experts argue that these observational trials are biased because many of the women taking estrogen had modified their lifestyles to maintain their weight, control their diet, and exercise regularly.³² Indeed, the randomized, placebo-controlled Heart and Estrogen Replacement Study (HERS) and both arms of the WHI trial found no evidence for a significant increase or decrease in CHD events.^33-35

Time from menopause to HRT may be key

Both the HERS and WHI trials enrolled older women who had entered menopause a few months to several years before starting HRT.³⁶ In addition, the estrogen-progestin arm of the WHI trial lacked sufficient power to detect a significant difference in CHD outcomes.³⁷

The WHI findings contrast those of the large, ongoing, observational Nurses Health Study, which has shown a consistent decrease in CHD incidence in women who began HRT with the onset of menopausal symptoms.^27-30 The most recent data suggest that the interval between menopause and the start of HRT may explain the different findings in randomized, controlled trials and observational studies.³⁸ The WHI data support this theory: CHD was lower in women who began taking HRT within 5 years of menopause, compared with women who initiated HRT more than 5 years afterward.³⁶ In addition, data from the estrogen-only arm of the WHI show fewer CHD events in women younger than 60.³⁴

Several other studies support this hypothesis:

The surgically postmenopausal cynomolgus macaque had a lower rate of atherosclerotic plaque development when estrogen was given, with or without a progestin.^39,40
In the Rancho Bernardo study, women who had used HRT had less cardiac calcification documented by computed tomography, compared with nonusers.⁴¹
Estrogen has been shown, by measurement of carotid intimal medial thickness, to inhibit atherosclerotic plaque in humans.⁴²
Older women with established atherosclerosis do not undergo any significant change in plaque size with the use of exogenous estrogen.⁴³