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Risks of Hormone Therapy

Nov 2011 – by D. Chelmow, MD

Hormone therapy (HT) has been in use for many years. Based on retrospective studies and theoretical considerations, it was widely prescribed to prevent coronary heart disease. While initially thought to be almost uniformly beneficial, a number of risks were well accepted. More recently, randomized controlled trials were performed to rigorously test the benefits against heart disease, raising questions about its efficacy for preventing coronary artery disease, and at the same time, confirming many of the risks. Discussion of HT risks (and benefits) is further complicated by differing pharmacologic effects of various estrogens and progestins and that effects may vary with age and time of HT initiation. Conjugated equine estrogen (CEE), with and without medroxyprogesterone, has been the most thoroughly studied.

The Women's Health Initiative (WHI) was a large study designed to formally study the putative protective benefit of hormone therapy against coronary artery disease. It is the most important single study for information about clinical outcomes of HT, and will be discussed here. It is very important to note that it is a single study, only used a single estrogen and progestin type, and was designed to answer specific questions. It is important not to extrapolate the results far beyond what the trial was designed to do, and not to further compound its limitations by supplementing with inadequate retrospective and surrogate outcome data.

The WHI contained two placebo controlled trials separately examining estrogen therapy (ET) with CEE alone in over 10,000 women with hysterectomies (JAMA 2004), and combined CEE and medroxyprogesterone in over 16,000 women with intact uteri (JAMA 2002). The trials were stopped early by the data and safety monitoring board, but given the large number of subjects and systematic data collection, they give useful estimates of HT risk.

 ETCombined HT
HR95% CIRR95% CI
CHD0.910.75-1.121.291.02-1.63
Breast Cancer0.770.59-1.011.261.00-1.59
Stroke1.391.10-1.771.411.07-1.85
PE1.340.87-2.062.131.39-3.25

The risk of thromboembolism had long been accepted, and although only pulmonary embolism (PE) was included in the WHI adjusted analysis, similar increased risk was noted for deep vein thrombosis. Elevated risk of stroke was noted in both studies. Gallbladder disease is generally accepted to be more frequent in HT users (Endocrine Society Statement).

HT has been implicated in increased risk for several cancers. Unopposed estrogen in patients with intact uteri clearly raises the risks of endometrial hyperplasia and cancer. Among women on combined hormonal therapy, no increased risk has been observed. Long term use of ET alone has been associated with a small increased risk of ovarian cancer (Endocrine Society Statement). Based on epidemiologic data, hormone therapy was long considered to increase risk for breast cancer. Interestingly, in the WHI study, estrogen alone did not show increased risk, and actually showed a nonsignificant decrease in risk. In the WHI combined HT study, there was a suggestion of a 26% increased risk, consistent with the epidemiologic data. Risk within this group appeared to vary with age. Overall, combined estrogen and progestin therapy increased the risk of invasive breast cancer, which could occur within 3 to 5 years of initiation and rose progressively beyond that time. However, for the subgroup of first-time combined HT users, there did not appear to be an increased risk after 5.2 years, particularly in those starting HT several years after the onset of menopause. (Endocrine Society Statement) A drop in breast cancer incidence was noted after the publication of the WHI data, attributed to the subsequent decrease in HT use.

Most disturbing from the randomized trials, and most controversial at present, is that HT could potentially raise risk for several of the problems for which it was originally thought beneficial. For many years, HT use was thought to universally protect against coronary artery disease. The Heart and Estrogen/Progestin Replacement Study (HERS), designed to test secondary prevention in women with preexisting CHD, the women who were thought to be most likely to benefit from HT, showed increased risk in the first year of use, although the intervention and placebo arms appeared equivalent by year 4 (ACOG Committee Opinion #420). The WHI ET trial showed no difference, while the combined HT arm actually showed a slight increased risk overall (RR 1.29, 95% CI 1.02-1.63). It is important to note that the trial was stopped early when it became clear that the study would not achieve its intended end point of showing benefit. As with breast cancer, risk may vary with age at time of HT initiation. ACOG (Committee Opinion 420) reviews this data at length. Briefly, a supplementary analysis of WHI data in combined HT users who entered the study between ages 50-59 showed a nonsignificant increase in risk of combined CHD events in this age group (RR 1.29 95% CI .79 to 2.12), and that when estrogen alone and combined HT users were pooled, a decreased mortality was noted in this age group. In addition, there is data suggesting benefits on surrogate outcomes including lipids, glucose, insulin, and coronary-artery calcification scores. Some theorize a "timing hypothesis", where HT may be beneficial for select patients. However there is no high quality evidence supporting using HT for primary or secondary cardiac prevention in any postmenopausal population.

Observational trials suggested that hormone therapy decreased the risk of Alzheimer’s disease and improved cognitive function. In the WHI memory study, a randomized trial studying the effect of HT on cognitive outcomes, women in the HT group experienced a significant, two-fold increased risk of dementia, most frequently Alzheimer’s disease. HT was also noted to impair cognition as measured by the Modified Mini-Mental Status Examination. (Shifren, 2010)

This document was intended to focus on risks, but it is important to keep the magnitude of these risks in perspective, as absolute risks are low. For example, the RR of 1.29 in combined HT users aged 50-59 noted above translates to an absolute risk of 1.0% in the placebo group and 1.33% in the HT group, or an incremental risk of 0.33% over the study period, equivalent to an additional CHD event for every 303 HT users in this age group. HT clearly has some benefits, particularly treatment of menopausal hot flashes and prevention of hip fractures. Particularly for hot flashes, available alternatives are significantly less effective, and despite the risks, there are circumstances where HT is clearly indicated. In these situations, current recommendations are to use HT in the lowest effective dose for the shortest possible period of time. In addition to true risks, there are side effects including breast tenderness and irregular bleeding.

Shifren JL and Shiff I. Role of hormone therapy and the management of menopause. Obstet Gynecol 2010;115:839-55.

Hormone therapy and heart disease. ACOG Committee Opinion #420. American College of Obstetricians and Gynecologists. Obstet Gynecol 2008;112:1189-92.

The Women’s Health Initiative Steering Committee. Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy: The Women’s Health Initiative Randomized Controlled Trial. JAMA. 2004;291:1701-12

Writing Group for the Women’s Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial. JAMA. 2002;288:321-33

Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, Gower BA, Henderson VW, Jarjour WN, Karas RH, Kleerekoper M, Lobo RA, Manson JA, Marsden J, Martin KA, Martin L, Pinkerton JV, Rubinow DR, Teede H, Thiboutot DM, Utian WH. Executive Summary: Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement. J Clin Endocrinol Metab. 2010;95:S1–66.