Teachable Moment

Do I Really Need to Stop Taking ?

Chelsea W. Fox, MD; Bruce A. Lessey, MD, PhD; and Paul B. Miller, MD

From the Department of OB/GYN, Greenville Health System, Greenville, SC (C.W.F., B.A.L., P.B.M.), and University of South Carolina School of Medicine Greenville, Greenville, SC (B.A.L., P.B.M.)

Story From the Front Line (HT).3 However, the Women’s Health Initia- tive (WHI), a large randomized controlled trial D.H. is a healthy 58-year-old woman who went (RCT) aimed to address the effect of HT on CVD, through menopause at 54, with the onset of hot breast cancer, and osteoporosis, discontinued the flashes, vaginal dryness, forgetfulness, and fre- estrogen plus progestin arm because of lack of quent nighttime awakenings. She was offered any demonstrable cardioprotective effect, exces- hormone replacement for symptomatic relief sive breast cancers (RR 1.26; 95% CI, 1.0–1.6), and shortly after the onset of menopause and because an increased risk in the Global Index of Harm.4 she has a uterus was put on combined conjugated The impact of these results was profound, with equine estrogen (CEE) and medroxyprogester- many women discontinuing their HT. However, one acetate. She has a total cholesterol of 212, a when CEE was analyzed alone, the adverse effect high-density lipoprotein of 43, and a family his- on breast cancer virtually went away with a RR tory of heart disease in a maternal aunt. She has of 0.77 (95% CI, 0.6–1.0), but still there was a also been treated long term with cabergoline for slight increased risk for all CVD (RR 1.12; 95% a -secreting pituitary adenoma, which CI, 1.0–1.2).4 is currently well controlled. In retrospect, the WHI was not designed to During the past year, she saw her internist who answer the question of whether estrogen can pre- strongly recommended that she discontinue vent heart attacks in newly menopausal women estrogen treatment secondary to concern for without heart disease. It enrolled older women increased cardiovascular disease (CVD) risk. She (average age of 63) who were more likely to have was prescribed an herbal supplement and told to advanced stages of atherosclerosis, supporting exercise more often. She is happily married and conclusions from the Heart and Estrogen/proges- notes new onset of vaginal dryness, dyspareunia, tin Replacement Study (HERS) study, which sug- and return of hot flashes and sleep disturbances gested that HRT in women with known coronary since she recently discontinued her hormone artery disease might be at increased risk, at least replacement therapy (HRT). When seen for her in the first year of treatment.5,6 refills for medications for her adenoma, she asked her reproductive endocrinologist, “Do I really With the passage of time since the landmark need to stop taking estrogen?” WHI study, there have been further re-analyses that suggested younger women on estrogen bene- Teachable Moment fit disproportionately compared to older women.7 Myocardial infarction (MI) is the greatest risk A 13-year follow-up of the WHI showed the group for death in postmenopausal North American of women ages 50–59 at randomization who women.1 Data from over 30 observational stud- received CEEs had a 40% lower risk of MI than ies have strongly suggested that estrogen is pro- those who received placebo, whereas no effect tective against heart disease.2 For example, the was seen in women who were ages 60 or older at Nurse’s Health Study showed that ever users and randomization.8 Furthermore, subsequent analy- current users had 0.5 (95% CI, 0.3–0.8, P = .007) ses from the WHI have shown the absolute risk and 0.3 (95% CI, 0.2–0.6, P = .001) relative risks of adverse effects (measured by the global index (RR), respectively, for coronary disease compared including stroke, pulmonary embolism, colorec- to never users of menopausal hormonal therapy tal cancer, endometrial cancer, hip fracture, and

92 GHS Proc. November 2016; 1 (2): 92-93 DO I REALLY NEED TO STOP TAKING ESTROGEN? death) is much lower for younger women than for the group than in the placebo group Correspondence older women on HRT (12 excess cases per 10 000 (absolute difference 0.0034 mm/year, P = .008), Address to: women annually for ages 50–59 years compared whereas the rate of CIMT progression in the Chelsea Fox, MD, to 38 for ages 70–79 years).8 late-postmenopausal group was similar in the Greenville Health estradiol and placebo groups (difference 0.0012 System, Department In a smaller, more recent RCT, the Danish Oste- mm/year, P = .29). of OB/GYN, 890 W 9 oporosis Prevention Study, women were ran- Faris Rd, Suite 470, domized to estrogen and acetate The Global Consensus Statement on Menopausal Greenville, SC 29605 or placebo if they had a uterus, and 2 mg oral Hormone Therapy, endorsed by the American ([email protected]) estradiol or placebo if they did not. Over 16 years Society for Reproductive Medicine and the North of follow-up, there was a reduction in CVD end- American Menopause Society, states menopausal points with an RR of 0.61 (95% CI, 0.4–0.9). These hormone therapy (MHT) is the most effective studies support a “critical window” hypothesis, treatment for vasomotor symptoms associated suggesting women receive the greatest cardiovas- with menopause, particularly for women less cular benefit from HRT when started immedi- than 60 years of age or within 10 years of meno- ately at the onset of menopause. pause.11 Furthermore, randomized clinical trials and observational data have provided evidence The recently published ELITE (Early versus Late that MHT may actually decrease coronary heart Intervention Trial with Estradiol) trial was spe- disease and all-cause mortality when initiated in cifically designed to test this hormone-timing women less than 60 years of age and within 10 10 hypothesis. This RCT stratified postmeno- years of menopause.11 pausal women into either early postmenopausal (<6 years) or late postmenopausal (≥10 years) MHT should be considered as a safe option for groups and randomized them to receive oral symptomatic, healthy, early-menopausal patients, estradiol (with vaginal progesterone if they had such as D.H., who should have the right to be a uterus) or placebo. The primary outcome was involved in decisions about discontinuation of the rate of change in carotid-artery intima-me- their HT regimens. Given the prevalence of heart dia thickness (CIMT) assessed by ultrasound disease in North America, if estrogen is a benefi- every 6 months. After 5 years of intervention, cial prevention tool, it deserves further research the rate of CIMT progression in the early-post- and dialogue between healthcare providers and menopausal group was significantly lower in their patients.

References

1. Cummings SR, Black DM, Rubin SM. Lifetime risks 6. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus of hip, Colles’, or vertebral fracture and coronary progestin and the risk of coronary heart disease. N heart disease among white postmenopausal women. Engl J Med. 2003;349:523-34. Arch Intern Med. 1989;149:2445-8. 7. Harman SM. Menopausal hormone treatment car- 2. Barrett-Connor E, Grady D. Hormone replacement diovascular disease: another look at an unresolved therapy, heart disease, and other considerations. conundrum. Fertil Steril. 2014;101:887-97. Annu Rev Public Health. 1998;19:55-72. 8. Manson JE, Chlebowski RT, Stefanick ML, et al. 3. Stampfer MJ, Willett WC, Colditz GA, Rosner B, Menopausal hormone therapy and health outcomes Speizer FE, Hennekens CH. A prospective study of during the intervention and extended poststopping postmenopausal estrogen therapy and coronary phases of the Women’s Health Initiative randomi- heart disease. N Engl J Med. 1985;313:1044-9. zaed trials. JAMA. 2013;310:1353-68. 4. Anderson GL, Limacher M, Assaf AR, et al. Effects 9. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of conjugated equine estrogen in postmenopausal of hormone replacement therapy on cardiovascu- women with hysterectomy: the Women’s Health lar events in recently postmenopausal women: ran- Initiative randomized controlled trial. JAMA. domised trial. BMJ. 2012;345:e6409. 2004;291:1701-12. 10. Hodis HN, Mack WJ, Henderson VW, et al. Vascular 5. Hulley S, Grady D, Bush T, Furberg C, Herrington effects of early versus late postmenopausal treatment D, Riggs B, Vittinghoff E. Randomized trial of estro- with estradiol. N Engl J Med. 2016;374:1221-31. gen plus progestin for secondary prevention of coro- 11. Villiers TJ, Gass ML, Haines, CJ, Hall JE, Lobo nary heart disease in postmenopausal women. Heart RA, Pierroz DD, Rees M. Global consensus state- and Estrogen/progestin Replacement Study (HERS) ment on menopausal hormone therapy. Climacteric. Research Group. JAMA. 1998;280:605-13. 2013;16:203-4.

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