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#88 Hormone Therapy: Does Timing Make a Difference?

Is there evidence that starting combination oral hormone therapy (HT) closer to menopause result in reduced risk of harm or even possible benefit?

Evidence supporting the timing hypothesis of HT is not convincing. There is no consistent evidence of benefit with HT beyond symptomatic relief. Smaller but real risks are likely present even in those close to menopause.

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Randomized controlled trial (RCT):1 1006 women (mean age 52) randomized to HT or nothing x10 years 
  • Statistically significant reduction in composite outcome (death, hospitalization for heart failure, and myocardial infarction) in HT users 
    • Hazard ratio (HR) 0.48 (0.26-0.87) 
    • Limitations: Secondary analysis of an osteoporosis study with this outcome defined post-hoc; open-label design; included estrogen-only group; low event rate. 
Women’s Health Initiative (WHI) subgroup analysis:2  
  • Combination HT within 10 years of menopause had non-statistically significant: 
    • Reduced coronary heart disease (CHD): HR 0.88 (0.54-1.43) 
    • Increased stroke: HR 1.58 (0.81-3.05) 
    • Overall more harms than benefits (global index): HR 1.09 (0.87-1.37) 
  • Limitations: Subgroup analysis; >130 statistical tests, only 2 statistically significant (6-7 expected by chance alone). 
2nd subgroup analysis of WHI3 (>300 comparisons) reported increased breast cancer if HT started <5 years after menopause versus >5 years (p=0.03).  Cochrane review of 19 RCTs (40,410 patients):4 
  • Subgroup analysis showed decreased mortality and CHD in HT users <10 years post-menopause, but not >10 years 
  • No evidence that risk of stroke or venous thromboembolism (VTE) lower if HT started <10 years of menopause 
  • Limitations: Risk reductions driven by above RCT1 and estrogen-only group of WHI (hysterectomy patients), which is not likely generalizable to patients without hysterectomy 
  • Older systematic review of 30 RCTs found similar effects on mortality for age <60 versus >60.5 
  • HT is effective for vasomotor and some urogenital symptoms in post-menopausal women.6 
  • Another Cochrane review7 of 23 RCTs (42,830 patients, mean >60 years) reported small statistically-significant increased risk for cardiovascular events, VTE, stroke, and breast cancer with HT. 
updated aug 13, 2016 by ricky

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  • Christina Korownyk MD CCFP
  • Loren Regier BSP BA

1. Schierbeck LL, Rejnmark L, Tofteng CL, et al. BMJ 2012;345:e6409.

2. Rossouw JE, Prentice RL, Manson JE, et al. JAMA 2007;297:1465-77.

3. Prentice RL, Manson JE, Langer RD, et al. Am J Epidemiol 2009;170:12-23.

4. Boardman HMP, Hartley L, Eisinga A, et al. Cochrane Database Syst Rev 2015;3:CD002229.

5. Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. J Gen Intern Med 2004;19:791-804.

6. Nelson H, Haney E, Humphrey L, et al. Management of menopause-related symptoms: Evidence report/Technology Assessment No. 120; Rockville, Md: Agency for Healthcare Research and Quality; 2005.

7. Marjoribanks J, Farquhar C, Roberts H, et al. Cochrane Database Syst Rev 2012;7:CD004143.

Authors do not have any conflicts of interest to declare.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.