Blog of the Society for Menstrual Cycle Research

When Can We Write the Obituary for the Critical Timing Hypothesis?

October 12th, 2012 by Chris Hitchcock

What Happened?

The highlight of last week’s meeting of the North American Menopause Society (NAMS) meeting was a presentation of the primary results of the KEEPS study (Kronos Early Estrogen Prevention Study). A press release describing the findings, along with a list of FAQ (frequently asked questions), is available on the Kronos website. KEEPS was designed to confirm the critical timing hypothesis by looking at the use of menopausal hormone therapy in healthy women who were 6-36 months from their last menstrual period. Primary outcomes were progression of two atherosclerosis markers: carotid artery wall thickness (cIMT) and coronary artery calcification (CAC). In both cases, there were no statistically significant differences among the three groups (two hormone therapy formulations and a placebo group). The study failed to meet the stated goals by the stated criteria. Medical and popular coverage of these preliminary, non-peer-reviewed results have been almost uniformly positive, advocating renewed use of estrogen as menopausal therapy to women, provided they are young and healthy.

The timing hypothesis1 was born out of the collective cognitive dissonance following the unexpected findings of the Women’s Health Initiative, which failed to confirm the widespread belief that menopausal hormone therapy (specifically, estrogen) would protect menopausal women from cardiovascular disease.

The birth of KEEPS

Soon after the results of the Women’s Health Initiative were published, the discredited idea of menopausal hormone therapy for the prevention of cardiovascular disease was resurrected in the form of the critical timing hypothesis. In 2005, the KEEPS study was launched with much fanfare in the popular press and the medical literature. The lead editorial2 in the journal Climacteric heralded it as a move “[t]owards safer women, safer doses, safer routes and safer timing of administration of safer menopausal therapies,” and the journal invited an article describing the study design3.

Study Design

KEEPS is a “prospective, randomized, controlled trial designed, using findings from basic science studies, to test the hypothesis that MHT when initiated early in menopause reduces progression of atherosclerosis. KEEPS participants are younger, healthier, and within 3 years of menopause thus matching more closely demographics of women in prior observational and epidemiological studies than women in the Women’s Health Initiative hormone trials. KEEPS will provide information relevant to the critical timing hypothesis for MHT use in reducing risk for CVD.”4 The target sample size was 450 women completing the study, with a goal of at least 150 women in each arm. The recruitment goal was 720 women.

Rather than using the synthetic hormones (conjugated equine estrogen, CEE and medroxyprogesterone acetate, MPA) from the WHI, KEEPS included more “natural” hormonal products, comparing oral conjugated equine estrogen (o-CEE, derived from pregnant mares’ urine, and taken as a pill – Premarin, 0.45 mg) with transdermal estradiol (t-E2, taken by patch – Climara, 50 mcg). Estrogen taken alone causes endometrial cancer; KEEPS added oral micronized progesterone (OMP, 200 mg for 12 days per month), which is identical to the human hormone molecule.

The three arms were:

  1. PLACEBO – placebo pill, placebo patch, placebo OMP
  2. o-CEE + OMP – active pill, placebo patch, active OMP
  3. t-E2 + OMP – placebo pill, active patch, active OMP

The purpose of KEEPS was to test the critical timing hypothesis, that is, to answer the question:

Does estrogen therapy, when administered during the critical timing period, protect women from cardiovascular decline?

A study of this size and duration in healthy young(er) women cannot hope to address clinical outcomes, such as stroke, heart attack and the like. Therefore the study had two surrogate markers of atherosclerosis (a part of cardiovascular health) as primary outcomes:

  1. Rate of change in the thickness of the wall of the carotid artery (CIMT)
  2. Amount of arterial calcification of the coronary artery (CAC)

Both measures have strong evidence linking them to future cardiovascular disease.

Recruitment and Retention 4, 5

KEEPS met recruitment targets (727 randomized women at 8 centres) and exceeded retention targets (466 women completed all 4 years of the trial, and an additional 118 women discontinued study medication but continued to be followed for 4 years).

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