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).


CIMT progression was low and similar across all 3 treatment groups over 4 years.
CAC progression was not statistically significantly different among the 3 treatment groups. However, there was some trend towards less progression in the active hormone groups.


Given that “the rationale that earlier intervention than that performed in the WHI and HERS trials will provide cardiovascular benefit to women is the driving force behind the Kronos Early Estrogen Prevention Study, or KEEPS,” we might expect press releases and media coverage to address this aspect of the study. For example, the headlines might read:

  • KEEPS fails to support timing hypothesis
  • Is the timing hypothesis dead?
  • Estrogen does not prevent cardiovascular disease progression, even close to menopause

Instead, the headlines read:

In my survey of Google News articles, I found only one article that seemed critical of the news.

Susan Perry, the author, rightly notes that the headlines are premature, because the study has not yet gone through scientific peer review. And, as this quote indicates, there is many a change between first presentation and final publication:

“It’s being framed as countering the WHI study — which people have had a long time to digest, re-analyze and pick apart,” wrote Gary Schwitzer, publisher of the Minnesota-based HealthNewsReview website, which reviews and rates health-related news articles, in an e-mail response to my questions about Wednesday’s media reports. “Shouldn’t we at least hear the presentation at the meeting and hear discussion before jumping to conclusions, etching new stone tablets, and framing this as countering the WHI? How can one even give a cogent comparative reaction when you’re hearing a brief abstract or presentation at a meeting?”
“It’s often not a good batting average when you track what eventually results from work presented in talks at scientific meetings,” he added.

The author goes on to quote various medical commentators who greet these results with more skepticism and concern. Good for her!

So, my suggested headline for the study results and their media coverage so far?

Estrogen for Heart Disease Prevention: A Hypothesis That Will Not Die


References & Notes:

1. Hodis HN, Collins P, Mack WJ, Schierbeck LL.(2012)”The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective.” Climacteric. 2012 Jun;15(3):217-28.

2. MacLennan, A. H. and D. W. Sturdee (2005). “Towards safer women, safer doses, safer routes and safer timing of administration of safer menopausal therapies.” Climacteric 8(1): 1-2.

3. Harman, S. M., E. A. Brinton, et al. (2005). “KEEPS: The Kronos Early Estrogen Prevention Study.” Climacteric 8(1): 3-12.

4. Miller, V. M., D. M. Black, et al. (2009). “Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS).” J Cardiovasc Transl Res 2(3): 228-239.

5. NAMS Keeps Report (Oct 3, 2012). “KEEPS results give new insight into hormone therapy”.

13 responses to “When Can We Write the Obituary for the Critical Timing Hypothesis?”

  1. Chris, Thanks for a clear-headed look at a confusing issue. I can’t believe the extrapolation that’s been made from this study’s results. I think you should send this to HuffPost for consideration. It deserves a broader audience.

  2. Paula Derry says:

    Chris–A clear presentation with the detail needed to draw conclusions about the study.

  3. […] it is a fact, although the evidence for it has been at the very best arguable and weak.  A recent SMCR blog post by Chris Hitchcock analyzed media misreporting of the results of another research […]

  4. Jonathan says:

    This is the best analysis of the preliminary KEEPS results I have seen. While the quality of life benefits for symptomatic women are not contested by this trial, the 2 basic hypotheses: estrogen would slow plaque buildup and help with cognition did not pan out.

    What’s interesting, though, is that the data from the Premarin arm of the study are being spun to look as though this form of estrogen helps with memory, mood, anxiety, and depression. According to the press release, transdermal estradiol had no cognitive or mood benefit and caused a slight increase in subjective memory problems and impaired ability to recall past events (this makes sense since high estrogen has been shown to have deleterious effects on brain health in older women). But with Premarin, there is this alleged benefit. What I think will be glossed over and completely ignored are the effects of progesterone – that Premarin users may have done better in this trial NOT because of the Premarin itself but rather because the pill form of estrogen gets metabolized quicker and does not cause sustained high blood levels the way patch estrogen does. So in this respect, it is quite possible that the progesterone component was exerting the benefit in the Premarin users – improved anxiety, tension and mood, all of which SEEM like progesterone effects since it is a calming hormone for the central nervous system.

    While there haven’t been any press releases with regard to side effects, I have HEARD that preliminary analyses indicate that the transdermal estradiol arm may have experienced more vaginal bleeding and abnormal mammograms, thus indicating the estrogen dose was either too high or the progesterone dose was insufficient to counteract these estrogen caused side effects.

    Either way, I hope experts such as Dr. Jerilynn Prior and other women’s health advocates who aren’t estrogen disciples are able to sound the alarm that this trial has, essentially, debunked the timing hypothesis, that estrogen does not prevent heart disease or preserve cognitive function in menopausal women.

  5. Stefano says:

    Have the results of KEEPS been published in a peer-reviewed journal? If so, could you please provide me with a ref?

  6. Chris Hitchcock says:

    There are a number of papers analyzing the cross-sectional results, but I haven’t seen the primary results of the study yet. is a good, publicly available search tool to look.

  7. Traci Wiseman says:

    Someone should alert all the women who have regained their sanity, health and general sense of well-being through bio-identical estradiol & testosterone & progesterone to the “superior scientific” findings of WHI study! These women should just get back in the kitchen & slowly fade away instead of being so self-centered & unwilling to SUFFER through the natural progression of menopause.

    Walk a mile in the shoes of a woman who has been treated by several doctors who adhere to the WHI scare tactics and then thankfully finds a doctor like Elizabeth Vliet who has been successfully treating hormonal imbalance brought on by menopause for years. It’s amazing how one’s perspective is effected when you finally find a doctor who actually CARES for their patients.

    Give me bio-identical estradiol and a balanced amount of testosterone, or give me death at the hands of deaf, dumb & blind physicians on their way to the golf course.

  8. Traci Wiseman says:

    I’m entertaining the thought that you would have greatly benefitted from being born with a uterus.

  9. Jonathan says:

    Traci, you might want to consider cutting back on the testosterone a little.

    My comments are about clinical research and methodology, not about symptom control. But anyway, feel free to fill up your tank with as much estradiol as you can get your hands on. Just know that it is an EXPERIMENT with unknown consequences.

  10. Traci Wiseman says:

    So funny. The typical male response. My remarks MUST be the result of my being hopped up on testosterone, right? Fortunately, I’m not intimidated by males who practice the art of dismissing females out of hand simply because they don’t see eye-to-eye with them.

    I realize you are approaching this from a clinical standpoint so let me ask you a few questions: What difference does it make if bio-identical HRT given early actually prevents heart disease or not? Does the study suggest it CAUSES heart disease? No. So again, what difference does that make to you? In fact, why does it seem to please you that the KEEPS study couldn’t substantiate the claim (or HOPE to many women)? Do you have a horse in this race? Because it kinda seems like you do. Why are you so dedicated to the WIH results given the fact that they used completely different hormones which were not bio-identical?

    I will be kind and give you the benefit of the doubt here; maybe you are genuinely concerned about women’s health and more specifically, their HRT options, because Suzanne Somers and others have fallen off the deep end. If that’s the case, I understand where you’re coming from.

    Look, I’m not talking Suzanne Somers end of the spectrum here. I’m talking about balanced, common sense when it comes to treating women who, at the onset of menopause, have become a person they no longer recognize – emotionally, physically or psychologically. The person they have been for 50 years has ceased to exist. When these women seek medical help, they are offered nothing but a plethora of anti-depressants and have the begeebeez scared out of them concerning HRT as a result of a clinical study that used hormones derived from a pregnant horse! The time, money and attention given to men’s health issues stand in stark contrast to those of females. Because of this, I think women are more than justified in being aggressive concerning their health issues whether it hurts anyone’s feelings or not.

    Indulge me a bit – Let’s say the majority of men can no longer concentrate as they once could, or get an erection or build/maintain muscle when they turn 50. So a drug is developed that restores all of these pre-50 abilities. . .but 30 years later they discover this drug PROMOTES heart disease and cancer and just for fun, can cause his penis to fall off. Mr. Man’s not happy.

    So years later they develop another drug that will also restore all his pre-50 abilities and while it doesn’t PREVENT heart disease or cancer or loss of his penis, studies have not shown that the drug CAUSES these things either. Is Mr. Man gonna take this new drug? I wonder if he would appreciate the opinion of some female who holds hard & fast to the fact that his penis MIGHT fall off if he takes the new drug. . .even though there is no evidence to support her opinion.

    There really are reputable doctors who listen to their patients and treat women with respect – unfortunately, they are few & far between. Dr. Elizabeth Vliet is one of those doctors. I encourage you to visit her website and educate yourself on the subject a bit further.

  11. Jonathan says:

    Listen, Traci, YOU hurled an insult at me FIRST. You are clearly irate about the contrarian viewpoints about HRT use of ANY kind presented here.

    I’m familiar with Dr. Vliet’s work (IT’S MY OVARIES, STUPID). And, no I disagree with her stance that bioidenticals are “better” than Premarin because these newer hormone formulations have not been sufficiently studied. Also, menopause is not a disease. It’s very uncomfortable for a great many women, and its symptoms should be treated appropriately. But postmenopause is not a state of deficiency, any more than pre-puberty is.

    My mother took Prempro for 5 years and got breast cancer, so NO, I have no horse in this race and no I’m not telling YOU or any other person what he/she should or shouldn’t do. Yes, WHI is “definitive” in that it answered the questions IT posed — do PREMARIN and PREMPRO prevent heart disease, dementia and fractures? (No, no and yes) So, what about bioidenticals? Well, trouble is no big trials have been done evaluating their risks and benefits. So we can guess all we want, but truth is, solid answers aren’t there. Moreover, preliminary data are not promising: bioidentical estradiol increases recurrent stroke and stroke death, causes a greater increase in breast density than Premarin (a risk factor for cancer) and, according to KEEPS, it doesn’t stall the earliest signs of heart disease. Now progesterone, not progestin, does have some clinical data to back up its use (for hot flashes, sleep, sleep APNEA, endometrial protection, and traumatic brain injury) so this hormone seems to be an exception. What I’m arguing about, mainly, is that any type of estrogen has risks. Estradiol is extremely potent, perhaps more so than Premarin (which is comprised of mostly estrone sulfate (weaker) and a mixture of other “horse” estrogens not found in a woman’s body). Sure, estradiol is “natural”….so is mercury! That in no way means it’s SAFE. For example, I’m not someone who takes a stroll through the woods, indiscriminately eating a bunch of nondescript berries or foliage of plants I’m unfamiliar with. Why? Because, they might just be poisonous! Now, of course, estradiol is not “poison”; it’s produced in the bodies of both sexes at different amounts. Still, that doesn’t mean a menopausal woman will protect her health by boosting her levels to those of a 20 year old. At the very least, that hasn’t been studied. And a qualified, competent physician would not recommend that without evidence. And the small amount of trial evidence we do have doesn’t look too promising.

    Anyway, I think I’m done with this conversation. Trying to present objective information in response to some reactionary diatribe is fruitless. Nevertheless Ms. Wiseman, I have no desire whatsoever to take away your precious hormones from you. It’s YOUR health, not mine.

  12. Chris Hitchcock says:

    Traci, this article was about the discrepancy between the build up to the results of the KEEPS study and the actual presentation of the results.

    Hormones used as therapy for actual symptoms is a very different topic than hormones for all women to prevent heart disease or other rationales. When the WHI was designed, many women were advised and even pressured to take hormone ‘replacement’ therapy by their physicians. The WHI was an unprecedentedly expensive and extensive trial of the popular beliefs of the day, that the synthetic hormones such as in PremPro would prevent heart disease in older women. It was a sensible study to do at the time. I agree, in an ideal world tests would be done on bio identicals. In fact, my colleague Jerilynn Prior and I have published the results of a randomized trial of oral micronized progesterone for treating hot flushes and night sweats for women no longer menstruating. Progesterone alone is effective therapy.

    I am somewhat horrified by how rapidly these comments have turned into personal attacks. Please use the comment section as a place for respectful discussion.

  13. Traci Wiseman says:

    First of all, I was not hurling an insult or personally attacking anyone. In my opinion, Jonathan’s post hinted at an attitude prevalent in the overall discussion of HRT – too many women are simply “grasping at straws” to combat the “natural progression” of menopause. If anything is insulting, it would be that attitude.

    Considering his follow-up remarks, my instincts proved correct. I realize, however, this may not be the appropriate thread to speak against, 1) the fact that women’s health issues have always been treated as less important than men’s or 2) the insulting, arrogant way a person with no uterus or ovaries can not only dismiss the suffering of menopausal women but goes a step further by ridiculing them for being passionate and hopeful in their efforts to be healed.

    If I, alone, have been insulting in this thread, I could understand your singling me out. If you have reviewed his comments and found nothing chauvinistic or insulting, I, with respect, simply have to question your objectivity.

    I will now leave you all to the enjoyment of your discussion without further comment.

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