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:

Pfizer to pay $72 Million in Philadelphia PremPro Case

December 9th, 2011 by Chris Hitchcock

Three women who developed breast cancer after their use of combination hormone therapy have been initially awarded $72 million by a jury in Philadelphia, with further judgement about punitive damages still to come. The case concerns the use of PremPro, a combination of conjugated equine estrogen and medroxyprogesterone made by Wyeth. Wyeth has since been purchased by Pfizer. Women’s Health Initiative trial results released in 2002 found an increased risk of breast cancer in those randomized to estrogen + progestin compared with placebo. Earlier this year, Pfizer announced that it has set aside $772 million in its budget for settling PremPro lawsuits.

Prior to 2002, hormone replacement therapy was often recommended to otherwise healthy women as a health-enhancing preventative therapy. SMCR has long held that menopause is a natural stage in women’s lives, rather than a condition to be treated. Hormone therapy is no longer recommended for the prevention of disease in healthy women.


Cardiovascular deaths increase with steady aging, not menopause

September 27th, 2011 by Chris Hitchcock

Earlier this month, researchers published a statistical analysis of mortality data in England, Wales and the United States, disproving the common statement that, after menopause, women face increased rates of mortality from heart disease. There are other studies that have come to similar conclusions, but there are a few things that make this study different. One is that it drew on epidemiological data from three different parts of the world, which reduces the likelihood of a local coincidence. A second is that they took care to create longitudinal data sets, comparing women born in different birth decades with the appropriate mortality over time. In doing so, they avoided the problems of cross-sectional data.

The authors found that there was a steady exponential increase in risk with age, and that there was no sign of accelerated risk at the typical age of menopause (50). They compared different versions of mortality curves, and were able to show that a two-stage model of mortality with a hinge at menopause was not a good fit to the data.

These findings have received national and international coverage, and are a major blow to the argument that menopausal women require premenopausal hormones to retain premenopausal protection from cardiovascular risk. Menopausal women are older than premenopausal women, and that is why they are more likely to die from cardiovascular disease, not because of the hormonal changes of menopause.

Menopause Isn’t for Dummies

September 23rd, 2011 by Elizabeth Kissling

Roseanne’s Nuts was one of the delights of summer 2011, especially for those of us who have missed the comedic talents of Roseanne Barr. If you don’t watch television (or are outside the US), Roseanne’s Nuts is Roseanne Barr’s return to episodic television, this time in the form of a reality show set on the star’s 40-acre macadamia nut farm in Hawaii. When her eponymous sitcom ended in 1997, she made a couple of attempts at talk show hosting, then left L.A. and the limelight to raise her youngest son and macadamias in Hawaii. He’s now a teenager, and the nuts are ready to harvest.

An ongoing thread of the show is Roseanne’s plan to harvest and distribute her nuts as a low-cost protein source for impoverished people. Each episode also has its own self-contained, seemingly unscripted plotline. Unlike many of today’s popular reality shows, however, there are no manipulated showdowns or drunken feuds. Much of the time, Roseanne and her family seem like everyone else’s family — if only the rest of us could live off sitcom residuals and were followed around by a camera crew. There is laughter and teasing, and some conflict underpinned with genuine affection, but everything isn’t always tidily resolved in 22 minutes.

In the Episode #15 (original air date September 10), 58-year-old Roseanne copes with continuing symptoms of menopause. It’s handled so honestly (for the most part) that I’m going to overlook the fact that the episode was titled “Menopause for Dummies”.* The episode opens with Johnny Argent, Roseanne’s manpanion**, sharing a list of menopause symptoms he has found on the internet. Roseanne acknowledges having them all, except for tingling in her extremities, and decides to visit her friend, Dr. Allen, and to investigate whether she should receive hormone treatments. (The full episode can be watched online at until Oct. 11; preview a short clip at right.)

-+-+-+- SPOILERS AHEAD -+-+-+-

Roseanne visits Dr. Allen — on camera, of course — this is a reality show — and explains her concerns. He asks about her libido and her sex life, and she replies, “It’s like an old person’s”. She responds forthrightly to his suggestion that dryness may be the cause of her ‘feminine itching’: “that’s all dried up like a sonofabitch”. Dr. Allen wants to measure Roseanne’s hormone levels with a 24-hour urine test, as he believes that will provide more precise information than any blood test. Roseanne is horrified by his description of her contribution to the procedure (“You pee in a bucket for 24 hours”), but even more horrified by his other recommendation: she needs to exercise.

Roseanne tells the camera — the proxy for us, the audience at home — that she doesn’t know if she’ll go on hormones or not. Her women friends recommend red wine, saying it’s bad for menopause (“because it makes you sweat”) but good for the libido. Her eldest son Jake is delighted to hear that his mom is considering hormones, telling the camera, “After eight years of being batshit crazy, I think she’s finally ready. I’m so happy — once she gets hormones, my life’s gonna be a lot easier.”

Some of my SMCR colleagues who study menopause may cringe at these scenes, but I think they’re representative of the kind of communication many women experience around menopause; that is, well-meaning, if ill-informed, advice from friends and family. It feels like the kinds of conversations lots of us have in our own living rooms and front porches. It is this feeling of unscripted authenticity that draws viewers to Roseanne’s Nuts. I also note the special irony of menopause; after 20 or 30 years of our hormones being blamed for erratic and irritable behavior, we’re now advised to consume hormones to rein in our erratic and irritable “batshit crazy” behavior.

This sense of authenticity and realism continues in the scenes where Roseanne works out with the trainer recommended by Dr. Allen. The trainer eases Roseanne into aerobic activity, but Roseanne is reluctant and uncomfortable, especially when the trainer starts to show enthusiasm and high-fives Roseanne. She tells the trainer, “I hate the fact that I’m supposed to act like I like it. That’s not gonna work for me. I don’t like it. I can’t lie through it.”

I couldn’t help but think what a great, if implicit, endorsement this is for Health At Every Size. Roseanne gives up on the trainer and exercise after one workout, because exercise for its own sake is seldom enjoyable to those who haven’t been active. HAES encourages people to find pleasure in moving one’s body — whether walking the dog, doing yoga, swimming, bicycling, or whatever — and doing the activity for the joy it provides rather than for an external goal. HAES also affirms Roseanne’s belief that “if you’re fat, it’s probably because you had fat parents and no amount of dieting will change that”.

In the final scenes, Roseanne and Johnny try to follow Dr. Allen’s last bit of advice, apparently delivered off-camera, to be “more romantic” to jump-start her stalled libido. The camera follows them to dinner, where they alternate between trying to enact cultural expectations of a romantic dinner and discussing their own relationship, concluding that “sex isn’t what it’s all about”.

As the final credits begin, Roseanne faces the camera and announces her final decision about hormone treatments:

Hormone Therapy and the Brain

November 24th, 2010 by Elizabeth Kissling

Medical-Anatomical-Superior-half-of-diseased-brainSo there’s a surge today in news stories about how hormone treatment for menopause (popularly known as ‘hormone replacement therapy’ or HRT) benefits the brain, apparently based on publicity over this study published in Hormones and Behavior. In media interviews, the researchers suggest that HT enhances the communication between left and right sides of the brain, making the older women’s brains more similar to those of younger women. The researchers had the women perform tasks designed to demonstrate fine motor coordination, such as tapping buttons with different fingers. Of the 62 women in the study, the 36 on hormone treatments showed higher levels of motor coordination, leading the researchers to conclude that hormone treatments, especially estrogen, “exert positive effects on the motor system thereby counteracting an age-related reorganization.”

Admittedly, I have not read the entire study, just the abstract and press summaries, but would you consider me too cynical if I suggested that the publicity this research report is receiving is more about promoting the use the hormones among menopausal women than the significance of the research findings?

Latest News on Hormone Therapy

June 23rd, 2010 by Elizabeth Kissling
Wellcome Library, London // CC 2.0

Wellcome Library, London // CC 2.0

The Endocrine Society has released a new, peer-reviewed statement on the risks and benefits of hormone therapy for menopausal women. The upshot is that risks and benefits vary depending on the age of the patient and the length of time since menopause:

One interesting finding . . . was that women who start hormone therapy within 10 years of menopause have a 30% to 40% reduction in total mortality.

In addition, in the 50 to 55 age group the task force concluded that hormone therapy reduced hot flashes and overactive bladder and that vaginal estrogen reduced recurrent urinary tract infections. The evidence also showed that hormone therapy reduced pain on intercourse and improved quality of life.

Given that there are thousands of lawsuits pending over the role of HT in breast cancer, I was especially interested in this nugget of new information:

“Our conclusion is that [the estrogen/progestin hormone combination] didn’t cause breast cancer — it caused preexisting tumors to grow to a size where they became detectable.”

More on life-giving female fluids

April 23rd, 2010 by Chris Hitchcock

When I was pregnant and then learning to breast-feed my daughter, my doula told me that breast milk had great anti-biotic properties, and that it was good to use on eye-infections and cuts. Turns out that there is science behind that. Not only that, but now scientists have shown that breast milk contains substances that may kill cancerous cells. They’re calling the extracted substance HAMLET – not sure why a substance extracted from lactating women would be named after a grieving, tortured young man struggling with suicidal and homicidal thoughts, but I’ll leave more thoughts on that to those who are better at post-modern analysis.

It reminds me of the idea of harvesting stem-cells from menstrual blood. And also some questions about that. Like, is this one of the cases where it matters what produced the menstrual blood? Not all episodes of menstrual bleeding are the same. So how does stem cell quality differ among these different sources of uterine blood?

  • a normal ovulatory cycle
  • normal-length but anovulatory cycle
  • very long or irregular cycles, which tend to be anovulatory
  • withdrawal bleed when you are on the pill
  • or even a post-menopausal vaginal bleed from taking sequential hormone therapy

I don’t even know if anyone is asking these questions, because there is relatively little interest or appreciation in the varieties of sources of menstrual blood and how it might change its quality.

Time and Time Again

April 18th, 2010 by Elizabeth Kissling

Guest Post by Paula S. Derry, Ph.D.

Déjà vu

An article in today’s New York Times Magazine recounts the author’s experience with a debilitating depression that began during her perimenopause, the transitional time leading up to menopause.   For her, prescription estrogen was a life-saver that alleviated her symptoms.  The article places her experience in the context of research on the Timing Hypothesis, an idea that arose after the Women’s Health Initiative, or WHI, research project.  WHI clinical trials documented that hormone supplements after menopause did not, as had previously been assumed, lower a woman’s risk of heart disease.  Heart disease risk was not lower, and, in fact, when a number of chronic illnesses were considered together, the medication did more harm than good overall.  The Timing Hypothesis is the idea that the WHI was fundamentally flawed, because hormones must be started right around the time of menopause to have a health-promoting effect and the subjects in WHI were on average over 60; if started when a woman is older, when chronic illnesses have already started, the hormones are actually harmful rather than helpful.  The Sunday New York Times article presents this idea uncritically, without quoting any of the many experts who do not find it plausible or convincing, and, in addition, presents a lurid, unscientific  description of perimenopausal hormonal dynamics with words like “ricocheting hormones” and an “upheaval” that causes a “hellacious strain” on the brain. The author suggests that WHI was  a poorly planned study that asked the wrong questions with the wrong methodology.  The Timing Hypothesis, if true, might lead to a cure for Alzheimers and have other important health repercussions.

Time for a reality check.

Let’s go back in time to before the WHI research. Beginning in the 1980s, professionals asserted that hormone therapies were safe and effective to prevent chronic illnesses, especially heart disease, in postmenopausal women.   This idea was aggressively promoted, and it was not limited to women around the time of menopause.  Clinical trials are required to prove that a new medication is safe and effective before the Food and Drug Administration will approve that medication. However, once approved and available on the market, it is okay for doctors to use their judgment and prescribe the drug for whatever use they believe is reasonable.  Many of the claims for estrogen were for this kind of off-label use because there was no clinical trial proof that estrogens reduced heart disease, made women “feel better,” or improved their lives in many other ways being claimed.  However, other kinds of evidence made it seem plausible. There were “biologically plausible” mechanisms–this means that because of things we know about the body–like the fact that there are estrogen receptors in the brain–it is plausible, we can hypothesize a way that  estrogen would have a certain health effect.  There were the personal experiences of women. There was the idea that menopause was intrinsically unhealthy and that women were not meant to “outlive their ovaries.” Using estrogens was compared by some to using vitamin supplements or to a diabetic using insulin. There was a strong conviction among certain enthusiastic scientists and practitioners, some of them highly respected individuals, that it was all so. Professional groups of various sorts frequently issue opinions about medications; here, many groups offered the opinion that all women be offered hormone treatment.  Physicians were encouraged to prescribe hormones for disease prevention because it was so certain that it would help their patients, rather than waiting for the slow process of clinical trials to take place. Wyeth, a pharmaceutical company,  asked the FDA to approve estrogen for heart disease prevention even without clinical trials.

Typically, what was said was that women would benefit from using hormones. There was little or no discussion that estrogen needed to be started around the time of menopause to be effective. In fact, when the FDA declined Wyeth’s request for approval, the company, in order to provide clinical trial data for the FDA,  financed a study of secondary prevention–giving estrogens to women who already had had a heart attack, the very older sicker women that the Timing Hypothesis says will not benefit–believing that there was a good enough chance that estrogen would be beneficial to warrant their financing the study.

The WHI was based on the idea that if a medication is being advocated for widespread use, it should be tested by a clinical trial.  The main question tested by the WHI clinical trial was this:  Were hormones effective in preventing heart disease, as was the common wisdom of the day?  The answer was unambiguous:  No.  Even though many prestigious researchers and physicians claimed with great enthusiasm that this was the case, even though it would have been a great thing if you could find a way to prevent heart disease, even though there were plausible biological mechanisms, even though it fit in with a common-sense idea that menopause was an estrogen deficiency disease–it just wasn’t true.

The Timing Hypothesis arose from the ashes of WHI.  This hypothesis says, well, yes, we have evidence that, overall, hormones don’t prevent heart disease, but we can’t believe we were wrong:  Maybe age-related differences are important.  As portrayed in the New York Times article, we once again have prestigious researchers, plausible biological mechanisms, terrible medical problems that might be prevented if only this were true, health problems caused by hormones being minimized, portraying menopause as an estrogen deficiency disease, comparing estrogens to reading glasses.  And we have the suggestion that all women, not just women having menopause-related problems, complications, or distress, might re-examine using hormones.  And again, we have an absence of evidence.

Another Risk Associated with Hormone Therapy

February 7th, 2010 by Elizabeth Kissling

A study to be published in the British Medical Journal’s Thorax,* which focuses on respiratory medicine, finds that estrogen-only hormone treatment for menopause symptoms is associated with higher risk of asthma. The study involved nearly 58,000 women over 12 years. The researchers compared women who had never used any form of hormone treatment, women who used estrogen plus progestin, and women who used estrogen only treatment.Cartoon drawing of human lungs

The women who had used hormone treatments were 21% more likely to develop asthma; those who had used estrogen-only treatments showed a 54% higher overall risk of asthma.

Asthma is generally more common in young women after menarche, and more severe in women than in men.

*Neither the study nor the abstract appear to be available online.

Newsflash: Women get older with or without hormone therapy

January 5th, 2010 by Elizabeth Kissling

Cover of journal MENOPAUSEAs we have often noted here, one of the key reasons the marketing of hormone therapy for menopausal women has been so successful is the misguided belief that menopause is an estrogen-deficiency disease. Among other purported disadvantages of the decline in estrogen that accompanies normal aging was the belief that this decline caused muscle loss and other declines in physical functioning. (Muscle cells have receptors for estrogen, and recent research has linked higher blood levels of the hormone to greater muscle strength in elderly women.)

But the Women’s Health Initiative (WHI) is still providing new information about the lack of benefits of HT. (For those who are new around here, the WHI is a large US clinical trial begun in 1991, in which thousands of postmenopausal women were randomly assigned to take either HT or placebo pills. The study was abruptly ended ahead of schedule in 2002, when researchers discovered that the women taking the hormones had higher risks of heart attack, stroke, breast cancer, and blood clots – the very conditions the drugs were assumed to prevent – than placebo users.) In a new study based on a subgroup of 2400 women to be published in a forthcoming issue of Menopause (February 2010), both the women using HT and the placebo groups showed similar dips in muscle strength and walking speed over six years. In other words, women get older and show physical indications of aging with or without hormone therapy.

Readers should note that statements published in re: Cycling are those of individual authors and do not necessarily reflect the positions of the Society as a whole.