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:

The woman, the serpent and the cycle

March 13th, 2012 by Chris Hitchcock

According to a recent study, women are best at picking out a picture with a snake during the days immediately before their period. You might think this would be a surprise, given the general idea of premenstrual compromise in women. Mind you, there isn’t much data to support poorer thinking or performance for women during the premenstrual period.

However, the authors were able to salvage the idea of premenstrual compromise here. They argue that about 30% of women have premenstrual syndrome, and most of the rest of us show some kind of cyclicity. And so they attribute the 200 millisecond (1/5 of a second) faster response to anxiety and fear. Either that, or it is maternal instinct, protecting the small cluster of cells that might possibly be an impending pregnancy.

Media has picked this up, with headlines about PMS being good for something after all.

Sometimes it seems that women can’t win for losing.

Warning: Pfizer Generic Birth Control Pill Recall

February 1st, 2012 by Chris Hitchcock


Pfizer has announced that there was a mistake in packaging some of their generic oral contraceptive pills Lo/Ovral(R)-28 and Norgestrel/Ethinyl Estradiol Tablets.

The mistakes seem to have been in the sequence of placebo (sugar pills) and perhaps in the ingredients.

Please check the FDA web site for details.


Childhood abuse and menarcheal age

January 17th, 2012 by Chris Hitchcock

Last month I wrote about menarcheal age in Ethiopian girls, and that food insecurity leads to a delay in the onset of menstruation. This fits with the general response of the reproductive system to energetic stress – low energy leads to suppression of the hypothalamus, which interferes with ovulatation and, in stronger cases, with menstruation itself.

But, it would seem, not all stressors are the same. Over the past decade or so, a series of studies have shown that, unlike food shortages, the stresses of childhood neglect, abuse, and even the absence of a father tend to accelerate rather than delay puberty.

So how do researchers understand the effects of these different types of stress during development? The leading hypothesis is an evolutionary one, based on something called life history theory. The theory is that there is a tradeoff between reproduction and survival. Early energy put into reproduction comes at a cost of long term survival, and delayed reproduction may result in no reproduction at all unless the chances of surviving are good. This can be used to understand different life history strategies such as weeds (early reproduction, short survival) versus trees (later reproduction, longer survival). It can be used to look at different strategies within a species. And it can also be used to look at a contingent strategy within a species, one that is expressed in different ways depending on the circumstances.

In the case of humans and abuse during development, the argument is that abuse, neglect and the absence of a father all indicate more adverse conditions, in which long-term survival is less likely, and accelerated reproduction is favored.

There is good reason to be cautious when assessing evolutionary arguments about humans, especially when sex and reproduction come into the story. However, in this case the data are persuasive. Here are a few links to articles that have addressed the topic:

Childhood abuse and early menarche: findings from the black women’s health study.

Childhood sexual abuse and early menarche: the direction of their relationship and its implications.

A life history assessment of early childhood sexual abuse in women.

Sexual trajectories of abused and neglected youths

Age of menarche: the role of some psychosocial factors.

Food insecurity is associated with later puberty

December 20th, 2011 by Chris Hitchcock

Many girls in Africa have insecure access to food, that is, they worry about getting enough food, and they sometimes eat less than they want, or go without food. There are two theories about how this might affect the onset of menstruation (menarche). One is that the limitations in energy and nutrition might slow development, resulting in a later menarcheal age. The other evolutionary theory is that early life stressors trigger a shift in so-called life history strategy, leading to accelerated development and an earlier menarche. In a recent article in the journal Reproductive Biology and Endocrinology, researchers from Ethiopia, Belgium and the USA presented data from the first two years of the Jimma Longitudinal Family Survey of Youth to contrast these two theories. The survey was conducted in southwest Ethiopia, sampling across rural, urban and small town areas and including boys and girls. Data about the household and the girls’ experience of food insecurity were assessed by questionnaire in the first year, and in the second year girls were asked whether and how old they were when they first menstruated. 900 girls, with an average age of 14.8 at baseline, participated in both of the first two years of the five year study.

Overall, girls who reported some degree of food insecurity (n=225/900) were similar in age, region (urban, semi-urban, rural), and nutritional status (whether they were short for age). However, they were more likely to be in a male-headed household, tended to be in middle income rather than high income households, and reported more domestic work than those reporting food security. Overall, girls with moderate to severe food insecurity were significantly less likely to have undergone menarche. The estimate of the age at menarche was one year older for Ethiopian girls who have insecure access to food.

Girls in the developing world experience menarche at an older age than those in the developed world, and, with development, other countries are experiencing the secular change of earlier age at menarche. In this study, the estimated age at menarche was younger in urban centres (14) than in semi-urban or urban areas (15), and girls in high income households had an earlier menarche, suggesting that improved food security may be part of the puzzle explaining these changes.

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.


Earlier menopause with ovary-saving hysterectomy

November 22nd, 2011 by Chris Hitchcock

Recently Heather Dillaway blogged about the challenges and frustrations of naming, and this blog continues with that theme, looking at a recent article about increased rates of “ovarian failure” following ovary-preserving hysterectomy.

Ovary-saving hysterectomy linked to early menopause,” reads the USA Today on-line headline, and the article opens with the statement that:

Younger women who have a hysterectomy that spares the ovaries are almost twice as likely to go through early menopause as women who do not have their uteruses removed, according to a new study. 

It’s an alarming statement, and one likely to alarm an already anxious woman. The study in question was a longitudinal study following 406 women aged 30-47 at the time of their surgery and a control group of 465 similar-aged women who did not have a hysterectomy. The study will be published in the December 2011 issue of the peer-reviewed journal Obstetrics & Gynecology, and the news coverage was drawn from the Duke University press release, entitled “Hysterectomy Increases Risk for Earlier Menopause In Younger Women”.

The first challenge of naming is in the subtle difference between the press release’s earlier menopause, and the USA today article’s early menopause. Early menopause is defined as menopause that occurs before the age of 40; the earlier menopause in the article is a difference of about 2 years — an important difference.

In women who no longer have menstrual flow, how did the authors establish menopausal status, or “ovarian failure”, as they called it? In women with a uterus, menstrual flow is a convenient landmark, which is roughly aligned with the hormonal changes to decide when menopause (or is it post-menopause?) has begun. We assume that 12 months without menstrual flow likely means that there will be no further flow (although that is not always true), and that it is a good estimate of when ovarian hormonal cycles have stopped. In this article, the authors used an annual blood sample to measure a hormone called FSH (follicular stimulating hormone). FSH is high in menopausal women, and an FSH>40 IU/L was used as a criterion for reaching menopause. However, we have known since 1994 that a high FSH level is not diagnostic of menopause, and, indeed, 6 of the 504 women were excluded because they had a baseline FSH > 40 IU/L, despite having menstruated within the previous three months. Regularly cycling women in their 40’s can have high FSH levels, and later have low FSH levels and ovulatory cycles. In menstruating women, blood samples would also be timed, which is not possible for women who don’t menstruate. It would be interesting to know how the high FSH criterion corresponded to menstrual cycle history in the control group.

Studies like this are hard to do. The authors were careful — they enrolled women prior to surgery and followed control women in the same way. To get 403 women with complete data, they started with over 900 women.  The controls were fairly well matched — similar in age, age at first period, c-section and oral contraceptive history. However, women undergoing surgery were more likely to have had at least one full-term pregnancy (84.5% vs 68.3% in controls), and more likely to have had a previous tubal ligation. In addition, fibroids, endometriosis, ovarian cysts and previous surgery for fibroids were more common in those having a hysterectomy. Both the hysterectomy itself and the history of previous surgery, particularly tubal ligation, may also contribute to a difference between the two groups. Finally, women with hysterectomy were heavier than the control group.

By following the two groups, the authors were able to estimate that hysterectomy accelerated the rate of reaching the FSH threshold by about 2 years. This is consistent with other research, and fits with the finding that hysterectomy and other reproductive surgeries are associated with a lower rate of breast cancer, presumably due to lower estrogen exposure.

So, how does this fit with the frustration and complexity of naming? One frustration is with the persistent use of the value-laden term “ovarian failure” in the medical literature. But in this particular population, a large part of the frustration is technical. Perimenopausal hormones are changeable, and without menstrual flow as a landmark, it is even harder to estimate where a particular woman is on her transition into her menopausal years. We might learn more with daily hormone samples over a longer period of time, but that would be hard for women to do and would cost too much. If a single high FSH value is one step along the pathway to menopause, and if hysterectomy doesn’t change the timing of that step along the path, and if women scheduled for hysterectomy aren’t already further along that path than the controls, then these data give us some idea of the effect of hysterectomy on when women reach menopause.

There is more I could write about the technical details of this one paper, and perhaps that is another point to make — scientific articles are complicated logical arguments, and critiquing them from within science is challenging to fit into a blog format.

Some recent news about Hot Flushes and Night Sweats

October 25th, 2011 by Chris Hitchcock

Prevalence of Hot Flushes and Night Sweats in UK women 54-65

In a new, large (over 10 000 women)  survey of UK women aged 54-65, Myra Hunter and colleagues reported on the proportion of women who have hot flushes and night sweats (HF/NS), and on how frequent and bothersome they found them. Surprisingly, they did not find a difference across ages; 54% of women reported that they currently experienced hot flushes and/or night sweats, and this was as true for women in their mid-60’s as in their mid-50’s. Current users of hormone therapy were less likely to have current HF/NS, while those who had discontinued hormone therapy were more likely to have HF/NS compared with never users. It is common to think that HF/NS last for 2-5 years in a woman’s early 50’s. This study suggests that there is a need for therapies that are effective and can be used safely for a much longer duration.

FDA says no to Pristiq for (Post)Menopausal Hot Flushes

In early September, the US FDA (Food and Drug Administration) turned down Pfizer’s request to market it’s antidepressant drug, Pristiq, as a treatment for hot flushes in menopausal women. Pfizer inherited Pristiq when it acquired Wyeth (makers of the hormone therapy medication PremPro).  This is the first anti-depressant to seek official approval for this indication, although there has been research and promotion of antidepressants as alternative, non-hormonal, off-label medications for vasomotor symptoms (hot flushes and night sweats) for some time.

Perhaps not surprisingly, there has been little coverage of this in the media, as contrasted with the coverage of the various steps towards this point.

I have noticed that when a drug therapy is approved or takes a step along the path towards approval, news coverage is general and widespread. When there is a hitch in the approval process, often only the financial markets pick up the story, because it affects share values. However, there is an article in Medscape that provides more background on the history of this application.


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.

There’s still time to register for SMCR 2011 in Pittsburgh

May 13th, 2011 by Chris Hitchcock

SMCR 2011 will be held in Pittsburgh, PA at Chatham University from June 2-4, 2011. The conference is warm, supportive and interesting, and is an excellent opportunity to be exposed to the richness of multidisciplinary perspectives on the menstrual cycle and women’s reproductive physiology from a diversity of feminist, woman-centred perspectives. It is a research conference, and provides a venue for collegial interactions across disciplines such as nursing, medicine, psychology, anthropology, women’s studies, communications, and film studies. It also provides a venue for activists and researchers to meet. Interested lay people are also welcome to attend.

The title of this year’s conference is Embodied Consciousness, Informed Choices: Critical Perspectives On the Menstrual Cycle. The keynote speech will be given by Dr. Sharra Vostral, Associate Professor of Gender and Women’s Studies and History at the University of Illinois, and author of Under Wraps: A History of Menstrual Hygiene Technology (2008). Dr. Vostral’s current research centers on the innovation of Rely tampons and the emergence of Toxic Shock Syndrome.

Two plenary panels are scheduled: One on stigma associated with menstruation, broadly considered, and a second on sustainable menstrual management in both developing and developed countries. A preliminary draft of the conference schedule can be viewed on the conference web site.

This year, we have been able to secure inexpensive dorm accommodation. To register, go to this link. To promote the conference, please share this blog posting, or download and print this poster and place it where interested colleagues may find it.

Please join us, and take this opportunity to support the Society and meet the faces behind Re:Cycling.

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.