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).

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 Lifetime.com until Oct. 11; preview a short clip at right.)

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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.”

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?

Trying to Handle the Hype Around “Hot Flash Havoc”

October 6th, 2010 by Heather Dillaway

Hot-Flash-HavocOkay, I haven’t seen the film in full yet. And, yes, I’ll admit right up front that I’m not menopausal yet. And for many readers  this may be enough to discount what I might say here, but….

I have interviewed quite a number of menopausal women in the last ten years and very few have been as negative about menopause as the new documentary, Hot Flash Havoc. It was just released this summer and was screened at the Aspen FilmFest 2010 this week, and from the writeups in the Aspen Times and Snowmass Sun this past weekend, this documentary is definitely a winner.

If you like to think about your normal processes as problematic and in need of fixing, that is. Now, I’m not saying that there aren’t awful signs and symptoms that individual women have to find a better way of dealing with and that we shouldn’t busy ourselves with finding ways to make bothersome signs and symptoms dissipate (this is indeed an important activity), but the sense I get from reading all of the writeups of the film and watching the various trailers for the film on YouTube is that Hot Flash Havoc (and its filmmaker, Heidi Houston) define menopause as a crisis that is wrecking middle-aged women’s lives everywhere.

In addition, the entire film seems to be advocating a gentler critique of WHI results and for women to increase their usage of hormone therapies. Overall, I feel like this film moves us backwards rather than forwards in our search to help women answer questions about their own midlife experiences. Houston is quoted in interviews as saying things like “let’s fix our women” by helping them “manage menopause.” Seriously? I feel like I’m reading Robert Wilson’s 1966 work about keeping women “feminine forever.”

Speaking of which, men’s desires and needs seem to figure prominently in this film, in that menopausal women are portrayed as doing damage to men. Can’t we move on from ideas like this?

And I’m not the only one critiquing this film, by the way. Other bloggers hate it too. This is NOT a film worth supporting at all, unless we believe that menopause is a terrible thing, and a condition that needs to be fixed.

I have my critiques of Menopause! The Musical, but compared to Hot Flash Havoc, Menopause! The Musical is great!!!!

Ghostwritten articles funded by Wyeth overstated benefits and downplayed harms

September 8th, 2010 by Chris Hitchcock

An open-access article published in PLOS Medicine yesterday, Dr. Adriane Fugh-Berman, associate professor in the Department of Physiology at Georgetown University Medical Center in Washington DC, presents an article describing the ways in which the pharmaceutical industry used a medical education & communication company to produce ghostwritten articles that inserted marketing messages into articles published in medical journals.

This article is the first academic analysis of the 1500 documents unsealed in recent litigation against the pharmaceutical giant Wyeth (now part of Pfizer). It reveals the ways in which pharmaceutical companies use ghostwriters to insert marketing messages into articles published in medical journals. Dr. Adriane Fugh-Berman, associate professor in the Department of Physiology at Georgetown University Medical Center in Washington DC, analyzed dozens of ghostwritten reviews and commentaries published in medical journals and journal supplements that were used to promote unproven benefits and downplay harms of Prempro—a brand of menopausal hormone therapy (HT)—and to cast competing therapies in a negative light. These articles were widely circulated to drug reps and doctors to disseminate the company’s marketing messages. The analysis appears in this week’s PLoS Medicine.

Wyeth used a medical education & communication company, DesignWrite, to produce ghostwritten articles in order to mitigate the perceived risks of breast cancer associated with HT, to defend the unsupported cardiovascular ‘‘benefits’’ of HT, and to promote off-label, unproven uses of HT such as the prevention of dementia, Parkinson’s disease, vision problems, and wrinkles, writes Fugh-Berman.

The analysis revealed that DesignWrite was paid US$25,000 to ghostwrite articles reporting clinical trials, including four manuscripts on the HOPE trials of low-dose Prempro. DesignWrite was also assigned to write 20 review articles about the drug, for which they were paid US$20,000 each.

The analysis concludes that “Given the growing evidence that ghostwriting has been used to promote HT and other highly promoted drugs, the medical profession must take steps to ensure that prescribers renounce participation in ghostwriting, and to ensure that unscrupulous relationships between industry and academia are avoided rather than courted.”

In July 2009, PLoS Medicine, represented by the public interest law firm Public Justice, and The New York Times acted as intervenors in litigation against menopausal hormone manufacturers by 14,000 plaintiffs whose claims related to the development of breast cancer while taking the hormone therapy Prempro (conjugated equine estrogens). This resulted in a US federal court decision to release approximately 1500 documents to the public. The Wyeth Ghostwriting Archive is available at http://www.plosmedicine.org/static/ghostwriting.action or through the UCSF Drug Information Document Archive at http://dida.library.ucsf.edu/documents.jsp

Funding: The author received no specific funding for this article.

Competing Interests: Dr. Fugh-Berman was a paid expert witness on behalf of plaintiffs in the litigation referred to in this paper. She was not paid for any part of researching or writing this paper. Dr. Fugh-Berman directs PharmedOut, a Georgetown University-based project founded with public money from the Attorney General Consumer and Prescriber Grant program and currently supported by individual donations.

Citation: Fugh-Berman AJ (2010) The Haunting of Medical Journals: How Ghostwriting Sold ‘‘HRT’’. PLoS Med 7(9): e1000335. doi:10.1371/journal.pmed.1000335

(This blog largely lifted from the article press-release).

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.