The Women’s Health Initiative and the law of unintended consequences

Issue: October 2015

ByWulf H. Utian, MD PhD DSc FRCOG FACOG FICS

The investigators in the Women’s Health Initiative study announced the premature termination of the estrogen/progestogen therapy arm of the study in July 2002, warning women of dangers of hormone therapy after menopause. Unfortunately, that warning caused hundreds of thousands of women to run from postmenopausal hormone therapy, a treatment that posed little risk and offered benefit to many of them.

Inappropriate extrapolation

The primary objective of the WHI, undertaken largely in older women, was to determine the effect of these hormones on cardiovascular disease — and not to study menopause. In fact, the final major WHI analysis, published in 2013, showed benefit to exceed risk in the younger estrogen-only users, and this later analysis also demonstrated minimal risks of combined therapy in younger postmenopausal women.

At the time of the termination announcement in 2002, I wrote: “While the merits and demerits of the data and the wisdom of the decision to terminate this arm of the WHI study will be debated for years, the manner in which the study was terminated was poorly planned, abrupt and inhumane. Predictably, the media response was enormous, ranging from thoughtful to sensational. Panic was caused, numerous women discontinued therapy, and women and their health providers alike have been thrown into a state of confusion, distrust and quandary of what to do next.” I stand by what I wrote, and history confirms the accuracy of this comment.

Unanticipated effects

The discontinuation of the WHI study resulted in several unintended consequences. The early postmenopausal women aged 45 to 60 years who abruptly stopped taking these hormones may have been subject to a triple jeopardy. Firstly, there is mounting evidence for increasing incidence of mortality from complications of CVD and osteoporosis. Secondly, millions of women have avoided symptom-relieving medications that for most carried very little risk, certainly no greater risk than many other frequently used long-term medications, such as statins.

Finally, the fear created by the negative publicity about postmenopausal HT spawned a new industry of herbal products for menopausal symptoms, most of which are ineffectual. It also resulted in the bioidentical/compounding HT industry, which involves the marketing of non-FDA-approved compounds, such as estriol, and non-FDA-approved compounded mixtures of estradiol and progesterone, with claims that these untested concoctions are natural and do not carry the risk of conventional, approved products. Of course, that is not true, and early reports now suggest that the compounded products may be associated with an increase in the incidence of uterine cancer.

The bottom line is that investigators and the public should beware of extrapolating meaning from findings beyond what the data actually show. The law of unintended consequences can come into play, and good intentions may reap negative health outcomes.

References:
Karim R, et al. Menopause. 2011;18:1172-1177.
Manson JE, et al. JAMA. 2013;310:1353-1368.
North American Menopause Society. Menopause. 2015;doi:10.1097/GME.0000000000000546.
North American Menopause Society. Menopause. 2015;doi:10.1097/GME.0000000000000553.
Rossouw JE, et al. JAMA. 2002;288:321-333.
Sarrel PM, et al. Am J Public Health. 2013;103:1583-1588.
Utian WH. Menopause Management. 2002;11:6-7.
Utian WH. Climacteric. 2012;15:320-325.

For more information:
Wulf H. Utian, MD, PhD, DSc, FRCOG, FACOG, FICS, is founder of The International Menopause Society and The North American Menopause Society and is currently executive director of NAMS. Utian can be reached at The North American Menopause Society, 5900 Landerbrook Drive, Suite 390, Mayfield Heights, OH 44124; email: wulf@utianllc.com. Utian reports no relevant financial disclosures.