How Much Have Women — and Society — Benefited from the Women's Health Initiative Findings?

Summary and Comment |
May 8, 2014

How Much Have Women — and Society — Benefited from the Women's Health Initiative Findings?

  1. Andrew M. Kaunitz MD

Disease-simulation analysis suggests substantial economic benefits but failed to consider other important outcomes.

  1. Andrew M. Kaunitz MD

After findings from the Women's Health Initiative (WHI) estrogen plus progestin (EPT) clinical trial — a $260 million undertaking — were published in 2002, use of EPT and estrogen-only hormone therapy (HT) by U.S. women plummeted. Now, investigators have estimated the clinical and economic effects of this trial from a payer perspective. They developed a disease-simulation model to evaluate the trial's impact from 2003 to 2012 on women (age range, 50–79) with an intact uterus and estimated outcomes of a “WHI scenario” (based on lower prevalence of HT use resulting from WHI findings) versus a “no-WHI” scenario (based on trends in HT use before the WHI).

In the WHI scenario compared with the no-WHI scenario, 126,000 fewer cases of breast cancer, 76,000 fewer cases of cardiovascular disease, and 80,000 fewer cases of venous thromboembolism occurred, as well as 263,000 more fractures and 15,000 more cases of colorectal cancer. The authors estimated that the WHI resulted in $35.2 billion savings in medical expenditures (principally due to fewer prescriptions for EPT and associated office visits).


At first glance, the clinical and economic benefits of the Women's Health Initiative estrogen plus progestin trial seem enormous. However, I am surprised that the authors did not consider other key issues. Less use of systemic hormone therapy has resulted in many more women suffering from bothersome vasomotor and sleep-related menopausal symptoms. In addition, the authors did not account for the major decrease in use of estrogen-only therapy by women with hysterectomies. Given that ET lowers risk for breast cancer and cardiovascular disease, declines in its use have resulted in increased morbidity and mortality from these conditions. Lastly, because the profound reduction in use of systemic HT has not been accompanied by greater use of vaginal estrogen, a substantial increase in symptomatic vulvovaginal atrophy with attendant sexual dysfunction and impaired quality of life has resulted.

Editor Disclosures at Time of Publication

  • Disclosures for Andrew M. Kaunitz MD at time of publication Consultant / Advisory board Actavis plc; Bayer AG; Merck; Teva Pharmaceutical Industries Limited; UpToDate Royalties UpToDate Grant / Research support Trimel Pharmaceuticals Corp; TherapeuticsMD; NIH Editorial boards Contraception; Menopause; Contraceptive Technology Update; OBG Management; Medscape OB/GYN & Women’s Health Leadership positions in professional societies North American Menopause Society (Secretary)


Reader Comments (7)

Andrew Kaunitz, MD Physician, Obstetrics/Gynecology, University of Florida Health Sciences Center - Jacksonville
Competing Interests: Editor-in-Chief, Journal Watch Women's Health

Ms. Zimmerman's comments seem to be directed more at the Women’s Health Initiative than at my summary of Roth et al's analysis. Nonetheless, one clear area of common ground we have is that all hormone therapy is not the same. For example, the WHI assessed oral estrogen therapy only, and found that an elevated risk of venous thromboembolism (VTE) represents the statistically most prominent risk associated with such treatment. In contrast, transdermal estradiol-based hormone therapy regimens appear to have no impact on VTE risk.

Elizabeth Price FRCPath Physician, Pathology, Retired

The benefits from WHI findings have been huge. However, even randomised studies have the difficulty of finding genuine control women who have never been given hormones (for contraception, menopause, fertility, period pains etc etc)

The adverse effects of these hormones are inevitably understimated!

E WARD Physician, Family Medicine/General Practice

Where is Dr. Kaunitz's evidence supporting a large increase in genital or sexual symptoms in women who choose not to take HRT? A hot flash lasts on the order of seconds. How can a physician justify the longer-lasting side effects of exogenous hormone therapy for a completely natural milestone in life?

Sage wheeler Physician, Family Medicine/General Practice, SageMED Bellevue, WA

Amen, Darlene. The only update we need from WHI is an apology for such a poorly done study.

Wilton Braund Physician, Endocrinology, Private Practice and University Teaching Hospital

By my back-of-the-envelope calculation on Rossouw, et al's publication in 2002 (JAMA 288: 321-333) the combination of medroxyprogesterone and conjugated equine estrogens prevented about 55 colon cancers for every 60 breast cancers that it caused. Why, then do you quote the Roth article as showing such a big discrepancy in the numbers of breast cancers (125,000 fewer) and bowel cancers (15,000 more)? Is this an error of transcription in your review? Or is there a large hole in Roth's analysis?

Ellen CG Grant, MBChB, DOsbstRCOG Physician, Neurology, Retired

Most women in WHI studies had taken contraceptive or HRT hormones before being randomised. Thus means those randomised to take HRT were not compared with never ever users and adverse effects are inevitably underestimated

Major HRT trials were stopped prematurely because of increases in cancers and vascular diseases – if they had been continued the results would have been worse. So why is HRT still being promoted?1,2

Professor Jim Thornton, a former President of the Royal College of Obstetrics and Gynaecologists, noted the effect on mortality from all causes is in the opposite direction from benefit when only randomised trials are included.3

Many women get withdrawal hot flushes on stopping HRT. Progestogens and oestrogens can be addictive and difficult to stop.4 HRT is also a major cause of mental illness with an increased risk of suicide.5

It is no longer believed that HRT prevents colorectal cancer. There was no benefit from either estrogen-alone or estrogen plus progestogen in the WHI clinical trial and observational study after 7 to 8 years of intervention and follow-up.6 Hazard ratios (95% confidence intervals) from the WHI observational study were 0.80 (0.53-1.20) for estrogen and 1.15 (0.74-1.79) for estrogen plus progestogen. Also there was no protective effect on colorectal mortality.

The bad effects of using progestogens and oestrogens are overwhelming:-

Doubling of mortality from breast cancer 7

Doubling of mortality from ovarian cancer 8

Doubling of mortality from lung cancer 9

Doubling of deaths from suicide and suspected suicide 5

Doubling of cervical adenocarcinomas 10

4-5 fold increase in invasive cervical cancers 11

5 fold increase in endometrial cancer (oestrogens) 12

Doubling (or up to 6 times) of primary venous thrombosis 13

81% increase in myocardial infarctions (at one year) 14

44 -55% increase in ischemic strokes 15,16

Doubling (or up to 5 times) increases in migraine headaches and vascular over-reactivity 17,18

Increases in osteoporosis due to micro-thrombi in bones, mineral deficiencies, and decreases in serum bone alkaline phosphatase 19,20

Progestins, can activate 3 times more progesterone receptors than progesterone. It is progesterone and not oestrogens which immediately increase vascular endometrial growth factor which increase the metastatic spread of breast cancer.

HRT has been a health disaster for too long but it was welcome news that the fall in use due to the WHI results reduced breast cancer mortality in middle aged women.

1. Hickey M, Elliot J, Davison SL. Hormone replacement therapy. BMJ 2012;344:e763

2 Kmietowicz Z. Articles disputing link between HRT and breast cancer are “ridiculous”. BMJ 2012; 344:e513.

3 Thornton JG. Re: Hormone replacement therapy. BMJ 18 February 2012

4 White M, Grant ECG. Addiction to oestrogen and progesterone. J Nutr Environ Med 1998; 8:117-120.

5 Price EH. Increased risk of mental illness and suicide in oral contraceptive and hormone replacement therapy in studies. J Nutr Environ Med 1998; 8:121-127.

6 Prentice RL, Pettinger M, Beresford SA, et al. Colorectal cancer in relation to postmenopausal estrogen and estrogen plus progestin in the Women's Health Initiative clinical trial and observational study. Cancer Epidemiol Biomarkers Prev 2009;18:1531-7.

7 Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304:1684-92.

8 Beral V, Bull D, Green J, Reeves G for the Million Women Study Collaborators. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 2007;369:1703-1710.

9 Chlebowski RT, Schwartz AG, Wakelee H, et al; Women's Health Initiative Investigators. Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet 2009;374:1243-51.

0 J Green, A Berrington de Gonzalez, et al.. Risk factors for adenocarcinoma and squamous cell carcinoma of the cervix in women aged 20–44 years: the UK National Case–Control Study of Cervical Cancer. Br J Cancer 2003; 89: 2078–2086.

11 Zondervan KT, Carpenter LM, Painter R, Vessey MP. Oral contraceptives and cervical cancer--further findings from the Oxford Family Planning Association contraceptive study. Br J Cancer 1996;73:1291-7.

12 Persson I, Yuen J, Bergkvist L, Schairer C. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy--long-term follow-up of a Swedish cohort. Int J Cancer. 1996;67:327-32.

13 Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348:977-80.

14 Manson JE, Hsia J, Johnson KC, et al; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-34.

15 Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al; WHI Investigators. Effects of conjugated equine estrogen on stroke in the Women's Health Initiative. Circulation 2006;113:2425-34.

Darlene Zimmermann Yale MPH "88 Other Healthcare Professional, Other, N/A

Calling the WHI research a gold standard in 2014 is absurd!!

The WHI research has been discredited for so long and by so many!

HRT is preventative, not the therapy has to begin in a small window of time just before or at the time of menopause--- before disease processes begin. The average age of women subjects in WHI was well beyond menopause where disease processes had already taken hold.

But further, many many studies exist that explicitly demonstrate the correlation between synthetic progesTINs and many types of women's cancer. (Happy to forward these papers if there is anyone who is really reading this email??) In addition, continuous, combination therapy has been proven to be carcinogenic..(again happy to forward all my research papers and references)

Synthetic progesTIN (as opposed to bio-identical progesterone) has been shown to be carcinogenic in many well-designed European research studies as well as a few American studies. The time has come for publications and other media sources to start making this distinction so that women and their Gynecologists can understand risk distinctions.

A simple google search can inform of this distinction.

Using the word progestin to cover all forms of synthetic and bio-identical progesterone does great harm to women as well as being a term that is misguided and misleading. MOST IMPORTANTLY, the research quantifying the two types of formulations (synthetic vs bio-identical) in a double -blind placebo research design..HAS NEVER been need to ask WHY has this research never been attempted?

Formulations of HRT that use Estrogen and bio-identical progesterone are almost as heart-protective as Estrogen alone.(PEPI Trial, 1995) Progestins negate this heart protective effect of Estrogen. Yet the media continues to publish that HRT is not heart-protective.

Since that landmark PEPI study that showed that estrogen with bio-identical progesterone is heart-protective ,almost to the point of estrogen alone,, we have learned of other deleterious effects of synthetic progestins and for the life of me I cannot understand any physician prescribing it knowing what the researchers know.

Simplistically and incorrectly, all HRT is lumped together as one entity and as all having the same result. This mindset used by the media and many doctors as well as medical researchers, is false, misleading and harms women's health by having women make choices about HRT based on false information.

Ignored are different routes of administration, molecules that are different in their chemical bonds, dosing that is sequential or continuous, and the fact that women's bodies whose size and weight vary, are all different chemical factories. All these variables are ignored by researchers who should be smart enough to realize the implications.

With HRT "ONE SIZE DOES NOT FIT ALL". Not only are there different kinds of estrogen and progesterone preparation, but the media and researchers use the terms progesterone and progestin interchangeably.

Progestogens are synthetic molecules that are different than the molecules made in a woman's body, whose actions in women's bodies only mimic the action of progesterone and are not the same.

Not only do progestogens have a different potency, but most importantly, chemically, the progestin molecule doesn't even resemble the molecule made by a woman's body and is not recognized by women's immune systems.

In this way progestogens wreak havoc on women's bodies.

And for this reason a woman's body does not identify progestogens and does not respond in the same way as it would to a progesterone whose molecule is identical to the progesterone molecule made by a woman's body..

Synthetic progestogens/progestins(there are many preparations by different drug companies) are different chemically and herein lies one of the dilemmas.

Not only has synthetic progestin been implicated in breast cancer when given in a combination tablet such as the prempro used in WHI study (estrogen and progestin combined together and then dosed 365 days a year ,keeping in mind that there is not a woman alive whose body manufactures progesterone 365 days a year)
( Cancer,2003, mar 15;97:1387-92) but in 1990 researchers in England concluded,"....if estrogens reduce the risk of cardiovascular disease principally through lipid and lipoprotein mechanisms, then the additions of synthetic progestogens may not only negate this benefit, but may actually increase the risk."
"Due diligence" before publishing this outdated and misleading article in the Ann Intern Med should have been undertaken by the editors. Worse, this kind of information, used by women to make decisions about their health, is harmful to women everywhere.

Darlene Zimmermann MPH Yale'88

Your Comment

(will not be published)

Filtered HTML

  • Allowed HTML tags: <a> <em> <strong> <cite> <blockquote> <code> <ul> <ol> <li> <dl> <dt> <dd>
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Do you have any conflict of interest to disclose?
This question is for testing whether you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

* Required

Reader comments are intended to encourage lively discussion of clinical topics with your peers in the medical community. We ask that you keep your remarks to a reasonable length, and we reserve the right to withhold publication of remarks that do not meet this standard.

PRIVACY: We will not use your email address, submitted for a comment, for any other purpose nor sell, rent, or share your e-mail address with any third parties. Please see our Privacy Policy.