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Menopausal HRT with non-bioidentical hormones - the WHI studies

What exactly did the notorious WHI (Women's Health Initiative) study show?

It is well established menopausal HRT with estrogen alone or estrogen combined with progesterone or progestin significantly relieves symptoms of menopause and prevents osteoporosis.[1-4] However, in 2002, the principal results of the Women’s Health Initiative (WHI) trial were published in the prestigious Journal of the American Medical Association.[5] 

From 1993 through 1998 about 16,608 healthy postmenopausal women aged 50 to 79 years had been enrolled in a study with the aim to specifically investigate health effects of menopause HRT (Hormone Replacement Therapy).[5]
All women enrolled had an intact uterus and received either the most commonly prescribed
HRT in the United States at the time - 0.625 mg/day of CEE (conjugated equine estrogen) plus 2.5 mg/day of medroxy-progesterone acetate (MPA) (sold under the brand name Prempro® or Premphase®) - or placebo.[5] 

Note: As described elsewhere What are Bioidentical Hormones CEE and MPA are non-bioidentical hormones.

These are the type of hormones that were used in the well-known WHI studies.

In an upcoming article we will outline the effects of bioidentical HRT, and contrast bioidentical estrogen/progesterone with non-bioidentical estrogen/progestin.

The planned duration of the study was 8.5 years, however it was stopped early after 5.2 years because the incidence of invasive breast cancer exceeded the acceptable rate and the global index statistic showed that risks were exceeding benefits. More specifically, the results showed the following in the CCE + MPA group:

- 26% increased risk of breast cancer

- 29% increased risk of myocardial infarction or death from cardiovascular disease  

- 41% increased risk of cerebral vascular accident

- 200% increased risk of venous thrombotic disease/embolism, deep vein thrombosis, and pulmonary embolism (blockage of an artery in the lungs by fat, air, a blood clot, or tumor cells).

The conclusions drawn from this study was that administration of 0.625 mg/day of CEE and 2.5 mg/day of MPA is not appropriate for the primary prevention of cardiovascular disease in menopausal women, and furthermore increases risk of invasive breast cancer, cerebrovascular accident, venous thromboembolism, deep vein thrombosis, and pulmonary embolism.

Additionally, in a secondary study, the results of which were published in 2003, the Women’s Health Initiative Memory Study (WHIMS) revealed that women aged 65 years or older who received the same combination of 0.625 mg/day of CEE and 2.5 mg/day of MPA had double the risk of dementia compared with women not taking these hormones.[6] 
A WHI follow up study published in 2005 reported that while estrogen plus progestin HRT relieves some menopausal symptoms, such as vasomotor symptoms and vaginal or genital dryness, it also comes with side effects, such as bleeding, breast tenderness, and an increased likelihood of gynecologic surgery.[3] Increased breast tenderness during use of CEE + MPA has been associated with increased subsequent breast cancer risk.[7] This supports the earlier 2002 milestone report of an increased incidence of breast cancer.[5] All these findings support the conclusion that the risks of non-bioidentical estrogen and non-bioidentical progesterone outweigh the benefits.
Currently, all classes of estrogens and progestogens (progesterones and progestin) that are being sold in the United States, and are formulated for HRT as opposed to contraception, carry a black box warning on the package insert to notify consumers of the risks of these products, as discovered during the WHI trial.

What about estrogen only HRT

(aka estrogen monotherapy or unopposed estrogen therapy)?

Because progestin markedly increases the risk of breast cancer relative to estrogen use alone [8], a WHI follow up study investigated menopause therapy with estrogen only.[9] Enrolled were 10,739 postmenopausal women, aged 50-79 years, with prior hysterectomy (surgery that removes the uterus). The intervention was non-bioidentical estrogen (conjugated equine estrogen [CEE]) 0.625 mg/day or placebo. After 6.8 years, this study was also terminated early because of unacceptable risk-to-benefit ratio. The alarming results were:[9]

- 39% increased risk of stroke
- 34% increased risk of pulmonary embolism (blockage of an artery in the lungs by fat, air, a blood clot, or tumor cells)
The conclusion from this study was that non-bioidentical estrogen should not be recommended for chronic disease prevention in postmenopausal women.[9]

Aftermath of the WHI studies

Widespread media coverage of results of the WHI studies led to a marked decline in sales and use of postmenopausal hormones.[10] One year following the publication of WHI results, prescriptions for Prempro® (horse urine-derived estrogens and a synthetic progestin, both non-bioidentical hormones) fell by 66% and those for Premarin® (horse urine-derived estrogens, non-bioidentical) fell by 33%.[11] 

An interesting observation that was made after this marked reduction in non-bioidentical HRT prescribing and use was a concomitant decline in breast cancer incidence.[12, 13] A study published in 2006 reported that a 68% drop in the use of non-bioidentical estrogen combined with non-bioidentical progestin was paralleled by 10% decline in breast cancer incidence.[12] Another study found a 22.6 % decline in breast cancer incidence.[14]

Alternative solutions to treatment of menopausal symptoms

Understandingly, today many women refuse non-bioidentical HRT and seek out alternative therapies for treatment of their menopausal symptoms. [11, 15]

Studies show that bioidentical estrogen and biodentical progesterone is one solution to achieve this. We will cover this in upcoming articles.

The other less well acknowledged, albeit effective, solution is testosterone therapy for menopausal women, which we have covered in a previous articles:

Testosterone Therapy vs. Estrogen Therapy in Surgically Menopausal Women - effectiveness comparison

Beneficial effects of testosterone therapy on menopause symptoms and quality of life

Testosterone in women - is it physiological and clinically important?


1.            Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet. Gynecol. Dec 1998;92(6):982-988.

2.            Morris EP, Burbos N. Menopausal symptoms. Clinical evidence. 2010;2010.

3.            Barnabei VM, Cochrane BB, Aragaki AK, et al. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet. Gynecol. May 2005;105(5 Pt 1):1063-1073.

4.            National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms. Ann. Intern. Med. Jun 21 2005;142(12 Pt 1):1003-1013.

5.            Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. Jul 17 2002;288(3):321-333.

6.            Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. May 28 2003;289(20):2651-2662.

7.            Crandall CJ, Aragaki AK, Cauley JA, et al. Breast tenderness and breast cancer risk in the estrogen plus progestin and estrogen-alone women's health initiative clinical trials. Breast Cancer Res. Treat. Feb 2012;132(1):275-285.

8.            Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J. Natl. Cancer Inst. Feb 16 2000;92(4):328-332.

9.            Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. Apr 14 2004;291(14):1701-1712.

10.          Haas JS, Kaplan CP, Gerstenberger EP, Kerlikowske K. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann. Intern. Med. Feb 3 2004;140(3):184-188.

11.          Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA. Jan 7 2004;291(1):47-53.

12.          Clarke CA, Glaser SL, Uratsu CS, Selby JV, Kushi LH, Herrinton LJ. Recent declines in hormone therapy utilization and breast cancer incidence: clinical and population-based evidence. J. Clin. Oncol. Nov 20 2006;24(33):e49-50.

13.          Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N. Engl. J. Med. Apr 19 2007;356(16):1670-1674.

14.          Robbins AS, Clarke CA. Regional changes in hormone therapy use and breast cancer incidence in California from 2001 to 2004. J. Clin. Oncol. Aug 10 2007;25(23):3437-3439.

15.          McIntosh J, Blalock SJ. Effects of media coverage of Women's Health Initiative study on attitudes and behavior of women receiving hormone replacement therapy. Am. J. Health. Syst. Pharm. Jan 1 2005;62(1):69-74.