Hormone replacement therapy: the aftermath of WHI and HERS studies
Hormone replacement therapy: the aftermath of WHI and HERS studies |
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Key words: Women's Health Initiative, Estrogen/progestin Replacement Study, Hormone Replacement Therapy.
Introduction
The two large randomized clinical trials––the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI)––of continuous-combined estrogen–progestin therapy (HRT) for postmenopausal women 1,2 have been reported as providing new and shocking information on HRT. WHI is a huge study of 161,809 postmenopausal women aged 50-79 years. In the combined HRT arm 16,608 women with an intact uterus were randomized to receive placebo or conjugated equine oestrogen (0.625mg) plus medroxyprogesterone acetate (2.5mg) daily. The study was planned to run for 8 years but was stopped after 5.2years due to increased incidence of breast cancer in the treatment group. There was no increase in total mortality of all causes between the 2 groups.
However, there were on a negative note:
1. 26% increase in breast cancer rate (up from 30 to 38 women/ 10,000)
2. 29% increase in heart attack rate (up from 30 to 37 women / 10,000)
3. 41% increase in stroke rate (up from 21% to 29% per 10,000)
4. doubled incidence of blood clots (18 per 10,000 women).
On a positive note the study revealed:
1. 33% decrease in hip fracture rate (down from 15 to 10 per 10000)
2. 37% decrease in colorectal cancer rate (16 to 10 women per 10,000)
Future prescribing of HRT could be fraught with legal implications as regulatory authorities continue to assess the fall-out from WHI study. However, the results of the WHI and HERS studies are the direct consequences of unsuitable population selection, terribly wide inclusion criteria and the incongruous treatment choices.
Discussion
The first part of an interesting review on aftermath of WHI study by Andrea Riccardo Genazzani and Marco Gambacciani in Maturitas 3 stated that the most recent WHI study , the women similar to the HERS population can hardly be seen (and even less likely treated with hormones) by the gynaecologist 4. The study population is the major problem also for the interpretation of the WHI trial. The WHI study included women aged 50–79. In the HRT arm, 33.4% were 50–59, 45.3% were 60–69, and 21.3% were 70–79: with a mean age 63.2 years. The WHI population was more similar to the HERS population. These women are rather different from the healthier and younger women coming to Menopause Clinics 4. A vast proportion of the WHI women were not as healthy as the authors claim. About 7.7% had prior cardiovascular disease, 12.5% had elevated cholesterol levels requiring medication, 35.7% were on treatment for hypertension, 35% were overweight (BMI 25–29) and 35% were obese (BMI>30). However, in these women described as healthy (?), just a single HRT combination and strength was used. The WHI study medication (0.625 mg/day of conjugated equine estrogens plus 2.5 mg/day of medroxyprogesterone acetate) is suitable for the healthy perimenopausal 50-year-old women. This prescription is questionable if prescribed for example to a 79-year-old, obese subject suffering from hypertension. The high dropout rate as well as the high proportion of women who had undergone hysterectomy (procedures increased by 30% in the HRT group) clearly indicated that the treatment was inappropriate for a vast proportion of these women.
Therefore, the WHI results are questionable and uncertain even if obtained from a gold standard randomized clinical trial, and for sure these data cannot be extrapolated to the younger and healthier perimenopausal women.
In a further review by Martina from University of Berlin 5 Germany, she believes that to study the effect of one specific HRT combination on coronary heart disease was the primary outcome of WHI. Today we have to move beyond the negative results of WHI regarding cardio protection. We need to refocus on established knowledge of how to decrease the risk of heart disease in women of all ages, in particular ageing women.
There are well-studied strategies to reduce risk, some of which are briefly listed here 5
a) To abandon smoking,
b) Treatment of hypertension if present,
c) To check eating habits and try to decrease the amount of saturated fats and trans-fatty acids, increase the amount of fish, vegetables, legumes, and nuts,
d) To perform moderate-intensity physical activity for at least 30 minutes per day
e) To engage in weight management programmes through caloric restrictions and increased caloric expenditure,
f) Diabetes management to achieve near-normal fasting plasma glucose
Conclusion
All these measures and pharmacotherapies such as statins, ACE inhibitors, both of which are effective in lowering the risk of heart disease in women, are not known to increase the risk of breast cancer7.
In the mean time, there are also other good news from the Women's Health Initiative, which are much less commented upon. The WHI observational cohort study provided data upon the effects of walking, vigorous exercise and hours spent sitting on cardiovascular risk. Clearly, physical activity is inversely correlated to cardiovascular risk and the effects can be large. 8
References
1. Hulley S, Grady D, Bush T, et al., for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605–13.
2. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–33.
3 Andrea Riccardo Genazzani, Marco Gambacciani HERS and WHI: unsuitable selection of study population. Maturitas 2003 Vol 44 (1): 11-18
4 Gambacciani M, Rosano GM, Monteleone P, Fini M, Genazzani AR. Clinical relevance of the HERS trial. Lancet 2002;360(9333):64.
5 Martina Dören . The good news from WHI. Maturitas 2003 Vol 44 (1) : 11-18
6 Pearson TA, Blair SN, Daniels SR et al. AHA Guidelines for primary prevention of cardiovascular disease and stroke: 2002 update. Circulation 2002; 106:388–91.
7 International Position Paper on Women's Health and Menopause: a comprehensive approach. National Heart, Lung and Blood Institute, Office of Research on Women's Health, National Institute of Health, Giovanni Lorenzini Medical Foundation, NIH Publication No. 02-3284, July 2002.
8 Manson JA, Greenland P, LaCroix AZ et al. Walking compared with vigorous exercise for the prevention of cardiovascular events in women. New Engl J Med 2002; 347:716–25.
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