Written by Joyce Smith, BS. A four-year treatment of hormonal therapy improved symptoms of menopause and did not increase cardiovascular disease (CVD) risk compared to the control group.
KEEPS is a four-year, randomized, placebo-controlled clinical study 1 of low-dose oral or transdermal estrogen and cyclic monthly progesterone that was given to 718 healthy postmenopausal women ages 42 – 59 within three years following menopause. It was designed to address gaps in the effects of menopausal hormone treatments (HT) on cardiovascular health and other effects of menopause after the premature termination of the Women’s Health Initiative (WHI) 2. In spite of the large scale and high cost of the WHI, many questions remained unanswered and some new questions arose, the most critical being whether the WHI findings were affected by the fact that most women in the hormone trials were five or more years postmenopausal on study entry and many had existing CVD. Excluded from the KEEPS were women with CVD including coronary artery calcium (CAC) scores of 50 or higher, levels of plasma cholesterol or triglycerides that would normally be treated with lipid-lowering drugs, severe obesity, and heavy smokers. In addition to the primary KEEPS study, there was also a cognitive health study and other ancillary studies.
Women, free of pre-existing cardiovascular disease, were divided into two treatment groups one of which received 0.45 mg/d oral conjugated equine estrogens (o-CEE) rather than the higher 0.625 mg/d used in the WHI. The second group received 50 μg/d of transdermal 17β-estradiol (t-E) via a skin patch. Both treatment groups received 200 mg/d of micronized progesterone for the first 12 days of each month instead of the synthetic medroxyprogesterone acetate (MPA) that was used as a continuous regime in women with a uterus in the WHI. The placebo group of women were administered matching placebo pill, skin patch, and 12 days of a placebo capsule.
The primary goal of the KEEPS was to determine if HT, given to women without pre-existing CVD, would slow the progression of subclinical atherosclerosis as indicated by changes in carotid artery intima-media thickness (CIMT). Secondary goals included evaluation of risk factors for cardiovascular disease and measurement of coronary artery calcium (CAC). The average annual increases in CIMT (0.007 mm/y) were similar across all three treatment groups. There were no statistically significant differences in changes in CAC scores among the three treatment groups with an average increase of about 19% over the 4-year course of the KEEPS trial. Blood pressure did not change significantly across any of the treatment groups.
A total of 662 women were enrolled in the cognitive study and were all free of depression, dementia and memory deficits at baseline. An extensive battery of tests measuring cognition and mood were administered at 12, 18, 36, and 48 months. There were no beneficial effects of HT on cognition; however, compared to placebo, the o-CEE group improved significantly with respect to measures of depression and anxiety.
Additional ancillary studies were conducted that provided an integrated picture of the cardiovascular health of the KEEPS cohort, as well as insights into potential mechanisms by which HT might affect the progression of cardiovascular disease. After receiving HT for 4 years, the HT groups both had reduced menopausal symptoms, including hot flashes and night sweats, improved sleep quality and bone mineral density, and significant improvements in sexual function compared to the placebo group.
The conclusions from the WHI study 2 led to reduced estrogen prescribing for moderate to severe menopausal symptoms 3,4 and reduced funding for further research. Fortunately the KEEPS study and others that followed have demonstrated no increase in CVD risk from HT 5-7 which will hopefully enable clinicians to better characterize the benefits and risks of HT for their patients.
Source: Miller, Virginia M., Fredrick Naftolin, Sanjay Asthana, Dennis M. Black, Eliot A. Brinton, Matthew J. Budoff, Marcelle I. Cedars et al. “The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?.” Menopause (2019).
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Posted January 21, 2020.
Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.
References:
- Miller VM, Naftolin F, Asthana S, et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned? Menopause. 2019.
- Rossouw JE. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. Jama. 2002;288:321-333.
- Lobo R. What the future holds for women after menopause: where we have been, where we are, and where we want to go. Climacteric. 2014;17(sup2):12-17.
- Constantine GD, Kessler G, Graham S, Goldstein SR. Increased Incidence of Endometrial Cancer Following the Women’s Health Initiative: An Assessment of Risk Factors. Journal of Women’s Health. 2019;28(2):237-243.
- Boardman HM, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post‐menopausal women. Cochrane Database of Systematic Reviews. 2015(3).
- Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2017;1:Cd004143.
- Abdi F, Mobedi H, Bayat F, Mosaffa N, Dolatian M, Tehrani FR. The effects of transdermal estrogen delivery on bone mineral density in postmenopausal women: a meta-analysis. Iranian journal of pharmaceutical research: IJPR. 2017;16(1):380.
