Research ReportRationale and design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS cognitive and affective sub study (KEEPS Cog)
Introduction
Prior to the publication of the Women's Health Initiative (WHI) and the WHI Memory Study (WHIMS) findings (Espeland et al., 2004, Rapp et al., 2003, Shumaker et al., 2004, 2003), hormone therapy (HT) was thought to significantly reduce a woman's risk for cardiovascular disease, osteoporosis, sexual dysfunction, certain cancers and dementia. This belief was based on a large body of basic science and epidemiological evidence indicating that HT elicited salutary cardiovascular effects and could potentially reduce the risk of Alzheimer's disease (AD), all while alleviating menopausal symptoms (Hogervorst et al., 2009). In 2002, the primary results from the WHI showed no cardiovascular benefit of HT, and the WHIMS indicated an increased risk of dementia. Consequently, findings from observational studies conducted prior to the WHI were attributed to the ‘healthy-user’ bias (Wharton et al., 2009). Still, support for the potential beneficial effects of HT on cardiovascular outcomes and cognition continues to mount from observational (including WHIMS data (Henderson et al., 2007)), clinical and prospective cohort studies (Gleason et al., 2006, Krug et al., 2006, Lokken et al., 2006, Yonker et al., 2006, Zandi et al., 2002). This manuscript describes the issues raised by the WHI and WHIMS and presents the most recent results and ongoing HT-related research studies designed to address these issues, including the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective sub study (KEEPS Cog).
Section snippets
Issues raised by the WHI and the WHIMS
In 2002, the conjugated equine estrogen+medroxyprogesterone acetate (CEE+MPA) portion of the WHI trial was halted because of a trend toward increased breast cancer, although this relationship was not statistically significant. Soon after, the CEE alone arm of the trial was halted because of a perceived lack of benefit of HT. While terminated early, the WHI was the largest clinical trial ever conducted and served to resolve questions surrounding certain forms of HT administration (i.e., CEE) in
The critical period hypothesis
Arguably the most important issue raised by the WHI was the ‘critical period’ hypothesis. Before the WHI trials, most data citing cardiovascular benefits of HT came from studies with recently menopausal women, who are most often prescribed HT to combat menopausal symptoms. In contrast, the average age of participants enrolled in the WHI trials was 63 years at HT administration onset, which is 12 years after the average age of menopause in the United States (Hsia et al., 2006, Manson et al., 2003
Hormone therapy formulations—Estradiol vs. estrone
Another major methodological issue raised by the WHI and the WHIMS was the form of HT employed. Oral CEE is the most widely used estrogen for HT in the Unites States. CEE is a formulation comprised of estrone sulfate and at least ten other hormones, some of which are non-human (Espeland et al., 2004). Estradiol is comprised of 17β-estradiol, the most potent and natural human form of estrogen in premenopausal women. The estrogen receptor (ER) binding potency of estrone is approximately 2/3 the
Route of hormone therapy administration
The CEE used in the WHI and WHIMS was an oral HT formulation (Guay et al., 2007). Oral estrogens are subject to extensive hepatic metabolism and result in an estrone to estradiol ratio of approximately 5:1 to 7:1 (Hodis et al., 2001). Additionally, oral estrogen administration increases the risk of venous thromboembolic (VTE) complications by inducing pro-coagulant proteins during first-pass hepatic metabolism. Some researchers have proposed that opposed CEE-induced cerebrovascular changes
Cyclical micronized progesterone vs. continuous administration of medroxyprogesterone acetate (MPA)
Women who have a uterus are prescribed a progestin in addition to an estrogen because unopposed estrogens markedly increase the risk of endometrial cancer. Some synthetic progestins and their metabolites have been shown to have deleterious cognitive effects (Paganini-Hill et al., 1996), either by exerting sedative (Freeman et al., 1992, Soderpalm et al., 2004) and adverse mood effects (Freeman et al., 1992), or possibly by accelerating cognitive decline (Rice et al., 2000). Evidence from
The Kronos Early Estrogen Prevention Study (KEEPS)
To address the above mentioned issues raised by the WHI and WHIMS, investigators conducted a nine-site, randomized, double blind placebo-controlled clinical trial, called the Kronos Early Estrogen Prevention Study (KEEPS; NCT000154180). Our hypothesis was that HT initiated early after menopause (i.e., prior to the appearance of advanced atherosclerotic lesions) would prevent progression of atherosclerosis. Women were randomized if they were aged 42 to 58 years, at least 6 months but no more
The KEEPS-cognitive and affective sub study (KEEPS-Cog)
An ancillary study of KEEPS, funded by the National Institutes of Health's National Institute on Aging (NIH-NIA), called the KEEPS Cognitive and Affective study (KEEPS Cog) evaluated the differential efficacy of transdermal estradiol and oral CEE on measures of cognitive function and mood in women enrolled in the parent KEEPS study. The collection of baseline cognitive data from over 700 women enrolled in the KEEPS Cog study was recently completed. The KEEPS Cog study is the first multi-site,
Recent studies supporting the use of hormone therapy during the menopausal transition
Recent evidence from two large studies Schierbeck et al. (2012)(Shao et al., 2012 #9523]) examining effects of long-term HT, offer additional support for a protective effect of HT against cardiovascular outcomes and AD. The Danish Osteoporosis Prevention Study is an open label randomized trial comprised of 1006 women over ten years. In this trial, investigators reported that women randomly assigned to estradiol therapy vs. placebo had a significantly reduced risk of mortality, heart failure,
Conclusion
Findings of the KEEPS and KEEPS Cog have the potential to affect clinical care practices and health decisions for many millions of women, particularly in regard to disease prevention (Miller et al., 2009). If there proves to be a window of time in the early post menopause when initiation of long-term HT has a net beneficial effect, then women can feel reassured that treatment of their menopausal symptoms when they are likely to be the most severe, can concurrently protect their vascular system,
References (32)
Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer's
J. Steroid Biochem. Mol. Biol.
(2003)Oral micronized progesterone
Clin. Ther.
(1999)A 3-day estrogen treatment improves prefrontal cortex-dependent cognitive function in postmenopausal women
Psychoneuroendocrinology
(2006)Hormone replacement therapy, hormone levels, and lipoprotein cholesterol concentrations in elderly women
Am. J. Obstet. Gynecol.
(1996)Progression of coronary calcium on serial electron beam tomographic scanning is greater in patients with future myocardial infarction
Am. J. Cardiol.
(2003)Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications—a review
Contraception
(1987)Administration of progesterone produces mild sedative-like effects in men and women
Psychoneuroendocrinology
(2004)Cognitive benefits of hormone therapy: cardiovascular factors and healthy-user bias
Maturitas
(2009)Effects of hormone replacement on progression of coronary calcium as measured by electron beam tomography
J. Women's Health
(2005)Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study
JAMA
(2004)