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Brain Res. Author manuscript; available in PMC 2013 August 01.
NIH-PA Author Manuscript Published in final edited form as: Brain Res. 2013 June 13; 1514: 12–17. doi:10.1016/j.brainres.2013.04.011.
Rationale and Design of the Kronos Early Estrogen Prevention
Study (KEEPS) and the KEEPS Cognitive and Affective Sub
Study (KEEPS Cog).
Whitney Wharton, PhD1,3, Carey E. Gleason, PhD1,2,3, Virginia M. Miller, PhD4, and Sanjay
Asthana, MD1,2,3
1Department of Medicine, University of Wisconsin, School of Medicine and Public Health,
Madison, WI 53792, USA
2Geriatric Research, Education and Clinical Center (GRECC), William S. Middleton MemorialVeterans Hospital, Madison, WI 53705 USA 3Wisconsin Alzheimer's Disease Research Center, (ADRC) Madison, WI 53792 USA NIH-PA Author Manuscript 4Surgery & Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905 USA Prior to the publication of the Women's Health Initiative (WHI) and the WHI MemoryStudy (WHIMS) findings [1–4], hormone therapy (HT) was thought to significantly reduce awoman's risk for cardiovascular disease, osteoporosis, sexual dysfunction, certain cancersand dementia. This belief was based on a large body of basic science and epidemiologicalevidence indicating that HT elicited salutary cardiovascular effects and could potentiallyreduce the risk of Alzheimer's disease (AD), all while alleviating menopausal symptoms(Hogervorst et al). In 2002, the primary results from the WHI showed no cardiovascularbenefit 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 [5{Matthews, 1996 #5848]. Still, support for the potential beneficialeffects of HT on cardiovascular outcomes and cognition continues to mount fromobservational (including WHIMS data [6]), clinical and prospective cohort studies [7–11].
NIH-PA Author Manuscript This manuscript describes the issues raised by the WHI and WHIMS and presents the mostrecent results and ongoing HT-related research studies designed to address these issues,including the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitiveand Affective sub study (KEEPS Cog).
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 ofthe trial was halted because of a perceived lack of benefit of HT. While terminated early, theWHI was the largest clinical trial ever conducted and served to resolve questionssurrounding certain forms of HT administration (i.e. CEE) in older women, while raisingimportant methodical issues driving current HT-related research.
Correspondence: Whitney Wharton, Ph.D., University of Wisconsin, Department of Medicine & Public Health, William S. MiddletonVA Hospital, 2500 Overlook Terrace, Madison, WI 53705, 608.256.1901 ext 11620, [email protected].
Wharton et al.
The Critical Period Hypothesis
Arguably the most important issue raised by the WHI was the ‘critical period' hypothesis.
NIH-PA Author Manuscript Before the WHI trials, most data citing cardiovascular benefits of HT came from studieswith recently menopausal women, who are most often prescribed HT to combat menopausalsymptoms. In contrast, the average age of participants enrolled in the WHI trials was 63years at HT administration onset, which is 12 years after the average age of menopause inthe United States [12, 13]. Because atherosclerosis progresses gradually before declaringitself with a clinical event [60, 64], a significant number of women in the WHI likely hadsubclinical atherosclerosis at randomization [14]. The presence of subclinical disease mighthave accounted for the tendency for cardiovascualr events to be increased early in the WHI,just as in the cardiovascualr prevention study with HT, the Heart and Estrogen/ProgestinReplacement Study (HERS), which began concurrently with the WHI. The HERS showedthat in women with preexisting disease, there was an increase in cardiovascualr events in thefirst few years of the trial. Although continued use of HT was associated with a reversal ofthis trend, the major conclusion from that trial was that women with preexisting coronaryheart disease were not candidates for HT [14][47].
Hormone Therapy Formulations - Estradiol vs. Estrone
Another major methodological issue raised by the WHI and the WHIMS was the form of HT NIH-PA Author Manuscript employed. Oral CEE is the most widely used estrogen for HT in the Unites States. CEE is aformulation comprised of estrone sulfate and at least ten other hormones, some of which arenon-human [4]. Estradiol is comprised of 17β-estradiol, the most potent and natural humanform of estrogen in premenopausal women. The estrogen receptor (ER) binding potency ofestrone is approximately ⅔ the affinity of estradiol to the ERα, and about ⅓ the potency ofestradiol for ERβ [8]. Additionally, estrone and estradiol likely have differential potenciesfor membrane mediated actions [9]. Thus, estradiol may be more effective than estroneformulations of HT.
If the purpose of HT is to control menopausal symptoms and prevent bone loss, the variousforms of HT may be interchangeable [15]. However, if the goal of HT is to achieve ahormone state closer to that observed prior to menopause, in order to maintaincardiovascular and neurobiological systems, administration of an estradiol HT would bepreferable to CEE formulations. As discussed, the predominant form of estrogen inpremenopausal women is estradiol, the levels of which decline more than estrone levels aftermenopause. However, in contrast to basic science research, many clinical studies evaluatingcognitive efficacy of hormone therapies in healthy older women have utilized CEE. Toaddress this issue, the KEEPS and KEEPS Cog trials examined the extent to which oral CEE NIH-PA Author Manuscript and 17β estradiol influenced cardiovascular risk factors and cognition, in addition toaddressing the ‘critical period' hypothesis.
Route of Hormone Therapy Administration
The CEE used in the WHI and WHIMS was an oral HT formulation [16]. Oral estrogens aresubject to extensive hepatic metabolism and result in an estrone to estradiol ratio ofapproximately 5:1 to 7:1 [10]. Additionally, oral estrogen administration increases the riskof venous thromboembolic (VTE) complications by inducing pro-coagulant proteins duringfirst-pass hepatic metabolism. Some researchers have proposed that opposed CEE-inducedcerebrovascular changes might underlie increased risk for dementia described by WHIMSdata [11]. In contrast to oral formulations, transdermal estrogen administration bypasseshepatic metabolism and results in a steady-state concentration of estradiol with an estrone :estradiol ratio of 1:1, approximating that seen prior to menopause. Another advantage oftransdermal estradiol is that, unlike oral preparations, it does not increase binding Brain Res. Author manuscript; available in PMC 2013 August 01.
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glycoproteins, such as sex hormone binding globulin (SHBG), which results in higherplasma concentrations of free estradiol. Thus, date suggests that not only is HT formulation NIH-PA Author Manuscript influential, but the route of administration is also important. KEEPS will provide the firstdirect comparison of effects of long-term use of oral versus transdermal HT onatherosclerosis in women. Moreover, KEEPS will evaluate mode of treatment deliverysimilar to what has been used in the majority of basic science studies; namely transdermaldelivery for estradiol HT and oral delivery for CEE.
Cyclical Micronized Progesterone vs. Continuous Administration of
Medroxyprogesterone Acetate (MPA)
Women who have a uterus are prescribed a progestin in addition to an estrogen becauseunopposed estrogens markedly increase the risk of endometrial cancer. Some syntheticprogestins and their metabolites have been shown to have deleterious cognitive effects [17],either by exerting sedative [18, 19] and adverse mood effects [19], or possibly byaccelerating cognitive decline [20]. Evidence from epidemiological studies shows thatsynthetic progestins, including medroxyprogesterone acetate (MPA), can lead to decreasedperformance on measures of cognition [17], and a greater rate of cognitive decline [20].
Additionally, there is emerging evidence from basic science research that MPA attenuatesthe neuroprotective potential of estrogen and fails to protect against glutamate toxicity [21].
NIH-PA Author Manuscript Conversely, natural forms of endogenous progesterone may exert beneficialneuropathological and cognitive effects.
Prometrium® is an oral form of progesterone which is bio-identical to the progesteroneproduced by the ovaries. In contrast to synthetic progestins, Prometrium® has not beenshown to be associated with the adverse effects related to heart disease, lipid metabolism orthrombo-embolic diseases, and is available in a micronized formulation to increasebioavailability [22, 23]. While it is unknown if an exogenous progestational agent will act asthe endogenous hormone, cyclic administration of a form simulating the endogenous humanmolecule is theoretically preferred because it more closely approximate the premenopausalhormone milieu compared to chronic dosing with MPA. Because undergoing a hysterectomywas an exclusion for participation the KEEPS trial, all participants were administeredcombined HT (or placebo). To avoid MPA-related complications discussed above, and totest the efficacy of cyclical administration of bio-identical progesterone, all women in theKEEPS were administered natural, micronized progesterone.
The Kronos Early Estrogen Prevention Study (KEEPS)
NIH-PA Author Manuscript To address the above mentioned issues raised by the WHI and WHIMS, investigatorsconducted a nine-site, randomized, double blind placebo-controlled clinical trial, called theKronos Early Estrogen Prevention Study (KEEPS; NCT000154180). Our hypothesis wasthat HT initiated early after menopause (i.e., prior to the appearance of advancedatherosclerotic lesions) would prevent progression of atherosclerosis. Women wererandomized if they were aged 42 to 58 years, at least 6 months but no more than 36 monthspostmenopausal and in good general health with a normal mammogram (See Harman et al.
for a detailed study description [24]). Also, only with plasma follicle-stimulating hormone(FSH) level ≥ 35 ng/mL and/or E2 levels <40 pg/mL were eligible. Women were excluded ifthey self-reported prior or current cardiovascular disease, including myocardial infarction,angina, congestive heart failure, thromboembolic disease. Exclusion criteria also includedsmoking more than 10 cigarettes per day, a BMI > 35 mm2/kg, dyslipidemia (LDLcholesterol > 190 mg/dL), hypertriglyceridemia (triglycerides > 400 mg/dL), anduncontrolled hypertension (systolic blood pressure > 150 mm Hg and/or diastolic bloodpressure > 95 mm Hg) or glucose > 126 mg/dL. The purpose of the stringent inclusion Brain Res. Author manuscript; available in PMC 2013 August 01.
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guidelines was to ensure that women enrolled in KEEPS and KEEPS Cog did not haveexisting preclinical vascular disease, which as discussed above, likely contributed to the NIH-PA Author Manuscript increased incidence of vascular disease in the WHI, and later development of dementia inthe WHIMS.
The primary objective of the KEEPS was to evaluate the differential efficacy of oral CEE(Premarin® 0.45 mg/day) and transdermal 17β estradiol (Climara® 50 µg/day) versusplacebo on progression of atherosclerosis as defined by carotid intima–media thickness(CIMT) [25] and coronary arterial calcification (CAC) [26] in women within three years oftheir last menstrual period. The trial began in July, 2005 with complete enrollment of 728participants in June 2008. The last study visit took place in March 2012 and manuscriptpreparation is currently underway. Women meeting inclusion criteria were randomized todaily placebo, oral CEE, or transdermal 17β estradiol with placebo or micronized oralprogesterone (Prometrium® 200mg) for the first 12 days of each month. Secondaryobjectives included a systematic characterization of the effects of HT on measures ofinflammation and blood hypercoagulability.
All laboratory and cognitive testing took place at one of nine clinical testing sites including:Brigham and Women's Hospital, Boston, MA, Columbia University College of Physiciansand Surgeons, New York, NY, Mayo Clinic, Rochester, MN, Montefiore Medical Center, NIH-PA Author Manuscript Bronx, NY, Kronos Longevity Research Institute, Phoenix, AZ, University of California atSan Francisco, San Francisco, CA, University of Utah School of Medicine, Salt Lake City,UT, University of Washington School of Medicine; Tacoma, WA, or Yale UniversitySchool of Medicine, New Haven, CT. All participants underwent an extensive medical andmedication history, ultrasound testing, physical exam, laboratory blood tests, andneuroimaging (at the Mayo clinical center only). A description of testing has been describedin a previous publication {Harman, 2005 #2867}.
The KEEPS-Cognitive and Affective Sub Study (KEEPS-Cog)
An ancillary study of KEEPS, funded by the National Institutes of Health's NationalInstitute on Aging (NIH-NIA), called the KEEPS Cognitive and Affective study (KEEPSCog) evaluated the differential efficacy of transdermal estradiol and oral CEE on measuresof cognitive function and mood in women enrolled in the parent KEEPS study. Thecollection of baseline cognitive data from over 700 women enrolled in the KEEPS Cogstudy was recently completed. The KEEPS Cog study is the first multi-site, randomized,placebo-controlled, double-blind, parallel-group design clinical study that will address majorHT-related issues raised by WHI and WHIMS. Specifically, the KEEPS Cog study willcompare the differential efficacy of CEE and transdermal estradiol on a comprehensive NIH-PA Author Manuscript battery of cognition and mood measures, sensitive to cognition changes associated with HTin perimenopausal and recently-postmenopausal women. The hypothesis of the KEEPS Cogstudy is that, compared to CEE, treatment with transdermal estradiol will enhance cognitivefunction of healthy peri- and early menopausal women (i.e., decreased rate of cognitivedecline or enhanced rate of cognitive improvement compared to placebo-treated group). Thebattery of cognitive tests and mood inventories are administered at baseline and months 18,36, and 48 during treatment (see Table 1). The evaluations at months 18 and 48 willcharacterize the effects of estrogen therapy alone; thus testing will occur while subjects arenot taking the progesterone challenge. The evaluation at month 36 will be timed to assessthe effects of estrogen plus progesterone, and will be performed between days 6 and 12 ofthe progesterone challenge.
Ultimately, the KEEPS Cog study will build upon the knowledge gained by WHIMS,addressing unresolved questions of pivotal clinical significance that need to be Brain Res. Author manuscript; available in PMC 2013 August 01.
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systematically evaluated in well-designed human studies. The study will provide insightinto: 1) whether there is cognitive benefit or harm associated with HT administered during NIH-PA Author Manuscript the ‘critical period' (as opposed to late postmenopausal HT investigated in WHIMS), 2)whether there are differential cognitive effects of various estrogen formulations (CEE vs.
estradiol), 3) if there is a preferred route of estrogen administration (oral vs. transdermal), 4)whether a cyclic micronized progestin is associated with cognitive benefit, and 5) what arethe most sensitive psychometric measures to characterize potential effects of estrogen oncognition and mood.
Given the adverse findings of WHIMS in postmenopausal women and the fact that HT isstill approved for the treatment of menopausal symptoms commonly experienced byyounger perimenopausal women, it is critical that the potential cognitive effects of HT, bothbeneficial and adverse, be identified in women undergoing menopausal transition. TheKEEPS Cog study will be the first clinical study to characterize the differential effects oforal CEE and transdermal estradiol on cognitive function of perimenopausal women.
Additionally, results of the KEEPS Cog study will provide pivotal data and an exclusiveopportunity for future studies to follow the KEEPS cohort over an extended period of 20–25years to determine whether HT initiated during the perimenopausal period could delay orpreferably prevent future development of neurodegenerative diseases like Mild CognitiveImpairment (MCI) and AD. Bhavnani [27] has argued that the WHI was not a true primary NIH-PA Author Manuscript prevention study given the advanced age and prevalence of obesity among its participants,and the likelihood that many were beyond the opportunity to ‘prevent' disease. A follow-upto the KEEPS Cog study would help clarify this important question.
Recent Studies Supporting the use of Hormone Therapy during the
Recent evidence from two large studies [28{Shao, 2012 #9523]} examining effects of long-term HT, offer additional support for a protective effect of HT against cardiovascularoutcomes and AD. The Danish Osteoporosis Prevention Study is an open label randomizedtrial comprised of 1,006 women over ten years. In this trial, investigators reported thatwomen randomly assigned to estradiol therapy vs. placebo had a significantly reduced riskof mortality, heart failure, and myocardial infarction, without any increase in risk of cancer,venous thromboembolism (VTE) or stroke. Unlike the WHI, participants were young (meanage 49.7 years), healthy (mean BMI of 25.2 and BP 130/81 mm Hg), and recentlymenopausal (mean time since menopause approx. seven months). After ten years ofrandomized treatment, participants were followed for another six years, during which timethe reduction in primary vascular outcomes was still present and not associated with an NIH-PA Author Manuscript increase in any cancer.
A recent analysis of the population-based Cache County Study comprised of 1,768 womenexamined whether the association of HT with AD varies with timing or type of HTformulation. Investigators reported that women who used HT within 5 years of menopausehad a 30% reduced risk for developing AD in later life, especially if the duration of use was10 years or longer. Moreover, while results suggest that HT may be beneficial if taken nearmenopause, HT (particularly opposed HT formulations) initiated in later life may beassociated with increased AD risk. These findings offer strong support for a beneficial effectof HT on cardiovascular outcomes and protection from AD if initiated during themenopausal transition.
Thus, many in the scientific community agree that while the risk of cardiovascular eventsand dementia associated with HT has been clarified for women over the age of 65, numerous Brain Res. Author manuscript; available in PMC 2013 August 01.
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questions remain including the ‘critical period' hypothesis, influence of HT formulation androute of delivery, and whether HT may be useful for primary prevention of dementia [29].
NIH-PA Author Manuscript Findings of the KEEPS and KEEPS Cog have the potential to affect clinical care practicesand health decisions for many millions of women, particularly in regard to diseaseprevention [14]. If there proves to be a window of time in the early postmenopause wheninitiation of long-term HT has a net beneficial effect, then women can feel reassured thattreatment of their menopausal symptoms when they are likely to be the most severe, canconcurrently protect their vascular system, reduce bone reabsorption, or even elicitneuroprotection from dementia in late life.
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NIH-PA Author Manuscript Cognitive Battery for Kronos Early Estrogen Prevention Study-Cognitive and Affective Study (KEEPS-CA) DOMAIN OR CONSTRUCT MEASURED
Included in
INTELLIGENCE: Baseline only Primary Mental Abilities*-Vocab152, 153 GLOBAL COGNITION: Modified Mini-Mental State Exam154 VERBAL AND VISUAL MEMORY: California Verbal Learning Test-2*155 NYU Paragraph Recall Test156 Prospective Memory Test152, 153 Benton Visual Retention Test157 Controlled Oral Word Association Test FAS/Animals/Fruits/Vegetables158 ATTENTION AND EXECUTIVE FUNCTION: Divided Attention Trail Making Test version A & B158 NIH-PA Author Manuscript Selective Attention Stroop Test (Golden Version)159 Auditory Working Memory: Letter-Number Sequencing WMS-3160 Digit Span WMS-3160 Visual Working Memory: COMPUTERIZED COGNITIVE TESTS: 3D Mental Rotation162 Visual Sensitivity Test162 Selective Attention Profile of Mood States163 Beck Depression Inventory164 Brief Patient Health Questionnaire165 SUBJECTIVE MEMORY COMPLAINTS: Memory Function Questionnaire166 NIH-PA Author Manuscript †Women's Health Initiative Memory Study1–4 ‡Women's Health Initiative Study of Cognitive Aging152,167 *Administration to match Resnick et al.'s WHISCA battery152 Brain Res. Author manuscript; available in PMC 2013 August 01.

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