Long Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50–55 Years

Abstract

Background

Postmenopausal hormone therapy with conjugated equine estrogens (CEE) may adversely affect older women’s cognitive function. It is not known whether this extends to younger women.

Methods

1,326 postmenopausal women, who had begun treatment in two randomized placebo-controlled clinical trials of hormone therapy when aged 50–55 years, were assessed with an annual telephone-administered cognitive battery that included measures of global (primary outcome) and domain-specific cognitive functions (verbal memory, attention, executive function, verbal fluency, and working memory). The clinical trials in which they participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate (MPA) over an average of 7.0 years. Cognitive testing was conducted an average of 7.2 years following the end of the trials, when women had mean age 67.2 years, and repeated one year later.

Results

Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean [95% confidence interval] intervention effect of 0.02 [−0.08,0.12]standard deviation units (p=0.66). Similarly, no overall differences were found for any individual cognitive domain (all p>0.15). Pre-specified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy: mean treatment effects of −0.17 [−0.33, −0.02] and −0.25 [−0.42, −0.08], respectively, however this may be a chance finding. We are not able to address whether initiating hormone therapy during the menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term.

Conclusions

CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50–55 years.

INTRODUCTION

The Women’s Health Initiative Memory Study (WHIMS) demonstrated that postmenopausal hormone therapy with conjugated equine estrogens (CEE), when prescribed to women aged 65 years and older, produced deficits in global and domain-specific cognitive functioning.^1–3 On average these were small; however, deficits persisted for years after cessation of hormone therapy.³ They occurred with decreases in brain volumes linked to increased incidence of cognitive impairment.^4,5

In contrast, observational and cohort studies and considerable basic science research suggest that there may be a “window of opportunity,” perhaps co-incident with the loss of ovarian function during menopause, when hormone therapy may promote or preserve brain health.^6–9 Meta-analyses of clinical trials and systematic literature reviews do not find consistent evidence of benefit,^10,11 however the window-of-opportunity hypothesis remains of great interest and public health importance as hormone therapy continues to be widely prescribed for managing menopausal symptoms.¹²

The Women’s Health Initiative Memory Study of Younger Women (WHIMSY) tested whether prescribing CEE-based hormone therapy to postmenopausal women ages 50–54 years has longer-term effects on cognitive function. We present its primary findings.

METHODS

The Women’s Health Initiative (WHI) included two parallel placebo-controlled trials of CEE-based regimens.¹³ Volunteers were postmenopausal and appropriate candidates to receive these medications. Women currently using hormone therapy were eligible after a 3-month washout. Enrollment occurred from 1996–1999 at 40 academic research centers. Active therapies were 0.625 mg/day CEE in women post-hysterectomy and 0.625 g/day CEE combined with 2.5 mg/day MPA in women with a uterus and were compared to matching placebos. The trial among women without prior hysterectomy (CEE+MPA) was terminated July, 2002;¹⁴ the trial among women with prior hysterectomy (CEE-Alone) was terminated February, 2004.¹⁵ Study therapies were stopped at these times. Women were unmasked, but follow-up continued.

WHIMSY volunteers had begun screening for WHI enrollment when aged 50–54 years (and initiated their assigned WHI treatment when aged 50–55 years), were currently followed by the WHI, and had hearing acuity adequate for telephone interviews. All provided written informed consent; protocols were approved by local Institutional Review Boards.

Cognitive function

Trained, masked staff collected cognitive data with telephone-administered assessments that have been shown to be valid.¹⁶ The primary outcome was global cognitive function, assessed with the Telephone Interview for Cognitive Status-modified (TICS-m), a 14-question test with scores ranging from 0 to 50.¹⁷ Its selection paralleled use of global cognitive function as the primary cognitive outcome in WHIMS.¹⁸ Secondary outcomes included:

• 12-point East Boston Memory Test (EBMT) for immediate and delayed verbal memory;¹⁹

• Oral Trail Making Test (OTMT), a modification of the Trail Making Test (TMT),²⁰ a validated measure of attention (Part A) and executive function (Part B),²¹ scored as time in seconds;

• Verbal Fluency-Animals (VF-A) test totaling the number of unique spontaneously named animals in 1 minute;²² and

• Digit Span (DS) subtest of the Wechsler Adult Intelligence Scale-Revised measuring attention and working memory with the longest correct span length recalled for digits forward and backward.²³

Covariates and potential confounders

WHI had collected baseline demographic, lifestyle, and clinical data related to the risk of cognitive impairment via self-report and standardized assessments.¹³ Adherence was computed as the average proportion of assigned study medication use, based on pill counts. Years of on-trial exposure were computed by summing each woman’s adherence rates (based on pill counts) across years of trial follow-up.

Statistical methods

Cognitive measures from two annual assessments were analyzed as repeated data to estimate women’s average level of cognitive function. General linear models with covariate-adjustment were used to assess mean differences between intervention groups,²⁵ as pre-specified in the protocol. Results from generalized estimating equations were similar and are not reported. To facilitate comparisons among tests, measures were normalized by dividing the difference between individual scores and the cohort-wide mean by the scores’ standard deviation and ordered so that higher values reflected better performance. A composite measure was computed by averaging normalized scores across tests. Pre-specified subgroup analyses were performed using tests of interactions. Primary analyses followed intention-to-treat, with women grouped according to treatment assignment.

RESULTS

WHIMSY enrolled 1,326 (of 1,372 potentially eligible women who agreed to contact). They averaged (range) 7.0 (3.9, 10.1) years of follow-up during the WHI trials, which ended 7.2 (5.4, 10.1) years prior to WHIMSY enrollment (Figure 1). Women averaged 67.2 (62.9, 73.5) at their first assessment. The second assessment was conducted on 1,168 (88.1%) women with mean age 68.1 years. Times between assessments for treatment groups were similar (p=0.64).

Figure 1.

CONSORT diagram describing WHIMSY enrollment and retention.

There was reasonable balance in important potential confounders at WHI enrollment between women who had been assigned active versus placebo therapy (Table 1, all p>0.05). Markers of exposure to therapy, based on average pill counts and the sum of pill counts across trial follow-up, were also similar between arms (p>0.20).

Table 1.

Distribution of risk factors for cognitive impairment at the time of WHI randomization for WHIMSY participants grouped by WHI treatment assignment.

Risk Factor for Cognitive Impairment	WHI Assignment Mean (SD) or N (%)		p-value
	Hormone Therapy N=696	Placebo N=630
Age, yrs	53.0 (1.3)	52.9 (1.3)	0.36
Age at Last Menstrual Period, yrs	46.1 (6.3)	46.1 (6.2)	0.89
Education
High school or less	112 (16.3)	97 (15.5)	0.70
At least some college	577 (83.7)	530 (84.5)
Race/Ethnicity
African-American	85 (12.2)	80 (12.7)
American Indian	2 (0.3)	3 (0.5)
Asian	9 (1.3)	5 (0.8)	0.46
Hispanic	29 (4.2)	28 (4.4)
Non-Hispanic White	557 (80.0)	509 (80.8)
Other/Multiple	14 (2.0)	5 (0.8)
Smoking Status
Never	337 (48.6)	299 (47.7)
Former	203 (31.5)	226 (36.0)	0.37
Current	106 (16.4)	102 (16.3)
Alcohol Intake
None	159 (22.9)	155 (24.8)
<1 per day	471 (68.0)	401 (64.1)	0.27
≥1 per day	63 (9.1)	70 (11.2)
Body Mass Index—kg/m2
<20	16 (2.3)	14 (2.2)
20–25	208 (30.0)	170 (27.1)
25–29	217 (31.3)	192 (30.6)	0.62
30–34	145 (20.9)	137 (21.9)
≥ 35	107 (15.4)	114 (18.2)
Hypertension Status
No	547 (78.6)	497 (78.9)	0.94
Yes	146 (21.0)	131 (20.8)
Missing	3 (0.4)	2 (0.3)
Prior Cardiovascular Disease*
No	542 (77.9)	510 (81.0)	0.30
Yes	44 (6.3)	39 (6.2)
Missing	110 (15.8)	81 (12.9)
Hysterectomy
No	432 (62.1)	382 (60.6)	0.59
Yes	264 (37.9)	248 (39.4)
Age at Hysterectomy, yrs
<30	30 (11.4)	35 (14.1)
30–34	60 (22.8)	55 (22.2)
35–39	59 (22.4)	52 (21.0)	0.70
40–44	51 (19.4)	57 (23.0)
45–49	55 (20.9)	41 (16.5)
50–54	8 (3.0)	8 (3.2)
Years Since Last Regular Menstrual Period
Prior hysterectomy	8.4 (7.5)	9.6 (8.6)	0.11
No prior hysterectomy	3.9 (3.4)	4.0 (2.8)	0.69
Prior Hormone Therapy At WHI Recruitment
Never	336 (52.1)	279 (46.8)	0.090
Past	203 (31.5)	222 (37.2)
Current	106 (16.4)	915 (15.9)
Adherence (% expected)	0.82 (0.22)	0.83 (0.20)	0.41
Exposure: Adherence x Years	5.51 (2.47)	5.35 (2.53)	0.24

^*Other CVD defined as MI, angina, PCTA, stroke, or CABG

Table 2 presents mean cognitive function scores averaged over time, with adjustment for age and visit year. For TICS-m, there was essentially no difference in the mean scores between women who had been assigned to active versus placebo therapy (p=0.66). This finding was consistent for both CEE+MPA and CEE-Alone therapies (p=0.23). Similarly, there were no overall treatment differences for any other measure of cognitive function, including the composite score. This held for CEE+MPA and CEE-Alone therapies and for all cognitive measures, except verbal fluency. CEE-Alone therapy was associated with 0.17 standard deviation worse mean scores on verbal fluency with a 95% confidence interval that excluded zero [−0.33,−0.02]; CEE+MPA was associated with 0.07 standard deviation better mean scores on this test, however its confidence interval included zero [−0.06,0.19]. Covariate-adjustment for the risk factors for cognitive impairment in Table 1 did not materially alter findings (data not shown).

Table 2.

Mean cognitive function test scores averaged over time for women grouped by treatment assignment with adjustment for age and visit.

Cognitive Function Test	Treatment Assignment				Mean Standardized Difference HT Minus Placebo:* SD Units [95% CI]	p-value HT vs Placebo	p-value MPA vs No MPA
	CEE+MPA Mean (SE)	CEE+MPA Placebo Mean (SE)	CEE Mean (SE)	CEE Placebo Mean (SE)
Global cognitive function
TICS-m	38.08 (0.20)	38.26 (0.21)	37.67 (0.26)	37.28 (0.27)	0.02 [−0.08, 0.12]	0.66	0.23
Verbal Memory
EBMT immediate	10.20 (0.07)	10.17 (0.07)	9.98 (0.09)	10.01 (0.09)	−0.00 [−0.09, 0.09]	0.97	0.70
EBMT delayed	9.88 (0.08)	9.78 (0.08)	9.57 (0.10)	9.59 (0.10)	0.02 [−0.07, 0.12]	0.67	0.49
Sum	20.08 (0.13)	19.95 (0.14)	19.55 (0.17)	19.61 (0.18)	0.01 [−0.08, 0.11]	0.82	0.56
Attention
OTMT-A	8.95 (0.13)	8.57 (0.14)	8.97 (0.16)	8.93 (0.17)	−0.06 [−0.15, 0.03]	0.16	0.26
Executive function
OTMT-B	43.26 (2.19)	42.14 (2.32)	46.76 (2.81)	50.02 (2.91)	−0.00 [−0.10, 0.10]	0.95	0.35
Verbal fluency
VF-A	21.04 (0.25)	20.65 (0.27)	18.90 (0.33)	19.91 (0.34)	−0.05 [−0.15, 0.05]	0.29	0.02
Working memory
Digits forward	8.33 (0.11)	8.60 (0.12)	8.64 (0.14)	8.48 (0.14)	−0.02 [−0.12, 0.08]	0.66	0.09
Digits backward	7.10 (0.11)	7.09 (0.12)	7.26 (0.14)	7.11 (0.15)	0.03 [−0.07, 0.13]	0.55	0.62
Sum	15.42 (0.20)	15.69 (0.22)	15.90 (0.26)	15.59 (0.27)	0.00 [−0.10, 0.11]	0.93	0.23
Composite	0.03 (0.04)	0.04 (0.05)	−0.09 (0.06)	−0.08 (0.06)	−0.01 [−0.11, 0.09]	0.78	0.94

^*Ordered so that positive score indicates better cognitive function in HT; Logarithm transformations used for executive function

¹Fitted mean (95% confidence interval) treatment effects for verbal fluency: CEE+MPA 0.07 [−0.06,0.19]; CEE −0.17 [−0.33,−0.02]

Adherence and overall exposure were weakly correlated with higher executive function scores (partial r=0.06, p=0.003; r =0.05, p=0.02), but had little correlation with scores from any other domains or the composite score. Adherence and overall exposure were not related to the size of the treatment effect for any measure of cognitive function, based on tests of interaction (p>0.30).

The WHIMSY protocol pre-specified three subgroup analyses to compare treatment effects for women grouped by: assignment to unopposed or opposed CEE therapy (i.e. hysterectomy status), self-reported age at last menstrual period, and prior use of hormone therapy. Table 2 describes the subgroup analyses related to the type of CEE regimen; Table 3 summarizes the other two analyses. There was little evidence of differential effects for any measure of cognitive function, with one exception. For verbal fluency, worse treatment-related performance was seen among women reporting prior hormone therapy use that had ceased before WHI enrollment. Prior hormone therapy use was associated with longer time since last menstrual period (p<0.001): compared to non-users, these times averaged 2.1 years longer for prior users and 0.2 years longer for current users. Because prior use of hormone therapy more often occurred among women with prior hysterectomy, we fitted a model that included treatment interactions with both hysterectomy status and prior use. Both interactions were independently statistically significant: women reporting prior hormone therapy use (interaction p=0.01) and those with prior hysterectomy (interaction p=0.03) appeared to have treatment-attributable deficits in verbal fluency that were not apparent, on average, in other women.

Table 3.

Consistency of intervention effects for women grouped by characteristics at WHI enrollment: time since last menstrual period and prior use of hormone therapy.

Cognitive Function Test	Years Between WHI Enrollment and Last Menstrual Period**			Prior Use of Hormone Therapy
	0–4 years N=643 Mean [95% CI]*	5+ years N=404 Mean [95% CI]*	p-value	No N=615 Mean [95% CI]*	Former N=425 Mean [95% CI]*	Current N=201 Mean [95% CI]*	p-value
Global cognitive function	0.10 [−0.04, 0.24]	−0.09 [−0.27, 0.09]	0.10	0.10 [−0.04, 0.25]	−0.11 [−0.29, 0.06]	0.06 [−0.20, 0.31]	0.17
Verbal memory	0.05 [−0.09, 0.18]	0.03 [−0.13, 0.20]	0.92	0.09 [−0.04, 0.23]	−0.01 [−0.17, 0.15]	−0.02 [−0.26, 0.22]	0.56
Attention	−0.06 [−0.17, 0.04]	−0.04 [−0.17, 0.09]	0.79	−0.08 [−0.18, 0.03]	0.01 [−0.11, 0.14]	−0.07 [−0.25, 0.12]	0.54
Executive function	0.02 [−0.12, 0.16]	0.09 [−0.09, 0.26]	0.56	−0.07 [−0.22, 0.07]	0.13 [−0.04, 0.30]	−0.04 [−0.29, 0.21]	0.18
Verbal fluency	0.07 [−0.07, 0.21]	−0.14 [−0.32, 0.04]	0.07	0.10 [−0.04, 0.24]	−0.25 [−0.42,−0.08]	0.04 [−0.21, 0.29]	0.008
Working memory	0.00 [−0.14, 0.15]	0.01 [−0.17, 0.19]	0.97	0.02 [−0.13, 0.17]	0.02 [−0.15, 0.20]	0.00 [−0.26, 0.26]	0.99
Composite	0.05 [−0.09, 0.19]	−0.01 [−0.19, 0.16]	0.56	0.07 [−0.07, 0.21]	−0.04 [−0.21, 0.13]	−0.01 [−0.26, 0.24]	0.61
Geriatric depression scale	−0.01 [−0.15, 0.13]	0.01 [−0.16, 0.19]	0.81	0.09 [−0.05, 0.23]	0.01 [−0.16, 0.18]	−0.24 [−0.49, 0.01]	0.07

^*Positive value signals that women assigned to hormone therapy had better mean performance than women assigned to placebo; Logarithm transformations used for executive function

^**Missing for N=279 women for last menstrual period (CEE+MPA: 137; CEE-Alone: 142) and N=85 for prior use of hormone therapy

Among women assigned to hormone therapy during WHI, 28 (4.0%) reported use at some time during post-trial follow-up, compared to 24 (3.8%) among women who had been assigned to placebo (p=0.82). Post-trial use of hormone therapy had no associations with any cognitive function measure (all p>0.18).

Power projections for WHIMSY were based on the WHIMS Modified MiniMental State Exam global cognitive scores.² The recruitment goal of 2,240 women was projected to provide 91% power to detect a mean difference of 0.5 units in this test across two exams, which corresponds to 0.10 to 0.15 standard deviations for these test scores as collected at baseline in WHIMS. WHIMSY fell short of this recruitment goal, enrolling 1,326 women. Post hoc power projections based on observed data yielded 80% (90%) power to detect a mean difference of 0.15 (0.18) standard deviations, which translates to 0.65 (0.75) TICS-m units.

DISCUSSION

In a large heterogeneous cohort of postmenopausal women aged 50–55 years, WHIMSY tested whether random assignment to an average 7-year prescription of CEE therapies produced long-term cognitive benefits or deficits compared to placebo. For the primary outcome of global cognitive function, and for specific cognitive domains and a composite of individual tests, no evidence for overall benefit or harm was found. There was some evidence that assignment to hormone therapy was associated with relatively poorer performance on verbal fluency among pre-specified subgroups of prior hysterectomy or prior use, however type 1 error was not controlled across the several domain-specific measures. There was also no evidence for differential treatment effects related to on-trial adherence or years of exposure. The original balance between treatment groups afforded by randomization did not appear to be eroded. WHIMSY fell short of its recruitment goal, but maintained adequate power to detect the relatively small mean differences targeted during its design.

Comparison to WHIMS

WHIMS found that prescribing 4–5 years of CEE-based therapy to women older than 65 years produced a mean relative decrement of 0.07 (standard error=0.03) standard deviations in global cognitive function, as assessed with the Modified Mini-Mental State Exam.² In the 2,304 of its women enrolled in the Women’s Health Initiative Study of Cognitive Aging (WHISCA), this on-trial relative deficit was maintained through a mean (standard deviation) of 2.4 (1.1) and 4.0 (1.3) years after the termination of the WHI CEE-alone and CEE+MPA trials respectively, averaging 0.07 (0.03) standard deviations during post-trial follow-up.³ The endurance of this effect on global cognitive function supports the choice of the TICS-m as the primary outcome measure for WHIMSY.

WHISCA found modest decrements in other domains WHIMSY assessed. A test of verbal memory (California Verbal Learning Test²⁶) had an average [95% confidence interval] decrement of 0.039 [−0.028,0.106] on-trial and 0.013 [−0.056,0.082] post-trial standard deviations, neither statistically significant. A test of attention and working memory (Digit Span Forward and Backward) had average decrements of 0.064 [−0.009,0.146]on-trial and 0.039 [−0.034,0.112] post-trial, also not significant. A test of semantic verbal fluency similar to the measure used in WHIMSY had a larger on-trial average decrement of 0.083 [0.016,0.150], but little post-trial decrement: 0.006 [−0.063,0.075]. For each of these domains, post-trial relative decrements were smaller than on-trial decrements, only reaching nominal significance for verbal fluency (p=0.009). Because WHIMSY had fewer women and less follow-up, it cannot rule out deficits (or benefits) as small as in WHISCA.

Subgroup analyses

In general, the absence of differences in cognitive function between women assigned to active versus placebo therapy was consistent between CEE-alone and CEE+MPA regimens, and for subgroups based on time since last menstrual period or prior hormone therapy use. The one exception was verbal fluency, which appeared to be adversely affected among women assigned to CEE-alone therapy compared to CEE+MPA therapy and among women with prior (but not current) hormone therapy use compared to no prior use. WHISCA also found that post-trial differences between women who had been assigned to active versus placebo therapy in the CEE-Alone and CEE+MPA trials were similar for global cognitive function, verbal memory, and attention and working memory. Similar to WHIMSY, it also found marginal differences in the post-trial effects of CEE-Alone versus CEE+MPA therapy on verbal fluency: women assigned to CEE-Alone therapy had mean (standard error) scores 0.092 (0.060) standard deviations worse than placebo, while women who had been assigned to CEE+MPA therapy averaged 0.039 (0.044) standard deviations better than placebo (interaction p=0.08).³ While the magnitudes of these possible treatment-related differences in verbal fluency are small, the similarity in the trends across the trials raises the possibility that CEE-alone therapy may be associated with small longer-term adverse effects on verbal fluency. However, this finding could have resulted by chance.

Others have found verbal fluency to be improved,²⁷ unchanged,^28,29 or harmed³⁰ by hormone therapy. Higher levels of endogenous estrogens have been associated with greater declines in verbal fluency in older women.³¹ Because all women receiving CEE-Alone therapy had prior hysterectomy, which may be a risk factor on its own for cognitive impairment,³² it may be that women’s response to hormone therapy depends on whether loss of endogenous estrogens is gradual or precipitous.³³

Magnitude of detectable intervention effects

WHIMSY had sufficient power to rule out mean treatment effects of 0.15 standard deviations, within its original design specifications, supporting the use of its telephone based battery. Telephone-based cognitive assessments are becoming more widely used in trials and cohort studies.³⁴

The larger WHIMS and WHISCA trials, which featured more cognitive assessments over time, detected CEE-related mean decrements of 0.06 to 0.08 standard deviations in cognitive function.^1–3 Despite these relatively small mean differences, CEE-based therapy among women >65 years of age resulted in a 75% increase in the hazard for dementia and significant decrements in brain volumes.^4,35 It is possible that hormone therapy could have had a similar small effect on cognitive function in younger women that may have clinical significance, but for which WHIMSY was underpowered to detect. Two findings argue against this. First, both the primary outcome, a measure of global cognitive function, and the composite outcome formed by averaging all test scores, had essentially no treatment effects. Secondly, there was no evidence that differences between intervention groups varied depending on markers of adherence or on-trial exposure. There was, across both arms, a trend for better adherence among women with higher levels of executive function: we interpret this as reflecting an increased ability to adhere to the study protocol rather than a treatment effect.

Limitations

WHIMSY does not address whether initiating hormone therapy during menopause and maintaining therapy until symptoms pass affects cognitive function, either in the short or longer term. All enrollees had no therapy for at least 3 months prior to randomization; their last menstrual period had occurred an average of 4 (no prior hysterectomy) to 8 years (prior hysterectomy) years before WHI enrollment. As volunteers for a clinical trial and post-trial follow-up, these women may not represent more general populations [Espeland, 2013]. Women had been unmasked to their treatment assignment, which could have influenced their willingness to participate in WHIMSY and their performance on cognitive tests, however good balance was maintained between treatment groups for important risk factors for cognitive dysfunction. Pre-treatment levels of cognitive function were not assessed, however the WHIMSY cohorts were well-balanced with respect to pre-treatment risk factors for cognitive impairment; covariate adjustment for these did not materially affect estimated treatment effects.

Summary

Our findings provide reassurance that CEE-based therapies when administered to women earlier in the postmenopausal period do not appear to convey long term adverse consequences for cognitive function. While we cannot rule out acute benefits or harm, these do not appear to be present to any degree an average of seven years after cessation of therapy. One exception may be for minor longer term disturbances of verbal fluency for women prescribed CEE-Alone, however this may be a chance finding.

WHIMSY Clinical Coordinating Center: (Wake Forest School of Medicine, Winston-Salem, NC): Sally Shumaker, Mark Espeland, Steven Rapp, Claudine Legault, Laura Coker, Maggie Dailey, Michelle Naughton, Beverly Snively, Iris Leng, Kaycee Sink, Anne L. Vaughan.

WHIMSY Clinical Centers: (Albert Einstein College of Medicine, Bronx, NY): Sylvia Wassertheil-Smoller; (Baylor College of Medicine, Houston, TX): Aleksandar Rajkovic; (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA): JoAnn Manson; (Emory University, Atlanta, GA): Lawrence Phillips; (Fred Hutchinson Cancer Research Center, Seattle, WA): Andrea LaCroix; (George Washington University Medical Center, Washington, DC): Richard Katz; (Harbor-UCLA Research and Education Institute, Torrance, CA): Rowan Chlebowski; (Kaiser Permanente Center for Health Research, Portland, OR): Frances Lynch; (Kaiser Permanente Division of Research, Oakland, CA): Bette Caan; (Medical College of Wisconsin, Milwaukee, WI): Jane Morley Kotchen; (MedSTAR Research Institute, Washington, DC): Barbara Howard; (Memorial Hospital of Rhode Island, Pawtucket, RI): Charles Eaton; (Northwestern University, Chicago, IL): Sandra Weintraub; (Cook County Hospital, Rush-Presbyterian St. Luke’s Medical Center, Chicago, IL): Lynda Powell; (Stanford Center for Research in Disease Prevention, Stanford University, Stanford, CA): Marcia L. Stefanick; (State University of New York at Stony Brook, Stony Brook, NY): Dorothy Lane; (The Ohio State University, Columbus, OH): Rebecca Jackson; (University of Alabama at Birmingham, Birmingham, AL): Beth Lewis; (University of Arizona, Tucson/Phoenix, Tucson, AZ): Cynthia Thompson; (University of Buffalo, Buffalo, NY): Jean Wactawski-Wende; (University of California at Davis, Sacramento, CA): John Robbins; (University of California at Irvine, Orange, CA): Allan Hubbell; (University of California at Los Angeles, Los Angeles, CA): Lauren Nathan; (University of Cincinnati, Cincinnati, OH): Margery Gass; (University of Florida, Gainesville/Jacksonville, Gainesville, FL): Marian Limacher; (University of Hawaii, Honolulu, HI): Kamal Masaki; (University of Iowa, Iowa City/Davenport, Iowa City, IA): Jennifer Robinson; (University of Massachusetts, Worcester, MA): Judith Ockene; (University of Medicine and Dentistry of New Jersey, Newark, NJ): Norman Lasser; (University of Medicine and Dentistry of New Jersey, New Brunswick, NJ): John Kostis; (University of Minnesota, Minneapolis, MN): Richard Grimm; (University of Nevada, Reno, NV): Robert Brunner; (University of North Carolina, Chapel Hill, NC): Carol Murphy; (University of Pittsburgh, Pittsburgh, PA): Lewis Kuller; (University of Tennessee at Memphis, Memphis, TN): Karen Johnson; (University of Texas Health Science Center, San Antonio, TX): Donald Royall; (University of Washington, Seattle, WA): Shirley Beresford; (University of Wisconsin, Madison, WI): Gloria Sarto; (Wake Forest University Health Sciences, Winston-Salem, NC): Mara Vitolins; and (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI): Michael Simon.

SHORT LIST OF WHI INVESTIGATORS

Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller Clinical Coordinating Center: Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg

Investigators and Academic Centers: (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL)Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker

Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker

For a list of all the investigators who have contributed to WHI science, please visit: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf