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Hormone replacement therapy (HRT) in early menopause caused no apparent harm to patients' cognitive function, according to long-term follow-up of participants in clinical trials.

Neurocognitive testing as much as 17 years after use of HRT showed no substantive differences between women randomized to HRT and those treated with placebo, according to Mark A. Espeland, PhD, of Wake Forest University in Winston-Salem, N.C., and co-authors.

Investigators found no detrimental effects of HRT on global cognitive function or on any of the domains assessed by the test battery, as reported online in JAMA Internal Medicine.

The results also showed no obvious benefits of HRT with respect to cognitive function.

"Our findings provide reassurance that conjugated equine estrogen-based therapies, when administered to women earlier in the postmenopausal period, do not seem to convey long-term adverse consequences for cognitive function," researchers said.

"Although we cannot rule out acute benefits or harm, these do not appear to be present to any degree a mean of 7 years after cessation of therapy," they added.

The Women's Health Initiative Memory Study (WHIMS) showed global and domain-specific cognitive deficits in women ≥65 treated with conjugated equine estrogen (CEE). Though small, the deficits persisted for years after discontinuation of hormone therapy. The deficits occurred in association with decreases in brain volume.

Data from observational and preclinical studies have suggested that initiation of HRT at the same time of menopausal loss of ovarian function might promote or preserve cognitive function, according to the authors' background information. Meta-analyses of clinical trials have failed to demonstrate a consistent evidence of benefit.

The window-of-opportunity hypothesis regarding cognitive benefits of HRT has persisted because of continued widespread use of hormone therapy to manage menopausal systems, the authors continued. The WHI Memory Study of Younger Women (WHIMSY) evaluated the long-term effects of CEE-based therapy on cognitive function in postmenopausal women 50 to 55.

Espeland and colleagues analyzed data for 1,326 participants in two randomized trials of CEE-based therapy. The patients were 50 to 55 at enrollment in the trials and were treated for an average of 7 years. WHIMSY investigators initially evaluated cognitive function an average of 7.2 years after the trials ended, when the patients' mean age was 67.2. A follow-up assessment occurred a year later.

The authors noted that the study participants did not undergo a cognitive assessment prior to randomization. However, they noted that the HRT and placebo groups were well balanced with respect to risk factors for cognitive impairment. Moreover, covariate adjustment did not substantively affect the results.

The primary outcome of WHIMSY was global cognitive function, as assessed by the Telephone Interview for Cognitive Status-modified (TICSm) test. Secondary outcomes were assessed by validated instruments and included:

• Immediate and delayed verbal memory
• Attention and executive function
• Verbal fluency
• Working memory

Comparing the HRT and placebo groups, Espeland and colleagues found no significant difference in global cognitive function (P=0.66). Scores on each of the domains evaluated separately also showed no evidence of a treatment effect (positive or negative) with HRT (P>0.15 for all comparisons).

Prespecified subgroup analyses revealed some evidence that HRT with CEE-based regimens might have adversely affected verbal fluency in women with prior hysterectomy (treatment effect -0.17, 95% CI -0.33 to -0.02) or HRT (-0.25, 95% CI -0.42 to -0.08).

The findings offered a mix of reassurance and disappointment, according to the author of an accompanying editorial. WHIMSY revealed no evidence of a detrimental effect on cognitive function but also found no evidence of substantial beneficial effects on cognitive function. However, the lack of a definitive answer should not be a deterrent to future investigations.

"With the rapid aging of our population, identifying means of maintaining cognition into older ages has become a public health necessity," wrote Francine Grodstein, ScD, of Harvard School of Public Health. "The WHIMSY trial represents an excellent and cost-efficient utilization of precious scientific assets and hopefully will set the stage for more and similar creative approaches to scientific discovery for promoting cognitive health."

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