Menopause and the Impact of Hormone Replacement on Chronic Disease: Current Controversies and Findings
December 2014
Volume 5, Issue 4

Review of the Effects of Postmenopausal Hormone Therapy on Cognition and Mood Illustrates Mixed Results

Fertil Steril. 2014;101:898-904

Introduction: Early epidemiologic studies suggested that hormone therapy is neuroprotective. However, more recent results from the Women's Health Initiative (WHI) and Women's Health Initiative Memory Study (WHIMS), published beginning in 2003, suggested that prolonged use of orally administered opposed conjugated equine estrogen (ie, CEE plus progestin) was linked to cognitive decline and dementia, leading to the trials being stopped early. In addition, the Heart and Estrogen/Progestin Replacement Study (HERS, published in 2002) found that long-term use of orally administered opposed CEE (CEE + P) was linked to poorer cognitive performance.

Methods: The authors conducted a literature review of clinical and observational studies published after 2000, using the search terms "hormone therapy and cognition," and "hormone therapy and mood."

Results: Observational and randomized controlled studies show conflicting findings regarding the effects of hormone therapy on cognition and on mood. We have summarized the key findings of all included studies in the Table (see below). A number of methodologic variables may be responsible for these differing findings, including formulation and dose of hormone therapy, route of administration, timing of initiation, treatment duration, and baseline health of study participants.

In general, transdermal estradiol and micronized progesterone given shortly after menopause appear to be associated with beneficial effects on cognitive and affective function.

Conclusion: A review of randomized clinical trials and observational studies published since 2000 was not conclusive, revealing mixed findings regarding the effects of hormone therapy on cognition and mood. The authors suggest that findings from the Kronos Early Estrogen Prevention Study (KEEPS) and other randomized controlled studies may provide more conclusive evidence.

Table. Key Findings from Clinical Studies of the Effects of Hormone Therapy on Cognition and Mood

Study Key Findings
Observational Studies on Cognition
Zandi et al, 2002
  • Women who used hormone therapya had a 2.5-fold lower incidence of Alzheimer’s disease compared with the incidence in men, according to prospective data from the Cache County Study
Shao et al, 2012
  • Women who used any type of hormone therapy within 5 years of menopause had a 30% reduced risk for Alzheimer’s disease, with longer-term use linked to greater benefit, according to a retrospective analysis of the Cache County Study
  • E+P initiated after the age of 70 years was linked to an increased risk for Alzheimer’s disease


Study
Key Findings
Randomized Controlled Studies on Cognition
Albertazzi et al, 2000 
  • Combination therapy with norethisterone and estradiol or tibolone for 6 months was associated with improved semantic memory (P<0.001) compared with placebo in 22 postmenopausal women (aged 51-57 years)
Asthana et al, 2001
  • In 20 older postmenopausal women with Alzheimer’s disease, use of 0.10 mg/day of 17β-estradiol for 8 weeks was associated with significant improvement in verbal memory, visual memory, and attention compared with placebo
Shaywitz et al, 2003
  • Crossover study in 60 postmenopausal women (age 32.8-64.9 years; mean 51.2 years) showed improved oral reading (P<0.05) and verbal memory performance (P<0.001) when taking CEE compared to when taking placebo.

Schiff et al, 2005
  • Crossover study in 19 cognitively normal postmenopausal women showed improved simple reaction time following 12-week treatment with transdermal estradiol compared with placebo; in contrast, no benefit of hormone therapy was found for verbal/visual memory, attention, or working memory
Wolf et al, 2005
  • 24-week treatment with estradiol or estradiol/progesterone treatment did not affect cognition in older hysterectomized women (age 58-75 years)
Almeida et al, 2006
  • 20-week trial of estradiol or placebo in 115 women (age ≥70 years) found that hormone therapy was linked to greater improvement in immediate face recall; however, the placebo group showed stronger verbal memory and fluency

Joffe et al, 2006
  • 12-week trial showed significant improvement in verbal memory (specifically reduced errors of perseveration) in healthy perimenopausal and postmenopausal women (n=52) taking estradiol 0.05 mg/day (P=0.03) compared with placebo in a trial of 52
Maki et al, 2007
  • Pilot study of 180 healthy postmenopausal women (age 45-55 years), no cognitive benefit was found with conjugated equine estrogen 0.625 mg/MPA 2.5 mg for 4 months compared with placebo; a trend toward a negative effect of hormone therapy on verbal memory was found (“COGENT” study)
Alhola et al, 2010
  • 16 postmenopausal women (age 58-70 years) randomized to estradiol valerate plus norethisterone for 6 months showed significant improvements in verbal memory compared to a placebo group (P=0.024) and a slight decline in auditory attention (P=0.025)

Möller et al, 2010
  • Treatment with estradiol valerate plus testosterone for 48 weeks decreased immediate verbal memory (P<0.05) compared with estradiol valerate plus placebo in postmenopausal women (n=44; mean age, 54 years)
  • Simple verbal attention decreased in the estradiol valerate plus placebo group but was unchanged in the estradiol valerate plus testosterone group; the difference was not statistically significant
Kocoska-Mara et al, 2011
  • 4-week treatment with testosterone or estrogen therapy did not alter verbal fluency, verbal memory, or spatial ability in a study of 200 postmenopausal women (aged 50-65 years)
Sherwin and Grigorova, 2011
  • CEE plus micronized progesterone for 3 months was linked to a significant improvement in working memory (P=0.032) and a non-significant decline in verbal memory compared with baseline measures in a trial of 24 postmenopausal women (mean age, 55 years)
  • CEE plus MPA was not associated with cognitive change
 Wharton et al, 2011
  • 3-month treatment with transdermal 17β-estradiol, both unopposed and combined with MPA, was associated with improvements in visual memory (P=0.015) and semantic memory (P=0.036) in 43 postmenopausal women with moderate Alzheimer’s disease


Study
Key Findings
Observational Studies on Mood
Whooley et al, 2000
  • Cross-sectional study found link between current use of unopposed estrogen and a decreased risk of depressive symptoms in older women
Stephens et al, 2006
  • Cross-sectional comparison showed no effect of hormone therapy (either E alone or E+P) on mood; however, prospective follow-up of 17 women showed mood improvements after 3 months of hormone therapy use.
Amore et al, 2007
  • Cross-sectional survey of 1,345 women shows that postmenopausal women have higher levels of depression and sexual symptoms than premenopausal women, and use of hormone therapya had no effect on mood symptoms.
Toffol et al, 2013
  • In 2 population-based studies, use of hormone therapy in the previous month in peri- and post-menopausal women was associated with worse depression and anxiety. There was no difference in mood symptoms based on type of hormone therapy (ie, estrogen alone vs E+P).
Kornstein et al, 2013
  • Among women taking antidepressants in the STAR*D study, hormone therapya and menopausal status were not associated with changes in mood.

Study Key Findings
Randomized Controlled Studies on Mood
Albertazzi et al, 2000 
  • Single-blind study of 14 postmenopausal women (aged 51 to 57 years) randomized to tiboloneb versus continuous combined norethisterone acetate and oestradiol for 6 months showed no effect of either hormone therapy on mood
Schmidt et al, 2000
  • In a study of 34 women with perimenopause-related depression, mood rating scale scores were significantly decreased in women taking 17β-estradiol at 3 weeks and 6 weeks of treatment compared with baseline levels (P<0.01). A full or partial response was found in 80% of women, compared with 22% of women taking placebo
Soares et al, 2001
  • In 50 perimenopausal women with depressive disorders, remission of depression occurred in 68% of those treated with 17β-estradiol for 12 weeks and 20% of women given placebo (P=0.001)
Onalan et al, 2005
  • Prospective study of 286 postmenopausal women given CEE plus 2.5 mg MPA, CEE plus 5 mg MPA, or 2.5 mg tiboloneb for 12 months showed that all 3 treatments improved depressive symptoms compared to calcium supplementation (placebo; P<0.05)
Schiff et al, 2005
  • In a crossover study involving 19 postmenopausal women (age >60 years) without depression, administration of transdermal estradiol 50 mg/24 hours over 3 months was associated with significant improvement in scores on a depression rating scale (P=0.05)
Karşidaǧ et al, 2012
  • In a study of 183 menopausal women, use of transdermal or oral estradiol in combination with norethisterone for 3 months was associated with significantly improved scores on anxiety and depression screening measures


aStudy did not state the type of hormone therapy used.
bTibolone is a synthetic hormone with potential E and P effects, classified as a selective tissue estrogenic activity regulator. It is not approved for use in the United States.
CEE, conjugated equine estrogens; E+P, estrogen plus progestin; MPA, medroxyprogesterone acetate; STAR*D, Sequenced Treatment Alternatives to Relieve Depression
Data extracted from Fischer B, Gleason C, Asthana S. Effects of hormone therapy on cognition and mood. Fertil Steril. 2014;101(4):898-904.

Commentary

Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in reproductive and neuroendocrinology, and an Attending in Medicine, Massachusetts General Hospital, Boston, MA.

While early studies suggested that postmenopausal hormone therapy (HT) provided a measure of neuroprotection, WHI and other studies noted a link between HT and poorer cognitive performance. These later studies (WHI and HERS) involved women over 65 years old, and used oral (versus transdermal) estrogen + progestin (MPA), 2 factors which Fischer and colleagues suggest may impact study results. The authors thus set out to review a selection of randomized clinical trials and observational studies published since 2000. The key characteristics and findings of their included studies are summarized in the Table (above Commentary).

The authors looked at studies investigating the impact of postmenopausal HT on cognition, and on mood. The reviewed cognition studies often focused on different endpoints (as well as different cohorts and interventions).

The two observational studies on cognition looked at Alzheimer's Disease (AD) as the primary endpoint. The randomized controlled trials (RCTs) used variable measures of memory (eg, semantic or working; verbal, visual, or oral), attention (eg, auditory), verbal fluency, spatial ability, and reaction time. One of the larger studies, of 115 women (age >70 years), had variable results, with the placebo group faring better in verbal memory and fluency than the HT group (which fared better in face recall). Two of the RCTs looked at women diagnosed with AD; both revealed improvements on HT, though it should be noted that these were relatively small studies (N=20 and 43), particularly given the potential variability in the disease.

The observational mood studies showed largely negative or null results (the one exception being the earliest observational study included,1 and involved up to 6,000 subjects. Results from the RCTs on mood were more positive. Of note, a number of the studies looked at women with depressive disorders or symptoms; the largest reviewed trial (n=286) found that subjects on 1 year of CEE + MPA (2.5 or 5 mg) or on tibolone versus calcium supplementation showed improvement in depressive symptoms.2 (Tibolone is a synthetic hormone with potential E and P effects, and is classified as a selective tissue estrogenic activity regulator. It is not approved for use in the United States.) The authors concluded that HT may be of benefit in women with perimenopausal or postmenopausal depression.

Of note, observational studies—while often large—do not speak to causality, only to association. While results of RCTs may be more definitive, many of the included RCTs are limited by small cohort size, and differences in age and health of cohort, and timing, type, and duration of HT. Fischer and colleagues specifically suggest that transdermal estradiol and micronized progesterone more closely approximate the premenopausal state and may offer benefits over oral estrogen and the synthetic progestin MPA, citing review evidence that MPA may interfere with the cognitive benefit of estradiol.

In addition to pointing out the relevance of methodology, the authors discuss 2 theories, which may help explain discrepancies in results. One, already discussed in the context of cardiovascular health, is the timing hypothesis—that HRT initiated closer to menopause may have a beneficial effect, while that benefit is lost if initiated later. Some results of the included studies do offer support for this hypothesis. Fischer and colleagues also conjure the "healthy cell bias theory," suggesting that those women who take perimenopausal HRT are healthier than those who do not, and that it is the differences in baseline health that account for the effects of HRT.

In summary, Fischer and colleagues caution against dismissing the potential benefits of postmenopausal hormone therapy for cognition (including neurodegenerative diseases) and mood. They suggest that the KEEPS-Cog study (as summarized in the overview, designed to study oral E+P versus transdermal E+P versus placebo in women within 3 years of menopause) will provide more definitive insights into the effects of oral E+P and transdermal E+P on cognition and mood.3

References

1. Whooley MA, Grady D, Cauley JA. Postmenopausal estrogen therapy and depressive symptoms in older women. J Gen Intern Med. 2000;15(8):535-541.

2. Onalan G, Onalan R, Selam B, Akar M, Gunenc Z, Topcuoglu A. Mood scores in relation to hormone replacement therapies during menopause: a prospective randomized trial. Tohoku J Exp Med. 2005;207:223-231.

3. Wharton W, Gleason CE, Miller VM, Asthana S. Rationale and design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective sub study (KEEPS Cog). Brain Res. 2013;1514:12-17.

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