Review of the Effects of Postmenopausal Hormone Therapy on Cognition and Mood Illustrates Mixed Results
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 |
|
| Shao et al, 2012 |
|
Study |
Key Findings |
|---|---|
| Randomized Controlled Studies on Cognition | |
| Albertazzi et al, 2000 |
|
| Asthana et al, 2001 |
|
| Shaywitz et al, 2003 |
|
Schiff et al, 2005 |
|
| Wolf et al, 2005 |
|
| Almeida et al, 2006 |
|
Joffe et al, 2006 |
|
| Maki et al, 2007 |
|
| Alhola et al, 2010 |
|
Möller et al, 2010 |
|
| Kocoska-Mara et al, 2011 |
|
| Sherwin and Grigorova, 2011 |
|
| Wharton et al, 2011 |
|
Study |
Key Findings |
|---|---|
| Observational Studies on Mood | |
| Whooley et al, 2000 |
|
| Stephens et al, 2006 |
|
| Amore et al, 2007 |
|
| Toffol et al, 2013 |
|
| Kornstein et al, 2013 |
|
| Study | Key Findings |
|---|---|
| Randomized Controlled Studies on Mood | |
| Albertazzi et al, 2000 |
|
| Schmidt et al, 2000 |
|
| Soares et al, 2001 |
|
| Onalan et al, 2005 |
|
| Schiff et al, 2005 |
|
| Karşidaǧ et al, 2012 |
|
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.
