Estrogen exposure across the lifespan appears to be associated with risk of depression during the menopausal transition, according to findings from the Study of Women’s Health Across the Nation, or SWAN.

Specifically, a longer total duration of estradiol exposure was found to be protective against depression during the menopausal transition, Dr. Claudio N. Soares reported at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

Dr. Claudio N. Soares
“What the data show is that for each year of increased premenopausal exposure to estrogen, you reduce by 15% the risk for developing depression after entering the menopausal transition. So the longer the exposure, the lower the risk,” said Dr. Soares of McMaster University, Hamilton, Ont.

The menopausal transition has been shown in numerous studies to be a time of increased depression risk, and endocrinologic factors have been hypothesized as contributing to vulnerability to depression. It has remained unclear, however, why some women are at increased risk compared with others.

Studies have shown that estrogen exposure can improve depression, but the question of whether estrogen exposure prior to the menopausal transition would affect depression risk during the transition had not been addressed, Dr. Soares noted.

To assess factors – including lifetime exposure to estrogen (based on the time from age at menarche to the age at menopause) – that might contribute to depression risk during this reproductive phase, Dr. Soares and his colleagues analyzed data from more than 1,200 women who participated in SWAN, a seven-site, longitudinal, epidemiologic study designed to examine the physical, biological, and psychological changes that women undergo during their middle and menopausal years.

The average duration of estradiol exposure in the women (who were aged 42-52 years at study entry and who have been followed for nearly 10 years) was about 36 years. A longer duration of exposure prior to the menopausal transition was associated with a lower risk of having a score of less than 16 on the CES-D (Center for Epidemiologic Studies-Depression) scale during the transition (hazard ratio, 0.847 after adjustment for numerous factors, including age, ethnicity, education, study site, premenopausal depression, current and ever antidepressant use, baseline smoking, and time in study), Dr. Soares said.

“The next question is, what is happening during that time of exposure that could be exacerbating risk?” he said, noting, for example, that some interesting data show that oral contraceptive use may affect depression exacerbations. When investigators looked at oral contraceptive use as a continuous variable in this study, it was shown to be associated with an even greater protective effect.

However, other factors also could modulate exposure to estrogen exposure, such as the number of pregnancies and duration of breastfeeding. The next step of the analysis will look at such interactions, he said.

Thus far, the findings indicate that the relationship between depression and the menopausal transition is complex and is associated with both current and historic reproductive endocrinology, Dr. Soares said.

This study was supported by the North American Menopause Society. SWAN was supported by grants from the National Institutes of Health. Dr. Soares disclosed financial relationships with AstraZeneca, Bristol-Myers Squibb, CIHR, Eli Lilly, Lundbeck, Moven Pharmaceuticals, NARSAD, and Pfizer, but reported having no conflicts with respect to this study.