Anxiety is a common, but understudied complaint in midlife women, and increases during the menopausal transition. Changes in estrogen are dramatic during the menopausal transition, and indirect data suggest a potential role for estrogen, particularly estrogen receptor beta, in mediating anxiety. Two subtypes of the estrogen receptor, alpha and beta (ER-alpha and ER-beta), appear to be critically involved in the expression of anxiety in females. Compounds that preferentially target ER-beta, including plant-derived estrogens (phytoestrogens), lower both anxiety behaviors and responsivity to discrete stressors, including social stress, in laboratory animals. The primary aim of this proposal is to carry out the first study to translate these preclinical studies to humans by comparing and contrasting of the effects of phytoestrogens, estradiol, and placebo on daily anxiety and responses to moderate psychosocial stress in the laboratory. Another major focus is emotional and non-emotional cognition. This focus stems from evidence that estrogen can affect the negative impact of glucocorticoids on memory.
These aims will be accomplished in a 12-week randomized placebo- controlled, clinical trial comparing three treatments: 1) a widely used phytoestrogen supplement (Novasoy(R) 400, 55 mg tablet twice daily);2) oral estradiol (1 mg/daily);and 3) placebo (identical appearing tablets twice daily) in 120 healthy women in the menopausal transition (40 per group). To measure anxiety, women will complete daily mood diaries at baseline and throughout the treatment period. To measure responsivity to psychosocial stress, parallel forms of the Trier Social Stress Test, a widely used laboratory induction that involves unanticipated public speaking and social evaluative fear, will be used to induce moderate psychosocial stress before and after treatment. At both laboratory sessions, measures of subjective stress, cortisol, and emotional memory performance will be obtained during a control condition and during the psychosocial stress condition. The results from this clinical trial will add critical information about the importance of estrogen changes at midlife as a contributing factor for anxiety and stress symptoms in midlife women. Positive findings would provide a rationale for subsequent investigations of ER-beta agonists in the treatment of anxiety symptoms and disorders in women.

Public Health Relevance

The prevalence of anxiety disorders is higher in women compared to men, and increases significantly in women at midlife (after age 45) but not men. Anxiety traits in non-clinical samples are also more common in women than men and worsen during hormonal transitional states, including the menopausal transition. To further our understanding of treatment options for women with anxiety during the menopausal transition, this study aims to test the effects of two widely used menopausal therapies, estradiol and phytoestrogens, on daily anxiety and stress responsivity, and the cognitive effects of daily and provoked stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH083782-04
Application #
8274899
Study Section
Interventions Committee for Adult Mood and Anxiety Disorders (ITMA)
Program Officer
Evans, Jovier D
Project Start
2009-06-16
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$485,354
Indirect Cost
$176,215
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Rubin, Leah H; Maki, Pauline M (2015) Elucidating postpartum depression through statistics. Lancet Psychiatry 2:6-8
Kantarci, Kejal; Maki, Pauline M (2014) Past hormone therapy in older women: does the brain recover from adverse effects? Neurology 82:380-1
Maki, Pauline (2013) Is timing everything? New insights into why the effect of estrogen therapy on memory might be age dependent. Endocrinology 154:2570-2
Maki, Pauline M (2013) Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies. Menopause 20:695-709
Maki, P M; Henderson, V W (2012) Hormone therapy, dementia, and cognition: the Women's Health Initiative 10 years on. Climacteric 15:256-62
Greendale, Gail A; Derby, Carol A; Maki, Pauline M (2011) Perimenopause and cognition. Obstet Gynecol Clin North Am 38:519-35