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Cortical -Aminobutyric Acid Levels Across the Menstrual Cycle in Healthy Women and Those With Premenstrual Dysphoric Disorder

A Proton Magnetic Resonance Spectroscopy Study

C. Neill Epperson, MD; Kristin Haga, PhD; Graeme F. Mason, PhD; Edward Sellers, MD; Ralitza Gueorguieva, PhD; Wenjiang Zhang, PhD; Erica Weiss, MD; Douglas L. Rothman, PhD; John H. Krystal, MD

Arch Gen Psychiatry. 2002;59:851-858.

Background  There is increasing support for the hypothesis that gonadal steroids involved in the regulation of the human menstrual cycle modulate -aminobutyric acid (GABA) neuronal function. This study tests the hypothesis that cortical GABA neuronal function, reflected in brain GABA concentrations, fluctuates across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder (PMDD) and that a menstrual cycle phase–dependent abnormality in brain GABA concentrations in women diagnosed as having PMDD would reflect altered central response to circulating gonadal and neuroactive steroids.

Methods  Fourteen healthy menstruating women and 9 women diagnosed as having PMDD were recruited from a women's behavioral health research program located at a university-based medical center. The women underwent serial proton magnetic resonance spectroscopic measurements of occipital cortex GABA levels across the menstrual cycle (primary outcome measure) and had blood drawn for gonadal hormone and neurosteroid levels determined on each scan day (secondary outcome measure).

Results  There was a significant group x phase interaction with most of the finding explained by the reduction in cortical GABA levels during the follicular phase in those with PMDD compared with healthy controls. Cortical GABA levels declined across the menstrual cycle in healthy women, whereas women with PMDD experienced an increase in cortical GABA levels from the follicular phase to the mid luteal and late luteal phases. Significant between-group differences in the relationship between hormones and GABA were observed for estradiol, progesterone, and allopregnanolone.

Conclusions  These data strongly suggest that the GABAergic system is substantially modulated by menstrual cycle phase in healthy women and those with PMDD. Furthermore, they raise the possibility of disturbances in cortical GABA neuronal function and modulation by neuroactive steroids as potentially important contributors to the pathogenesis of PMDD.

From the Departments of Psychiatry (Drs Epperson, Haga, Mason, Gueorguieva, Weiss, and Krystal), Obstetrics and Gynecology (Dr Epperson), Diagnostic Radiology (Dr Rothman), and Epidemiology and Public Health (Dr Gueorguieva), Yale University School of Medicine, New Haven, Conn; and Department of Pharmacology, University of Toronto School of Medicine, Toronto, Ontario (Drs Sellers and Zhang).

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