Unraveling Individual Variability in Hormonal Mood Swings

Guest post by Brenda Patoine

The stereotype of women’s “inexplicable” mood swings has long provided fodder for comics and cartoonists, but for scientists trying to understand the underlying biology, hormonal depression is no joke.

Endocrine-related affective mood disorders show up in different forms in different phases of life, from premenstrual dysphoric disorder (PMDD) during otherwise normal menstrual cycling, to post-partum depression following childbirth, to mood disruptions around and after menopause. Yet these disorders don’t affect all women, and in fact, most women do not experience them.

“How is it that some women experience a change in affective state as a result of hormones whereas a majority of women do not?” Peter Schmidt, M.D. asked in a July 8 webinar sponsored by the National Institute of Mental Health (NIMH). “That really is the million-dollar question.”

As chief of behavioral endocrinology at NIMH, Schmidt’s laboratory has conducted a series of studies trying to unravel the hormonal contributions to women’s depression and answer the overriding question of individual vulnerability. The lab’s investigations of PMDD revealed a hormonal trigger–an initial change in steroid level that preceded the negative affective state–plus an underlying susceptibility that makes some women more vulnerable. Using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), they identified two brain regions that appear to be regulated by sex steroids: the medial orbital frontal cortex, which is involved in many social behaviors and stress, and an area in the subgenual cingulate called A25.

A25 is of particular interest, Schmidt said, because previous research has identified structural and functional abnormalities in this region in people with depression. It has one of the highest concentrations of serotonin neurons in the brain and is a primary region targeted by deep brain stimulation for treating depression.

Even if A25 represents a neuroanatomical locus for PMDD, the question of individual susceptibility remains. Reasoning that genetic differences could explain why some women suffer and others do not, Schmidt’s team focused on a gene known as COMT based on data suggesting its many interactions with sex steroids. They identified women with different variations (alleles) of the COMT gene and conducted scans to analyze brain activity in response to different hormonal states (i.e., in the presence of estradiol or progesterone, or the absence of both), and found significant differences depending upon which allelic variation of the COMT gene the women carried.

“This study showed that a simple variation in one gene for one enzyme could interact with and convey a differential response in that brain region to a specific hormone condition,” said Schmidt.

The researchers then asked whether women with PMDD might also have intrinsic differences in gene expression–which genes are “on” or “off” in a given state. Using a cell-based model to compare patterns of gene expression, they zeroed in on a pathway known as the ESC/E(Z) Complex, a group of 13 inter-related genes that is known to be an important epigenetic modifier, meaning it can switch genes on or off to regulate gene expression in cells. “We think this pathway represents a fundamental cellular difference that may underlie some of the differential sensitivity to steroids in women with PMDD,” said Schmidt.

“These findings and others will allow us to disentangle one of the most important questions in psychiatry: why people respond to the same signal in a different way.”

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