Elsevier

Biological Psychiatry

Volume 54, Issue 7, 1 October 2003, Pages 757-762
Biological Psychiatry

Abnormal luteal phase excitability of the motor cortex in women with premenstrual syndrome

https://doi.org/10.1016/S0006-3223(02)01924-8Get rights and content

Abstract

Background

Premenstrual syndrome (PMS) involves an aberrant behavioral response to normal hormone secretion. Pathogenetic theories posit abnormal modulation of γ-aminobutyric acid (GABA) transmission in the brain by neuroactive metabolites of progesterone (neurosteroids). In earlier transcranial magnetic stimulation (TMS) studies of the motor cortex, we showed that inhibition increases in the luteal phase, consistent with neurosteroid action at the GABAA receptor. Here, we studied women with PMS to see if their response to endogenous progesterone differed from that of control subjects.

Methods

We studied nine women with PMS and 14 control subjects during the midfollicular and luteal phases with paired TMS. Subthreshold conditioning TMS was followed by test stimulation that produced a motor evoked potential (MEP) in a hand muscle. We gave pairs at each of seven intervals (2–10 msec) and unconditioned stimuli, measuring the amplitude ratio of the average MEP from the pairs at each interval to that from the unconditioned stimuli (ratio < 1 = inhibition).

Results

Both groups showed the same follicular phase response to paired TMS. Control subjects showed more inhibition in the luteal phase. Women with PMS showed relative facilitation.

Conclusions

This is the first physiological evidence for an abnormal brain response to progesterone in PMS.

Introduction

There is evidence suggesting that an abnormal brain response to an essentially normal secretion pattern of the ovarian steroids, estradiol and progesterone, forms the physiological basis of the premenstrual syndrome (PMS; Schmidt et al 1998). These hormones and their metabolites have potent effects on brain function. For example, estradiol increases neuronal excitability Wong et al 1996, Woolley 1999 and lowers the threshold for epileptic seizures (Morrell 1999) by increasing the activity of glutamate, the principal excitatory neurotransmitter in the brain. Progesterone is metabolized to neuroactive compounds, the neurosteroids, some of which bind to a site on the alpha subunit of the γ-aminobutyric acid A (GABAA) receptor, increasing its activity in response to GABA binding (Paul and Purdy 1992) in a manner analogous to the action of the benzodiazepine sedatives and anxiolytics. Like other GABA agonists, neurosteroids reduce neuronal excitability in the cerebral cortex, raising the seizure threshold (Morrell 1999) and blocking anxiety (Brot et al 1997).

Indirect data suggest that in PMS, a disorder of neurosteroid metabolism or action leads to a luteal phase deficit in GABA-mediated inhibition. For instance, women with PMS are reported to have decreased serum GABA levels in the late luteal phase (Halbreich et al 1996). Drug challenge studies have shown decreased behavioral sensitivity both to benzodiazepines (Sundstrom et al 1997) and to the GABA agonist neurosteroid pregnenolone (Sundstrom et al 1998) and greater sensitivity to benzodiazepine receptor antagonism with flumazenil relative to control subjects (Le Melledo et al 2000). Recently, Epperson et al (2002), using magnetic resonance spectroscopy, found that GABA levels in the occipital cortex were abnormally low in the follicular phase and increased abnormally in the luteal phase. They interpreted this increase as implying a possible luteal phase defect in GABA function. Despite these results, convincing physiologic evidence of a defect in luteal phase GABAergic function has yet to be obtained.

Recently adopted noninvasive techniques can test the function of specific neuronal circuits and are beginning to be used to analyze the effects of drugs and other agents in vivo in humans. The amplitude of the muscle response, or motor evoked potential (MEP), produced by transcranial magnetic stimulation (TMS) of the motor cortex reflects the integration of synaptic inputs by the cortical and spinal motoneurons (Figure 1 A). The MEP can be modulated by a preceding “conditioning” stimulus delivered with an intensity below the MEP threshold (Kujirai et al 1993). This occurs even when the conditioning pulse is too weak to produce spinal cord activity, indicating a purely cortical site of interaction between the stimuli. Depending on the interstimulus interval (ISI), the predominant effect of the first stimulus on the second is inhibition or facilitation (Figure 1, B and C). The relative degree of inhibition and facilitation, summed over ISIs, is affected by GABAergic drugs, for example, the benzodiazepines (Ziemann et al 1998). In earlier studies of healthy women Smith et al 1999, Smith et al 2002, we showed that there is less inhibition and more facilitation in the follicular phase under the unopposed excitatory influence of estrogen, which facilitates the action of glutamate, the principal excitatory neurotransmitter in the cerebral cortex; however, in the luteal phase, the balance shifts in favor of inhibition, presumably reflecting the added effect of the progesterone-derived neurosteroids. The theory of a luteal phase deficiency in GABAergic function in PMS predicts that affected women should show less inhibition and more facilitation than matched control subjects. In the study described here, we compared women with and without PMS in a TMS experiment to test the hypothesis that the increase in paired-pulse inhibition, seen and attributed to progesterone in our earlier studies, would be attenuated in women with PMS. Some of these data have been published in abstract form (Smith et al 2000).

Section snippets

Methods and materials

Medication-free women with regular menstrual cycles were selected from respondents to newspaper advertisements for healthy volunteers and women with menstrual-cycle-related mood changes. For 3 months before entry into the study, all prospective participants were screened with a daily visual analog scale for self-rating of affective symptoms including sadness, anxiety, irritability, and mood stability and of somatic symptoms including breast discomfort, bloating, and fatigue. The diagnostic

Results

As expected, the women with PMS had a significantly greater increase in symptoms in the luteal phase than did the control women, both when the scores were collapsed across all scales [group * phase interaction: F(1,21) = 23.8; p = .0002] and on the individual scales (all ps ≤ .01).

No significant differences were found in hormone levels between the groups (see Table 1) and there were no significant correlations between the serum levels of either hormone and the symptom ratings or the

Discussion

In this study, women with PMS showed neurophysiological changes from the follicular to the luteal phase that were significantly different from those of a control group. Specifically, in the PMS group, the luteal phase increase in circulating progesterone was accompanied by an increase in the excitability of the output cells of the motor cortex. This contrasts with the decreased excitability shown by the control subjects in this study and two similar groups of healthy women in our previous

Acknowledgements

The work was supported by National Institute of Neurological Disorders and Stroke and National Institute of Mental Health intramural program funding.

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