The biology of premenstrual dysphoric disorder (PMDD) is far from clear.

Reproductive hormones have been thought to be implicated because women experience its symptoms during the luteal phase of the menstrual cycle—the two weeks or so following ovulation where the reproductive hormones progesterone and estrogen are elevated. However, the levels of progesterone and estrogen at this phase of the menstrual cycle are no higher in PMDD subjects than in non-PMDD ones, so the cause of PMDD must be due to more than just elevations in progesterone and estrogen.

A study published in the June 19 advance online version of Molecular Psychiatry supports such a hypothesis. It has found that a dose of progesterone can activate the amygdala in mentally and physically healthy young women. Thus PMDD may be due, at least in part, to an excess of progesterone in the luteal phase exciting the amygdala, the researchers believe.

Progesterone is known to produce anxiety in animals, and it appears to do so by acting on the amygdala. So Guido van Wingen, a doctoral candidate at Radboud University Nijmegen Medical Center in Nijmegen, the Netherlands, and his colleagues suspected that progesterone might provoke anxiety and other symptoms of PMDD by acting on the amygdala.

To test their hypothesis, they gave an oral placebo to 18 mentally and physically healthy young women in the follicular phase (day 2-7) of their menstrual cycles, when endogenous progesterone is low. Subjects were then shown visual stimuli known to robustly engage the amygdala, and functional magnetic resonance imaging (fMRI) was used to measure the reaction of their amygdalae to the stimuli. Then when the subjects were in the follicular phase of another of their menstrual cycles, they received an oral administration of progesterone, which increased levels of progesterone to the levels that they normally would have experienced during the luteal phase of their menstrual cycles. Again they were shown visual stimuli known to robustly engage the amygdala, and again fMRI was used to measure amygdala reactivity.

The researchers t hen compared amygdala reactivity, finding that it was significantly greater under the influence of progesterone than in the control situation. In contrast, progesterone did not influence neural activity in other brain areas any more than the control situation did.

Thus, even though the results were obtained in women without PMDD, the imaging results implied that PMDD may be due, at least in part, to a surge in progesterone during the luteal phase of the menstrual cycle and subsequent amygdala activation.

The researchers also suggested that progesterone-induced amygdala activity could affect the processing in other brain regions relevant for mood regulation. For example, they found that progesterone decreased the functional connection of the amygdala with the fusiform gyrus, a brain region involved in the processing of angry or fearful face stimuli, and that progesterone increased the functional coupling of the amygdala with the dorsal anterior cingulate gyrus, a brain region activated during the evaluation of threatening stimuli.

Recently, a variation in the ESR1 gene, which codes for an estrogen receptor, was found to dist inguish women with PMDD from women without it (Psychiatric News, August 17). If PMDD is indeed due to an elevated level of progesterone exciting the amygdala, then how does this gene variant fit into the picture? Van Wingen told Psychiatric News that he didn't know, but added, "Our results indicate that progesterone modulates the interactions between the amygdala and prefrontal cortex." Thus, it's possible, he speculated, that PMDD could be due to a surge in progesterone exciting the amygdala and then to the prefrontal cortex not being able to halt the excitement due to altered estrogen sensitivity.

Although PMDD is not officially recognized as a mental disorder in DSM, it is listed in the DSM-IV-TR appendix as a condition worthy of further study. The U.S. Food and Drug Administration has approved four medications to treat the condition—the antidepressants fluoxetine (marketed as Sarafem), sertraline (Zoloft), and paroxetine controlled-release (Paxil CR), and the oral contraceptive drospirenone and ethinyl estradiol combination (Yaz).

The study was funded by the Radboud University Nijmegen Medical Center, the European Union, and the Swedish Research Council.

An abstract of "Progesterone Selectively Increases Amygdala Reactivity in Women" is posted at<www.nature.com/mp/journal/vaop/ncurrent/abs/4002030a.html>.▪