Progesterone, Anxiety Affect Premenstrual Dysphoric Disorder

Deborah Brauser

October 18, 2013

BARCELONA, Spain ― Sex hormone levels and anxiety may influence menstrual cycle–related brain reactivity in women with premenstrual dysphoric disorder (PMDD), new research suggests.

Inger Sundström Poromaa, MD, PhD, discussed results from several recently published studies, as well as newly completed findings that are currently in the manuscript stage, here at the 26th European College of Neuropsychopharmacology (ECNP) Congress.

"Contrary to expectation, women with PMDD show increased amygdala activity early in their cycles when progesterone is low, suggesting that heightened emotional responses may be a vulnerability factor in PMDD," Dr. Sundström Poromaa, who is from the Department of Women's and Children's Health at Uppsala University in Sweden, told meeting attendees.

She added that the findings contribute to a better understanding of the role female sex hormones have on PMDD symptoms ― and may help to eventually explain the increased prevalence of mood disorders, such as depression, in women.

PMDD, a severe form of premenstrual syndrome that affects roughly 3% to 5% of women of reproductive age, was moved from the appendix section "for further study" in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) to the main body of the recently published DSM-5, and is classified as a mood disorder.

Dr. Sundström Poromaa told Medscape Medical News after the presentation that selective serotonin reuptake inhibitors (SSRIs) should be considered as first-line treatment for women with PMDD.

"What is unique is that we can treat them for only 10 to 14 days of each cycle. You don't take them continuously, but only when symptoms occur. And response is rapid. However, these patients often instead request treatment that targets the hormonal causes of the disorder."

Hormonal Disorder

Symptoms of PMDD include anger, irritability, anxiety, and a depressed mood ― all of which occur in the luteal (latter or second-half) phase of the menstrual cycle, about 1 to 2 weeks before the start of menses. It is also commonly considered to be "a hormonal disorder with psychiatric expression," according to a press release from the ECNP.

Dr. Inger Sundström Poromaa

"As a gynecologist, I believe PMDD is driven by the female sex hormone progesterone," said Dr. Sundström Poromaa, adding that there is very little progesterone during the follicular phase.

In one of the studies she discussed that was recently published by her investigative team, 15 women with PMDD and 14 without the disorder underwent functional magnetic resonance imaging scans during both the follicular and the late luteal phases of their menstrual cycles.

All participants also completed an emotional processing task related to anxiety control before undergoing the scans. This task included looking at photos of faces showing negative reactions, as well as war scenes, spiders, and snakes.

Results showed that after being exposed to the emotional processing task, the women with PMDD had higher amygdala activation during the follicular phase, showing impaired anxiety control, than did the women without PMDD, but they did not show higher activation in the luteal phase.

"This was not what we expected, and was opposite of what we hypothesized. They were having the highest reactivity when they were feeling the best," said Dr. Sundström Poromaa.

In addition, very low progesterone levels during the follicular phase were significantly correlated with the increased amygdala activation.

"Our interpretation is that PMDD women are indeed hyper-responsive to even low progesterone levels, and that the amygdala successively habituates to the increasing luteal phase progesterone levels."

Anxiety Modulates Reactivity

Interestingly, patients with PMDD who also had high scores on trait anxiety (signifying that they were more anxious at baseline) displayed increased emotion-induced right amygdala reactivity in the luteal phase. Those with low anxiety scores showed the opposite pattern.

"Our findings suggest that anxiety proneness and progesterone levels modulate menstrual cycle related amygdala reactivity in women with PMDD," write the investigators.

In the newly completed study, Dr. Sundström Poromaa and colleagues sought to determine whether the type of emotional stimuli would make a difference. They carried out the same study design but examined the differences between reactions to various images considered to be social or nonsocial.

Results showed that the participants with PMDD had increased reactivity in the amygdala, insula, and anterior cingulate cortex (ACC) to socially relevant stimuli during the luteal phase, but not to nonsocial stimuli.

"This is sort of what we hypothesized in the beginning. We were just using the wrong paradigms to start with," said Dr. Sundström Poromaa.

"Overall, we see generally increased amygdala reactivity, which appears to be a baseline trait in these women, that is hyper-responsive to even low levels of progesterone. But we also see increased amygdala, insula, and ACC reactivity in the luteal phase ― but only when these women are exposed to socially relevant emotional stimuli," she added.

"Also, the response depends on type of personality and genetic makeup of these patients."

Diagnostic, Treatment Challenge

"I think it's very important to highlight that this is very elegant and very complex research," session moderator Hans-Ulrich Wittchen, PhD, from the Institute of Clinical Psychology and Psychotherapy at the Technical University of Dresden, Germany, said to attendees after the presentation.

Dr. Hans-Ulrich Wittchen

"It's not only a diagnostic challenge to find women with PMDD and with this profile, but the studies also found good comparisons," he said.

However, Dr. Wittchen, who was not involved with the research but was involved with the development of the recently published DSM-5, voiced concerns about the disorder overall and about its treatment.

"We've struggled with the issue of PMDD for the past 25 years. In each of the revisions of DSM, we ended up with the same dilemma," he told Medscape Medical News. "You try to specify, based on a little bit of research, a better way that something might be useful. And then you find out the changes you did are not really improving the therapy and the care of these women.

"Although we heard some very interesting and straightforward recommendations today, the fact is that the vast majority of PMDD women are actually not being taken care of. And the treatment that is working in some doesn't work in others," he added.

Dr. Wittchen noted that this is still a very controversial patient population, "although not so much from a research perspective." Instead, he said that clinicians are struggling with how to determine whether a patient really has PMDD ― especially because there is not yet a test that has proven feasible and economical.

"You have to do laboratory testing over the whole menstrual cycle and a standard assessment of all psychopathology features for a whole month, which is very hard to do in practice. So instead, you try to use retrospective recall, and it's just a very difficult diagnosis," he said.

As for interventions, he pointed out that past research has shown only marginal benefit from use of SSRIs or psychological treatment. "All together, sometimes they are okay, but it remains a challenge."

He added that the decision to include PMDD in the DSM was widely debated. "The women's representative groups actually didn't want to see it in the psychiatric diagnostic system. And I think you have to appreciate that it is indeed a problem that can be stigmatizing."

26th European College of Neuropsychopharmacology (ENCP) Congress. Press briefing given October 7, 2013.

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