Neurobiological Basis of Premenstrual Dysphoric Disorder (PMDD)

Introduction

“And the worst part was I was convinced that I had always been this miserable, and that I would always be this miserable, and it was never going to change. It felt as if someone had completely burned out the light in me and all happiness and joy and hope was gone…” [1].

This confession is not an isolated sentiment, but rather an unfortunately common experience for those suffering from Premenstrual Dysphoric Disorder (PMDD) [1]. That may come as a shock to many people—that such a profound and sentimental admission can be related to menstruation of all things. This is in part due to how menstruation is often trivialized and painted as taboo in mainstream society, with euphemisms such as “that time of the month,” “Aunt Flow,” and the like being used in lieu of “the real thing” [2]. Instead, people tend to be familiar with the widely recognized Premenstrual Syndrome (PMS) which is experienced by most people of reproductive age. However, in navigating the landscape of reproductive health, it becomes apparent that PMDD exists largely in the shadows, overlooked and scarcely acknowledged. With that being said, what exactly is PMDD?

Etiology and Pathophysiology Of PMDD

PMDD is an intensified form of PMS characterized by unusual and inexplicably severe physical, emotional, and behavioral symptoms that begin during the luteal phase of the menstrual cycle, wherein the uterine lining thickens right before menstruation occurs. Cognitive symptoms include irritability or anger, depressed mood, self-deprecating thoughts, anxiety, difficulty concentrating, and overwhelmedness, while behavioral and bodily symptoms include lack of energy, changes in food appetite, and/or cravings, breast pain, and bloating [3]. As “premenstrual” suggests, these symptoms subside or disappear during menstruation.

While PMS commonly affects menstruating women, with estimates suggesting that 30-40% of women of reproductive age (ages 15-49) regularly experience it, PMDD is experienced by only 3-8% of menstruating women [4][5].

There are several theories to explain the causes of PMDD, but the most prominent theory involves progesterone, a key female sex hormone involved in regulating the menstrual cycle and maintaining a healthy pregnancy. Progesterone levels are low throughout the menstrual cycle except during the luteal phase when it suddenly spikes in preparation for a pregnancy [6]. However, progesterone rapidly declines when no pregnancy occurs. This sudden fluctuation may be a factor in the development of PMDD. In one study, rats suddenly deprived of progesterone after long-term administration exhibited symptoms of PMDD [6]. Alternatively, some research suggests that PMDD etiology may have less to do with progesterone and more to do with its metabolic form, allopregnanolone (ALLO), which is known to positively enhance the effects of GABA on GABA_A receptor opening [7]. GABA_A is an inhibitory neurotransmitter that has an overall calming effect on the body by making neurons less likely to fire an action potential and consequently decreasing neurons’ abilities to receive and send chemical messages to one another [7]. So, it is thought that people with PMDD may have a heightened sensitivity to these sudden fluctuations in allopregnanolone levels, contributing to the mood disturbances seen in PMDD [8].

Another theory brings together the sex hormone estrogen and the neurotransmitter serotonin. Some work has suggested that during the menstrual cycle, serotonin levels vary under the influence of estrogen through exerting an effect on serotonin receptors and gene expression [9] [10]. This result is specifically relevant to PMDD not only because estrogen is an ovarian hormone but also because serotonin plays a role in mood regulation, which together can explain the erratic behavior in those with PMDD. Additionally, considering estrogen has serotonin-modulating properties, and given that selective serotonin reuptake inhibitors (SSRIs) are a common treatment for PMDD, exploring how estrogen affects serotonin becomes a promising avenue for understanding PMDD's causes [5].

Specific changes in the brain as a result of PMDD

There is neurobiological evidence for changes in the brain during PMDD. The most differentiating characteristic of PMDD is the emotional symptoms, so researchers have focused their investigations on the activity of brain regions involved with emotional regulation, experience, and expression.

THE PFC

The main region of focus in the brain for PMDD research is the prefrontal cortex (PFC). Although the prefrontal cortex (PFC) of the brain is responsible for abstract and higher-level brain functions, such as thought and judgment, it also controls emotional regulation and cognitive behaviors, processes that are attributed to PMDD affliction [11]. When comparing PFC regions between people with PMDD and those without, researchers found clear neurobiological differences. Specifically, a study done on the response of the PFC in anticipation of emotional stimuli found that during the luteal phase of the menstrual cycle, women with PFC have higher reactivity in the front medial PFC (mPFC) and dorsolateral PFC (dlPFC) during the anticipation of negative emotions in comparison to healthy women [11]. 

Although the levels of reactivity in the mPFC and dlPFC were not different between healthy women and women with PMDD when experiencing emotion, levels of estrogen and progesterone tended to increase with increased regional reactivity to positive emotional stimuli in women with PMDD [11]. This suggests that ovarian hormones (estrogen and progesterone) may be involved in the brain’s reactivity to positive stimuli [11].

Other studies have also documented abnormalities in dlPFC activation in women with PMDD during menstrual cycles[12]. A particular study found that both an earlier age of onset and a longer duration of PMDD correlated with abnormal dlPFC overactivation during menstrutation when using two different brain analysis techniques, PET scan and fMRI [12]. 

THE AMYGDALA AND INSULA

However, in another study, there was no similar pattern of activation in anticipation of negative emotions observed in the amygdala [12]. This was an interesting discovery, since the amygdala is a brain region responsible for impulsive emotional reactions and was thus expected to show activation. However, amygdala hyper-reactivity must still be considered, as perhaps the amygdala reacts more intensely in PMDD in response to particular socially relevant stimuli or triggers, and not just in the broad manner presented in the study [13]. In fact, one study found that in response to socially aversive stimuli, women with PMDD had greater activity in their amygdala and insula, another brain region, and lesser activity in the brain’s anterior cingulate cortex (ACC), while the opposite was found in healthy women [13]. 

Insular cortex activity has been associated with being aware of what’s happening to the body and reacting immediately and accordingly, while the ACC acts like a control center, tempering the initial reactions of the amygdala and insula [14] [15]. Since the ACC was found to be less active than the other two regions in women with PMDD, researchers suggested that the emotional responses of the amygdala and insula were not being tempered by the ACC. Such a relationship is indicative of a concept called “bottom-up processing” [13]. However, the opposite was true in healthy women and is indicative of “top-down processing” [13].  In bottom-up processing of social stimuli, the emotional centers of the brain play a reactive role to stimuli and aren’t regulated well by the thinking control centers, while in top-down processing, the thinking control centers help regulate the emotional centers’ reactions [16] [17]. This finding of bottom-up processing aligns with the symptoms of uncontrollable emotional patterns experienced by women with PMDD.

Furthermore, researchers speculated that during the luteal phase, women with PMDD weigh social situations more heavily than nonsocial situations, which could explain the amygdala and insula’s elevated activity [13]. However, other studies provide contradicting evidence, with ratings of social vs. nonsocial stimuli by participants remaining consistent across the whole menstrual cycle [18]. It is therefore possible that the amygdala in women with PMDD is just more active in social situations in comparison to the subjects’ ratings and thus could be a prerequisite for negative social interactions in PMDD during the luteal phase [13].

One proposed reason for this amygdala oversensitivity is progesterone levels. Though progesterone levels increased the same amount in women with PMDD and healthy controls, the increased progesterone levels only corresponded to increased amygdala activity in the subjects with PMDD [13]. This suggests that the amygdala may be over-sensitive to progesterone, which is one of the prime theories for PMDD etiology [13].

Current neurobiological treatments for PMDD

With some significant PMDD symptom causational theories and neurobiological differences established, there has also been discussion on what effective treatments for the disorder may look like. Correlated symptom improvement as a result of these treatments further helps validate the existence of PMDD, as it underscores its neurobiological basis.

SSRIs

Selective serotonin reuptake inhibitors (SSRIs) are generally considered the first-line treatment for PMDD. SSRIs are commonly used to treat depression, which shares many behavioral and emotional symptoms with PMDD, enabling SSRIs to also be effective in treating PMDD [19]. As the name suggests, SSRIs inhibit the reuptake of serotonin, which essentially means they allow greater levels of serotonin to remain in the gaps between neurons. This extended presence and a heightened level of serotonin enhance neural transmission between nerve cells, overall having a mood-balancing effect [19]. 

One kind of SSRI that has been shown to be effective in mitigating PMDD symptoms is fluoxetine. Specifically, studies have shown that intermittent dosing of Fluoxetine during the luteal phase of the menstrual cycle can improve symptoms sometimes even in as little time as 48 hours [20] [21].

Another kind of SSRI that can improve PMDD symptoms is Paroxetine. One study comparing the continuous treatment of Paroxetine against placebos demonstrated that it reduced symptoms with a response rate of 85% and most directly affected the symptom of irritability [22]. The same study also investigated intermittent treatment of Paroxetine and found that it was also effective, but had a weaker effect on mood and physical symptoms [22].

PROGESTERONE AND ALLOPREGNANOLONE

Because PMDD is marked by heightened sensitivity to the fluctuations in progesterone and its metabolite form, allopregnanolone, during the luteal phase of the menstrual cycle, one common avenue for treatment of PMDD is changing levels of progesterone. 

In one particular study, 37 women with PMDD were given daily micronized progesterone tablets, a specific formulation of progesterone that is more easily absorbed by the body, during their luteal phase [23]. After they were administered the tablets for the allotted time, 32 of 37 women reported having fully regressed symptoms. More importantly, 5 of the 7 with extremely severe symptoms also had some decrease in symptoms [23]. These findings suggest that such progesterone treatment may be sufficient for those with both milder and more severe versions of PMDD.

Conversely, a different study focused on the ability of ulipristal acetate (UPA), which blocks the progesterone effect by inhibiting receptors, to help alleviate depressive and anger symptoms of PMDD. When administered for three menstrual cycles, researchers observed that UPA helped 85% of subjects attain complete or partial remission. However, UPA did not have any significant effect on the physical symptoms of PMDD [24]. It is uncertain whether these effects were caused just by UPA alone through specific actions at the progesterone receptor or whether the lack of ovulation side effect of UPA helped mediate these effects, as anovulation naturally lowers progesterone levels, but it is likely a combination of both of these factors. Moreover, UPA also maintains estrogen levels during the mid-follicular phase of the menstrual cycle, when they normally rise [24]. This is significant because increased estrogen levels are associated with depressive symptoms, so the positive effects that UPA has on mood may be because it mitigates estrogen [24] [25]. However, this study was the first to investigate the effect of UPA on PMDD, so more research is needed to discern whether UPA can be a viable treatment.

Another study investigated alleviating PMDD symptoms by blocking the conversion of progesterone into allopregnanolone through an enzyme inhibitor called dutasteride [26]. In this study, 16 women with PMDD and 16 control women without PMDD were all given a placebo for one menstrual cycle and then were either assigned to a low or high dosage of dutasteride. It was found that those with PMDD in the low dosage group didn’t report any improvement in symptoms from the placebo cycle, while those in the high dosage group experienced alleviation of irritability, anxiety, and sadness as well as physical symptoms like bloating and food cravings. Importantly, 6 of 8 women with PMDD in the high dosage group no longer met the criteria for PMDD during the month in which they took the high dosage. Additionally, no change in negative affective state was observed in the control women after taking the dutasteride dosages, further supporting the hypothesis that women with PMDD may have an altered sensitivity to allopregnanolone. However, not all symptoms of PMDD were completely improved in the high dosage group, and while there were no adverse side effects for sexual interest nor breast pain like expected, dutasteride is known for having demasculinizing effects, which can impair male feature development and can be a concern during pregnancy, so there are still some drawbacks for this PMDD treatment [26].

Sepranolone is another valid treatment avenue to consider for PMDD, as it is a modulator of the GABA_A receptor, and mitigates the effects of allopregnanolone when bound to the receptor. In one study that administered both a placebo and sepranolone, symptoms of PMDD were reduced much more in women with PMDD when they were given sepranolone in comparison to the placebo [27]. Furthermore, there were no observable side effects of sepranolone. Interestingly, though, if subjects had an existing condition that exacerbated premenstrual symptoms separate from PMDD, the effectiveness of sepranolone in reducing symptoms was lessened. The timing of sepranolone treatment also seemed to be significant, as in some cases the sepranolone treatment was terminated too early, before the end of the luteal phase, and in these cases, symptoms reappeared [27].

Conclusion

PMDD is a rarer and more severe form of the commonly experienced PMS and is made distinct by its turbulent and emotional symptoms. Mechanistic theories for PMDD primarily point to ovarian hormones involved in the menstrual cycle, and specifically a particular oversensitivity to the sudden changes in hormones that accompany the menstrual cycle. These theories along with PMDD’s unique symptomatology suggest that there should be neurobiological differences in those with PMDD, and research has supported this, particularly with brain regions related to emotional regulation. Despite the substantial amount of evidence citing neurobiological differences in those with PMDD, treatments for the disorder are still a fairly dynamic field of study because of the wide variety of people suffering from PMDD. Ultimately, a sophisticated understanding of the relationship between neurobiology, hormonal dynamics, and treatment outcomes is essential for advancing our approach towards and management of PMDD.

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