Historically a taboo subject, menstruation has long been stigmatized as unclean and negative; provoking multiple complex cultural values.

Since starting to talk publically about periods, we know so much more about the biochemical basics and physical aspects of menstruation. We are now also beginning to better understand the underlying interplay of sex-hormones with neurotransmitters that create the harmony of a normal menstrual cycle, or the symptom havoc seen with PMS, or its more severe form PMDD. 

A Brief Overview of PMS & PMDD

Characterized by its cyclical onset around the time of menstruation, premenstrual syndrome (PMS) affects many women of reproductive age. Sometimes symptoms associated with PMS can be so severe that premenstrual dysphoric disorder (PMDD) arises. Working together, hormones and neurotransmitters contribute to PMS and PMDD.

Associations between the sex-hormones estrogen and progesterone with serotonin, and between the stress hormone cortisol with norepinephrine appear to make major contributions to symptoms of both PMS and PMDD. Interestingly, the GABA system, controlled in part by the progesterone metabolite allopregnanolone, appears to be profoundly altered in individuals with PMDD only during the latter part of the menstrual cycle, perhaps contributing to the extreme intensity of PMDD symptoms In this blog post, I will present recent findings related to understanding the pathology of PMS and PMDD.

Clinical Manifestations

Bouts of distressing symptoms during the premenstrual period have been recognized since antiquity. Upwards of 80% of women report at least mild premenstrual symptoms and approximately 50% report moderate-to-severe symptoms. PMS manifests as a rich bouquet of roughly 150 symptoms, including [1]:

• depressed mood
• irritability
• lethargy
• tension
• impatience
• aggression
• mood swings
• self-deprecating thoughts
• anxiety
• loss of control
• hopelessness
• difficulty concentrating
• sleep disturbances
• breast tenderness
• water retention
• abdominal pain

Fortunately, no one has all 150 of them.

The clinical diagnosis of PMS relies entirely on the timing of the symptoms in relation to menstruation, recognizing the cyclical and chronic nature of the syndrome. Ovulatory menstrual cycles typically last 25-32 days, with ovulation generally taking place 14 days after the onset of menses. The onset of symptom presentation can take place as early as ovulation, reaching maximum severity during the last 5 days of the menstrual cycle and the first 2 days of the next cycle [2]. Therefore, for a number of women, there may only be a few days each month without afflicting symptomatology.

PMS can be severe enough to cause functional impairment, as is seen with PMDD, or profoundly exacerbate existing health conditions:

• PMDD - debilitating in nature, PMDD is a luteal phase-specific syndrome on the severe end of the PMS spectrum. Approximately 3-8% of menstruating women suffer from the same constellation of symptoms as PMS but experienced at a much higher intensity. The burden of PMDD is a significant detriment to the quality of life for the patient [3].
• Menstrual Magnification – a number of psychiatric or somatic disorders can be exacerbated premenstrually. These include affective disorders (major depressive disorder, panic, dysthymia, and generalized anxiety disorder), allergies, migraines, epilepsy, diabetes, irritable bowel syndrome, chronic fatigue, asthma, and thyroid, adrenal or autoimmune disorders [3].

Etiology

The etiology of menstrually-related mood disorders is unclear, with several theories in play regarding sensitivity to underlying shifts in hormonal homeostasis. Specifically, the intricate inter-relationship between physical and psychological aspects of the premenstruum may be reflective of the interplay between gonadal hormones and neurotransmitter systems. Hormones and neurotransmitters share common receptor sites and pathways in the areas of the brain linked to regulation of complex processes such as mood. Fluctuating levels of progesterone and estradiol in the luteal phase may result in an altered neurotransmitter response to ovarian signaling and render some women particularly sensitive to these transformations.

Progesterone-Allopregnanolone-GABA Connection

Levels of progesterone and its neurosteroid metabolite allopregnanolone rise after ovulation, decrease right before the onset of bleeding and remain low during menses and the follicular phase [4]. Allopregnanolone is synthesized from progesterone both in the brain and in the systemic circulation. Allopregnanolone plays a prominent role in neurogenesis, reduces neuroinflammation, and maintains cholesterol homeostasis [5] [6]. Adequate levels of progesterone in the luteal phase of the cycle are important to maintaining normal levels of allopregnanolone. Allopregnanolone formed systemically, freely penetrates the blood brain barrier to access GABA-A receptors in tissues throughout the brain. Allopregnanolone is a potent positive allosteric modulator of GABA-A receptor - the major inhibitory system, or “off switch” in the CNS and the primary regulator of affect and cognitive functioning [7]. At relatively high levels, seen at the peak of the luteal phase, pregnancy, and with progesterone supplementation, allopregnanolone has calming, anxiolytic, anesthetic, and sedative effects [8] [9]. However, in some women, allopregnanolone can trigger severe mood shifts in the luteal phase of the menstrual cycle. There is little question that an abnormal response to progesterone or allopregnanolone lies at the heart of PMS/PMDD as these symptoms diminish with menses, and don’t recur again until the luteal phase when progesterone increases.

In some PMS sufferers, a surplus of estrogen or a progesterone deficiency in the luteal phase sets the stage for estrogen dominance, resulting in some of the PMS symptoms outlined above. Many clinicians, including Dr. John R. Lee and Dr. Tori Hudson, have observed in their practices that supplementation with topical progesterone may replenish the deficient allopregnanolone levels and prominently improve adverse symptomatology [10] [11].

The Allopregnanolone Paradox

While the majority of women manage the peaks and troughs of estrogen and progesterone throughout their menstrual cycle without adverse symptoms that affect their daily life, a small percentage respond to progesterone/allopregnanolone in the opposite manner and report exacerbated negative mood symptoms [4] [12]. In fact, in women with PMDD, symptomatology is relieved when ovarian hormones are suppressed altogether, which is why hormonal contraceptives that suppress endogenous progesterone synthesis are effective for treating PMDD [13]. Moreover, women receiving a 5alpha-reductase inhibitor to prevent formation of allopregnanolone from progesterone experience a profound reduction in several core PMDD symptoms, suggesting a pathophysiological effect of neurosteroids in general and allopregnanolone in particular in the etiology of PMDD [14]. 

Negative mood changes in PMDD related to the rising post-ovulatory allopregnanolone concentrations are quite perplexing and paradoxical to the largely calming nature of progesterone metabolites. There is no appreciable difference in serum levels of allopregnanolone in women with PMDD and controls, therefore the severity of the afflicting symptoms cannot be explained by a disparity in allopregnanolone levels [14] [15], at least those measured in serum. This begs the question: what factors make some women sensitive to allopregnanolone? Is it plausible that women with PMDD showing profound vulnerability to ovarian steroid cyclicity have a disturbance in GABA-A receptor function? 

Substantial Modulation of the GABAergic System in PMDD

The GABA-A receptor has to mix-and-match the five subunits throughout the menstrual cycle in different ways to adapt to the ever-changing hormonal flux. Women with PMDD have previously been reported to exhibit differences in GABA-A subunit structure and abnormal patterns of neural activation [16] [17] [18]. A recent study by Timby and colleagues tested individual sensitivity of the GABA-A receptor to allopregnanolone stimulation [15]. By monitoring GABA-A receptor activation, the authors discovered that women with PMDD are hypersensitive to intravenous allopregnanolone injections during the luteal phase of the cycle compared to their healthy counterparts [15].  The result implies altered central responsiveness to allopregnanolone resulting in deficient adaptation to ovarian cyclicity in PMDD. 

The leading theory to explain the altered response to allopregnanolone has to do with the structure of the GABA-A receptors. It is plausible that failure of the GABA-A receptor to adjust its subunit composition in a suitable manner and adapt to hormone fluctuations in general and allopregnanolone in particular in the premenstruum may potentially be involved in the development of PMDD and contribute to the extreme intensity of adverse symptoms [19]. 

Biphasic Effect

To make matters even more complex, negative mood increases correlated with increasing serum allopregnanolone levels show a biphasic effect [20]. The maximum concentration of allopregnanolone observed during the luteal phase of the cycle typically worsens the symptoms, but with a further increase in allopregnanolone with exogenous progesterone supplementation (oral or vaginal applications), the symptoms decrease in severity [21] [22]. [Note: a special attention ought to be dedicated to the form in which progesterone was administered in the above-mentioned studies. Oral progesterone undergoes first-pass metabolism, yielding high levels of allopregnanolone that readily crosses into the brain. With vaginal administration of progesterone, on the other hand, a smaller increase in allopregnanolone occurs]. 

Neurotransmitter GABA Levels are Also Altered in PMDD

Additional evidence supporting substantial GABAergic system dysregulation across the menstrual cycle in women with PMDD comes from brain imaging studies. Brain levels of the neurotransmitter GABA increase in PMDD but decrease in non-PMDD women during the luteal phase [23]. 

Therefore, altered brain levels of the neurotransmitter GABA, in concert with inappropriate assembly of the GABA receptor subunits, may be just the correct recipe for failure to develop a physiological tolerance to allopgregnanolone during luteal phase in PMDD and result in a functional hypersensitivity phenotype.

The Estradiol-Serotonin Connection Confers Genetic and Functional Links

Estradiol possesses potent serotonin-modulating properties ranging from regulating its synthesis and degradation to altering receptor expression [24]. Given the central nature of premenstrual symptoms, it is quite possible that women with PMS and PMDD are more sensitive to the effects of estradiol on the serotonin system. The serotonergic system serves a number of roles including balancing mood. Fluctuating serotonergic function appears to be limited to the luteal phase when estradiol is low in women with premenstrual mood disorders [25]. The changes in the serotonergic system in the luteal phase of PMS and PMDD sufferers include decreased production and subsequent deficiency in blood levels of serotonin [26].

The focus of recent work on understanding premenstrual mood disorders in the context of estradiol-serotonin interplay has implicated a genetic link. Polymorphisms in estrogen receptor alpha and the serotonin receptor 5HT-1A are associated with reduced serotonin neurotransmission and a predisposition to PMDD [27] [28]. 

SSRIs – The Gold-Standard Treatment for Moderate-Severe PMS and PMDD

Selective serotonin reuptake inhibitors (SSRIs) are effective at alleviating many of the psychological symptoms associated with PMS and PMDD, further implicating the involvement of the serotonergic system. In contrast to non-menstrual mood disorders, SSRI treatment is initiated as soon as symptoms begin and discontinued at menstruation.  The short onset of therapeutic action in PMS/PMDD could potentially be explained with SSRIs’ ability to enhance formation of allopregnanolone from progesterone by increasing the levels of 5alpha-reductase in the brain [26]. For PMDD sufferers, the allopregnanolone levels resulting from pharmacological doses of SSRIs may just be high enough to have a calming effect (see “Biphasic Effect” above).

Dysregulation of the HPA axis

A major effector pathway of the stress system, the hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in patients with depressive illness. Specifically, negative feedback inhibition is impaired and cortisol levels are increased [29]. Klatzkin and colleagues reported that women with menstrually related mood disorders also display dysregulation of the HPA axis with blunted norepinephrine stress reactivity and a decreased myocardial response to stress [30]. Moreover, PMDD patients exhibit an altered cortisol awakening response pattern further supporting HPA axis dysregulation in menstrual mood disorders [31]. The blunted stress reactivity in these individuals may partially explain the heightened luteal phase of affective symptom severity.

Final Thoughts

Exploration of PMS/PMDD sits alongside a broader aim of raising awareness of the mental health implications of gynecological conditions, which tend to be somewhat neglected. The debate over whether PMS/PMDD is a normal phenomenon or a syndrome/disorder requiring intervention is still ongoing. Appreciation of the tremendous fluctuation in the degree of symptom severity may lead to more stringent guidelines to conduct research on PMS/PMDD and allow for the emergence of new knowledge of menstrual cycle-linked mood changes.

Related Resources

• Blog: The Birth Control Pill Coin Flip - Head or Tails
• Blog: Menopause - Is It All In You Head?

References 

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