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Feel Awful at "That Time of The Month"? It's More than Just Your Hormones.
By Kate Placzek, PhD., ZRT Laboratory
Historically a taboo subject, menstruation has long been stigmatized as unclean and negative; provoking multiple complex cultural values.
Since starting to talk publicly 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.
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.
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 :
- depressed mood
- mood swings
- self-deprecating thoughts
- loss of control
- difficulty concentrating
- sleep disturbances
- breast tenderness
- water retention
- abdominal pain
Fortunately no one has all 150 of them.
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 . Therefore, for a number of women, there may only be a few days each month without afflicting symptomatology.
The aetiology 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.
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.
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.
The Allopregnanolone ParadoxWhile 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  . 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 . 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 .
Substantial Modulation of the GABAergic System in PMDD
To make matters even more complex, negative mood increases correlated with increasing serum allopregnanolone levels show a biphasic effect . 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  [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
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 . 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).
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 . 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 . Moreover, PMDD patients exhibit an altered cortisol awakening response pattern further supporting HPA axis dysregulation in menstrual mood disorders . 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.