PMS & PMDD: The Miserable Period

Introduction:

Premenstrual syndrome (PMS) is a combination of physical and emotional symptoms appearing 7-10 days before some (about 20-30%) women’s menstrual period. Symptoms that could vary in severity and types and among women would usually resolve by the start of the period. Common symptoms include bloating, water retention and swelling, feeling tired, irritability, and mood changes. The pathophysiology or mechanism of the symptoms development is due to the monthly ovulation that starts before menstruation and stops at the start of bleeding. (1)

The process of monthly ovulation for reproduction, consists of three ovarian cycles of follicular phase, ovulation and luteal phase; and three uterine cycles of menstruation, proliferative phase, and secretory phase. In the first ovarian cycle of follicular phase, under FSH (Follicular Stimulating Hormone) there is a gradual increase in the secretion of estrogen that stops the menstrual bleeding, thickening the lining of the uterus in its proliferative phase. Then in the luteal phase of ovarian cycle, Luteal hormone (LH) is released by the follicles or corpus luteum to produce an oocyte that only lives for 24 hours or less to be fertilized by sperm, when there will be secretion of large amounts of Progesterone to prepare the uterus for potential implantation or pregnancy. If implantation does not occur within approximately two weeks, the corpus luteum will involute, causing a sharp drop in levels of both progesterone and estrogen. The hormone drop causes the uterus to shed its lining in a process termed menstruation. (1)

 Real or Fake?!:

PMS in some women, about 3-8% could evolve to Premenstrual Dysphoric Disorder (PMDD) that is a more severe form of PMS with more emotional symptoms, resembling major depression. (1-2) PMS like its subject the female gender has a history of ignorance, degradation and subjugation by the dominant male society, including even the medical discipline. While up to 19th century, it was totally ignored and girls and women alike were accused of faking the symptoms and being all in their heads, later on in the 20th century and still in the 21st century, it has been and it is more a political and social subjects than a medical condition! Women, feminists and even physicians have been blamed for medicalization of PMS, perhaps for some personal gains at the workplace and else or for justification of its treatment. (3-5) Unfortunately and ironically, this medical subject well known to suffering female gender and the primary care physicians, has become a subject of discussion and annihilation even by sociologists and anthropologists that since women are conditioned to expect PMS, therefore they will have it and so it is more hypochondriacal than real! PMS by these groups that some are even women has been misnomered to be a cultural phenomenon that “grows in a positive feedback loop, and thus is a social construction that contributes to learned helplessness or convenient excuse.” and a justification for “rage or sadness”! (5-6)

 

A medical condition:

Despite the above kind of ignorance and downplay of medical conditions such as PMS and PMDD, the research is more and more showing the significance of these conditions as prodromal to more severe mood disorders in some women. First of all to prove that there is a pathophysiology underling the common monthly symptoms of PMS, research has demonstrated that there is even abnormal spontaneous brain activity in PMS patients and the severity of symptom is specifically related to the left middle frontal cortex and right anterior cingulate cortex (ACC). (7) Moreover functional MRI (fMRI) findings suggest that compared with normal group, women with PMS display more abnormal stress sensitivity, reflected in the decreased and increased functional connectivity within the default brain network, blunted stress perception and higher depression. (8) The single photon emission computed tomography, or SPECT Scan has shown decreases of regional cerebral blood flow (rCBF) in the temporal lobes at luteal phase compared with the follicular phase in PMS subjects. (9)

PMS and PMDD: Windows of vulnerability

The significance of PMS and PMDD is more apparent when we learn that both conditions are important risk factors for later episodes of mood disorders, such as major depression and postpartum depression (PPD). (10-11) Therefore it seems that there are “windows of vulnerability” at the hormonal and neurochemical interface in some women, placing them at greater risk for experiencing premenstrual disorders and depression during pregnancy, the postpartum, and menopausal transition. (12) Along this line PET studies examining 5-HT receptors during the follicular and luteal phases of the menstrual cycle have showed serotonergic dysregulation in women with PMDD relative to controls. (13) Further, PMDD symptoms, that to a lesser extent could be experienced by some women in their PMS, such as poor impulse control, depressed mood, irritability, and increased carbohydrate craving have been characterized as behavioral manifestations of reduced levels of serotonin in the brain. (14)

 The above findings are consistent with the hypothesized estrogen-serotonin link underlying women’s increased vulnerability to experience premenstrual disorders and depression in the postpartum. While our current knowledge for such underlying pathophysiology is unfortunately in its infancy, a review of all available literature in this area will be probed to explore this vulnerability further and finding the relationship between steroid sex hormonal fluctuations and the brain neurochemistry predisposing to PMS/PMDD and ultimately PPD. (10)

Estrogen is known to modulate the expression of genes that code for tryptophan hydroxylase (the synthesis enzyme of serotonin), the serotonin transporter, and the 5-HT1a autoreceptor. In addition, estrogen may affect genes that code for accessory proteins involved in the expression of these serotonin receptors, other molecules that are involved in serotonin degradation, or any of the 14 serotonin genes. (15) Moreover both sex hormones of estrogen and progesterone have been implicated in neurite outgrowth, synaptogenesis, dendritic branching, myelination and other important mechanisms of neural plasticity. The interactions between sex hormones and neurotransmitters also go beyond serotonin and involves as well dopamine, norepinephrine, GABA, glutamate and even neurotropic factors.

 Also some specialized brain regions have been demonstrated to express high densities for estrogen- and progesterone receptors, such as the amygdala, the hypothalamus, and the hippocampus. The interaction of these female sex hormones on Amygdala contributes to the irritability in PMS and PMDD, the interaction with hypothalamus corresponds with the impact of stress on estrogen, then on the brain through HPA (Hypothalamus-Pituitary-Adrenal) Axis, and lastly and not the least the interaction of these sex hormones with Hippocampus mediating the structural plasticity in the adult brain, and higher cognitive function. (16)

 To view PMS and PMDD only as an episodic and mild symptomatic conditions with no long-term impact on the individual is quite primitive thinking! The role of estrogen and progesterone on mood and above all the brain function is far beyond the menstrual period, and affects the whole life span of the female gender. In fact these hormones have significant trophic effects early in brain development that continue throughout adolescence and adulthood. The impact of these female sex hormones make the sexual differentiation of genders, men and women, not only on a superficial sexual level, but on deeper levels of cognitive, emotional, behavioral, motivational, and motor control and skills. (17-20)

 Both estrogen and progesterone act via classical genomic receptors as well as non-classical membrane-associated receptors, that are highly expressed in brain areas involved in emotion and cognition, such as amygdala and hippocampus. While these genomic actions of sex hormones require minutes to hours time, non-genomic modulation of the membrane receptors is mostly faster and requires only milliseconds to seconds. Both estrogen and progesterone exert acute effects on synaptic physiology through the activation of multiple intracellular signaling pathways, linked to the promotion of cell survival. (21-24)

 Since the absolute levels of ovarian hormones do not differ significantly between the PMS and PMDD women and healthy controls, there seems to be a heightened vulnerability of the central nervous system to normal ovarian function and physiological changes rather than hormone imbalance in these women. (25-27) Therefore it seems that it is not a hormonal or physiological pathology underlying the PMS and PMDD symptomatology, but a neurochemical vulnerability, that is a sensitivity or prodromal warning signs to the later development of major depression. For example, in PMDD, progesterone withdrawal is associated with allopregnanolone increase in the luteal phase, facilitating mood changes. (28) Allopregnanolone synthesized by progesterone is a potent modulator of GABA, the main brain inhibitory neurotransmitter, an action similar to other CNS depressants, such as benzodiazepines. (29-30) While healthy women show memory impairments when progesterone and its metabolites are administered exogenously, women with PMDD are more vulnerable to endogenous fluctuations of progesterone and allopregnanolone across the menstrual cycle, clinically manifested as irritability and impairment in working memory. (31)

 Voxel-Based Morphometry (VBM) MRI studies of the brain in women have found an increase in the gray matter density of the right anterior hippocampus, but a decrease in the right dorsal basal ganglia in the late-follicular phase compared to late luteal phase. Moreover significant differences in gray and white matter density between naturally cycling women and women using oral contraceptives (OC), with observing increased gray matter volume in prefrontal and temporal regions and white matter of the fornix of the brain in OC users have been reported. (32-34)

 The impact of female sex hormones and their monthly fluctuations in vulnerable women specially in the reproductive years, beginning with a heightened risk of developing a depressive episode following puberty, and overall prevalent depressive disorders 2-3 times more than in men. (35) A review of 44 studies in fertile women has found a positive correlation between suicide attempts and menstrual phases that are characterized by low estrogen levels. (36) Other than the hormonal fluctuations in vulnerable women who manifest PMS and PMDD during their monthly cycles, with an increased probability of developing later on post-partum depression and major depression, there is a more important underlying brain vulnerability as well. This neural vulnerability under the steroids sex hormones fluctuations, as some discussed above is across all neurotransmitters involved in mood regulation, from serotonin, norepinephrine, dopamine, glutamate, GABA, and even neurotropic factors such as BDNF. (37-42)

Conclusion:

PMS and PMDD are classical examples of prodromal stages to major medical conditions or disorders, in this case major depressive disorders. Understanding these prodromal stages as vulnerability windows, such as dysplasia a prodromal stage to cancer, is vital for prevention of progression of diseases. Monitoring and perhaps early proper intervention of such prodromal phases could save the individual a life-long sufferings, the family and the society a huge comfort and cost saving. PMS and PMDD while can cause familial turmoil, upon progression to major depressive disorders such as post-partum depression could cause more irreparable damages to a fetal life and the next generation.

 Recognition, monitoring and early intervention of these prodromal stages may often demand only a proper accommodation of such vulnerability. As a primal mood sensitivity in childhood and adolescence could progress to the later development of mood disorders such as depression and anxiety, an accommodation and proper containment of such sensitivity could intercept such progressions. In our case of discussion, if PMS and PMDD are monitored, controlled and accommodated non-medically before any conception, then a major mood disorder such as post-partum depression could be perhaps prevented. The future research needs to focus on exploration of such windows of vulnerability of PMS and PMDD to identify such underlying pathophysiology, so paving the path for the timely prevention of mood disorders progression in this vulnerable women population.

Dr.Mostafa Showraki, MD, FRCPC                                                                  Lecturer, School of Medicine, University of Toronto

Author: “ADHD:Revisited” Book/ “adhdrevisited.com”/”medicinerevisited.com”

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