The role of neurosteroids in Premenstrual Syndrome

Author: Martina Bertello
Date: 15/11/2014


Overview: what is the Premenstrual syndrome?

Premenstrual syndrome (PMS), also called premenstrual tension (PMT) is a collection of emotional symptoms, with or without physical symptoms, related to a woman's menstrual cycle. While most women of child-bearing age (up to 85%) report having experienced physical symptoms related to normal ovulatory function, such as bloating or breast tenderness, medical definitions of PMS are limited to a consistent pattern of emotional and physical symptoms occurring only during the luteal phase of the menstrual cycle that are of "sufficient severity to interfere with some aspects of life". In particular, emotional symptoms must be present consistently to diagnose PMS. The specific emotional and physical symptoms attributable to PMS vary from woman to woman, but each individual woman's pattern of symptoms is predictable, occurs consistently during the ten days prior to the start of the menstrual period, and vanishes either shortly before or shortly after the start of menstrual flow.
Two to ten percent of women have significant premenstrual symptoms that are separate from the normal discomfort associated with menstruation in healthy women.
Premenstrual dysphoric disorder (PMDD) consists of symptoms similar to, but more severe than, PMS, and while primarily mood-related, may include physical symptoms such as bloating. PMDD is classified as a repeating transitory cyclic disorder with similarities to unipolar depression, and several antidepressants have been approved as therapy.

Classification and external resources:

Patient UKPremenstrual syndrome

Many researchers started study the Premenstrual Syndrome of women in the 19th century. The first person to name and describe the premenstrual syndrome was Robert T. Frank when interest in PMS began to increase after it was used as a criminal defense in Britain during the early 1980s.
PMS was originally seen as an imagined disease. Women who reported its symptoms were often told it was "all in their head". Woman’s reproductive organs were thought to have complete control over them. Women were warned not to divert needed energy away from the uterus and ovaries. This view of limited energy ran very quickly up against a reality in 19th century America that young girls worked extremely long and hard hours in factories. Newspapers in the 19th century were peppered with remedies to help in the “tyrannous processes” of the menstrual cycle.
Advertisements for PMS curing pills were very common in the 19th century. An early 1837 advertisement for “Lady Huntingdon’s female pills” proclaims that they have rescued many young women from an “early grave”. Advertisements for PMS curing pills were very common in the 19th century. Another advertisement for the “Croskell’s female corrective pills” were meant to cure women of menstruation. The constant refrain throughout the advertisements of this period was that of female vulnerability and the side effects of menstrual obstruction.
These advertisements made PMS and menstruation seem like bodily defects, thus making female reproductive systems and bodies were seen as dysfunctional. These advertisements made it difficult for women to keep working the long and rigorous hours they had to in factories. The relationship between woman’s capacity to work and menstruation was a central issue during the 19th century.
In 1873 Edward Clarke published an influential book titled “Sex in Education”. Clarke came to the important conclusion that female operatives suffer less than schoolgirls because they “work their brain less”. This suggested that they have stronger bodies and a stronger reproductive “apparatus more normally constructed”.
Feminists later took opposition to Clarke’s argument that women should not leave the private sphere by showing how woman could function in the world outside the home in spite of their bodily functions and that “women do work better, and with much greater safety to health when their work is frequently intermitted; finally that they are required at all times, and have no special reference to the period of the menstrual flow”.
In order for a condition to be accepted as a disease by society, all parts of society must agree on it. Women have contributed to the rise of interest in PMS and society's acceptance of it as an illness. By legitimizing this disorder, women have contributed to the social construction of PMS as an illness.
The study of PMS symptoms is not a new development. Debates about the definition and validity of this syndrome have a long history. As stated above, growing public attention was given to PMS starting in the 1980s.Up until this point, there was little research done surrounding PMS and it was not seen as a social problem. By the 1980s, however, viewing PMS in a social context had begun to take more and more place.

The number of women who experience PMS depends entirely on the stringency of the definition of PMS. The World Health Organization estimates that 199 million women have premenstrual syndrome as of 2010 (5.8% of the female population). While 80% of menstruating women have experienced at least one symptom that could be attributed to PMS, estimates of prevalence range from as low as 3% to as high as 30%.


Premenstrual syndrome

Sign and symptoms
About 5% of women suffer from Premenstrual Dysphoric Disorder (PMDD), a more severe form of PMS in which nearly totally disabling mood symptoms predominate. PMS typically occur after ovulation, during the luteal phase of the menstrual cycle (beginning approximately 14 days before menstruation), and cease at menstruation or shortly thereafter. While a wide range of PMS symptoms are reported, the most common ones cluster as follows:

  • Physical symptoms: headaches, acne, breast tenderness, weight gain, appetite changes, fatigue, dizziness, hot flashes, nausea, vomiting, muscle aches, abdominal bloating, pelvic pressure, constipation, palpitations and changes in vision.
  • Mood-related symptoms: depression, sadness, irritability, tension, anxiety, tearfulness, restlessness, anger, loneliness, food cravings and change in libido.
  • Cognitive symptoms: mood swings, difficulty concentrating, decreased efficiency, confusion, forgetfulness, being accident-prone, social avoidance and angry outbursts.

In fact, practitioners find that most women's symptoms tend to fall into one of four typical subgroups: PMT-A (anxiety), PMT-C (cravings), PMT-D (depression), or PMT-H (hyperhydration, such as bloating and weight gain).The most consistent characteristic of PMS symptoms is that they reoccur on a regular basis, coinciding with a woman's menstrual cycle. However, while PMS symptoms tend to be cyclical in nature, even the patterns of that cycle may vary among women. So, it is not only the type of symptom but also the intensity or severity that can vary dramatically from woman to woman, and even for the same woman throughout her cycle. About 5% of women suffer from Premenstrual Dysphoric Disorder (PMDD), in which nearly totally disabling mood symptoms predominate.

PMS: From Puberty to Menopause

The role of Allopregnanolone

The relationship between the luteal phase of the menstrual cycle and symptom development in premenstrual dysphoric disorder/premenstrual syndrome (PMDD/ PMS) is self-evident. Symptoms starts after ovulation and then increase in parallel with the rise in serum progesterone during the luteal phase. The symptom severity reaches a peak during the last five premenstrual days or the first day of menstruation. Thereafter, the symptoms decline and disappear 3–4 days after the onset of menstrual bleeding. During the postmenstrual phase there is a period of well-being, closely following estrogen production, to the estradiol peak. This suggests that there is a symptom-provoking factor produced by the corpus luteum of the ovary. This is supported by the fact that in anovulatory cycles, spontaneous or induced, when a corpus luteum is not formed, no symptom cyclicity occurs. In order to understand progesterone-induced adverse mood effects, it is important to note that progesterone is to high degree metabolized to allopregnanolone (3-OH-5α-pregnan-20-one) and pregnanolone (3-OH-5β-pregnan-20-one), both of which act as agonists on the γ-aminobutyric acid A (GABA-A) receptor complex in the brain. The GABA transmitter system is the major inhibitory system in the CNS.

When GABA binds to the GABA-A receptor, the influx of chloride ions increases, hyperpolarizing the postsynaptic membrane and making the postsynaptic cell less prone to excitation. Allopregnanolone is a GABA-A receptor positive modulator and enhances the effect of GABA on the receptor. The behavioral and pharmacological characteristics are similar to ethanol, barbiturates, and benzodiazepines.
Neurosteroids, benzodiazepines, barbiturates, alcohol, and most anesthetic agents bind to the GABA-A receptor and increase the GABA-induced chloride ion influx by interacting with allosteric binding sites.
The symptoms induced by these GABA-A receptor active drugs include depressed mood, irritability, aggression, and other typical symptoms of PMS/PMDD.

Studies have shown disparity regarding behavioral effects of these neuroactive progesterone metabolites. Studies in animals and humans have reported typical GABA-A receptor agonistic effects such as sedation, anesthesia, antiepileptic effects, anxiolytic effects of high doses of allopregnanolone and pregnanolone.
Other studies in which women were given the endogenous substance allopregnanolone in doses that elevated the allopregnanolone in the blood to levels normally seen during pregnancy have also reported the negative effects of allopregnanolone, which has been shown to increase irritability/ aggression and inhibit learning.
The GABA-A receptor agonists are known to be anxiolytic, sedative, and antiepileptic. Why an increase in
allopregnanolone is related to development of negative mood is puzzling. It appears that benzodiazepines,
barbiturates, alcohol, and allopregnanolone possess bimodal action on mood symptoms. GABA-A receptor agonists in high doses are anxiolytic, antiaggressive, sedative/anesthetic, and antiepileptic. However, in low concentrations or doses, severe adverse emotional reactions are induced in a subset of individuals (2–3%) and moderate reactions in up to 20%. This paradoxical effect is induced by allopregnanolone, benzodiazepines, barbiturates, and ethanol.
In this way, allopregnanolone seem to have a bimodal effect on mood with an inverted U-shaped relationshipbetween concentration and effect. Negative mood increases with the rise in serum concentration of allopregnanolone up to a maximum, but then further increase in allopregnanolone concentration is associated with a decrease in the severity. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood.
There is evidence that steroid sensitivity in the brain differs between PMS/PMDD patients and controls. Negative effects of oral contraceptives on mood were found mainly in women with PMS/PMDD.
Add-back estradiol or progesterone, in women with PMS/PMDD and inhibited ovarian hormone production, gave rise to recurrence of symptoms. Moreover, patients with severe symptoms were less sensitive to the given pregnanolone or benzodiazepines compared to patients with more moderate symptoms. The findings suggest that patients with PMS/PMDD develop tolerance to the administration of GABA-A receptor allosteric agonists during the luteal phase.

Allopregnanolone and mood disorders, 2013

The role of progesterone and GABA in PMS/PMDD, 2007

Women without mood changes prior to menstruation are more sensitive to allopregnanolone immediately after menstruation and less sensitive before. On the other hand, sensitivity to allopregnanolone in women who suffer from severe PMS with pronounced mood shifts ahead of every period is the opposite: these women are more sensitive before than after. All of this may mean that they have less ability to adapt to hormonal variations prior to menstruation. It is unclear what causes this, however, but it may be that these individuals have an altered function in one of the brain's signal substance system, the GABA system. In addition decreased concentrations of allopregnanolone and progesterone, its precursor, lead us to hypothesis that patients with PMS may suffer from an inadequate production of ovarian neurosteroids in the luteal phase. This would lead to an impaired anxiolytic GABA-mediated response in stressful physiological and psychological conditions, and may in part explain various psychoneuroendocrine symptoms that arise during PMS.

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