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Epidemiology and Etiology of Premenstrual Syndromes:

Etiology
Ellen W. Freeman, PhD
Faculty and Disclosures

1. Overview
2. Etiology
References

ETIOLOGY
The etiology of PMS remains undefined. The following sections provide a brief description of current
theories and supporting evidence.

Sex Steroids
Although the sex steroids are not likely the sole cause of PMS, evidence suggests that circulating
levels of progesterone and estradiol are somehow involved. However, no consistent differences in
progesterone or estradiol levels have been identified between women with PMS and controls.
Additionally, progesterone has not been demonstrated to work better than placebo for treatment of
mood symptoms of PMS.[20,21]
Based on newer data, the dominant theory is that some women have abnormal sensitivity to the
normal changes of reproductive hormones throughout the menstrual cycle. [22] Circulating levels of
progesterone and estradiol remain within normal range; symptoms may be linked to fluctuation in
levels.
The strongest evidence for the involvement of sex steroids is the response of PMS symptoms to
suppression of ovulation via treatment with gonadotropin-releasing hormone (GnRH) such as
leuprolide acetate depot. It has been consistently demonstrated that GnRH treatment relieves
symptoms in individuals with "pure" PMS, eg, those without other comorbid conditions. [23-25]
Other findings suggest that the neuroactive progesterone metabolite allopregnanolone is associated
with PMS symptoms. Allopregnanolone modulates functioning of GABA receptors, the chief inhibitory
neurotransmitters in the central nervous system and thus, can mimic the effects of anxiolytic agents.
Some studies have demonstrated an association between allopregnanolone levels and symptom
severity, supporting an altered responsiveness of the GABA receptor complex in women with
PMS/PMDD.[26,27] It has also been shown that women with PMS/PMDD exhibit a higher ratio of
allopregnanolone to progesterone than controls, suggesting alterations in the metabolic pathway
involved in conversion of progesterone to allopregnanolone. [28] A subsequent study of responses of

women with PMDD to mental stress confirmed earlier data associating allopregnanolone with
symptoms, but only in those with a history of depression.[29]

Serotonin
It is currently believed that PMS involves central nervous system-mediated interactions between
neurosteroids and reproductive hormones. There is evidence that serotonergic activity or
dysregulation is a modulator of PMS.[30]Recent data showed that serotonergic function fluctuated
across the menstrual cycle of women with PMDD and that the pattern differed from women with PMS
without PMDD and from those of normal controls.[31]
The predominant clinical evidence for involvement of the serotonergic (5HT) system is the clear
response of mood and behavioral symptoms of PMS/PMDD to treatment with selective serotonin
reuptake inhibitors (SSRIs).[32,33] Meta-analysis of 15 randomized controlled trials of SSRI use for
PMS/PMDD showed that SSRIs were also effective for treating physical symptoms, although this
finding has not been consistently demonstrated in single studies.[33]

Beta-Endorphin
Beta-endorphin is hypothesized to be involved in the etiology of PMS because of biologic
characteristics that include, but are not limited to, inhibition of gonadotropin release during the luteal
phase of the menstrual cycle and effects on mood changes, pain perception, and appetite.
Symptoms of increased beta-endorphin levels (anxiety and agitation) and withdrawal (dysphoria,
mood lability, fatigue, reduced motor activity) resemble PMS symptoms. However, the putative role
of beta-endorphin in PMS remains poorly understood.

Luteal Phase Body Water or Sodium


Although severe swelling of the extremities and abdominal bloating are common complaints in
women with PMS, there is no good evidence of differences in body water or sodium levels during the
luteal phase compared with the follicular phase of the menstrual cycle. There is also no consistent
evidence of premenstrual weight gain or correlation between swelling or bloating and symptom
severity.[34] In an investigation focused specifically on bloatedness, the only significant change
identified was perception of an increase in body size; no increases in body weight or dimensions
were found.[35]
An aldosterone etiology for PMS symptoms has been proposed, and treatment with spironolactone,
an aldosterone agonist, has been shown to decrease premenstrual bloating and other PMS
associated symptoms.[36] However, differences in aldosterone levels have not been found in women
with PMS and controls.
Another possible explanation, provided by Wong and colleagues,[37] is based on identification of a
significant change in the capillary filtration coefficient (CFC) in women with severe bloating. They
found that the highest CFC values occurred premenstrually and the lowest values followed menses.
They concluded that the perception of bloatedness may be due to redistribution of body from the
intravascular to extravascular compartments, rather than to an absolute increase in body water.

SUMMARY
Clinically significant PMS is increasingly recognized as a chronic disorder that impairs relationships,
work productivity, and social activities. The prevalence of moderate to severe PMS appears to be
approximately 20% in reproductive-age women; with PMDD, the most severe form, affecting 5% to
8%. Risk factors for PMS/PMDD include stress, genetic factors, obesity, other health problems, a
history of depression or anxiety disorder, or other psychiatric disorders.
The etiology of PMS remains undefined. It appears that symptom control is at the brain level and is
not fully understood at this time. Neuroendocrine studies to identify pathways that link the gonadal

and serotonergic systems to the symptoms manifested in PMS and PMDD remain an important area
for identifying the etiology of this disorder.

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