Premenstrual Syndrome and Premenstrual Dysphoric Disorder: Quality of Life and Burden of Illness

Andrea J. Rapkin; Sharon A. Winer

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2009;9(2):157-170. 

In This Article

Etiology of PMS/PMDD and Comorbidity With Psychiatric and Medical Disorders

The precise etiology of this psychoneuroendocrine disorder has yet to be elucidated. Twin and family studies suggest heritability of PMS/PMDD.[14,15] PMS, PMDD, major depressive disorder (MDD), postpartum depression and anxiety disorders frequently co-occur in family members and these disorders are often comorbid in this population.[16] Although family history and past history of depression are risk factors, PMS/PMDD do not appear to be variants of MDD, anxiety disorder or personality disorder.[11] Women with PMDD have a 50-75% lifetime incidence of psychiatric disorders, such as major depression, seasonal affective disorder, post partum depression, anxiety and panic disorder.[17] The comorbidity with other affective and anxiety disorders contributes to the difficulty of determining the burden of illness specifically related to premenstrual disorders.

Much research has focused on the effect of progesterone, metabolites of progesterone, and estrogen on various neurotransmitters and neuropeptides, such as serotonin (5-HT) and GABA, in predisposed individuals. Altered whole-blood serotonin,[18,19] luteal phase neuroendocrine challenge tests with serotonergic precursors[20,21] and 5-HT binding with positron emission tomography brain imaging[22] have been reported in PMS. Serotonergic antidepressants relieve PMDD symptoms[23] but those antidepressants with noradrenergic or dopaminergic activity do not fare better than placebo.[24]

Ovulation is accepted to be a prerequisite for development of PMS/PMDD.[25] However, there also appears to be an abnormal reaction to rise and fall of ovarian steroids. Women with PMS, unlike asymptomatic control women, reported affective and somatic symptoms with exposure to normal levels of estrogen or progesterone after hormonal suppression with a gonadotropin-releasing hormone (GnRH) agonist.[26]

The major hormonal byproduct of ovulation is progesterone. Metabolites of the progesterone produced by the corpus luteum in the ovary, the adrenal and in the brain are potent modulators of the GABAA receptor.[27] GABA is the main inhibitory neurotransmitter in the brain. Abnormal peripheral levels of one of these progesterone metabolites, allopregnanolone (ALLO) have been found in some but not all studies.[28,29,30] In susceptible women with PMS, the exposure to the mid cycle rise in ALLO has been hypothesized to initiate PMS symptoms; and in animals exposure to ALLO results in configurationally changes in the GABAA receptor rendering it unresponsive to further GABAergic modulation.[31,32]

Various studies have investigated whether abnormalities in calcium metabolism play a role in the genesis of symptoms in women with PMS and PMDD. A detailed study investigating cyclical changes in calcium metabolism in women with PMDD concluded that there was lower ionized serum calcium in the PMDD group compared with asymptomatic women during the menstrual phase and additionally, in the PMDD group, there was significantly lower urinary calcium excretion during the late follicular phase, mid-cycle, and the early luteal phase. There is also lower serum vitamin D during the luteal phase in women with PMDD.[33]

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