Premenstrual syndrome and dysphoric disorder

PMS and PMDD occur in women with ovulatory cycles, and they do not occur before puberty or after menopause. This association implies a role of gonadal steroid hormones. Absence of PMS/PMDD during pregnancy (in addition to supporting evidence) suggests that changing levels of gonadal steroid hormones play a role in PMS/PMDD.[15] However, there is growing evidence that women with a history of PMS/PMDD have an increased risk of postnatal depression, even in the absence of a history of depression.[16] A woman's response to the changing hormone levels will trigger symptoms in susceptible women, believed to occur via interaction with, and under the influence of, central neurotransmitters.[17][18][19][20][21] Studies show no difference in absolute levels of gonadal steroid hormones, their ratios, or their metabolites between women with PMS or PMDD and controls.[22][23]

Dietary factors and vitamin deficiencies have been implicated, as has alcohol consumption.[24][25][26][27][28][29][30] Further research is required to elucidate their roles.

Twin studies have demonstrated a genetic component to the development of PMS/PMDD (with environmental influence as an additive effect).[31]

Women with severe PMS have been noted to have a higher prevalence of personality disorders, particularly obsessive-compulsive personality disorder, which, although not necessarily associated with greater severity of premenstrual symptoms, is related to poorer life functioning.[32] It is more likely that PMS and PMDD cause stress than vice versa. There is little evidence supporting the role of stress or personality disorders as external aetiological factors for PMS or PMDD.[33] One study found that history of childhood trauma was higher in women who experience PMS/PMDD.[34] One meta-analysis found that women with PMS/PMDD are also at risk for suicidal behaviours. Results from this review of 13 studies revealed that women with PMDD are almost seven times more likely to attempt suicide, and almost four times more likely to exhibit suicidal ideation, than those without PMDD. Women with PMS are at a higher risk for suicidal ideation, but not suicide attempt.[35]

Gonadal steroid hormones have an implied role in the pathophysiology of PMS/PMDD because it occurs only in ovulatory women and is characterised by menstrual cyclicity. Resolution of symptoms using gonadotrophin-releasing hormone agonists to suppress ovarian function supports this hypothesis.[26][36][37][38]

Although oestrogen and progesterone are considered necessary for the symptoms of PMS/PMDD, their presence is not sufficient to cause the syndrome, nor are simple excesses or deficiencies. Rather, the exposure to changing levels of these hormones is necessary, and the woman's response to these changes leads to symptoms.[18] For example, serum levels of progesterone are normal in women with PMS, and blocking the effect of progesterone with mifepristone (a progesterone receptor antagonist) has not been shown to relieve PMS.[39]

Current evidence suggests that there is an interaction of the changing hormonal levels with central neurotransmitters.[21] The serotonin system is most often implicated, but the beta-endorphin, gamma-aminobutyric acid (GABA), and autonomic nervous systems have each been considered in the pathogenesis of these disorders.[40][41][42][43]

Studies on variations in progesterone and oestrogen levels during the menstrual cycle have found corticosteroid-induced changes in the opioid, GABA, and serotonergic systems, and differences in serotonin levels, in women with PMS compared with those without PMS.[44][45][46][47] Serotonergic drugs, such as fenfluramine, and selective serotonin-reuptake inhibitors (SSRIs), such as fluoxetine, relieve PMS symptoms.[41]

Despite recognising the interaction of changing hormonal levels and central neurotransmitters, it is not clear why some women have symptomatic responses to gonadal steroid cyclicity and others do not. Theories include a pathological response to progesterone exposure or withdrawal via the GABA-agonist progesterone metabolite allopregnanolone. SSRIs, which are effective in the treatment of PMS/PMDD, have been shown to affect allopregnanolone levels.[40][48]

Oestrogen receptor alpha polymorphic variants in women with PMS/PMDD are thought to be involved in the regulation of non-reproductive behaviours, although the clinical significance is as yet unknown.[43][49][50]

The spectrum of premenstrual disorders is a matter of degree. Central to all is their relationship to the menstrual cycle phase, and the cessation of symptoms with the onset of menses. Further classification includes:

Premenstrual symptoms: physical symptoms such as abdominal bloating, breast tenderness, headache or minor mood changes
Premenstrual syndrome (PMS): repetitive, cyclical, physical, and behavioural symptoms occurring in the luteal phase of the menstrual cycle
Premenstrual dysphoric disorder (PMDD): a more severe form of the disorder that is classified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) as a mental illness.

The International Society for Premenstrual Disorders also recognises 'variant premenstrual disorders', which include premenstrual exacerbations of another medical or psychological condition, symptoms from exogenous progesterone administration, symptoms from ovarian activity other than ovulation, and symptoms from continued ovarian activity in the presence of suppressed menstruation.[6] The variant premenstrual disorders are not discussed further in this topic.

Pathophysiology

Classification