Premenstrual symptoms are very common, affecting about half of women in reproductive age worldwide [22]. However, prevalence rates vary widely in different studies and countries depending on samples, methods of investigation and diagnostic criteria. Disparities may also derive from genetic and socio-cultural factors, including diet and life-style, stressors, personal attitudes, coping behaviors, workload and family responsibilities [22]. Available surveys in community populations indicate that PMS affects 20–30% of women, whereas PMDD ranges between 1.2 and 6.4% [23], with black women being significantly less likely to experience PMDD and PMS than white women (odds ratio (OR) 0.44, 95% confidence interval (CI) 0.25–0.79 and OR 0.64, 95% CI 0.47–0.88, respectively), similarly to what is observed in other mental health disorders [24]. Both conditions significantly reduce quality of life and raise societal costs associated with decreased work productivity, work absenteeism and increased use of health care services [25]. Prevalence and impact of PMS/PMDD are strong priorities to implement preventive strategies in young women [26]. Health care providers (HCPs) should be aware that premenstrual symptoms might fluctuate over time with no clear impact of age or reproductive stage, apart from menopausal transition [27,28]. Another relevant factor is that combined oral contraceptives (COCs), the most studied type of combined hormonal contraception (CHC), may improve overall premenstrual symptomatology in women with PMS/PMDD, but not premenstrual depressive symptoms [29]. Behavioral risk factors, especially smoking and adiposity, are overrepresented in women with PMS/PMDD, confirming their link to emotional vulnerability. Indeed, smoking was associated with an increased risk of premenstrual disorders (OR = 1.56 (95% CI: 1.25–1.93)). Stratified by diagnosis, the effect size estimate was higher for PMDD (OR = 3.15 (95% CI: 2.20–4.52)) than for PMS (OR = 1.27 (95% CI: 1.16–1.39)) [30]. A strong linear relationship between body mass index (BMI) at baseline and risk of incident PMS, with each 1 kg/m² increase in BMI associated with a significant 3% increase in PMS risk (95% confidence interval (CI) 1.01–1.05), was evident [31]. In particular, women with BMI ≥ 27.5 kg/m² at baseline had significantly higher risks of PMS than women with BMI < 20 kg/m², following adjustment for age, smoking, physical activity, and other factors [31]. Intake of alcohol was associated with a moderate increase in the risk of PMS (OR = 1.45, 95% CI: 1.17 to 1.79), especially heavy drinking (OR = 1.79, 95% CI: 1.39 to 2.32) as compared to no or light drinking [32]. Studies on the effect of exercise have many methodological biases with some suggesting improvement of premenstrual symptoms [33]. Other proven risk factors include traumatic events, which greatly increased the odds of developing PMDD at follow-up (OR = 4.2, 95% CI = 1.2 to 12.0). Likewise, a history of anxiety disorder (OR = 2.5, 95% CI = 1.1 to 5.5) and elevated daily conflict scores (OR = 1.6, 95% CI = 1.1 to 2.3) predicted PMDD [34]. Depression may be strongly comorbid [17,18], in particular postnatally [35], and women with PMDD should be considered a high-risk group for suicidality, including increased vulnerabilities for suicidal thoughts, ideation, plans and attempts [36]. Other comorbidities include eating disorders, mainly bulimia and binge eating [37], and migraine [38]. The co-occurrence with pathological manifestations displaying premenstrual exacerbations supports a common neuroendocrine etiology [2,3]. Medical conditions such as anemia and endocrine disorders (namely thyroid and adrenal dysfunctions and hyperprolactinemia) [13], as well as chronic pelvic pain, fibromyalgia and any other inflammatory disorders [39,40], may mimic PMS/PMDD symptoms. HCPs should make a differential diagnosis to establish an individualized treatment plan [3,8,13].

The most characteristic aspect of PMS/PMDD is the temporal relation between the appearance of symptoms and the menstrual phase, indicating a role for gonadal steroid hormones and their metabolites in influencing the plethora of biological systems that contribute to the adjustments required to fulfil reproductive goals. However, women with PMS/PMDD do not show abnormalities in the reproductive hormone release pattern; rather, they seem to display a more sensitive neuroendocrine threshold to cyclical variations of estrogens and progesterone [41,42], which may give origin to catamential symptoms and exacerbation of mood disorders during reproductive transitions [43,44]. Data on other circulating hormones (prolactin, testosterone, cortisol, dehydroepiandrosterone sulphate, and thyroxine) are discordant and fail to separate women with PMS/PMDD from controls. However, they may be relevant to some individual somatic symptoms, for instance cyclic mastalgia or water retention [13].

Many genetic and epigenetic factors influence the neuroendocrine threshold of premenstrual symptoms according to the biopsychosocial model. Severity of mood symptoms and associated distress should guide clinical judgement [8,13]. However, both HCPs and women have their personal view of the set point of such threshold, explaining variable epidemiology of PMS/PMDD symptoms [23]. If the diagnostic threshold is too high, clinically relevant premenstrual symptoms may be underestimated and PMS/PMDD remain untreated. If it is too low, paraphysiologic variations in menstrual cycle-related well-being can be over-treated (Figure 1). The central nervous system (CNS) is one of the main target tissues for reproductive hormones but it is also a source of neurosteroids, which are involved throughout genomic and non-genomic mechanisms in a vast array of CNS functions [45,46,47] far beyond the scope of the present overview. Here, we report the key concepts relevant to the current understanding of pathophysiology and potential treatment targets of PMS/PMDD.