Epidemiology and pathogenesis of premenstrual syndrome and premenstrual dysphoric disorder

INTRODUCTION — The premenstrual syndrome (PMS) and the more severe variant of premenstrual dysphoric disorder (PMDD), also called late luteal phase dysphoric disorder in previous versions of the Diagnostic and Statistical Manual (DSM), are characterized by the presence of physical and/or behavioral symptoms that occur repetitively in the second half of the menstrual cycle and often the first few days of menses. The severity of PMS or PMDD symptoms lead to interference with some aspects of the female's life, including social relations, work in or outside the home, etc. The most common physical manifestation is abdominal bloating [1,2]. Breast tenderness and headaches are also common (table 1). The emotional symptoms lead to greater impairment than do physical symptoms [3].

The diagnosis of PMDD is discussed in greater detail elsewhere. The clinical manifestations, diagnosis, and treatment of PMS/PMDD are discussed separately. (See "Clinical manifestations and diagnosis of premenstrual syndrome and premenstrual dysphoric disorder" and "Treatment of premenstrual syndrome and premenstrual dysphoric disorder".)

EPIDEMIOLOGY — Premenstrual dysphoric disorder (PMDD), as defined by the American Psychiatric Association (APA) Diagnostic and Statistical Manual, Fifth Edition (DSM-5), can be differentiated from premenstrual syndrome (PMS) by the presence of at least five symptoms, including one affective symptom, such as mood swings, irritability, and/or depression [4].

The prevalence of PMS and PMDD in the population have been overestimated because of the failure to apply strict diagnostic criteria (see "Clinical manifestations and diagnosis of premenstrual syndrome and premenstrual dysphoric disorder", section on 'Diagnostic criteria'). Estimates as high as 80 percent have been reported for PMS, based upon the inclusion of females who have any form of premenstrual mood or physical symptoms [5]. When one applies strict inclusion criteria, estimates for PMS are around 20 to 30 percent and 2 percent for PMDD, as illustrated by three community studies that used prospective ratings to determine the diagnosis [6-9]. (See "Clinical manifestations and diagnosis of premenstrual syndrome and premenstrual dysphoric disorder", section on 'Evaluation'.)

PMS is described in diverse cultural settings, even among females who are not generally aware of the disorder. As an example, similar rates of the disorder are reported in Mediterranean countries, the Middle East, Iceland, Kenya, New Zealand, and Asia [10-13]. The point prevalence of retrospectively reported symptoms range from 2.8 to 6.4 percent [14,15]. In an international survey of 7226 females in Europe, South America, and Asia, the frequency of PMS symptoms is similar across countries and regions, but females in some countries, such as Pakistan, are less familiar with the term PMS when compared with European females [16]. Symptoms that are most commonly reported are abdominal bloating, cramps, irritability, mastalgia, and joint and back pains.

In the United States, Black females were less likely to experience PMDD than White females. The prevalence of PMDD was 2.9 percent among Black females versus 4.4 percent among White females [17].

RISK FACTORS — The role of genetic factors in the predisposition to premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) is an area of active exploration, although definitive findings are not yet available. It does not appear that females with and without PMDD inherit different alleles of the serotonin transporter. Some studies suggest a possible association with the estrogen receptor alpha (ESR1) gene [18-20]. In one report, cells from females with and without PMDD showed different response patterns to components of the ESC/E(Z) (Extra Sex Combs/Enhancer of Zeste) complex that includes the ESR1 gene [21].

Other possible risk factors for the development of PMDD include lower education and cigarette smoking [22], a history of traumatic events or anxiety disorder, and higher "daily hassle scores" [23], although these are risk factors for a number of mood and anxiety disorders.

PATHOGENESIS — The available evidence suggests that premenstrual syndrome (PMS) is a disorder triggered by changes in gonadal steroids during the luteal phase in susceptible females. This is thought to result from the interaction between cyclic changes in ovarian steroids and the functioning of central neurotransmitters. The neurotransmitter that is most implicated in the manifestations of PMS is serotonin, although there is evidence to implicate beta-endorphin, gamma-aminobutyric acid (GABA), and the autonomic nervous system.

In addition, some of the systemic manifestations, such as the feeling of bloating, may be produced by peripheral mechanisms. There may also be a role for calcium dysregulation in the pathogenesis of PMS [24].

Ovarian steroids — A central role for ovarian steroids in the etiology of PMS is strongly supported by a series of experiments in which "medical ovariectomy" using a gonadotropin-releasing hormone (GnRH) agonist led to dramatic resolution of PMS symptoms [5,25,26]. However, cyclic changes in ovarian steroids do not appear to be the sole cause of PMS symptoms, as daily serum estrogen and progesterone concentrations are similar in females with PMS/premenstrual dysphoric disorder (PMDD) and controls [27,28].

Deficiencies in progesterone, progesterone metabolites (some of which have anxiolytic properties), and the progesterone receptor have also been proposed as possible mediators of PMS/PMDD. However, as noted, serum progesterone concentrations are normal in females with PMS. In addition, serum concentrations of the progesterone metabolites, allopregnanolone and pregnenolone, are similar in females with PMS compared with normal females [29]. Lastly, blocking the effect of progesterone in the luteal phase with a progesterone receptor antagonist (mifepristone) does not alleviate the symptoms of PMS [30]. It is possible that females with PMS/PMDD may have more sensitive downregulation of central estrogen receptors in response to normal levels of progesterone. This possibility is suggested by the documentation of hot flushes, identical physiologically to menopausal hot flushes, during the late luteal phase in females with clinically severe PMS [31].

Although females with PMS have normal concentrations of serum estrogen and progesterone, they may have an abnormal response to normal hormonal changes. In a double-blind, crossover trial of females with PMS, for example, 10 females who received leuprolide had a significant decrease in symptoms compared with females who received placebo [25]. However, subsequent administration of either estrogen or progesterone in addition to leuprolide resulted in a significant recurrence of symptoms. In contrast, no changes in mood occurred in 15 control females without PMS who received the same regimen, or in five females with PMS who were given leuprolide plus placebo postmenopausal hormone therapy. These findings suggest that gonadal steroids are necessary, but not sufficient, to cause symptoms of PMS. The biological basis for these findings are related to a 2014 paper exploring genetic pathways for risk. (See 'Risk factors' above.)

Neurotransmitters — Based upon in vitro data and animal studies, there is evidence that cyclic fluctuations in circulating estrogen and progesterone cause marked changes in the opioid [32], GABA [33], and serotonin [34] systems. At one time, it was thought that the symptom constellation of PMS resulted from steroid-induced changes in the opioid system. Differences in peripheral beta-endorphin levels are observed in females with PMS compared with controls in the periovulatory and premenstrual phases of the cycle [35-37]. However, attempts to confirm these peripheral findings with provocative tests to probe central opiate activity have not been successful [38].

The potential role of the GABAergic system in PMS has not been extensively investigated. However, in vitro data suggesting this system is modulated by progestin are corroborated indirectly by the observation that the benzodiazepine alprazolam is effective in treating PMS symptoms [39] (see "Treatment of premenstrual syndrome and premenstrual dysphoric disorder", section on 'Other therapies'). In addition, low levels of the progesterone metabolite allopregnanolone, which enhances GABA-A receptor function and possesses anxiolytic effects, is thought to have a mechanistic role [40]. Clinical trial data finding that an antagonist to allopregnanolone, administered prior to the rise in luteal phase progesterone and allopregnanolone levels, blunts symptoms to a greater extent than does placebo [41]. Data on whether serum allopregnanolone concentrations differ between symptomatic and asymptomatic females conflict, but peripheral levels may not reflect central levels nor does it speak to receptor activity [29,40].

Evidence continues to support a role for serotonin in the etiology of PMS. This can be illustrated by the following findings:

●Patients with PMS, when compared with controls, have lower whole blood serotonin and platelet serotonin uptake and imipramine binding during the luteal phase of the menstrual cycle [42-46], and higher cerebrospinal fluid levels of the serotonin metabolite 5-hydroxyindoleacetic acid as compared with the dopamine metabolite homovanillic acid [47].

●The symptoms of PMS are ameliorated by the serotonin agonist fenfluramine [48] and aggravated by acute depletion of the serotonin precursor tryptophan [49]. In addition, serotonin reuptake inhibitors, such as fluoxetine, are one of the most effective drugs for the treatment of PMS.

●Administration of metergoline, a serotonin antagonist, to fluoxetine-treated females with PMDD causes a return of mood symptoms [50]. (See "Treatment of premenstrual syndrome and premenstrual dysphoric disorder".)

●Serotonin reuptake inhibitors may influence the metabolic pathway of progesterone and allopregnanolone production [51].

Role of vitamins and minerals — Attempts to detect vitamin deficiency in females with PMS have been unsuccessful, and vitamin therapies are not considered to be an effective therapy.

No differences in vitamin E, vitamin A, or vitamin B6 levels are found [52,53]. However, in one cohort study, females with high intakes of the B vitamins thiamine and riboflavin from food sources were less likely to develop PMS than those who had low intakes [54]. No significant associations were seen between PMS and dietary intake of other B vitamins. Intake of B vitamins from supplements was not associated with a lower risk of PMS. Several vitamins and dietary supplements, including vitamin B6, vitamin E, vitex agnus castus, calcium, and magnesium, were studied as therapeutic agents for PMS; however, evidence that any of these, with the exception of vitex agnus castus, is more effective than placebo is inconsistent. (See "Treatment of premenstrual syndrome and premenstrual dysphoric disorder", section on 'Other'.)

Several reports suggest that patients with PMS may have lower levels of intracellular magnesium over the course of the menstrual cycle [55,56], although studies of altered serum levels have produced inconsistent results [57-59]. One well-conducted study showed an improvement in total PMS symptom scores and affective symptoms with the administration of magnesium pyrrolidone carboxylic acid (360 mg three times daily in the second half of the menstrual cycle) [60]. However, in other studies, magnesium was ineffective. (See "Treatment of premenstrual syndrome and premenstrual dysphoric disorder", section on 'Other'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of premenstrual dysphoric disorder".)

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●Basics topics (see "Patient education: Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) (The Basics)")

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SUMMARY

●Definitions – The premenstrual syndrome (PMS) is characterized by the presence of both physical and behavioral symptoms that occur repetitively in the second half of the menstrual cycle and interfere with some aspects of the female's life. Premenstrual dysphoric disorder (PMDD) is a severe form of PMS in which symptoms of anger, irritability, and internal tension are prominent. (See "Clinical manifestations and diagnosis of premenstrual syndrome and premenstrual dysphoric disorder".)

●Prevalence - Clinically significant PMS affects 20 to 30 percent of females with regular menstrual cycles, while true PMDD affects only approximately 2 percent of females in this group. (See 'Epidemiology' above.)

●Risk factors - Both genetic and environmental factors play a role in the development of premenstrual symptoms. (See 'Risk factors' above.)

•Preliminary evidence suggests that risk for PMDD is associated with genetic variation in ESR1, the estrogen receptor alpha gene. (See 'Risk factors' above.)

•Other possible risk factors for the development of PMDD include lower education, cigarette smoking, and a history of traumatic events or anxiety disorder. (See 'Risk factors' above.)

●Pathogenesis

•In the normal menstrual cycle, cyclic fluctuations in luteal phase estrogen and progesterone concentrations cause marked changes in neurotransmitters, most notably, the serotonin system. (See 'Pathogenesis' above.)

•Females with PMS/PMDD have normal concentrations of serum estrogen and progesterone, but they appear to have an abnormal neurotransmitter response (in particular, serotonin) to luteal phase hormonal changes. (See 'Neurotransmitters' above.)

•Among the neurotransmitters, serotonin appears to play the most important role in the etiology of PMS/PMDD, as illustrated by the following observations:

•Selective serotonin reuptake inhibitors (SSRIs) are the most effective therapy for the disorder. (See "Treatment of premenstrual syndrome and premenstrual dysphoric disorder", section on 'Other'.)

•When females with PMDD who are symptom-free on SSRI therapy are subsequently treated with a serotonin antagonist, they experience a return in their mood symptoms. (See 'Neurotransmitters' above.)

•Limited data suggest that high intake of vitamin B6 (from the diet, but not from supplements) is associated with a lower risk of PMS/PMDD. A number of vitamins and dietary supplements, including vitamin B6, vitamin E, vitex agnus castus, calcium, and magnesium, have been studied as therapeutic agents for PMS; however, evidence that any of these is more effective than placebo, which has a 30 percent response rate, is inconsistent. (See 'Role of vitamins and minerals' above and "Treatment of premenstrual syndrome and premenstrual dysphoric disorder", section on 'Other'.)