Ellen W. Freeman
Table Of Contents
Ellen W. Freeman, PhD
The premenstrual syndromes (PMS) are characterized by mood and behavioral changes that occur for several days to 2 weeks before menses, followed by symptom relief in the postmenstrual phase of the cycle. The severity and the regular occurrence of the symptoms in the premenstrual phase are the essential components of the diagnosis. The term PMS as used by clinicians and the public is generic, imprecise, and commonly applied to numerous symptoms that range from the mild and normal physiologic changes of the menstrual cycle to clinically significant symptoms that limit or impair normal functioning. Historically, premenstrual symptoms have been difficult to diagnose and treat because of the lack of diagnostic criteria and any scientific evidence of treatment efficacy. However, in recent years, randomized controlled trials and other well-designed studies have defined diagnostic criteria and identified effective treatments for moderate to severe PMS and/or premenstrual dysphoric disorder (PMDD), a severe form of PMS as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV).1
PMS was defined by an NIMH consensus workshop group in 1983 as: “A constellation of mood, behavioral, and/or physical symptoms that have a regular cyclical relationship to the luteal phase of the menstrual cycle, are present in most if not all cycles, and remit by the end of the menstrual flow with a symptom-free interval of at least one week each cycle.”2 The essential characteristic of PMS is the timing of the symptoms, with the severity occurring premenstrually and a symptom-free interval after menses.
The American College of Obstetricians and Gynecologists (ACOG) published a revised practice bulletin in 2000 for the management of premenstrual syndrome.3 The key elements of a PMS diagnosis as identified by ACOG include the following: (1) symptoms consistent with PMS; (2) restriction of the symptoms to the luteal phase of the menstrual cycle; (3) confirmation of the symptom pattern by prospective assessment; (4) the symptoms cause functional impairment; and (5) exclusion of other diagnoses that may better explain the symptoms.
The attempt to provide specific diagnostic criteria for PMS was first made by the American Psychiatric Association. The initial set of criteria was termed late luteal phase dysphoric disorder (same as PMDD) and was described in the third edition (revised) of the Diagnostic and Statistical Manual (DSM-III-R).4 The LLPDD criteria were subsequently slightly revised by adding a symptom (fears of loss of control) and renaming the disorder PMDD, which was included as a diagnosis for further study in DSM-IV.1 By providing diagnostic criteria, PMDD has played an important role in the conduct of clinical trials to determine the efficacy of treatments for the disorder. However, as with other definitions of PMS, the key elements of symptom severity and degree of change over the menstrual cycle are not specifically quantified, and published studies continue to differ in the samples selected on the basis of these criteria.
In this chapter, the term PMS is used to signify clinically significant PMS and includes the severe form of PMDD. The term PMDD is retained when studies clearly used the PMDD diagnosis.
Numerous symptoms have traditionally been associated with PMS (Table 1). The range of symptoms is particularly extensive when there is no clear diagnosis of PMS that distinguishes the disorder from other comorbid conditions that may account for the symptoms. It is underscored that many other disorders, both physical and psychiatric, are exacerbated premenstrually or occur as a comorbid disorder with PMS (see later). However, when a careful diagnosis is made to distinguish PMS from other conditions, a much smaller group of symptoms appears typical of the syndrome, most commonly mood symptoms, accompanied by other specific physical and behavioral symptoms (Table 2).
(Gise LH: Premenstrual syndromes. In Lemcke DP, Pattison J, Marshall LA, et al (eds): Primary Care of Women, pp 410–419. Norwalk, Appleton and Lange, 1994.)
Among women who have been carefully screened for clinically significant PMS, mood symptoms are typically predominant (irritability, anxiety, tension, mood swings, feeling out of control, depression). Almost always accompanying the mood symptoms are behavioral symptoms such as fatigue, decreased interest, food cravings, sleep disturbance, poor concentration, and physical symptoms, most commonly, abdominal swelling and breast tenderness (see Table 2).
Some recent studies suggest that irritability and tension are the cardinal symptoms of the syndrome.5,6,7 Although depressive symptoms such as low mood, fatigue, appetite changes, sleep difficulties, and decreased concentration are frequent symptoms of women with PMS, increasing evidence suggests that PMS is not simply a variant of depression but has distinct underlying mechanisms that differ from those of other depressive disorders.8
Premenstrual Exacerbation of Symptoms and Comorbidity
Premenstrual exacerbation of the symptoms of another underlying medical or psychiatric disorder is common. For example, more the 50% of patients experiencing major depression reported a clear-cut premenstrual exacerbation of their symptoms.9 Among the most common medical disorders that may be exacerbated premenstrually include asthma,10,11 migraine,12 seizure disorders,13 allergies, thyroid disorders, irritable bowel syndrome, and chronic fatigue syndrome.3
The premenstrual phase may represent a vulnerable time for women with mood disorders to have worsening symptoms of severe depression.9 A lifetime history of depression ranges from approximately 20% to 76% in samples of women with PMS or PMDD.14 The premenstrual phase is a risk factor for exacerbations of panic symptoms in women with panic disorder.15,16 Severe premenstrual symptoms were associated with increased alcohol use premenstrually.17,18 A family history of alcoholism was related to premenstrual alcohol consumption and the severity of premenstrual symptoms.19 Premenstrual exacerbation of symptoms may occur in other conditions such as schizophrenia.20
Alternatively, the premenstrual symptoms may be distinct from those of the underlying disorder and indicate PMS in conjunction with another diagnosis (comorbidity). The most common comorbid diagnosis with PMS may be dysmenorrhea. There appears to be a strong association among mood disorders that occur with the menstrual cycle, postpartum, and in the perimenopause.21,22,23 A history of premenstrual depression is a risk factor for postpartum depression24 and menopausal symptoms.25 There is some preliminary evidence that PMS over time may progress to clinical depression.26,27,28
In a population-based survey of 1194 women, classification of the premenstrual symptoms using an empirically derived algorithm showed that 16% had minimal symptoms, 67% had moderate symptoms, 12.6% had severe symptoms, and 4.5% had PMDD.33
In another recent population-based survey, the prevalence of PMDD in the population of reproductive-aged women was estimated at 6%, with an additional 19% identified as near-threshold cases that were highly symptomatic but had four rather than five symptoms required for the PMDD diagnosis.34 In yet another community-based study, 8% of menstruating women had severe premenstrual symptoms and 14% had moderate premenstrual symptoms that were significantly associated with functional impairment.5 These estimates consistently suggest that approximately 20% of women experience severe premenstrual symptoms and are consistent with the clinical evidence that many women who seek treatment for PMS do not meet the stringent criteria for PMDD.35
Reports of risk factors for PMS have been inconsistent and contradictory. In a current population-based study, symptom severity decreased with age and with oral contraceptive use.33 Greater symptom severity was associated with comorbidities. Racial differences were observed, with Hispanics reporting greater symptom severity, Asians reporting less symptom severity, and blacks reporting the same symptom severity compared to whites. Symptom severity was not associated with education, employment, marital status, number of children, strenuous exercise, or current smoking.33 Other risk factors that have been suggested include nulliparity,36 earlier age at menarche,37,38 higher body mass index,8,37 greater alcohol consumption,37,39,40,41 more caffeine consumption,41 and higher levels of perceived stress.37,39 Oral contraceptive use36,42 and regular physical activity43,44 have been identified as protective factors.
Costs of Premenstrual Syndrome
The morbidity of PMS is caused by its severity, chronicity, and resulting impairment in work, relationships, and activities. PMS appears to be a chronic disorder, with one-fourth to one-half of the nonpregnant reproductive lifespan compromised by disruptive symptoms that return in the luteal phase of each menstrual cycle.
The level of impairment as assessed by standard measures is significantly higher than community norms and is similar to that of major depressive disorder.45 Studies show that women with PMS report the greatest impairment in relationships32,45,46 and compromised work levels.32,45 Although one study reported increased absences from work,47 there has been little supporting evidence. A recent population-based study that included prospective daily symptom ratings to assess PMDD clearly identified decreased productivity and role limitation as a result of PMS but found little evidence of reduced time at work or other activities.48 While functioning is clearly impaired, the impairment is correlated with dysphoric mood symptoms45,48 and not with decrements in memory or learning.49,50
Inadequate treatment of mood disorders increases the costs of medical care and lost productivity.51,52 Reports show that even subsyndromal symptoms of dysphoric mood disorders are associated with increased medical and mental health services.53,54 A population-based study of PMDD reported that as premenstrual symptom severity increased, the likelihood of health care service use increased for visits to the emergency department, obstetrician/gynecologist, or alternative medicine providers.48
Understanding of the etiology of PMS remains limited. Circulating levels of reproductive hormones are normal,55,56 although there may be an underlying vulnerability to the normal fluctuations of one or more of these hormones.3,57The biochemical changes of PMS are believed to involve central nervous system-mediated interactions of the reproductive steroids with neurotransmitters.57 Serotonergic dysregulation is supported by the most evidence at the present time. There is also evidence of dysregulation of gamma amino butyric acid (GABA) receptor functioning in women's mood disorders.58,59
Evidence suggests that serotonergic activity plays varying roles in the modulation of PMS. Indications of abnormalities in markers of serotonergic transmission in women with severe PMS include evidence of a lowered platelet imipramine binding (a peripheral marker of serotonin [5-hydroxytryptamine, 5-HT] function) in the luteal phase,59 decreased platelet 5-HT content and 5-HT uptake during the luteal phase,60,61 and significantly decreased whole blood 5-HT levels premenstrually.62 PMS patients showed a lower 5-HT response to tryptophan (a 5-HT precursor) during the luteal phase compared with the follicular or mid luteal phase.63 Another study found no differences in platelet 5-HT2A receptor binding in PMDD patients compared with controls, but untreated PMDD women had a higher number of [3H]paroxetine binding sites in the follicular phase compared with healthy controls, a difference that disappeared with buserelin treatment, a GnRH agonist.64 These findings contribute to the hypothesis that serotonergic transmission is involved in PMS. Parry provides an extensive review of the role of central serotonergic dysfunction in PMS/PMDD.65
Results of challenge tests and studies to elucidate the mechanisms of PMS also provide evidence of serotonergic involvement in PMS symptoms. Depleting the 5-HT precursor tryptophan provoked PMS symptoms,66 while conversely, tryptophan supplementation relieved PMS symptoms.67,68 d-Fenfluramine, which releases serotonin and blocks its uptake, blocked food cravings and improved depressed mood in a controlled study of PMS subjects.69 Prolactin responses to buspirone challenge (a partial 5HT1A receptor agonist) were blunted in the follicular phase of women with late luteal phase disorder but not in healthy controls, suggesting that the subsensitivity of the 5-HT1a receptor may be a trait marker for the disorder.70
m-Chlorophenylpiperazine (m-CPP), a serotonin agonist, decreased symptoms in women with PMDD.71 Women with PMDD who received metergoline (a serotonin receptor antagonist) experienced the return of PMDD symptoms compared with healthy comparisons who did not.72
Animal experiments suggest that serotonin has inhibitory effects on aggression and irritability, which is a predominant symptom of PMS.6 Fluoxetine reduced aggressive behavior that was elicited by administration of estradiol and progesterone to ovariectomized rats.73 Inhibition of serotonin reuptake reduced depression in animal models74 but also reduced sexual receptivity in estrous rats.75 These animal models suggest links between serotonergic transmission and cycle-dependent behaviors associated with steroid hormones.
The predominant evidence for involvement of the serotonergic (5HT) system is the clear response of PMS and PMDD patients to serotonergic antidepressants, including fluoxetine,76,77,78,79,80,81 sertraline,82,83,84,85,86 paroxetine,87 citalopram,88 venlafaxine,89 and clomipramine.90,91 The satisfactory response rates in these studies range from 52% to 69%, with placebo improvement ranging from 15% to 47%. Furthermore, the response to serotonin reuptake inhibitor (SSRI) appears to be more rapid in treatment for PMS than is commonly observed for other depressive disorders. While treatment response indicates that serotonergic medications can control PMS symptoms, the pharmacologic reasons for this are not known. It is speculated that the mechanism of action in PMS differs from that of other mood disorders or that SSRI treatment corrects an underlying serotonergic dysfunction.
Although serotonergic activity appears to modulate PMS symptoms, it is unlikely that it is the causal factor. It is also unlikely that the gonadal steroids are the causal factor, although it appears that PMS requires the sex steroids.57 No consistent differences in progesterone and estradiol levels have been identified between women with PMS and controls. The dominant theoretical view is that the normal gonadal steroid fluctuations of the menstrual cycle trigger an abnormal serotonergic response in vulnerable women.
The strongest evidence of the involvement of the sex hormones is the response of women with PMS and no other comorbid condition to GnRH suppression of ovulation, which consistently relieves PMS symptoms.57,92,93,94,95,96,97,98 Further strong evidence of a necessary association of the gonadal steroids in PMS is from a controlled study that showed that PMS symptoms were induced with physiologic doses of estradiol and progesterone in PMS subjects but not in asymptomatic controls.57 Manipulation of peripheral levels of ovarian steroids with induction of menses by mifepristone with or without preserving the corpus luteum with human chorionic gonadotropin did not change the premenstrual symptoms in women with carefully diagnosed PMDD.99 This evidence indicated that the hormonal effects associated with PMS may occur before the luteal phase of the cycle.
The progesterone metabolite, allopregnanolone, modulates GABA receptor functioning similar to the barbiturates and benzodiazepines and can mimic the anxiolytic effect of these agents.100,101 PMS shares clinical features such as comorbidity with panic disorder, panic-type responses to lactate infusion, or carbon dioxide inhalation,102,103,104 and moderate response to benzodiazepine therapy with GABA-mediated anxiety disorders.105 Studies suggest that allopregnanolone levels in PMS subjects may be related to symptom severity,106,107,108,109,110 and that the responsiveness of the GABAa receptor complex may be altered in women with PMS.111 Responses to an intravenous l-tryptophan challenge in women with premenstrual symptoms provided evidence for a possible interaction between the serotonergic system and allopregnanolone.112 There is some evidence that SSRIs increase activity of the enzyme that produces allopregnanolone in human brains,113 but this remains a theoretical possibility in PMS at present.
Progesterone deficiency was long believed to be the cause of PMS. However, there is no consistent evidence of altered progesterone levels in women with PMS,55,114,115 and progesterone therapy has clearly been shown to be not better than a placebo.116,117,118,119 The apparent contradiction between the role of gonadal steroids in PMS and the lack of effect of progesterone therapy may be related to the variability in conversion of progesterone to the active metabolite allopregnanolone,58,120,121 with a consequent lack of sufficiently high CNS levels of 3 α-reduced metabolites premenstrually in some women.58,122
Beta-endorphin was hypothesized to be involved in the etiology of PMS because of its characteristics that include inhibition of gonadotropin release during the luteal phase; modulation of biogenic amine, prostaglandin, vasopressin, and carbohydrate pathways; and influence on mood changes, pain perception, thirst, and appetite. Symptoms of increased beta-endorphin level (anxiety and agitation) and features of opiate withdrawal (dysphoria, mood lability, lethargy, reduced motor activity, and heightened libido) resemble PMS. Halbreich and Endicott hypothesized “that a premenstrual decrease of levels of endorphin may be involved in the pathophysiology of an atypical, depressive premenstrual syndrome while deregulation of endorphins may be involved in that of an anxious/agitated/depressive syndrome.”123 Administration of the antagonist naloxone in high doses produced PMS-like symptoms in normal women.124 Chuong and associates described a decrease in serum beta-endorphin compared with the follicular phase levels in women with PMS,125 results that were subsequently replicated.126,127 Administration of naltrexone in the ovulatory days of the cycle to prevent a beta-endorphin peak and consequent luteal phase withdrawal decreased premenstrual symptoms.128
Swelling in the premenstruum is commonly reported by women, but there is no good evidence of differences in sodium or body water in the luteal phase compared with the follicular phase. There is no consistent premenstrual weight gain in women with PMS and no correlation between symptom severity and edema.129,130 Based on an altered water-to-potassium ratio, it was suggested that fluid redistribution best explained the bloating reported in PMS.130 An analogous model to consider is idiopathic cyclic edema. Patients with cyclic edema have an exaggerated autonomic response to the upright posture that thereby activates both the catecholamine and the renin-angiotensin pathways.131 Renal dopamine, a diuretic and natriuretic that antagonizes the renin-angiotensin-aldosterone system and norepinephrine, is reduced.132 Investigation of dopamine metabolism in women with PMS may reveal value for dopaminergic agents, as has been shown for women with idiopathic edema.133
Prostaglandins are ubiquitous, and PMS symptoms touch most organ systems. CNS prostaglandins act as neurotransmitters to modify thirst, appetite, temperature, mood, vascular tone, seizure threshold, and hormones such as vasopressin. The prostaglandin synthetase inhibitor mefenamic acid improved symptoms of fatigue, mood swings, and irritability in women with PMS.134 It is not known whether the prostaglandin inhibition directly reduced these symptoms or whether the improvement resulted from correction of dysmenorrhea, a well-known benefit of nonsteroidal anti-inflammatory drug therapy, which in turn reduced other PMS symptoms. Low serum levels of the essential fatty acid prostaglandin precursor, cis-linoleic acid, were observed in women with PMS.135 However, review of seven placebo-controlled clinical trials of evening primrose oil for the treatment of PMS found no benefits greater than placebo.136
Genetic factors may be important in PMS. Study of twins indicated that premenstrual symptoms of depression and anxiety were moderately stable over time and strongly inheritable.137 The researchers concluded that the genetic and environmental risk factors for these premenstrual symptoms were not closely related to the genetic risk factors for lifetime depression. Another study found that the concordance for PMS in monozygotic twins was twice that if the twins were dizygotic twins.138
Premenstrual syndromes are diagnosed on the basis of the timing of the symptoms, which cross emotional, behavioral, and mood domains. For a diagnosis of PMS, the symptoms must occur during the 2 weeks before menses and subside during the menstrual flow. With remission of the symptoms, a symptom-free period occurs in the follicular phase between menses and ovulation. Clinically significant PMS is determined by the patient's seeking treatment and/or report of impaired functioning in relationships, work, or other activities. For a diagnosis of pure PMS, the symptoms must not be accounted for by other physical or psychiatric disorders. There are no hormonal measures, other laboratory tests, or physiologic measures that identify PMS. Such tests are useful only to identify or rule out other disorders that may be suspected in the diagnostic evaluation.
The most frequently reported symptoms of PMS include irritability, anxiety, nervous tension, mood swings, fatigue, depression, feeling overwhelmed or out of control, physical symptoms of swelling or bloating of the abdomen or extremities, appetite changes and food cravings, aches, and breast tenderness (see Table 2).
The specific symptoms appear to have little importance for the diagnosis. The critical elements are the relationship to menses, severity, and the degree of functional impairment. Women who seek medical treatment usually describe multiple symptoms, with the primary focus and most distressing problems typically focused on the mood and behavioral symptoms. Physical symptoms are widely experienced by women who do not perceive problems with premenstrual distress and are seldom sufficient for a clinical diagnosis of PMS without other mood or behavioral symptoms.
Diagnostic criteria for PMS are presented in the ACOG Practice Bulletin 15 of 2000.3 At least one of the listed affective or somatic symptoms must be experienced during the 5 days before menses in three prior menstrual cycles (Table 3) and relieved with the menstrual flow. The symptoms should be confirmed by two cycles of prospective reports. The symptoms cause identifiable impairment in the patient's functioning and are not accounted for by other physical or emotional disorders.
(American College of Obstetricians and Gynecologists. ACOG Practice Bulletin 15; 2000)
Premenstrual Dysphoric Disorder
The diagnostic criteria for PMDD are listed in the DSM-IV.1 These criteria were intended to diagnose a severe dysphoric form of PMS. The symptoms must be severe premenstrually and minimal or absent after menses. At least five of the 11 listed PMDD symptoms, including one or more of the mood symptoms, must meet these criteria. Physical symptoms, regardless of the number, are counted as a single symptom (Table 4). The symptoms must markedly interfere with functioning and not simply be an exacerbation of another physical or mental disorder. All criteria must be confirmed by prospective daily ratings for at least two menstrual cycles.
PMDD, premenstrual dysphoric disorder
Five or more symptoms must be severe premenstrually and remit after menses (Adapted from American Psychiatric Association )
There is no gold standard for operationalizing the premenstrual severity and postmenstrual remission level required for a PMDD diagnosis. The dependence of the diagnosis on subjective report of five specified symptoms without a standard method of determining severe and minimal levels results in marked differences among study samples identified as PMDD. Smith and associates demonstrated that the number of subjects identified by the PMDD criteria varies markedly by the rating scale used for symptom assessment.139 Increasing evidence indicates that approximately 5% to 8% meet stringent PMDD criteria.33,34 However, approximately 20% of women may experience severe PMS but not meet the PMDD criteria.33 There is no evidence that treatment response differs between a PMDD or PMS diagnosis in the few studies that have examined this issue.118,140
Differences Between Premenstrual Syndrome and Premenstrual Dysphoric Disorder
The most obvious difference between the PMS and PMDD diagnosis is the number of symptoms required. PMDD requires five of 11 identified symptoms; the ACOG diagnosis of PMS requires only one severe symptom consistent with PMS. The diagnoses are otherwise identical in their requirements for the menstrually related symptom pattern, confirmation by prospective ratings of the symptoms, impaired functioning and identification of other disorders that could account for the symptoms.
Daily Symptom Reports
The diagnosis of PMS and PMDD continues to be made from the patient's report of symptoms on a daily basis for at least two menstrual cycles. Numerous scales for daily symptom rating have been published and are available for use (Table 5). Daily symptom reports may be viewed as difficult to use in the primary care setting, but such reports can also help the busy clinician by swiftly demonstrating the patient's symptoms and indicating whether they are in fact linked to the menstrual cycle in the requisite pattern. Many women who report PMS will not confirm that the symptoms occur only premenstrually in daily symptom reports. Daily symptom reports are also helpful in indicating there may be other comorbidities when the reports show that symptoms occur randomly or throughout the menstrual cycle. The daily symptom reports are also an important educational tool for the patients. Patients can observe the patterns and severity of their symptoms over the menstrual cycle and gain an increased sense of control.
A medical history (with emphasis on reproductive events, mood disorders, and family history of PMS and other mood disorders), complete physical examination, and a gynecologic examination are important for the diagnosis. By definition, PMS occurs with regular ovulatory menstrual cycles in the normal range; irregular cycles require further gynecologic investigation.
Comorbid conditions should be identified, including dysmenorrhea, endometriosis, ovarian cysts, uterine fibroids, pelvic inflammatory disease, seizure disorders, migraine, thyroid disorders, asthma, allergies, diabetes, hepatic dysfunction, cancer, lupus, anemia, and infections. Psychiatric conditions that must be considered include mood disorders, substance abuse, eating disorder, anxiety disorders, and personality disorders (Table 6). It may be difficult to determine whether the symptoms are an exacerbation of a comorbid condition or PMS symptoms superimposed on another condition. In either case, the usual recommendation is to treat the underlying condition first, and then reassess and possibly add treatment for the symptoms that arise premenstrually.
PMS, premenstrual syndrome
At least two visits should be considered for the diagnostic evaluation. Evaluating the patient when she is premenstrual usually confirms the severity of the symptoms, but it is difficult to determine their overlap with other conditions. It is diagnostically useful to see the patient after menses when symptoms have abated. If symptoms are absent, it provides convincing evidence for the diagnosis. However, if symptoms are present in the follicular phase, the type and severity of the symptoms provide important diagnostic information for other comorbid conditions.
Effective treatments demonstrated by randomized placebo-controlled trials are available for PMS and PMDD. Accurate diagnosis is the first step. Support, education, symptom charting, and attention to health behaviors related to diet, exercise, alcohol, nicotine, caffeine, and stress management can be helpful, but if symptoms remain severe and interfere with the patient's usual functioning, pharmacologic treatment should be tried.
A large multicenter, randomized, double-blind study of calcium supplementation (600 mg twice daily) reduced premenstrual depression, fatigue, edema, and pain significantly more than the placebo in women with PMS.142 This is one of the few nonprescription treatments that has been examined in placebo-controlled study. However, the severity of the dysphoric mood symptoms was not indicated, and further information is required to determine the efficacy of this treatment for PMDD.
The rationale for use of vitamin B6 (pyridoxine) is that its physiologically active form is a cofactor in the synthesis of serotonin, dopamine, and certain prostaglandins. There have been numerous studies of vitamin B6 for PMS treatment, but the results are conflicting and inconclusive. A meta-analysis showed that vitamin B6 was approximately twice as likely as placebo to improve PMS symptoms overall, with an odds ratio for improvement in depressive symptoms of 1.69, but the researchers emphasized that there was very low confidence in the results because of the generally poor quality of the studies.143 There was no significant dose response, indicating that the amount of vitamin B6 was not associated with improvement. The use of megadoses of vitamin B6 (exceeding 100 mg/day) was found to cause peripheral neuropathies, an indication that caution and medical oversight are required with supraphysiologic dosing.
Dietary alterations that modify tryptophan levels have been shown to have effects on mood and cognition. Dexfenfluramine, which releases brain serotonin and blocks its reuptake, improved premenstrual dysphoric mood and normalized carbohydrate consumption in women with moderate to severe PMS.69 A study of carbohydrate intake in women with PMS indicated that carbohydrate cravings and subsequent carbohydrate intake significantly improved mood shortly thereafter.144 A formulated carbohydrate-rich beverage, which was known to increase tryptophan levels, improved the mood symptoms of PMS in preliminary studies.145,146
Many women know that healthy behaviors related to diet, exercise, alcohol use, nicotine, caffeine, and stress can reduce symptoms, and improving health behaviors may be therapeutic even if it is not specific for premenstrual symptoms. However, changing health behaviors is difficult, and if behavioral changes are recommended and not followed, both the clinicians and the women may become frustrated. This can be avoided by suggesting that a woman reflect on these health behaviors with the goal of making a selection, rather than making a specific recommendation. This approach also avoids a situation in which the patient feels that the clinician is not taking her problem seriously and offers only behavioral changes rather than medication.
Stress aggravates premenstrual symptoms as it does other medical conditions, and there is some evidence that stress response is impaired in women with PMS.37,111 Many women are quite aware of the sources of stress in their lives and, with little intervention other than the physician's encouragement and permission, are able to make significant changes to reduce the stress. Weekly group follow-up visits may facilitate compliance by offering support.147
Behavioral treatments that reduce stress or facilitate coping reduce PMS symptoms. Behavioral treatments that have helped PMDD include cognitive behavioral therapy,148,149,150 training in coping skills,151 and relaxation techniques.152
Regular aerobic exercise has been found to improve mood and to reduce the severity of premenstrual symptoms,153,154,155 possibly by increasing beta-endorphin levels in the brain. Estrogen and progesterone receptors in the brain are closely linked to endorphin function.156 Some studies have identified regular physical exercise as a protective factor for PMS,43,44 but other epidemiologic studies have not found any significant association between exercise and severity of premenstrual symptoms.33
Dietary modification is one of the most common treatments for premenstrual syndromes but lacks systematic study to determine its effectiveness. Because premenstrual symptoms mimic hypoglycemia, reduction of the intake of simple carbohydrates and eating healthy snacks at regular intervals to avoid extremes of hunger and satiety was traditionally recommended, but no premenstrual alteration of glucose metabolism has been demonstrated.157 In contrast, a carbohydrate meal without protein raised serotonin levels in the brain, improved mood, and reduced food craving.144 Carbohydrate intake improved mood symptoms of PMS145,146 (see CARBOHYDRATES section). Caffeine may aggravate premenstrual symptoms, and limiting caffeine intake may be therapeutic. Data suggest that women with premenstrual symptoms may self-medicate with caffeine, consequently exacerbating their symptoms.158 The postulate that there is a relationship between caffeine and premenstrual breast soreness is controversial, but many women report improved symptoms after eliminating xanthine beverages. Significant comorbidity between premenstrual syndromes and alcohol abuse means that this should be addressed in the diagnostic evaluation. Denial of substance abuse is characteristic and may significantly hinder and delay the diagnosis. Nicotine use should also be reviewed. Nicotine causes irritability and clinicians note that many women report improvement in premenstrual symptoms when they stop smoking.
Herbal treatments for PMS are used by increasing numbers of women, but scientific information on their efficacy for this disorder remains limited.141 In a prospective, randomized, placebo-controlled study, agnus castus extract (chaste-tree berry) administered daily for three menstrual cycles was significantly better than placebo,159 confirming results of two previous uncontrolled studies of this treatment.160,161 The participants in these studies were identified as having PMS, but the extent that severe symptoms responded to this treatment could not be determined from the report. Hypericum perforatum (St. John's wort; 900 μg per day) decreased premenstrual symptom scores in an uncontrolled study,162 but well-designed controlled studies are essential to determine the efficacy of this commonly used herbal treatment. Evening primrose oil has historically been a popular treatment for PMS, with at least seven placebo-controlled trials, but the well-controlled studies failed to find any beneficial effects for this treatment.136
Behavioral treatments that reduce stress or facilitate coping may reduce PMS symptoms. Behavioral treatments that have helped premenstrual dysphoric disorder include cognitive behavioral therapy,148,149,150,151,163 training in coping skills,151,164 and relaxation techniques.152
Numerous other complementary and alternative therapies showed no convincing evidence of efficacy for PMS in a review of 27 randomized controlled trials (dietary supplements, 13 trials; herbal medicines, 7 trials; biofeedback, 2 trials; homeopathy, relaxation, massage, reflexology, and chiropractic, 1 trial each).162 Although it is possible that methodologic issues obscured potential results, the researchers concluded that, based on scientific data, none could be recommended as a treatment for premenstrual syndromes.
Bright Light and Sleep Deprivation Therapy
Chronobiologic disturbances such as lower levels of melatonin and earlier offset of melatonin secretion have been found in women with PMS.165 Both bright light therapy and the dim light that was used as the placebo, administered daily for 1 premenstrual week, significantly reduced depressive symptoms in PMDD patients.166 A therapeutic effect was also reported for total sleep deprivation,167 early and late sleep deprivation in PMDD subjects;168 however, the strength of the responses over placebo treatment remain unclear. These interventions may provide alternative or adjunctive treatments for the management of PMS. The studies also suggest a link between dysphoric PMS and major depressive disorder, which has been shown to respond to bright light therapy and sleep deprivation protocols.169
The serotonergic antidepressants, particularly the selective SSRIs, are the first-line treatment for severe PMS and PMDD at this time. Modulating serotonergic function is consistent with the dominant theoretical view that the normal gonadal steroid fluctuations of the menstrual cycle trigger an abnormal serotonergic response in vulnerable women. (Indications of abnormalities in markers of serotonergic transmission are discussed). The United States Food and Drug Administration (FDA) has approved two SSRIs, fluoxetine and sertraline, for the indication of PMDD.
A meta-analysis of randomized controlled trials of SSRIs in treatment of PMS and PMDD concluded that these drugs were an effective first-line therapy, with an overall standard mean difference in favor of SSRIs equivalent to an odds ratio of 6.91.170 Secondary analysis showed that the SSRIs were as effective in treating physical and behavioral symptoms.171 Efficacy has been clearly shown in randomized, placebo-controlled, double-blind trials for fluoxetine,76,77,78,79,80,81 sertraline,82,83,84,85,86 paroxetine,87 citalopram,88 venlafaxine,89 and clomipramine.90,91 Small open-label studies showed that nefazodone172 and fluvoxamine173 also had response frequency in PMS treatment similar to those in the placebo-controlled studies of SSRIs.
Dosing With Serotonin Reuptake Inhibitor
Effective doses of SSRIs are consistently at the low end of the dose range for depression in all reports of PMS treatment (Table 7). Response is usually swift, with the greatest improvement in the first menstrual cycle of treatment and smaller increments with continued use or dose adjustments in the next one to two cycles. In the absence of sufficient response or dose-limiting side effects, the dose should be increased in the second and/or third cycles of treatment. An adequate trial of a serotonergic antidepressant is at least two menstrual cycles at a dose level known to be effective with a third cycle if there is a partial response. If a patient has an insufficient response or unacceptable side effects with an initial SSRI, it is reasonable to try another SSRI.174 Although all SSRIs have similar side effects, an individual patient may respond better to one SSRI than another. No clear predictors of response or side effects are identified at this time.
Side Effects of Serotonin Reuptake Inhibitor
Side effects are common when treatment is initiated but most are transient and disappear during the first treatment cycle. The most common side effects include headache, nausea, insomnia, fatigue or lethargy, diarrhea, decreased concentration, dizziness, and decreased libido or delayed orgasm.
It may be difficult to determine whether reports about sexual effects are medication-induced if there is no information about sexual functioning before initiating the drug regimen. Some women report that sexual side effects diminish with time and adjustment to the medication while others do not. The incidence of decreased sexual interest or delayed orgasm in the few published reports of PMS patients is approximately 9% to 16%. This is notably lower than the rates in the population of SSRI users, which were recently reported to be 36% to 43%.175 The PMS/PMDD reports of sexual side effects are from acute treatment trials that were not designed to include systematic assessment of sexual function, and they do not represent experience with long-term use of medication. Whether there is a true difference between PMS and major depression, with respect to this side effect, warrants further study.
Luteal Phase Dosing With Serotonin Reuptake Inhibitors
The use of medication only in the symptomatic luteal phase of the menstrual cycle is of particular interest in PMS because of the cyclic pattern of the symptoms, which include a clear symptom-free interval each month. Based on the rapid response of these patients to SSRIs, a number of preliminary studies examined luteal phase dosing regimens with SSRIs and consistently reported efficacy.82,84,85,86,88,91 Two large multicenter trials reported efficacy of fluoxetine176 and sertraline177 administered for the last 2 weeks of the menstrual cycle. A meta-analysis of 15 randomized placebo-controlled trial for PMS or PMDD found no significant difference in symptom reduction between continuous and intermittent dosing.170 Results from one controlled study thus far indicated that once weekly dosing in the two luteal phase weeks with a sustained release formulation of fluoxetine (90 mg, enteric-coated) was also effective.178
Luteal phase dosing is typically initiated 14 days before the expected onset of menstrual bleeding and concluded with the onset or within several days of menstrual bleeding. Several studies are currently investigating the efficacy of symptom-onset dosing, which for many women with PMS is an even shorter time period than the 2-week luteal phase.
As with continuous dosing, doses of the SSRI are usually low (at the starting dose indicated for depression or at one dose increase), and the medication is well tolerated. There is some suggestion that there may be fewer side effects with luteal phase dosing, but this remains an open question. It is also possible that the side effects of SSRIs that usually diminish with adjustment to the medication do not diminish as swiftly with intermittent dosing. Although luteal-phase dosing entails stopping the medication during each menstrual cycle, discontinuation symptoms have not been reported for this dosing regimen for PMS.
Insufficient Response to Serotonergic Antidepressants
The overall response of PMS patients to SSRIs is approximately 60% in controlled trials. No strong predictors of response have been consistently identified.179 An expert consensus group recommended the common clinical practice of shifting to a second SSRI when patients have an insufficient response or are intolerant to the initial SSRI.174 Augmenting an SSRI with other medications has not been systematically studied in PMS treatment. Switching to another class of medication, such as anxiolytics, is suggested, but there are no data that indicate whether nonresponders to an SSRI will respond to another class of medication. Nonresponse may also be caused by other comorbid disorders. A thorough review of the diagnosis and adjustments of the premenstrual doses of medication for the primary disorder should be considered before pursing other treatments for PMS.
The antidepressant response in PMS and PMDD appears to be associated with potent serotonergic activity and is not a general antidepressant effect. Other antidepressants, which are clearly effective for depressive disorders, such as desipramine (a tricyclic noradrenergic antidepressant),82 bupropion (a weak inhibitor of both serotonin and norepinephrine reuptake),80 and maprotiline (a selective noradrenaline reuptake inhibitor),87 were not more effective than the placebo in PMS treatment.
Alprazolam, a benzodiazepine, and buspirone showed modest efficacy for PMS in some studies,118,180,181,182,183 but not others.184,185 The advantage of alprazolam is that it can be taken with the onset of premenstrual symptoms. However, the well-known risk of dependence with alprazolam must be considered, and this medication should be tried only when the patient has symptoms clearly limited to the luteal phase (so that the medication is used for no more than 2 weeks in each cycle) and no history of substance abuse. The advantage of buspirone is that it does not have the risk of dependency. Its disadvantage is that its onset of action is not immediate like alprazolam and it must be used daily. These anxiolytic medications offer an alternative to antidepressants, but fewer patients responded, and the extent to which patients who did not respond to antidepressants respond to anxiolytics is not known.
Hormonal treatments for PMS are consistent with the evidence of hormonal involvement in the disorder57 and have been advocated for many years despite limited scientific evidence of their efficacy for PMS. Among the most effective hormonal treatments for symptom suppression are the gonadotropin-releasing hormone agonist (GnRHa) leuprolide, administered by monthly injection in depot form, and intranasal buserelin.94,95 Both significantly reduced premenstrual symptoms in the absence of ongoing depression.92,93 However, these medications are of limited use because of the risks associated with low estrogen levels that result from the suppression of ovulation, particularly osteoporosis, and these medications are viewed as appropriate primarily as a diagnostic tool or for patients who do not respond to other treatments. Results of investigations of add-back therapy using low-dose estrogen and progesterone in conjunction with a GnRHa are preliminary and do not yet definitively indicate that this is a safe and effective approach for long-term treatment.96,186,187 Limited data indicate that tibolone (a selective estrogen enzyme modulator) administered with a GnRHa in PMS treatment protects against the GnRHa bone loss and does not reduce the therapeutic effect of the agonist.188
Danazol, 100 to 400 mg/day, improved PMS symptoms,189,190,191 but unacceptable side effects including acne, hirsutism, weight gain, voice change, and vaginal dryness are serious limitations of this medication as a PMS treatment.
There are few randomized placebo-controlled studies of oral contraceptives (OCs) as a treatment for severe PMS or PMDD and, as yet, no consistent scientific evidence of their efficacy for the disorder.192,193 A recent trial of an oral contraceptive containing a new progestin, an analog of spironolactone with antimineralocorticoid and antiandrogenic activity, consistently reduced both the mood and physical symptoms of PMS.194,195 However, most symptom improvement did not significantly exceed the placebo improvement in the small sample, and additional studies with sufficient statistical power are in progress. A survey of 858 users of this same oral contraceptive (drospirenone [3 mg], ethinyl estradiol [EE; 60 μg]) indicated that premenstrual symptoms as assessed by the Moos Menstrual Distress Questionnaire (MDQ) significantly improved from baseline.196 There was also significant improvement in the general sense of well-being and in functioning of usual activities.
The results of current and future studies of new formulations or dosage adjustments of oral contraceptives may identify other effective treatments. A study of women who experienced symptoms each month during the placebo week of the standard oral contraceptive regimen (21/7 days) established that many women experience premenstrual or withdrawal symptoms during the hormone-free week of OC use and that continuous dosing with the OC alleviated these symptoms.197,198 In another study of an OC containing 20 μg EE and 100 μg levonorgestrel (LNG), one group used the pills in the standard regimen (21/7 days) and another group used only the active tablets for 168 days. The standard regimen group experienced the usual withdrawal symptoms, while the continuous group had less bloating and menstrual pain.199
From a clinical perspective, OCs are widely viewed as both improving and worsening PMS symptoms. Combination OCs have estrogenic and progestational effects that vary considerably among the more than 40 compounds available in the United States. Relative absorption of the hormones, peripheral conversion, the degree of follicular development in the placebo interval, individual susceptibility to monophasic or triphasic formulations, and side effects have large variations among women and are not well understood in relation to PMS. Moreover, OCs can have side effects of water retention, bloating, appetite changes, and depressed mood, which are also PMS symptoms. Some studies showed that OC users had fewer PMS symptoms than nonusers overall,200 but other investigations found few symptom differences between OC users and nonusers and no differences with respect to mood changes.201 In sum, there has been little empirical support or guidance for OCs as a treatment for PMS/PMDD, but current studies suggest that some new formulations and OC regimens may be effective.194,195,198
Estrogen and Progesterone
Estrogen therapy with dose regimens sufficient to maintain suppression of ovulation significantly decreased the dysphoric mood and physical symptoms of PMS.202,203,204 However, estrogen must be cycled with progesterone to reduce the risk of uterine cancer, and the extent to which exogenous progesterone results in return of PMS symptoms remains unclear. Progesterone treatment of PMS was advocated for many years, but numerous studies, including three large randomized controlled trials116,117,118 and a meta-analysis of 14 placebo-controlled trials,119 failed to show improvement significantly greater than placebo for the mood and behavioral symptoms of PMS.
Fluid retention is a common symptom of women with PMS, but there is no evidence that thiazide diuretics are of benefit for this disorder. Although women commonly report weight gain, objective measurements have found fluid redistribution to account for bloating and swelling, not weight gain.129,130 Spironolactone, an aldosterone antagonist with antiandrogenic properties, has shown a significant reduction in the somatic and affective symptoms of PMS in some but not all studies.205,206,207,208,209 The usual dose is 100 mg per day during the 14-day luteal phase.
Nonsteroidal Anti-inflammatory Drugs
Prostaglandin inhibitors are effective for dysmenorrhea and may be helpful for mild to moderate PMS symptoms.210,211,212 It is essential to clarify that dysmenorrhea is considered to be a distinct disorder and is not PMS. Many women with PMS also have dysmenorrhea, which may be relieved with the prostaglandin inhibitor. Mefenamic acid, 500 mg twice daily in placebo-controlled trials reduced headache, fatigue, pain, tension, irritability, and mood swings.211,212 There are no studies that compare this class of drugs with SSRIs or other medications shown to be effective for PMS or PMDD.
The placebo response is reliable, ubiquitous, and can be substantial and prolonged.213 Recent large, multi-enter, randomized, double-blind treatment trials reported placebo responses up to 48%.83,176,177
Although placebo effects are the bane of clinical trials, which must demonstrate that the studied treatment effect significantly exceeds the nonspecific effects in improvement of the treated condition, the nonspecific effects of medical treatment can also positively influence and enhance patient outcomes.214,215 In a study of characteristics of placebo responses in medical treatment of PMS, 20% of placebo-treated subjects showed sustained improvement for the 4-month duration of the investigation.216 Another 42% showed partial improvement with placebo treatment, while 39% were clearly unimproved in the 4 months of treatment. It appeared that some patients with severe PMS experienced significant and sustained improvement in response to the placebo, indicating the importance of nondrug factors in clinical care. Patients who sustained improvement for at least 2 consecutive months were more likely to remain improved. However, it is underscored that most PMS patients reported only partial or no improvement with placebo treatment and that effective pharmacologic treatment is also needed.
Long-Term Treatment of Premenstrual Syndrome
Nearly all published studies of treatment efficacy for PMS or PMDD are based on acute treatment of 2 to 3 months' duration. Anecdotal reports and several small pilot investigations suggest that PMS symptoms return within several months if medication is stopped.217,218,219,220 It also appears that untreated symptoms do not resolve spontaneously, as may occur in depression, but continue for many years, based on information from clinical trials, which report that the duration of the disorder before treatment is in the range of 8 to 10 years. These observations of chronic symptoms and the swift return of symptoms after stopping medication suggest that long-term maintenance treatment maybe appropriate for patients with clinically significant PMS, but as yet, no well-designed long-term maintenance studies have been reported.
Clinical Management of Premenstrual Syndrome
Management of patients who may have PMS begins with review of the patient's daily symptom report together with a physical examination and evaluation of the mood and behavioral symptoms to determine whether there are other physical or emotional problems that may account for the symptoms. As indicated in the ACOG guidelines (see Table 3), the women should meet standard diagnostic criteria and confirm the timing and menstrual relationship of their symptoms with prospective ratings. It is diagnostically useful to examine the patient in the postmenstrual phase of the cycle when the premenstrual symptoms have subsided. Symptoms or problems that are apparent after menses are not PMS and indicate underlying or concomitant problems that may account for the symptoms.
When a diagnosis of clinically significant PMS is confirmed by prospective ratings (preferably for at least two menstrual cycles), medication may be appropriate. The serotonergic antidepressants are the first-line treatment at present. Antidepressant dosages for PMS usually begin at the standard start level for depression. When an SSRI is initiated, some improvement is usually noted in the first cycle of treatment. In cases in which there is no significant improvement or dose-limiting side effects, the dose can be increased in the second or third cycle of treatment. As a general guideline, two to three menstrual cycles of treatment at adequate dose levels are sufficient to determine response. If the selected antidepressant is not helpful, another SSRI may be effective.
Most women who seek medical treatment for PMS can be helped with some form of treatment. If symptom relief does not occur with the initial treatment, another approach should be tried. Calcium supplementation has reported efficacy for PMS.142 Dietary alterations, exercise, or stress reduction programs are often helpful, particularly for women with less severe symptoms or in combination with medication. Based on evidence of efficacy, second-line treatments include anxiolytics, spironolactone, oral contraceptives, cognitive behavioral therapies, nutritional supplements, and bright light therapy. GnRHa is highly effective but has limited use for PMS because of the risks of a prolonged hypoestrogenic status. Further treatment recommendations based on levels of evidence are offered in the ACOG Practice Bulletin.3
Emerging from a long history with little understanding and many treatments of doubtful effect, clinically significant PMS is now recognized as a chronic disorder that impairs psychosocial functioning for a sizable number of women. Serotonergic antidepressants are the first-line treatment at this time. Using these medications only in the symptomatic luteal phase is effective for women with a diagnosis of clinically significant PMS or PMDD without other comorbid disorders. Although reproductive hormones may be involved in the disorder, hormonal treatments lack consistent scientific data on efficacy and safety for their use in PMS treatment. Further studies of hormonal treatments, particularly new formulations and altered dosing regimens of oral contraceptives, may provide future treatment options.
Beyond the efficacy of treatments that are demonstrated in short-term clinical trials, the cost-benefit issues of long-term maintenance of medication remain unanswered. While clinical experience dictates the use of augmentation strategies for patients who experience no response or a partial response to medications, there are no systematic studies that provide guidance for such approaches. There are also no studies of treatment strategies for premenstrual exacerbation of other disorders, a condition that may be more common that pure PMS. Finally, 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 the disorder.
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