WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Premenstrual physical and mood symptoms are common among reproductive-age women, but diagnostic criteria and treatment strategies to recognize premenstrual disorders are not always clearly understood. The definition of premenstrual syndrome (PMS) has been elusive because this condition is characterized by a wide variety of symptoms, most of which are immeasurable by objective standards. Any combinations of emotional or physical signs or symptoms that occur cyclically prior to menstruation and then regress or disappear during or after menstruation. Prospective documentation of symptoms is also necessary to differentiate the more common premenstrual syndrome (PMS), the cyclical luteal phase occurrence of symptoms severe enough to interfere with some aspects of life, from the less common premenstrual dysphoric disorder (PMDD), in which cyclical luteal phase occurrence of symptoms markedly interferes with work or social activities and relationships with others. Description of PMS can be traced at least as far back as the writings of Hippocrates. Modern investigation of PMS began in 1931 when the entity of "premenstrual tension'' was described.
The purpose of this document to examine the evidence for commonly used approaches in the treatment of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). Until recently, the difficulty in managing PMS / PMDD was largely attributed to imprecise diagnostic criteria, poorly designed clinical trials, and promotion of treatment options for which there was no scientific support. In the mid-1980s, however, rigorous criteria for the diagnosis of PMS / PMDD were defined. Since then, most studies of pathophysiology and treatment have met recognized standards of scientific design. Selective serotonin reuptake inhibitors (SSRIs) are found to be effective in treating PMS / PMDD symptoms and many other treatment options are discussed. Premenstrual syndrome (PMS) has been defined as "the cyclic occurrence of symptoms that are of sufficient severity to interfere with some aspects of life and that appear with consistent and predictable relationship to the menses". Although the symptoms themselves are not unique, the restriction of the symptoms to luteal phase of the menstrual cycle is pathognomonic of PMS. The American College of Obstetricians and Gynecologists (ACOG) criteria state that PMS can be diagnosed if the woman reports at least 1 of 6 affective symptoms (depression, angry outburst, irritability, anxiety, confusion, social withdrawal) or at least 1 of 4 somatic symptoms (breast tenderness, abdominal bloating, headache, swelling of extremities) (1):
Premenstrual syndrome (PMS) has been defined as "the cyclic occurrence of symptoms that are of sufficient severity to interfere with some aspects of life and that appear with consistent and predictable relationship to the menses". Although the symptoms themselves are not unique, the restriction of the symptoms to luteal phase of the menstrual cycle is pathognomonic of PMS. The American College of Obstetricians and Gynecologists (ACOG) criteria state that PMS can be diagnosed if the woman reports at least 1 of 6 affective symptoms (depression, angry outburst, irritability, anxiety, confusion, social withdrawal) or at least 1 of 4 somatic symptoms (breast tenderness, abdominal bloating, headache, swelling of extremities) (1):
Premenstrual dysphoric disorder (PMDD) as defined by the American Psychiatric Association (APA) in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR), require that, during the last week of the luteal phase in most menstrual cycles during the past year, a woman experienced at least 5 of the following symptoms, including at least 1 core symptom (5):
Symptoms must begin to remit within a few days after the onset of the follicular phase, be absent in the post-menses period, markedly interfere with work, school, or usual social activities, and be confirmed by prospective daily ratings of at least 2 consecutive cycles.
It is estimated that 20 to 40% of reproductive-age women experience premenstrual symptoms that meet ACOG criteria of PMS. In addition, about 3% to 9% of reproductive-age women meet the diagnostic criteria for PMDD (1). Premenstrual emotional changes and physical changes occur in up to 80% of women of reproductive age. Estimates regarding the incidence of PMS generally agree that 20-40% of these women experience some difficulty as a result of these changes during the premenstrual interval, and 2.5-5% report a significant impact on work, lifestyle, or relationships. Premenstrual symptoms are common and are considered a normal aspect of ovulatory cycles. Most surveys have found that as many as 85% of menstruating women report one or more premenstrual symptoms. Moderate to severe premenstrual syndrome, which may include clinically relevant physical, behavioral, and emotional symptoms, affect almost 18% of women of reproductive age. Severe symptoms that meet criteria for PMS, however, are much less common, with only 5-10% of women reporting significant impairment in their lifestyles because of PMDD.
A single cause for PMS / PMDD has not been identified. Multiple factors have been proposed, but 50 years of investigation have failed to provide a uniform hypothesis for the pathophysiology of PMS / PMDD. Since the symptoms occur prior to menses and resolve following menstrual bleeding, PMS / PMDD has been blamed on alterations in luteal estrogen or progesterone levels. No convincing association has been demonstrated between androgens and prolactin levels. Since PMS / PMDD is often associated with complaints of bloating and fluid retention, mineralocorticoid changes have been suspected as a potential cause (2). Other theories are, hypoglycemia, endorphin hypothesis, prostaglandin hypothesis and vitamin and mineral deficiencies.
Risk Factors: Advancing age often is cited as a risk factor for PMS / PMDD, based on surveys that find women are most likely to seek treatment after age 30 years. However, this syndrome can occur in menstruating women of any age. Genetics appears to play a role in PMS / PMDD; the concordance rate of PMS / PMDD is twice as high among monozygotic twins as among dizygotic twins. Although women with PMS have a high rate of affective disorders, a causal relationship has not yet been demonstrated. There are no significant personality profile differences between women with PMS and asymptomatic women. Furthermore, PMS is not more likely to be diagnosed in women with higher levels of stress. However, women who have PMS may not tolerate stress as well as women who do not have PMS. Premenstrual symptoms seem to affect women irrespective of culture of socioeconomic status, although specific symptoms may vary in frequency by culture.
Psychologic Hypothesis: Because many of the significant changes of PMS / PMDD strongly suggest an affective disorder, an underlying psychological abnormality has been sought as the primary problem in PMS / PMDD. Approximately 60% of women with a major affective disorder have been diagnosed as having a premenstrual affective syndrome. At least 30% of women with primary recurrent depression experience their first depressive episode during a time of significant hormonal change. In a psychological review of women with PMDD, between 57% and 100% of women were found to have a prior major depressive episode at least once in their lives in contrast to only 0% to 20% of women without PMDD (3).
Symptoms Associated with PMS:
Since the original description of PMS by Frank (1931), approximately 150 symptoms have been included in the list of possible premenstrual syndrome. It is any combination of emotional and physical signs or symptoms that occur cyclically prior to menstruation and then regress or disappear during or after menstruation (4). The key elements of the diagnosis are: a) symptoms consistent with PMS; b) restriction of these symptoms to the luteal phase of the menstrual cycle assessed prospectively; c) impairment of some facet of the woman's life; and d) exclusion of other diagnoses that may explain the symptoms.
Affective Symptoms: sadness, anxiety, anger, irritability, labile mood
Making the diagnosis of PMS has been problematic, since its specific etiology is unknown and there is no objective marker which can quantitate the existence or the severity of symptomatology or even the objective response to therapy.
The National Institutes of Mental Health criteria for diagnosis are: 1) a marked change of about 30% in the intensity of symptoms measured instrumentally, from cycle days 5 to 10 (as compared with those premenstrually), within the 6-day interval prior to menses and 2) documentation of these changes for at least two consecutive cycles. Another definition of PMS developed for research purposes by the University of California at San Diego are based on women's prospective self-reports. Their definition requires that patients have the cyclic manifestation of at least 1 of 6 behavioral symptoms and 1 of 4 somatic symptoms. Dysfunction in social or economic performance is included in this definition. Finally, the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, includes similar criteria for the diagnosis of premenstrual dysphoric disorder, which identifies women with PMDD who have more severe emotional symptoms (5).
A practical approach to PMS / PMDD:
In the clinical setting, a simple system in which the woman records the dates of her menstrual periods and notes her symptoms on a daily basis is usually sufficient. However, a variety of standardized instruments and diaries developed for research purposes are also available. The most commonly used are the Calendar of Premenstrual Experiences (COPE) and Prospective Record of the Impact and Severity of Menstruation (PRISM). Another type of instrument, the Visual Analogue Scales (VAS), may be especially appropriate in non-English-reading populations (6). A careful medical and psychologic history and physical examination in conjunction with the prospective symptom diary usually will direct the clinician toward the correct diagnosis. Laboratory testing should be restricted to the identification of other disorders suggested by the evaluation, such as measuring levels of thyroid-stimulating hormone when hypothyroidism is suspected. Routine measurement of steroid hormones or gonadotropins is not useful.
The phenomenon of menstrual magnification (sometimes called premenstrual or perimenstrual exacerbation) helps to explain this situation. Many medical and psychiatric conditions are exacerbated in the late luteal or menstrual phase of the cycle, leading a woman to believe that she must be experiencing PMS. The underlying mechanism of this increase in symptoms is not understood (7). The differential diagnosis of PMS therefore includes any medical and psychiatric condition that either has some of the many symptoms associated with PMS or is subject to menstrual magnification. Depressive disorders, which share a similar set of symptoms, are the most common consideration. Depressive disorders are also subject to the magnification effect, making the distinction from PMS / PMDD even more difficult. A key feature of depressive disorders, however, is that symptoms are almost always present every day of the cycle. Other psychiatric conditions that may be magnified are panic disorder and generalized anxiety disorder.
The most common medical disorders subject to menstrual magnification are migraines, seizure disorders, irritable bowel syndrome, asthma, chronic fatigue syndrome, and allergies. Endocrine abnormalities such as thyroid and adrenal disorders also should be considered. The diagnosis of these conditions usually is straight-forward because key symptoms are not part of the typical PMS / PMDD symptom set, and emotional symptoms are not prominent, as they are in PMS / PMDD. Finally, women in period of transition to menopause may have symptoms typical of PMS / PMDD, especially mood disturbance, fatigue, and hot flashes. Because menstrual periods often are less predictable, these women may be less aware of the relationship of the symptoms to the menstrual cycle. The correct diagnosis usually can be made by considering the patient's age, a history of recent menstrual cycle changes, and a symptom diary showing sporadic or daily occurrence of symptoms.
The cornerstone of treatment for PMS / PMDD remains a careful evaluation of symptoms and their chronicity. Since the placebo-response rate in women with PMS is high in virtually all studies, conservative supportive therapy may be effective in many patients. Premenstrual disorders, by definition, are associated with symptoms that interfere with some part of the patient's normal life, but there are usually no medical sequelae if the disorder is not treated. Therefore, the decision to treat the disorder should be based on the patient's desire for an improvement in her symptoms. Furthermore, because there is a wide range of symptom severity, the treatment approach should match the patient's need. A wide variety of supportive, lifestyle, and dietary supplemental approaches to PMS / PMDD have been recommended over the years, and a few of these have been demonstrated to have real benefit (8). Therefore, these strategies can be recommended to women with mild to moderate symptoms as a primary therapy and to women with severe symptoms as adjunctive therapy.
Exercise: Clinical studies of exercise demonstrate reduction in anger and depression in women who exercise. It has a profound effect on the hormones like cortisone, testosterone, prolactin, estrogens, and growth hormones. Aerobic exercise has been found in epidemiologic studies to be associated with fewer reported PMS / PMDD symptoms, and exercise has been found to reduce symptoms among people with depressive disorders.
Nutrition and Dietary Supplementation: It is unclear whether dietary changes offer a medicinal effect or placebo effect. Some studies show tea consumption and high carbohydrate diet during premenstrual phase is helpful. Some recommend vitamins as part of the treatment, especially vitamin B6. Doses in excess of 100 mg/d may cause medical harm, including peripheral neuropathy. One large multicenter well-designed trial of 466 women with PMS reported that 1,200 mg/d of calcium carbonate was efficacious in reducing total symptom scores. Two small trials have found that 200-400 mg of magnesium may be somewhat effective (9).
Minimal data is available on the effectiveness of vitamin E and the treatment of premenstrual syndrome. Vitamin E has been recommended as a treatment for mastalgia. Although effectiveness probably is minimal, no serious side effects are reported with vitamin E 400 IU/d, and as an antioxidant it has other beneficial effects. Well-designed scientific studies have not demonstrated that primrose oil is effective in the treatment of PMS. However, it may be useful in treating breast tenderness.
Pharmacology Therapy: The pharmacological approach to PMS / PMDD remains both empiric and controversial. The following medications have been tried: GnRH-agonist (Lupron), Danazol, oral contraceptives, and progestins. When the psychological symptoms predominate, specific anxiolytics or antidepressants are indicated. Recent anecdotal success with fluoxetine (Prozac) is encouraging. Other medications used are lithium, alprazolam (Xanax) sertraline (Zoloft), and buspirone (Buspar). Because of fluid retention are common in the luteal phase, diuretic therapy has been advocated. No evidence exists that thiazide diuretics are of benefit. Spironolactone, an aldosterone antagonist with antiandrogenic properties, is the only diuretic that has been shown to be of benefit in PMS. Usual dosage in most studies is 100 mg/d in the morning during the 14-day luteal phase. However, not all reports evaluating spironolactone for PMS have shown benefit. Historically, natural progesterone has been one of the most commonly employed therapies in women with PMS, but careful scientific scrutiny has not supported an overall benefit of this hormone when compared with placebo, whether administered as a vaginal suppository or as oral micronized progesterone. Progesterone may be helpful for specific psychologic symptoms, such as worrying.
Selective Serotonin Reuptake Inhibitors (SSRIs): The SSRIs are the initial drugs of choice for severe PMS / PMDD. Fluoxetine, sertraline, and paroxetine are the most common SSRIs studies for PMS / PMDD (10). Fluoxetine (Prozac) is the most studied drug of this group and dosages of 20-60 mg/d are recommended to relieve the symptoms. Another SSRI drug that has a beneficial effect is sertraline (Zoloft) and it is usually given in doses ranged between 50 to 150 mg/d. Intermittent therapy with an SSRI is given only during the symptomatic phase is also efficacious. The drug is started between 7 and 14 days before the next menstrual period, with the start day individualized to begin the medication at or just before the expected onset of symptoms. Side effects associated with fluoxetine include headaches, nausea, and jitteriness. Insomnia often can be avoided by early morning dosing or if appropriate by lowering the dosage. Decreased libido also is problematic in some patients. In cases in which improvement of libido is not seen after dosage changes, alternative therapies may be considered.
Selective serotonin reuptake inhibitors (SSRIs) are found to be effective in treating premenstrual symptoms, with continuous dosing regimen (11). The clinical implications of this report are threefold: 1) SSRIs (specifically, citalopram, fluoxetine, paroxetine, and sertraline) are effective for treatment of PMS / PMDD, 2) Continuous dosing regimens may be more effective than intermittent dosing regimens, and 3) The effect size observed, although significant, is smaller than previously reported. Future research should focus on the relative effect size observed with different SSRIs (perhaps with head-to-head trials), a better understanding of duration of treatment required, the relative effects on behavioral compared with psychological compared with physical symptoms, and a comprehensive look at adverse effects.
Oral Contraceptives: Although oral contraceptives are widely prescribed for the treatment of PMS, few data support their effectiveness. The evidence suggests that oral contraceptives should be considered if symptoms are physical, but may not be effective if mood symptoms are more prevalent. In one randomized trial, a triphasic formulation reduced physical symptoms but not mood alterations. In another study comparing triphasic and monophasic regimens, the monophasic formulation was less likely to cause mood alterations. Many patients experience breast tenderness, nausea, mood alterations, and other side effects the first few months of oral contraceptive use. The evidence suggests that oral contraceptives should be considered if symptoms are primarily physical, but may not be effective if mood symptoms are more prevalent. Drospirenone/20EE-24/4 [YAZ®] has been shown to be effective in treating mood, physical and behavioral symptoms of PMS / PMDD. The U.S. Food and Drug Administration (FDA) has approved 1 low-dose combination oral contraceptive that contains the progestin drospirenone and is administered using a regimen of 24 days of active pills in a 28-day cycle (12).
Gonadotropin-Releasing Hormone Agonists (GnRH): The hypoestrogenic side effects and cost of GnRH agonists limit the usefulness of this method except in severe cases of PMS / PMDD unresponsive to other treatment. If this therapy is to be used for more than a few months, bone loss becomes a concern. Add-back therapy also may result in the return of the symptoms. In a double-blind, placebo-controlled study of 10 women, with both estrogen add-back therapy alone and progesterone therapy alone were associated with a significant recurrence of symptoms. Another small rigorous study evaluated 8 women with severe PMS / PMDD. Administration of the GnRH agonist resulted in an improvement of approximately 75% in luteal phase symptom scores. The addition of estrogen as well as progesterone was associated with worsening of symptoms, but a similar worsening also was seen with placebo. In hormone therapy results in a return of symptoms, alendronate should be considered for osteoporosis prevention.
Surgical Therapy: In severe cases of PMS / PMDD, surgical oophorectomy or hysterectomy with removal of ovaries has been used successfully in women who no longer desire preservation of fertility. Surgery for PMS / PMDD is controversial because it is irreversible, it is associated with morbidity and mortality, and resulting hypoestrogenemia must be addressed to prevent long-term complications. If employed, this approach should be reserved for those severely affected patients who meet strict diagnostic criteria and who do not respond to any potentially effective therapy other than GnRH agonists. These limitations are critical, because a major cause of therapeutic failure with any of the described treatments is an incorrect diagnosis of PMS. It is advisable to perform a diagnostic trial with an agonist for a minimum of 3 months to determine if oophorectomy will be effective. An additional advantage to an extended trial with an agonist is the opportunity to assess the woman's tolerance for estrogen replacement therapy.
The following recommendations are based primarily on consensus and expert opinion:
Women in whom PMS / PMDD has been diagnosed should meet standard diagnostic criteria and should have the timing of their symptoms confirmed using a prospective symptom calendar. Risk factors such as increased imposed stress and specific personality profiles are not helpful in differentiating women with PMS / PMDD from those without PMS / PMDD. The SSRIs, particularly fluoxetine and sertraline, have been shown to be effective in treating PMS / PMDD. The bulk of scientific evidence does not support the usefulness of natural progesterone or primrose oil in the treatment of PMS. The use of GnRH agonists and surgical oophorectomy has been shown to be effective in PMS / PMDD. However, the side effects of GnRH agonists and oophorectomy limit their usefulness in most patients. Treatment with the anxiolytic alprazolam is effective in some patients. Its side effects limit its use as a first-line approach. Carbohydrate-rich foods and beverages may improve mood symptoms and food cravings in women with PMS and are a reasonable first-line approach in many patients. Calcium supplements have been shown to be effective in the treatment of PMS. Magnesium, vitamin B6, and vitamin E may have minimal effectiveness in the treatment of PMS. Oral contraceptives may improve physical symptoms of PMS / PMDD. The U. S. Food and Drug Administration (FDA) has approved 4 agents for the treatment of PMDD: 3 antidepressants (i.e., selective serotonin reuptake inhibitors [SSRIs]) and 1 low-dose combination oral contraceptive that contains the progestin drospirenone and is administered using a regimen of 24 days of active pills in a 28-day cycle (drospirenone/20EE-24/4 [YAZ®]). Drospirenone is unique among progestins used in combination oral contraceptives in that it has both anti-mineralocorticoid and anti-androgenic activities.
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