Premenstrual Disorders: A Primary Care Primer

Premenstrual disorders affect many women in the United States. These disorders range in severity from the mild, bothersome symptoms that occur in more than 75% of women with regular menstrual cycles, to premenstrual syndrome (PMS) and, finally, to the most severe and disabling, premenstrual dysphoric disorder (PMDD). Nearly 5 million American women have PMDD.

The disability associated with premenstrual disorders is substantial. Women with PMS have significantly higher absenteeism from work and more ambulatory health care visits.¹ In addition, women with premenstrual disorders have an average increase of $59 in direct annual health care costs and $4333 in indirect costs.²

Many women are reluctant to seek medical attention for premenstrual disorders, and many do not believe that treatment will help them. A survey of 455 US women found that 83% had premenstrual bloating, 79% had fatigue, and 77% had appetite changes, but only 45% of the women with severe symptoms had sought care.³

Some health care providers fail to recognize the symptoms of PMS and PMDD. In a Canadian study, 322 physicians were asked to diagnose PMS in a patient scenario with typical symptoms. Although 73% correctly diagnosed PMS, fewer than 1% would have required a 2-month prospective diary.⁴ Women with PMS reported that they had seen on average 4 physicians over a period of more than 5 years before the syndrome was correctly diagnosed.5 Up to 89% of women with PMDD do not receive a diagnosis.⁶

In this article, we review the diagnostic criteria for premenstrual disorders, and we discuss effective treatment approaches.

PATHOGENESIS

The etiology of premenstrual disorders is multifactorial; it is a complex interaction that involves genetic predisposition, the CNS, gonadal hormones, and other modulators.

Some women clearly have a genetic predisposition to the development of premenstrual symptoms. These women probably have an amplified sensitivity to cyclical changes in steroid hormones or a varied response to neurotransmitters. Although no single gene is responsible for premenstrual symptoms, twin studies have demonstrated that premenstrual symptoms such as depression and anxiety are heritable.⁷ In addition, a genetic predisposition to PMS is also associated with a predisposition to other psychiatric disorders.⁸

Many studies on the causes of PMS and PMDD have focused on reproductive hormones. Research has not shown that estrogen levels, follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels, or lack of progesterone are associated with premenstrual disorders.

Conclusive research on the role of reproductive hormones is complicated by constantly fluctuating serum levels. However, studies that have included many blood samples during the course of the day have been able to detect some differences between women with PMS and women without the syndrome. Facchinetti and colleagues⁹ found that women with PMS had increased pulse frequency of progesterone in the luteal phase compared with controls. Also, the amplitude of the progesterone pulses was significantly lower in the PMS group. An analysis of LH pulsatility demonstrated the same finding.

Although levels of the gonadal steroids are the same in patients with and without PMS, the patients’ responses to fluctuating levels of hormones are different. A study in which women were given gonadotropin-releasing hormone (GnRH) to induce “temporary menopause” demonstrated this finding. The women with PMS had decreased symptoms after administration of GnRH, but the symptoms returned when the estrogen and progesterone were replaced. Women without PMS had no change in symptoms when the same protocol was followed.¹⁰

Another area of research in the etiology of premenstrual disorders has centered on neurotransmitters, including γ-aminobutyric acid (GABA) and serotonin. Studies have demonstrated that a progesterone metabolite, allopregnanolone, affects the GABA receptor and probably plays a role in PMS symptoms. When allopregnanolone binds to the GABA_A receptor, it acts similarly to benzodiazepines and barbiturates by changing the frequency and duration of the chloride channel. There is evidence that luteal-phase allopregnanolone levels are significantly lower in women with PMS compared with controls.^11,12 Lower levels of this progesterone metabolite may affect the inhibitory action of GABA, leading to PMS symptoms.

Serotonin has also been implicated in the development of premenstrual symptoms. Rapkin and colleagues¹³ found that women with PMS have significantly lower serotonin levels during the mid and late luteal phases. A more recent study of 15 patients also found potential differences in serotonin and metabolite (5-hydroxyindoleacetic acid, or 5- HIAA) levels between controls and patients with PMS or PMDD.¹⁴

Another area of research focus has been the renin-angiotensinaldosterone system (RAAS). Many premenstrual symptoms, including bloating, breast swelling, and weight gain, are caused by fluid retention. Estrogen increases angiotensinogen production, which in turn leads to increased aldosterone levels and increased fluid retention. Under normal circumstances, progesterone competes with aldosterone and prevents fluid retention; however, in the late luteal phase, there is a decline in progesterone levels, which leads to an increase in the effect of estrogen.

DIAGNOSTIC CRITERIA

Symptoms. More than 100 physical and behavioral symptoms have been described in premenstrual disorders, including fatigue, irritability, “bloating,” breast tenderness, and mood lability. The symptoms are confined to the luteal phase of the menstrual cycle and resolve after the onset of menses.

The most important consideration in diagnosing premenstrual disorders concerns the timing of the symptoms. In order to accurately determine the severity and timing of the symptoms, prospective recording of symptoms for at least 2 consecutive months is required. Because symptom severity may vary significantly from month to month, patients may need to record their symptoms for more than 2 months.

Specific criteria. Specific criteria have been developed for the diagnosis of both PMS and PMDD. The PMS criteria were established by the American College of Obstetricians and Gynecologists (ACOG) in 2000.¹⁵ For a diagnosis of PMS, patients must have at least 1 somatic or affective symptom (these symptoms are listed in Table 1). The symptom must start within 5 days preceding menses, resolve by day 4 of menses, and be absent until at least day 12 of the next menstrual cycle. The symptoms must cause socioeconomic dysfunction, and they must not be attributable to another cause.

PMDD is diagnosed using the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) criteria.¹⁶ As with PMS, the diagnosis of PMDD relies on prospective charting for at least 2 consecutive menstrual cycles. The symptoms of PMDD must interfere with work, school, or other usual activities. Patients must have at least 5 symptoms, and 1 of these must be a core symptom:

• Feelings of sadness or hopelessness, or self-deprecating thoughts.
• Feeling tense, anxious, or “on edge.”
• Marked mood lability.
• Persistent irritability, anger, and increased interpersonal conflicts.

The other symptoms include the following:

• Fatigue.
• Change in sleep or eating patterns.
• Difficulty with concentration.
• Decreased interest in usual activities.
• Feeling overwhelmed or out of control.
• Other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sensation of bloating, and weight gain.

CLINICAL EVALUATION

During the initial visit, conduct a detailed history taking and physical examination to exclude other possible causes of the patient’s symptoms. Focus on the medical, psychosocial, psychosexual, and substance abuse history. The gynecological history should include the timing of the symptoms and the regularity of the menstrual cycle. Perform breast, pelvic, and thyroid examinations.

The differential diagnosis for premenstrual disorders is broad and includes breast disease, thyroid disease, anemia, other mood or anxiety disorders, and gynecological disorders, such as polycystic ovary syndrome or endometriosis. Suspicion of other underlying conditions directs any laboratory testing (eg, a chemistry profile, a complete blood cell count, or measurement of thyroidstimulating hormone level).

Patients who have mood symptoms associated with significant functional impairment or suicidal ideation should undergo a thorough psychiatric evaluation, preferably by a mental health professional. Ideally, mental examinations should be conducted during both the luteal and follicular phases. If the patient has symptoms during the follicular phase of the cycle as well as the luteal phase, referral to a psychiatrist may be indicated.

Because many medical disorders are exacerbated during the luteal phase, the timing of the symptoms is crucial to the diagnosis. The symptom diary, which allows you to determine the severity and the timing of the symptoms, is the cornerstone of a PMS or PMDD diagnosis. If the history and physical findings suggest a premenstrual disorder, give the patient a prospective record to complete before the follow-up appointment.

A number of symptom inventories are available. The Daily Record of Severity of Problems (DRSP) was designed to diagnose PMDD; it includes the 11 symptoms from the PMDD criteria, and it has shown high test-retest reliability.¹⁷ Other prospective diaries to track premenstrual symptoms include the Calendar of Premenstrual Experiences (COPE), the Penn Daily Symptom Report (DSR), and the Premenstrual Symptoms Screening Tool (PSST).^18,19 Although prospective charting is required for a diagnosis of PMS or PMDD, no specific symptom inventory is required.

Schedule a follow-up visit for 2 months after the initial encounter. At that time, the prospective symptom record can be reviewed. The record can help you determine whether the patient’s symptoms reflect a premenstrual disorder or whether they result from an exacerbation of another underlying condition. Because of symptom variability, charting over a course of 3 or more months may be necessary in some patients.

The use of the daily symptom records may be bothersome for both patients and clinicians. However, the records often serve to heighten patients’ awareness of their symptoms and increase their involvement in the diagnosis and management. If the patient is reluctant to record her symptoms, either her partner or a member of her family may assist in the data collection.

TREATMENT

The treatment of premenstrual disorders can be challenging. Patients have a wide variety of symptoms, and a number of pharmacological and nonpharmacological therapies have been studied. Nonpharmacological approaches, which are listed in Table 2, range from exercise and dietary modification to cognitive-behavioral therapy (CBT). Pharmacological interventions focus on many of the causative hormonal and neurotransmitter systems, including serotonin and the RAAS.

Nonpharmacological therapy. Many physicians recommend nonpharmacological therapies as a primary method of treating premenstrual symptoms. These therapies can be recommended at the initial visit, and patients can follow them while they complete their symptom charting.

Lifestyle changes. An increase in aerobic exercise is a reasonable goal for patients with premenstrual symptoms. The 2005 Dietary Guidelines for Americans recommend 30 minutes of physical activity on most days of the week.²⁰ Although there is not extensive research on exercise in women with premenstrual disorders, some reports have indicated that aerobic exercise may ameliorate some premenstrual symptoms, including fluid retention and mood.²¹

Dietary changes may also play a role in the management of premenstrual disorders. Studies have focused on the role of caffeine, sugar, fat, soy, and complex carbohydrates in the diet. Results from this research have not conclusively determined that modification of these specific dietary components ameliorates premenstrual symptoms.

Dietary and herbal supplements. Some data suggest that calcium supplementation may be beneficial in the management of premenstrual symptoms. A study of 497 women with moderate to severe premenstrual symptoms who were randomized to placebo or calcium supplementation found that calcium was associated with a significantly lower mean symptoms complex score.²²

Another potentially beneficial dietary supplement is pyridoxine, or vitamin B₆. A review of 9 trials of pyridoxine for premenstrual disorders concluded that vitamin B6 may be beneficial.²³ Dosages of B₆ should be lower than 100 mg/d because excessive amounts may lead to pyridoxine overdose neuropathy. Finally, some studies have indicated that chasteberry, Vitex agnus-castus, may be useful for treating PMS.^24,25

CBT. This is an effective treatment for premenstrual disorders. A small study that compared CBT and nonspecific treatment found CBT was associated with a significant reduction in premenstrual symptoms. ²⁶ Another trial that compared CBT with fluoxetine or combination therapy (CBT and fluoxetine) in women with PMDD found that the combination of the 2 treatments did not yield improved results. The patients treated with fluoxetine had more rapid improvement, but at 1-year follow-up those in the CBT group had better maintenance of their progress.²⁷

Pharmacological treatment. Drugs that have been approved by the FDA for the treatment of premenstrual disorders include selective serotonin reuptake inhibitors (SSRIs) and a novel oral contraceptive. In addition, several other medications have been used off-label with varying degrees of success in women with premenstrual disorders.

SSRIs. The SSRIs that have received FDA approval for treatment of PMDD are fluoxetine, sertraline, and paroxetine, controlled-release (CR). These medications have been studied extensively for the treatment of premenstrual symptoms; they may be dosed continuously or intermittently. Luteal-phase dosing generally should be started about 14 days before menses and continued until the onset of menstruation.

Fluoxetine was the first serotonergic agent to demonstrate effectiveness. An early study by Steiner and colleagues²⁸ included 313 women with premenstrual dysphoria. The patients were randomized to receive fluoxetine, either 20 or 60 mg/d, or placebo. The 20-mg dose was found to significantly reduce symptoms without many of the adverse effects associated with the 60-mg dose. Additional studies that employed the DRSP showed that fluoxetine, 20 mg, ameliorated symptoms with either continuous or intermittent dosing.29 The starting dosage of fluoxetine is 20 mg/d.

The other 2 SSRIs approved for treatment of PMDD, sertraline and paroxetine CR, have also been studied for both continuous and intermittent administration. The starting dosage of sertraline is 50 mg/d; it may be increased to either 150 mg/d for continuous dosing or 100 mg/d for luteal-phase dosing. Paroxetine CR is started at 12.5 mg/d; and the dosage may be increased to 25 mg/d using either dosing schedule.

The serotonergic antidepressants are effective for many women with PMDD. However, these medications are associated with adverse effects; the most common are anxiety, insomnia, nausea, and sexual dysfunction. Moreover, many women are reluctant to take an antidepressant. A survey of 170 women for whom an antidepressant had been prescribed for premenstrual symptoms revealed that 22 never started treatment and more than 60% of the women who did start treatment had discontinued the medication within 2 years.³⁰

Oral contraceptives. Although oral contraceptive pills (OCPs) have routinely been used to treat premenstrual symptoms, most trials have not demonstrated any efficacy. In fact, studies have found that women who are take OCPs may have worsening of their mood.³¹ Adverse effects associated with OCPs—including headache, weight changes, and nausea— are also symptoms of premenstrual disorders.

Many of the available OCPs contain ethinyl estradiol and a synthetic progestin. Because these synthetic progestins do not have an antimineralocorticoid effect, the estrogen effects on the RAAS predominate and cause PMS symptoms such as bloating and breast tenderness. A study by Sulak and colleagues³² also found that many symptoms occur during the hormone-free days of the OCP regimen.

One oral contraceptive has been approved by the FDA for the treatment of PMDD in women who desire contraception. Although this medication contains ethinyl estradiol, it also contains a novel progestin, drospirenone. Drospirenone is derived from 17α-spirolactone and has antimineralocorticoid properties similar to those of spironolactone. The combination of drospirenone 3 mg/ethinyl estradiol 20 μg is administered for 24 days followed by a 4-day hormonefree interval.

Two large trials studied this medication in patients with PMDD. A crossover trial by Pearlstein and colleagues³³ included 64 women with PMDD. Patients were randomized to either placebo or the oral contraceptive for 3 cycles and then switched to the other treatment after a 1-cycle washout period. Outcomes were based on total DRSP scores as well as scores on the Clinical Global Impressions– Improvement (CGI-I) scale. Based on the clinician ratings, nearly 62% of patients who received the oral contraceptive had a positive response compared with 31.8% of the placebo group.

The other study of this drospirenone- containing OCP included 450 women with PMDD who were randomized to the oral contraceptive or placebo. Based on a 50% improvement in DRSP scores as a marker of response, 48% of the women in the OCP group responded compared with 36% of the placebo group. The drospirenone 3 mg/ethinyl estradiol 20-μg formulation significantly improved DRSP scores for mood symptoms, physical symptoms, and behavioral symptoms.³⁴

Other medications. Spironolactone is used off-label to treat patients with PMS. This aldosterone receptor antagonist is the only diuretic that is effective in these patients. O’Brien and colleagues³⁵ showed that intermittent dosing of spironolactone reduced premenstrual symptoms in more than 80% of cycles. A more recent crossover study that compared luteal-phase use of spironolactone with placebo in 35 women with PMS demonstrated improved mood and reduced breast tenderness, swelling, and food cravings in the treatment group.³⁶

Other agents such as the benzodiazepine alprazolam and GnRH agonists have also been shown to be effective in the treatment of premenstrual disorders. Alprazolam should be administered only during the luteal phase in doses of 0.5 to 1 mg up to 3 times daily. Because the benzodiazepines are associated with adverse effects such as sedation and the possibility of dependence, alprazolam should be reserved for patients in whom other treatments have failed.

Similarly, the GnRH agonists should be used only in patients with severe symptoms. These medications cause a “temporary menopause,” and their long-term use may have negative cardiovascular and skeletal effects.