Premenstrual syndrome (PMS) is a recurrent constellation of affective and physical symptoms that begin during the luteal phase of the menstrual cycle and resolve completely or almost completely during the follicular phase. The number, severity, and duration of symptoms occur along a spectrum. It is estimated that 20% to 40% of women report premenstrual symptoms during the luteal phase, but only 5% to 10% of women report symptoms severe enough to significantly interfere with their lifestyle. The long-term natural history of PMS is unclear.
The fourth edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV) has defined a related syndrome, premenstrual dysphoric disorder (PMDD), to facilitate an accurate psychiatric diagnosis [see Table 1].1 The criteria for PMDD are also used to define research populations so that therapeutic responses can be quantitated and generalized. PMDD is often considered a variant of depression, an impression buttressed by the treatment efficacy of antidepres-sants, particularly selective serotonin reuptake inhibitors (SSRIs), in women who meet the criteria for PMDD.2-4
Pathogenesis
Most evidence suggests that PMS/PMDD is caused by aberrant responses of target tissues, particularly the brain, to normal fluctuations in serum levels of ovarian gonadal steroids.5-7 The causes of the untoward central nervous system responses are not firmly established8 [see Table 2], but several pathogenic mechanisms are currently being explored. Altered metabolism of progesterone by the CNS may lead to altered CNS reactivity and neurotransmission. Specifically, one of the principal metabolites of progesterone, allopregnanolone, decreases anxiety. Women with PMS show lower levels of allopregnanolone during their luteal phase9; they may instead produce a predominance of anxiogenic progesterone metabolites.
|
Table 1 DSM-IV Criteria for Premenstrual |
|
|
Dysphoric Disorder |
|
|
Symptoms occur in the luteal phase, with prospective confirmation of a 30% increase in symptoms during the luteal phase above the level in the follicular phase |
|
|
Not an exacerbation of major depression, panic dysthymia, or personality disorder |
|
|
Marked disturbance in functioning |
|
|
At least five of the following |
|
|
Marked lability |
headache, joint or muscle |
|
Marked irritability |
pain, bloating, weight |
|
Marked anxiety |
gain) |
|
Markedly depressed mood |
Avoidance of social activities |
|
Decreased interest |
Decreased productivity |
|
Lethargy |
Increased sensitivity to |
|
Difficulty concentrating |
rejection |
|
Food craving |
Feeling overwhelmed |
|
Hypersomnia or insomnia |
Feeling out of control |
|
Physical symptoms (breast tenderness or swelling, |
Increased interpersonal conflict |
PMS/PMDD may involve alterations in CNS neurotrans-mission that cause heightened reactivity to normal excursions in gonadal steroid levels. This exaggerated reactivity may be inherited or acquired. An acquired cause of altered CNS neuro-transmission is chronic stress. Chronobiologic disturbances documented in women with PMDD have been interpreted as evidence of an underlying aberration in CNS function.10 High levels of estrogen or of estrogen and progesterone may elicit or aggravate this underlying brain dysfunction, which would explain why symptoms are greatest during the luteal phase or at ovulation. In women with PMS/PMDD, but not in women without it, the symptom complex can be replicated by exposure to, followed by withdrawal from, exogenous estrogen and progesterone.11 There is also an association between PMS and dysmenorrhea, further suggesting that PMS is an exaggerated tissue response to normal hormonal changes.
Diagnosis
To warrant medical attention, evaluation, and intervention, premenstrual symptoms must be recurrent and sufficiently severe to interfere with daily work and social activities. To establish the diagnosis of PMS/PMDD, the clinician must confirm that the patient has the characteristic manifestations of the disorder at the appropriate time in her menstrual cycle.
It is also important to identify any concurrent conditions likely to complicate treatment [see Table 3]. Many women with PMS/PMDD have a personal or family history of alcoholism. A history of sexual abuse, particularly in childhood or adolescence, may be common in women with severe PMS.12 This population also has an increased personal and family history of posttraumatic stress disorder, mood disorders, schizophrenia, eating disorders, postpartum depression or psychosis, personality disorders, and anxiety disorders. A positive family history does not necessarily imply an inherited biologic vulnerability, because persistent exposure to dysfunctional family interactions is a chronic stress that can alter underlying CNS function.
Conclusive diagnosis of PMS or PMDD requires the documentation of concordance between symptoms and the luteal or periovulatory phase. The diagnosis of PMS/PMDD cannot be made in an anovulatory patient. Ideally, symptoms and menstrual dates should be followed prospectively to establish synchrony between the luteal phase and increase in symptoms. Two or more cycles and at least five symptoms [see Table 1] should be charted before the diagnosis is made. However, with a patient who is suffering severe psychological distress, there may not be time for prospective evaluation. Immediate referral to a psychiatrist may be indicated to prevent suicide or homicide.
If the menstrual cycle is irregular (menstrual cycle is ordinarily between 26 and 30 days) and there is no clear pattern of symptoms, the progesterone level should be measured weekly throughout a cycle to determine whether there is a luteal phase. A progesterone concentration greater than 5 ng/ml, or 15 nmol/L, is generally considered evidence that a woman is in the luteal phase and ovulation is impending. No rise in progesterone indicates anovulation, which may be stress induced. These patients may require further evaluation [see 16:I Amenorrhea]. Symptoms should be charted concurrently with progesterone levels. To meet the criteria for PMS/PMDD, the patient’s symptoms should become at least 30% more severe during the luteal phase (or when the progesterone concentration is greater than 5 ng/ml) than they were in the follicular phase.
|
Table 2 Potential Causes of PMS/PMDD |
|
Aberrant responses of target tissues, especially the brain, to normal gonadal steroid exposures mediated by the following: |
|
Opioid withdrawal |
|
Serotonergic imbalance |
|
Entrainment to endogenous cycles |
|
Chronobiologic disturbance |
|
Membrane effects of steroids or steroid metabolites |
|
Genomic effects of steroids |
|
Variation in steroid metabolism |
Differential diagnosis
If a patient has regular menses and severe dysmenorrhea but no behavioral symptoms, she should be evaluated for possible endometriosis [see 16:X Endometriosis]. As with all psychiatric diagnoses, it is important to exclude organic causes. In PMS/PMDD, it is especially important to exclude thyroid dysfunction (hyperthyroidism or hypothyroidism) and drug abuse or dependence as contributing factors.
Premenstrual changes in hormone levels can exacerbate underlying medical conditions, including migraine, epilepsy, asthma, irritable bowel syndrome, and diabetes mellitus.13 This is not PMS but may resemble it.
If behavioral symptoms are severe and are present throughout the menstrual cycle and if there is no clear pattern of increase in symptom severity during the luteal phase, another psychiatric diagnosis must be considered. The following psychiatric disorders must be excluded: major depression, panic and anxiety disorders, dysthymia, and personality disorder. Such patients should be referred to a psychiatrist for definitive diagnosis and treatment. The most important condition to exclude is depression.
Treatment
Available therapies for PMS/PMDD range from lifestyle modification to surgery. Sustained improvement in a woman with PMS/PMDD generally requires a combination of modalities. The severity of a patient’s symptoms and her response to particular modalities should guide the choice of therapies and the pace of their introduction. Mild cases can be treated with lifestyle modification and nonpharmacologic options; severe cases deserve immediate and aggressive intervention.
Nonpharmacologic therapy
Lifestyle interventions for PMS include institution of good sleep patterns and regular exercise. The patient should reduce or eliminate the use of tobacco, alcohol, and other drugs.
Dietary treatment helps some patients. Calcium supplementation may be beneficial.14 It has been suggested that diets high in carbohydrates and protein buttress the serotonergic axis.15 A diet high in tryptophan, a precursor of serotonin, may also be of benefit for mild PMS.
Full-spectrum bright-light therapy given in the evening has been shown to markedly reduce symptoms of PMS/PMDD. Its use can be limited to the luteal phase.Stress management is integral to lifestyle treatment. Biofeed-back,19 massage,20 and other relaxation methods may be helpful. Education, emotional support, and attention from the physician or therapist are instrumental. However, almost any intervention can be temporarily helpful, as the placebo response is quite high in this disorder.
Some women may wish to treat their PMS with herbal remedies, such as oil of primrose, chaste tree berries, or St. John’s wort [see Clinical Essentials:Xll Complementary and Alternative Medicine]. The use of herbal medicine and other complementary and alternative measures for PMS/PMDD has not been strongly validated in randomized, controlled trials, however.21
Behavioral Therapy
Patients with PMS may benefit from cognitive-behavioral therapy or interpersonal therapy. These are formal, structured psychotherapies designed to help patients institute behavioral changes and address cognitive patterns that sustain maladap-tative behavior. Response to treatment may take as long as 6 months, but the effects persist indefinitely. If a patient is having difficulty coping with her symptoms during the early months of psychotherapy, there is no reason not to add pharmacologic treatment. The effects of medication are more rapid in onset than those of psychotherapy, but the effects persist only as long as the patient takes the medication. The model of combined psychotherapy and pharmacotherapy is considered the most effective approach to major depression; it has not been formally tested in PMS/PMDD, but there is no reason to believe it would not work well in this disorder, given the similarities between depression and PMS/PMDD.
Disposition
Benefit from nonpharmacologic interventions should be evident within two menstrual cycles. If the patient has shown no improvement at all during that time, the clinician should move on to pharmacotherapy. Complete recovery is not to be expected, however; that seldom or never occurs, regardless of the therapy chosen. Nevertheless, it is unwise for the clinician to lower the patient’s expectations about these modalities, because enthusiasm inspires patients to participate in therapy and enhances the placebo effect. To set the stage for follow-up without lowering expectations, the clinician can tell the patient,"I want to see how you are doing in 2 months. If you are feeling perfectly fine and don’t want to come back in, just give me a call. In case you aren’t perfectly fine, though, I would rather see you back."
|
Table 3 Pertinent History in PMS/PMDD |
|
|
Reproductive events |
Sleep |
|
Dysmenorrhea |
Drug, alcohol, and medication use |
|
Psychosocial adjustments and stressors |
|
|
Endocrine disorders |
|
|
Diet |
Family and personal history of psychiatric disorders |
|
Exercise |
|
It is reasonable to wait more than 2 months for a response in a patient who has initiated behavioral therapy in a formal psychiatric setting. On the other hand, with a patient who is in severe psychological distress, 2 months may be too long to wait. The worst-case scenario is that such a patient will interpret a prescription of lifestyle modification and a distant follow-up appointment as a dismissal by her physician and, in the meantime, commit suicide or a homicide or ruin her life in some way. Clinicians who have limited psychiatric expertise or who practice in a stringent managed-care setting that severely restricts follow-up should refer severely distressed patients to a psychiatrist.
Pharmacologic Therapies for Somatic Symptoms
Bromocriptine (2.5 mg/day orally) has been promoted as treatment for breast tenderness. Spironolactone (25 to 50 mg/day orally) has been given to alleviate bloating. Non-steroidal anti-inflammatory drugs can be effective treatment for dysmenorrhea [see 16:IV Dysmenorrhea].
Progesterone treatment has been shown to be ineffective for PMS.22 Oral contraceptives are likely to aggravate rather than attenuate PMS/PMDD symptoms.
Pharmacologic Therapies for Affective Symptoms
Because the pathogenesis of PMS/PMDD probably involves an aberrant CNS response to normal ovarian function, the first-line treatment is to buttress CNS function with antidepressants. The SSRIs fluoxetine and sertraline have been shown to be ef-fective2-4; other agents in this class presumably would work but are not as well studied. Although use of SSRIs can be limited to the luteal phase (10 to 14 days), that approach is impractical for many patients, who may have difficulty determining when to start the drug. It is simpler for patients simply to take the medication every day.
Sertraline has a shorter half-life than fluoxetine. The advantage of a shorter half-life is that if the patient experiences unacceptable side effects, the side effects will fade more rapidly once the medication is discontinued. The most prominent side effect of SSRIs in patients with PMS/PMDD—and a common reason for poor compliance with SSRI therapy for the disorder—is sexual dysfunction.23 Some patients are willing to accept impaired libido as a trade-off for the relief of their symptoms. Buspirone is mildly effective for PMS/PMDD and may be a useful alternative in patients who find the sexual side effects unacceptable.24 Classified as an atypical antidepressant, buspirone tends to be used for the anxious variety of depression.
Benzodiazepine therapy with alprazolam, taken during the luteal phase, is appropriate for patients whose main symptom is anxiety.25 However, alprazolam has many more side effects than do SSRIs, even though the dose can be titrated to minimize side effects.
Pharmacologic Interventions That Alter Ovarian Steroid
Exposure
Patients with PMS/PMDD who fail to respond adequately to lifestyle modification and SSRI therapy or who refuse or are unable to follow such measures can be treated with go-nadotropin-releasing hormone (GnRH) agonist therapy (e.g., leuprolide, nafarelin, or goserelin).26-29 GnRH agonists effect a medical oophorectomy. They cannot be continued indefinitely without hormone replacement therapy because of concerns about the long-term deleterious effects of sustained hypoestro-genism. Add-back hormone regimens generally involve continuous exposure to small amounts of both estrogen and pro-gestin,29 thereby obviating the hormonal changes associated with a menstrual cycle.
There is a variety of hormonal preparations available for add-back regimens. It is usually a good idea to administer the estrogen and progestin separately at first, so that the response to each can be monitored. The progestin dose must be large enough to prevent endometrial hyperplasia but below the threshold for triggering PMS symptoms. Ongoing exposure to even small amounts of progestin (e.g., oral medroxyprogesterone acetate, 2.5 mg daily) may provoke symptoms, however.
The synthetic androgen danazol can be used to temporarily suppress endogenous ovarian function and provide an andro-genic environment. However, its side effects may be as problematic as the PMS/PMDD symptoms. The androgenic side effects of danazol include voice changes, hirsutism, and breast regression, all of which may be permanent.
Surgical Therapy
GnRH agonist therapy is expensive, so if a patient is responding very well to a GnRH agonist and has completed her childbearing, oophorectomy and hysterectomy may be a reasonable step. Surgery may also be the therapy of choice for patients who have sustained improvement with GnRH-agonist therapy but experience recurrent symptoms with add-back hormone regimens. Postoperatively, these patients are given hormone replacement therapy with continuous estrogen alone. Continuing SSRI therapy may be indicated.
