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Table.  

Five or more of the following symptoms must be present; at least 1 symptom must be from the first 4 listed:
  • Depressed mood or dysphoria

  • Anxiety or tension

  • Affective lability

  • Irritability

  • Decreased interest in usual activities

  • Concentration difficulties

  • Marked lack of energy

  • Marked change in appetite, overeating, or food cravings

  • Hyperinsomnia or insomnia

  • Feeling overwhelmed

  • Other physical symptoms, ie, breast tenderness, bloating
A. To be considered PMDD, symptoms must occur during the week before menstruation and remit a few days after onset of menses.
B. Symptoms must impair functioning at work, school, usual activities, or relationships.
C. Symptoms must not merely be an exacerbation of another disorder.
D. Criteria A, B, and C must be confirmed by patient prospective daily ratings of symptoms for at least 2 menstrual cycles.

Diagnostic Criteria for Premenstrual Dysphoric Disorder[2]

PMDD Spotlight: Diagnosis and Treatment

Authors: Sarah L. Berga, MD; Jessica B. Spencer, MD, MS; Celia E. Dominguez, MDFaculty and Disclosures

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Overview

Premenstrual syndrome (PMS) refers to the cyclic variation in mood and physical symptoms that appear during the week preceding the menstrual cycle and disappear after menses has ceased. The most severe form of the syndrome, premenstrual dysphoric disorder (PMDD), replaced the earlier diagnosis of late luteal phase dysphoric disorder[1] in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).[2] In the same year (2000), the American College of Obstetrics and Gynecology addressed the need for acceptance of PMDD as an important biopsychosocial entity, and published clinical management guidelines.[3]

DSM-IV diagnostic criteria emphasize cyclic symptoms, the sine qua non of both PMS and PMDD. The most frequently reported emotional symptoms include mood swings, anxiety, irritability, nervous tension, and depression. Common physical symptoms include breast tenderness, bloating, weight gain, and food cravings. In PMDD, the emotional symptoms predominate over physical complaints, and are severe enough to significantly compromise quality of life. Symptoms may start at any time after onset of menses, but women generally do not seek treatment until their late 20s or early 30s. It is critical to differentiate PMDD from other psychological conditions that may exacerbate premenstrually, such as major depression, bipolar disorder, or anxiety disorder. This requires careful observation and documentation of the emotional status of the individual in both the follicular and luteal phases of the menstrual cycle. Women meeting the diagnostic criteria for PMDD experience quality-of-life impairment that is comparable to those diagnosed with depression or anxiety disorders. However, the impairment is completely or almost entirely absent just after the onset of menses.

Etiology

PMS and PMDD demonstrate familial clustering and are governed by physiologic (chemical and hormonal), genetic, nutritional, and behavioral factors. Prior research into the possible etiologic factors affecting the presence of PMS has focused on differences in nutrition, fluid retention, hyperprolactinemia, prostaglandins, hormone levels, and neurotransmitters. These investigations have concomitantly led researchers to the evaluation of treatment-specific options.

Studies of twins have revealed a higher incidence of PMS symptoms in identical compared with nonidentical twins.[4] Environmental factors are important in predisposing a woman to the development of PMDD: A history of sexual abuse was found to be more likely.[5]

Physiology

Declining levels of estrogen and progesterone in the late luteal phase have been implicated in symptomatology, and cyclic fluctuations in ovarian hormones may lead to neurotransmitter disturbances. Low levels of serotonin and gamma-aminobutyric acid (GABA) have been associated with depression and anxiety, respectively. However, no studies have found abnormalities in the progesterone levels of women suffering from PMS/PMDD, and multiple double-blind trials have failed to confirm efficacy of vaginal progesterone therapy for the treatment of PMS.[6]

beta-Endorphins. Estrogen and progesterone increase beta-endorphins, and it has been hypothesized that PMS symptoms are due in part to a beta-endorphin withdrawal in the luteal phase.[7]

GABA system. Pregnenolone and its metabolite allopregnanolone are active at the GABAA receptor, and alterations in these hormones have been demonstrated in women with PMS.[8] Progestin supplementation has failed to show a benefit, but benzodiazepines potentiate GABA receptor activity and thus may be useful in the treatment of PMS and PMDD.[9]

Serotoninergic system. One of the most common theories of PMS predisposition is that a central deficiency in the serotoninergic system is present. Fenfluramine, a serotonin agonist, has been shown to improve symptoms of depression and anxiety and to suppress cravings for carbohydrates and fats.[10]

Research into the use of selective serotonin reuptake inhibitors (SSRIs) has been extensive, and multiple double-blind, placebo-controlled studies have demonstrated improved mood, anxiety, concentration, bloating, and breast tenderness.[11-14] Three agents are US Food and Drug Administration (FDA)-approved for the treatment of PMDD.[15]

Circadian system. Mood, appetite, and cognition are gated in part by circadian rhythmicity and what is termed "phase intactness." Thus, jet lag or internal desynchronization of physiologic and endocrine rhythms -- such as core body temperature, cortisol, and melatonin -- from each other, or from the ambient light-dark cycle, have been implicated in both depression and PMDD.[16] Serotonin insufficiency may underlie the lack of robust circadian position in women with PMS, and the tendency to have low or delayed melatonin rhythms.[17] Phototherapy has been used to buttress circadian internal and external synchronization in patients with PMDD.[18]

Summary. When taken in aggregate, the available data suggest that women with PMS or PMDD reflect an increased sensitivity, reactivity, or vulnerability to the expected gonadal steroid excursions that accompany an ovulatory menstrual cycle. Subsequently, treatment strategies depend on buttressing the brain, altering hormonal excursions, or both.

Clinical Presentation

Although the clinical presentation may be varied, common physical symptoms of PMS include breast tenderness, bloating, and nausea. Emotional symptoms may include depression, anger, mood swings, and irritability. In PMDD, the emotional symptoms typically predominate over the physical complaints, and markedly interfere with work or school, or with usual social activities and interpersonal relationships.

Diagnosis

Although no specific physical findings or tests can confirm the diagnosis of PMDD, both medical and psychologic conditions need to be evaluated. Diagnosis of PMDD is based on DSM-IV criteria ( Table ).

Because there is no easy way to confirm the diagnosis of PMDD, a careful differential diagnosis must be conducted. Other disorders, including drug use or abuse, psychiatric conditions, and endocrine disease, must be excluded.

The association with depression. Depression is almost twice as common in women as it is in men,[19] and depression-related symptoms are prevalent in those who suffer from PMDD. However, many women with major affective disorders have worsening symptoms premenstrually,[20] and are likely to have a first episode premenstrually or postpartum. Women treated for depression who are stable on psychotropic medications may also show breakthrough symptoms premenstrually. Additional confounders to diagnosis include the findings that women who have suffered PMDD have an increased risk for postpartum depression and menopausal affective disorders. To fulfill the DSM-IV diagnostic criteria, it is important to determine that the disturbance is not merely an exacerbation of the symptoms of another disorder, although symptoms of other disorders may be superimposed.

Evaluation

The work-up of patients suspected of having either PMS or PMDD should include a thorough history focusing on the proximity of the symptoms to menses and dissipation afterward, as well as evaluation for possible endocrine disturbances, which can present with similar physical, behavioral, or emotional symptoms. A validated instrument, such as the Daily Record of Severity of Problems (DRSP), is used by the patient for recording and rating daily symptoms over a 2-month time period (Figure). This instrument documents functional impairment using a 6-point scale.

Figure. Daily record of severity of problems.(Click to open)

Annotating monthly variations in physical and psychological symptoms helps elucidate whether symptoms are constant with exacerbation premenstrually, or occur solely premenstrually and disappear immediately after cessation of menses. The menstrual calendar should demonstrate a symptom-free interval within the follicular phase, with higher scores of symptoms in the last week preceding menses. The type and extent to which symptoms interfere with personal and professional life ultimately determine whether diagnostic criteria for PMDD are met. A calendar can also be used to help the patient understand her fluctuations and improve coping strategies.

If a premenstrual exacerbation of another mood disorder appears to be the case, psychological or psychiatric referral may be needed to evaluate for more complex psychiatric disorders. Formal psychometric testing, to evaluate if depression, anxiety, or panic disorders are playing a role in the patient's symptoms, should be considered when appropriate. Conditions to consider in the differential diagnosis are provided:

  1. Major depression;

  2. Minor depression (dysthymia);

  3. Generalized anxiety;

  4. Panic disorder;

  5. Bipolar illness (mood irritability);

  6. Drug use/abuse, including narcotics and alcohol; and

  7. Other.

A physical examination, including a pelvic examination, should be performed to rule out other medical conditions that can mimic PMS and PMDD:

  1. Anemia;

  2. Autoimmune disorders;

  3. Hypothyroidism;

  4. Diabetes;

  5. Seizure disorders;

  6. Endometriosis;

  7. Chronic fatigue syndrome;

  8. Fibromyalgia;

  9. Collagen vascular disease;

  10. Irritable bowel syndrome; and

  11. Idiopathic cyclic edema.

If dysmenorrhea or pelvic pain is a primary complaint, pelvic imaging should be performed. A diagnostic laparoscopy should also be considered to evaluate for endometriosis. Several endocrinopathies should also be excluded, including hypothyroidism, premature ovarian failure, diabetes or hypoglycemia, adrenal insufficiency, and Cushing's syndrome. A blood count for anemia is also warranted.

Therapeutic Intervention

Treatment for PMS depends on the severity of symptoms, and a combination of therapeutic approaches is likely to be most effective. These include exercise, dietary and lifestyle modifications, psychobehavioral therapies, and the appropriate use of medications. Although the following treatment options have been studied in the treatment of PMS, fewer have been evaluated specifically in women with PMDD.

Exercise

Aerobic exercise, running, and yoga are all potential treatment strategies in women with PMS. An increase in regular exercise has been shown to improve mood and other PMS symptoms.[21]

Mind-Body Techniques

Biofeedback, relaxation techniques, and phototherapy may also partially relieve PMS symptoms, and acupuncture and massage are useful in stress relief.[22,23]

Psychological Counseling

Several studies have demonstrated an improvement in PMS symptoms and coping mechanisms with cognitive-behavioral therapy (CBT).[24-27] CBT involves limited weekly sessions with a mental healthcare worker focusing on correcting the dysfunctional negative thoughts and developing effective coping strategies. The benefit of CBT over psychotherapy is that its impact accrues with time even after the CBT sessions end. Pharmacotherapy has a more rapid onset of action, but the benefits start to diminish with cessation of psychotropic medication. It is common to couple pharmacotherapy and CBT when therapy is initiated and then to taper the pharmacotherapy before stopping CBT sessions.

Dietary Modification

Increasing carbohydrate intake during the weeks preceding menstruation may help, possibly by increasing serotonin levels.[28] Reducing or eliminating alcohol, caffeine, refined sugar, salt, dairy products, and animal fats may also be beneficial.[29] A professional nutritionist or dietitian can advise women on dietary changes that may relieve symptoms.

Calcium, magnesium, and vitamin B6 supplements have reasonable evidence to support their use in PMS.[22,30] The strongest evidence for calcium supplementation comes from a placebo-controlled, randomized trial of 720 women over 3 menstrual cycles, which demonstrated a 50% reduction in PMS symptoms vs a 30% reduction in the placebo arm. This study used a dose of 1200 mg of calcium carbonate daily.

Magnesium supplementation at 400-800 mg/day may also improve pain symptoms associated with PMS, possibly by decreasing prostaglandin F2alpha. Vitamin B6 in a daily dose of up to 100 mg may improve breast tenderness and depression, but studies have produced conflicting results. Doses above 100 mg daily are not recommended because prolonged high doses of vitamin B6 are associated with neuropathy and ataxia.

Herbal Supplements

Chasteberry (Vitex agnus-castus) at a dose of 120 mg/day may reduce estrogen levels and increase progesterone and prolactin levels by suppressing follicle-stimulating hormone (FSH). Higher levels also inhibit prolactin levels via D2 receptor agonist effects. A randomized, double-blind, placebo-controlled study of the use of chasteberry in 170 women with PMS demonstrated a 52% improvement in PMS symptoms vs 24% placebo.[31] However, other studies have shown mixed results. Caution should be exercised with the use of chasteberry in women trying to conceive or in those on a dopamine antagonist.

Ginkgo (Ginkgo biloba) at 80 mg twice daily in the luteal phase and during menses has been shown to improve PMS symptoms as well.[32] This leaf extract will alter P450 enzyme activity and may also increase the risk of bleeding.

St. John's wort (Hypericum perforatum) 300 mg (0.3% 3 times a day) may improve mild depression and PMS symptoms, but no randomized controlled trial has been performed.[22]

Small, randomized studies have shown no benefit with evening primrose oil (Oenothera biennis).[33] Additionally, no randomized placebo-controlled studies have been conducted to assess efficacy of kava kava (Piper methysticum) and/or black cohosh (Cimicifuga racemosa).

Pharmacologic Treatment

Patients with PMDD often require medical treatment in addition to nonpharmacologic therapy. Agents are briefly described below.

Hormones

Although all oral contraceptives (OCs) suppress ovulation, use of some formulations has been associated with adverse mood and PMS-like symptoms. However, drospirenone, a relatively new progestin with antimineralocorticoid activity, also functions as an androgen receptor antagonist. An OC product that uses 24 days of active combined therapy -- drospirenone 3 mg/ethinyl estradiol 20 micrograms (mcg) -- was found to be more effective than placebo in the relief of both PMS and PMDD symptoms.[34] This OC formulation was approved by the FDA in late 2006 for treatment of PMDD in women electing to use the agent for birth control.

Gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide (Lupron), goserelin (Zoladex), and nafarelin (Synarel), are very affective in producing menopausal levels of estrogen and progesterone and have been shown to improve symptoms in women with severe PMDD.[35] However, GnRH agonists have side effects that are similar to symptoms of menopause, and when used without estrogen-add back therapy, can cause or worsen osteoporosis.

Danazol (Danocrine) 200 mg daily has demonstrated effectiveness in reducing mastalgia, dysmenorrhea, and mood symptoms.[36] It is not a desirable first-line therapy because it is androgenic and teratogenic.

Antidepressant Medications

The use of SSRIs for the treatment of PMDD has been well studied and remains the mainstay of treatment for the disorder.[37] Fluoxetine, sertraline, and paroxetine are all FDA-approved for the treatment of PMDD and have been shown in randomized, placebo-controlled studies to alleviate both physical and psychological symptoms. SSRIs are generally well tolerated and effective, even when taken only during the luteal phase.

Antidepressants with noradrenergic activity, such as buproprion, are less effective than serotonergic antidepressants, and are not FDA-approved for treatment of PMDD. Tricyclic antidepressants. such as nortriptyline and amitriptyline, may be useful in the patient with insomnia, but SSRIs are generally more effective for treating this condition.

Anxiolytics

Although none are FDA-approved for treatment of PMDD, anxiolytics may be a useful adjunctive therapy for patients with anxiety.[9] Benzodiazepines, such as alprazolam, clonazepam, and lorazepam, are fast-acting and can be used on an "as-needed" basis during the luteal phase. It is important to target these treatments only cyclically, because dependence and tolerance may occur. Buspirone, a serotonin agonist, may also be effective.

Nonsteroidal Anti-inflammatory Drugs

Although studies of mefenamic acid[37] and naproxen[38] have demonstrated an improvement in the physical symptoms of PMS, the psychological symptoms were not affected.

Other

Diuretics, such as spironolactone, have also been tried to alleviate the symptoms of bloating and breast tenderness,[39] but other studies have shown mixed results. Bromocriptine may also be useful for patients with extreme breast discomfort.

Conclusion

PMS is a collection of physical and emotional symptoms occurring during the second half of the menstrual cycle; those with emotional and physical symptoms severe enough to significantly affect their quality of life may meet the diagnostic criteria for PMDD. Implicated causes of PMS/PMDD include disturbances in nutrition, fluid retention, hyperprolactinemia, prostaglandins, hormone levels, and neurotransmitters.

The diagnosis of PMDD is made by demonstrating the association between symptoms and the luteal phase of the menstrual cycle. It is also important to exclude psychiatric or medical illnesses that can mimic PMDD.

To meet the goals of therapy, a multidisciplinary approach may be required. Any pharmacologic agent prescribed should be used for at least 3 menstrual cycles to determine efficacy. CBT, sleep and circadian hygiene, and any appropriate nutrition by diet or supplement (particularly calcium and magnesium) may be especially beneficial, in addition to the pharmacologic agent prescribed for treatment.

Supported by an independent educational grant from Bayer

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