Definition and Etiology

Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS) that causes marked social impairment in approximately 5 of 100 women. Women present with multiple physical and behavioral symptoms including fatigue, irritability, bloating, anxiety, breast tenderness, and mood lability which occur exclusively in the 10 to 14 days before menses. The exact cause of PMDD is unknown, but it is believed that the normal cyclic fluctuation of hormone levels in the menstrual cycle leads to symptoms.

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Prevalence and Risk Factors

PMS is a common condition that affects as many as 75% of menstruating women. It is characterized by a myriad of physical and behavioral symptoms that occur repetitively in the luteal phase of the menstrual cycle. Women with PMS often describe feelings of anger, fatigue, abdominal bloating, irritability, anxiety, breast tenderness, changes in appetite and sleep, and headaches. These symptoms usually do not preclude a woman from performing her day-to-day activities.

On the other hand, a very small subgroup of women (3%-8%)¹ in their late 20s to mid-30s suffer from a severe form of PMS that is serious enough to interfere with their daily functioning and personal relationships. These women suffer from PMDD, a condition first defined in 1987 in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) and subsequently modified in 2000 in the manual’s fourth revised text edition (DSM IV-TR).

Some women are more prone to PMDD, including women in their 20s to mid-30s,² women with an elevated body mass index,³ women with a prior history of mood disorders⁴ and women with low parity (fewer pregnancies lead to additional hormone exposure from more menstrual cycles).⁵ Genetic and psychosocial factors may also cause increased risk to develop PMDD.⁴

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Pathophysiology

A number of theories have been suggested to explain PMDD, but the most current theory suggests that cyclic changes in ovarian steroids interact with central neurotransmitters to create symptoms of PMDD.⁴ In other words, normal ovarian function rather than hormone imbalance is the inciting factor for PMDD-related biochemical events in the central nervous system.^4,6 Serotonin is the neurotransmitter most studied in PMDD, although there is likely a role for gamma-aminobutyric acid (GABA) and β-endorphin. Deficiencies of trace elements may also be implicated.

Ovarian Steroids

In 1984, Muse and associates⁷ studied the effects of medical ovariectomy using the gonadotropin-releasing hormone (GnRH) agonist leuprolide, which led to resolution of symptoms by eliminating the fluctuation of ovarian hormones. In the 6-month study of eight patients, symptoms resolved with GnRH treatment, but recurred when the medication was withdrawn.⁷ However, cyclic changes in ovarian steroids may not be the sole explanation for symptoms in PMDD. Estrogen and progesterone levels of control subjects and women with premenstrual symptoms have been shown to be the same, suggesting that affected women may have an abnormal response to normal hormone levels.⁷ Decreased levels of allopregnanolone, a metabolite of progesterone, has also been related to PMDD.⁸

Neurotransmitters

The three main neurotransmitters implicated in PMDD are serotonin, GABA, and β-endorphin. Evidence currently suggests a leading role for altered serotonin levels in the etiology of PMDD. Central serotonin levels are typically low in women with PMDD, and symptoms worsen with depletion of the serotonin precursor tryptophan.^{9, 10} Notably, many women report benefiting from selective serotonin reuptake inhibitors (SSRIs). The role of GABA has not been clearly defined, but some women improve with the GABA agonist alprazolam. Differences in β-endorphin levels between the periovulatory and premenstrual phases remain unconfirmed.

Vitamins and Minerals

Several attempts to link vitamin and mineral deficiencies with PMDD have been inconclusive. No observable differences have been found in levels of vitamin A, vitamin E, or vitamin B₆ in affected or unaffected women. Treatment with vitamin B₆ supplements has shown inconsistent results. Additionally, initial studies suggested that women with PMDD may have lower levels of magnesium,¹¹ although subsequent studies have not confirmed this finding.¹² Calcium levels may also be low in the premenstrual phase.¹³

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Diagnosis

PMDD is accurately diagnosed with a thorough history and physical examination and by excluding other causes for the patient’s symptoms. The history must review psychiatric disorders in the patient and her family. The clinician should distinguish PMDD from other psychiatric disorders with premenstrual exacerbation. Symptoms should be limited to the luteal phase (second half) of the menstrual cycle, and the patient must be symptom free in the follicular phase (first half).¹⁴ Symptoms must be of such magnitude that they markedly impair the woman’s day-to-day functioning and interpersonal relationships.¹⁴ These symptoms may include feelings of depression, hopelessness, mood swings, irritability, anxiety, anhedonia, sleep disturbances, fatigue, impairment in concentration, appetite changes, feeling out of control and physical symptoms such as bloating or breast pain.¹⁴ At least five or more of these symptoms should be documented to occur during most menstrual cycles, with one of the highlighted symptoms being present.¹⁴ The diagnosis should be confirmed by daily charting for at least two consecutive symptomatic menstrual cycles.¹⁴ Women must also not be on hormones, including oral contraceptives. They may coincide or be superimposed on an underlying psychiatric disorder.

Symptom Inventory

Several questionnaires can be used to record symptoms of PMDD, such as the Calendar of Premenstrual Experiences (COPE), the Moos Menstrual Distress Questionnaire (MDQ), the Premenstrual Assessment Form (PAF), and the Prospective Record of the Impact and Severity of Menstruation (PRISM). These forms are similar and are all cited in the literature. The patient should be advised to record her symptoms for at least 2 to 3 months using one of the symptom inventory forms to observe fluctuation of symptoms during the menstrual cycle. It has been suggested that there must be at least a 30% worsening of symptoms between the follicular and luteal phases in each cycle to diagnose PMDD, regardless of which assessment tool is used. The percentage of worsening is calculated by the formula.⁴

(luteal score – follicular score)/luteal score x 100 = % change

If no symptom-free period is present, it may be useful to refer the patient to a women’s health psychiatrist to evaluate for a mood or anxiety disorder.

Differential Diagnosis

Because PMDD is a diagnosis of exclusion, the clinician should rule out other conditions that may manifest similar signs or symptoms (Box 1).

Diagnostic Testing

No objective testing exists, but laboratory testing should include a complete blood count, chemistry profile, and thyroid-stimulating hormone to evaluate for anemia, electrolyte abnormalities, and thyroid problems, respectively.

Summary

• PMDD is a clinical diagnosis made after excluding other conditions.
• A symptom diary for at least 2 to 3 months is necessary to determine when symptoms occur (follicular or luteal phase of the menstrual cycle).
• Laboratory testing is useful to exclude anemia, electrolyte abnormalities, and thyroid problems.

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Treatment

Multiple treatment options are available for PMDD; however, no single intervention is effective for all women. Initial treatment should begin with lifestyle changes and then proceed to medications such as SSRIs (standard); anxiolytics (alprazolam and buspirone); ovulation suppressants (GnRH agonists, danazol, and oral contraceptive pills); and diuretics (Box 2). Radical treatment such as ovariectomy may be indicated in women refractory to medical treatment. Three studies have demonstrated complete resolution of symptoms in PMDD-affected patients after ovariectomy.^15-17 When considering ovariectomy in women of childbearing age, the clinician should remember that this drastic measure can increase the risks of cardiovascular disease and osteoporosis in the absence of adequate estrogen replacement therapy.

Lifestyle Modifications

Treatment should begin with a 2- to 3-month trial of lifestyle changes while the patient charts her symptoms. Dietary changes, such as reducing salt, sugar, caffeine, dairy products, and alcohol, often aid in decreasing fluid retention, irritability, and bloating. Eating frequent and small portions high in carbohydrates may improve symptoms; this is believed to occur by increasing relative tryptophan levels (a precursor in the serotonin pathway). Exercise, relaxation, and stress management also are recommended for a general state of well-being. Some women also benefit from yoga, which improves muscle flexibility and alleviates stress. If possible, women also can try to schedule their more challenging and stressful events during the follicular phase (as opposed to the luteal phase).

Selective Serotonin Reuptake Inhibitors

SSRIs are considered first-line pharmacologic treatment for PMDD. Studies have shown that intermittent luteal-phase dosing has fewer adverse effects and is just as effective as full-cycle dosing.^18-20 SSRIs have proved to be effective in more than 60% of treated patients.²¹

U.S. Food and Drug Administration (FDA)-approved options for daily luteal-phase dosing include fluoxetine 10 to 20 mg/day, sertraline 50 to 150 mg/day, and paroxetine CR 12.5 to 37.5 mg/day. A recent study showed that fluoxetine may be efficacious when given at a dose of 90 mg once weekly for 2 weeks in the luteal phase.²²

Side effects of SSRIs include sexual dysfunction, insomnia, fatigue, nervousness, headache, nausea, and diarrhea. These agents have a fast onset of action: 1 to 2 days in the treatment of PMDD as compared with their onset of action for depression.

Alprazolam

Alprazolam, a GABA agonist, is a benzodiazepine anxiolytic that is effective for symptoms such as tension, anxiety, irritability, and hostility. Treatment can be initiated at 0.25 mg three to four times daily in the luteal phase and tapered one to two times daily at the onset of menses, finally stopping 1 to 2 days after menses begin. It is considered a second-line treatment because of its addictive potential and should be carefully monitored.

Buspirone

Buspirone, a partial 5-HT₁ receptor agonist, has also been shown to have a weak beneficial effect, because of its anxiolytic properties. Unlike alprazolam, it is not addictive. Dosing may be given at 5 to 10 mg three times daily during the luteal phase.

GnRH Agonists

GnRH agonists are also effective in reducing PMDD symptoms. They downregulate GnRH receptors, causing a decrease in luteinizing hormone and follicle-stimulating hormone levels. This subsequently inhibits ovulation, which decreases estrogen and progesterone levels, thereby creating pharmacologic menopause. Treatment-limiting side effects include hot flashes, headaches, muscle aches, vaginal dryness, and irritability; therefore, this class of medication is reserved for patients with severe symptoms unresponsive to other medical treatment measures. GnRH agonists are expensive; they also have hypoestrogenic side effects, which cause concern for the development of osteoporosis. For this reason, they are not recommended for use longer than 6 months. If a GnRH agonist needs to be used for longer than 6 months, continued symptom relief can be provided by using add-back therapy with estrogen and progesterone.²³

Danazol

Danazol is a weak synthetic androgen antagonist/agonist inhibitor that suppresses ovarian steroid production by inhibiting luteinizing hormone and follicle-stimulating hormone secretion. It is given at 600 to 800 mg/day in divided doses. Danazol’s use is limited because of multiple androgenic and antiestrogenic side effects, including amenorrhea, weight gain, acne, fluid retention, hirsutism, hot flushes, vaginal dryness, possible teratogenicity and emotional lability.

Oral Contraceptives

The efficacy of oral contraceptive pills for the treatment of PMDD has not been established because of conflicting data, and more studies are indicated. Freeman and colleagues²⁴ showed that a unique oral contraceptive pill consisting of 30 µg ethinyl estradiol and 3 mg drospirenone (Yasmin) was beneficial for a number of symptoms, including bloating, breast tenderness and swelling. The combination agent also has antiandrogenic properties that may relieve acne and hirsutism.

Bromocriptine

Bromocriptine, a dopamine agonist, is useful in decreasing mastalgia by lowering prolactin levels. It is dosed as 2.5 mg once daily just before ovulation until the onset of menses. Side effects may include dizziness and nausea.

Diuretics

Spironolactone is the diuretic most studied because of its antimineralocorticoid and antiandrogenic properties. Symptoms most likely to improve include bloating, swelling, breast tenderness, and acne. It may be tried in dosages of 50 to 100 mg/day for 7 to 10 days during the luteal phase. Side effects, including lethargy, headache, and irregular menses, are more common during continuous dosing. Serum potassium levels should be monitored periodically because spironolactone can cause hyperkalemia.

Other Medications

Nonsteroidal anti-inflammatory drugs (NSAIDs) are available over the counter and are effective for dysmenorrhea. Generic names include ibuprofen and naproxen. Meclofenamate (Meclomen), an NSAID available by prescription, can reduce menstrual cramps and flow. The typical dose is 100 mg twice daily. Acetaminophen may also be beneficial for pain.

Alternative Therapies

Today, women are more likely to seek other integrative therapies for PMDD. One large trial has shown that 1,200 mg of elemental calcium daily, in divided doses, is effective in alleviating tension, anxiety, fluid retention, and food cravings.²⁵ Physicians are most often asked about vitamin supplementation; controlled studies with vitamin A, vitamin E, and vitamin B6 have failed to consistently show a benefit. Although popular, herbal products are not FDA-approved, and some have caused significant toxicities as well as drug-herb interactions. Other innovative therapies include acupuncture, biofeedback, homeopathy, massage, reflexology, and light therapy.²⁶

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