What are the effects of drug treatments in women with premenstrual syndrome (PMS)?

BENEFICIAL

Spironolactone. Randomized controlled trials (RCTs) found that luteal-phase spirono-lactone improved psychological and physical symptoms of PMS over two to six months compared with placebo.

LIKELY TO BE BENEFICIAL

Alprazolam. RCTs found that luteal-phase alprazolam improved most physical and psychological symptoms of PMS after three to six months' treatment compared with placebo, including severe symptoms in women with premenstrual dysphoric disorder. Mild adverse effects were common. Benzodiazepines are associated with dependence.

Buspirone. One RCT found that buspirone (luteal or continuous) was more effective than placebo in improving self-rated global improvement at four months in women with premenstrual dysphoric disorder. Results for individual psychological and physical symptoms were inconclusive. Mild adverse effects were common.

Gonadorelin Analogues for Less Than Six Months. One systematic review found that gonadorelin analogues reduced overall symptoms of PMS over three to six months compared with placebo. Women taking gonadorelin analogues were three times more likely to have adverse effects, including hot flashes, aches, night sweats, nausea, and headaches, than women taking placebo. The addition of hormonal add-back therapy to reduce long-term adverse effects did not reduce effectiveness. However, treatment with gonadorelin analogues without hormonal add-back for longer than six months carries a serious risk of osteoporosis, limiting their usefulness for long-term treatment.

Metolazone. One RCT found that luteal-phase metolazone reduced premenstrual swelling and weight gain, and improved mood symptoms compared with placebo.

Nonsteroidal Anti-inflammatory Drugs. RCTs found that luteal-phase mefenamic acid or naproxen sodium improved physical and psychological premenstrual symptoms over three to six months compared with placebo. The RCTs provided little information on adverse effects.

TRADE-OFF BETWEEN BENEFITS AND HARMS

Clomipramine. RCTs found that clomipramine (luteal or continuous) improved psychological symptoms of PMS over three treatment cycles, but not physical symptoms. A proportion of women stopped treatment because of adverse effects, such as drowsiness, nausea, vertigo, and headache.

Danazol. RCTs found that danazol reduced overall premenstrual symptoms after three months' treatment compared with placebo, but had important adverse effects associated with masculinization when used continuously in the long term.

Selective Serotonin Reuptake Inhibitors (SSRIS). One systematic review and subsequent RCTs found that SSRIs improved pre-menstrual symptoms over two to six cycles compared with placebo, but caused frequent adverse effects. Current evidence indicates no clear relationship between SSRIs and increased risk of suicide, but there is concern that SSRIs may increase the risks of self-harm and suicidal ideation. Regulatory authorities in Europe, including the United Kingdom, and in the United States have issued warnings about the use of SSRIs in children and adolescents.

What are the effects of hormonal treatments in women with PMS?

LIKELY TO BE BENEFICIAL

Contraceptives (Oral). One RCT found that oral contraceptives improved certain premenstrual symptoms (i.e., appetite, acne, and food cravings) compared with placebo, but did not improve mood-related symptoms on a 21/7 day schedule. Another RCT found that oral contraceptives improved mood-related symptoms (e.g., depression, anxiety, mood swings, irritability) and physical symptoms of premenstrual dysphoric disorder (e.g., increased appetite, breast tenderness, bloated sensation, headaches, muscle pain) compared with placebo on a 24/4 day schedule.

TRADE-OFF BETWEEN BENEFITS AND HARMS

Progesterone. One systematic review found an improvement in overall premenstrual symptoms in women taking luteal-phase progesterone for two to six months compared with placebo. A second systematic review (of two RCTs also included in the first review) found no overall improvement in premenstrual symptoms in women taking luteal-phase progesterone for two to four months compared with placebo.

Although the first review found a wide range of adverse effects associated with progesterone (including excessive bleeding, dysmenorrhea, abdominal pain, nausea, and headache), it found no significant difference in the frequency of withdrawals caused by adverse effects.

Progestogens. One systematic review found that pro-gestogens reduced premenstrual symptoms over three or four cycles compared with placebo. It found no significant difference between progestogens and placebo in the proportion of women who withdrew because of adverse effects. The most common adverse effects associated with progestogens are nausea, breast discomfort, headache, and menstrual irregularity. Progestogen may induce PMS symptoms in some women.

UNKNOWN EFFECTIVENESS

Estrogens. Limited evidence from one RCT suggested that continuous estradiol might improve symptoms of PMS after three months' treatment compared with placebo. However, the magnitude of any effect is unclear. Important adverse effects of estrogen include increased risk of breast cancer, endometrial cancer, stroke, and venous thromboembolic disease.

Tibolone. One small RCT found limited evidence that continuous tibolone improved premenstrual symptom score over six months compared with placebo (multivitamins).

What are the effects of psychological interventions in women with PMS?

UNKNOWN EFFECTIVENESS

Cognitive Behavior Therapy. Weak RCTs provided insufficient evidence to assess cognitive behavior therapy in women with PMS.

What are the effects of physical therapy in women with PMS?

UNKNOWN EFFECTIVENESS

Acupuncture. One small RCT found that acupuncture was effective in reducing premenstrual symptoms from baseline scores; however, sham acupuncture also reduced symptoms.

Bright Light Therapy. One systematic review of small RCTs found no significant difference between bright light therapy and placebo in reducing depressive symptoms related to premenstrual dysphoric disorder.

Chiropractic Manipulation. One weak crossover trial provided insufficient evidence to assess chiropractic manipulation in women with PMS.

Exercise. We found no systematic review or RCT of exercise in women with PMS.

Reflexology. One RCT found limited evidence that reflexology was better than sham reflexology in reducing premenstrual symptoms at eight weeks.

Relaxation. One RCT found limited evidence that relaxation treatment was better than reading leisure material or charting symptoms in reducing premenstrual symptoms over five months. Two further weak RCTs provided insufficient evidence to assess relaxation.

What are the effects of dietary supplements in women with PMS?

BENEFICIAL

Pyridoxine. One systematic review found that luteal-phase or continuous pyridoxine (vitamin B₆) was better than placebo in relieving overall symptoms of PMS over two to six months.

LIKELY TO BE BENEFICIAL

Calcium Supplements. Two RCTs identified by a systematic review found that calcium supplements improved symptoms compared with placebo.

UNKNOWN EFFECTIVENESS

Evening Primrose Oil. Weak RCTs provided insufficient evidence to assess the effects of evening primrose oil in women with premenstrual symptoms.

Magnesium Supplements. Weak RCTs provided insufficient evidence to assess the effects of magnesium supplements in women with PMS.

What are the effects of surgical treatments in women with PMS?

LIKELY TO BE BENEFICIAL

Hysterectomy with Bilateral Oophorectomy. We found no systematic review or RCT of hysterectomy alone or hysterectomy with bilateral oophorectomy in women with PMS. Cohort studies have found almost complete eradication of the symptoms of PMS after hysterectomy plus bilateral oophorectomy and continuous estrogen placement, and there is consensus that it is effective. Surgery is rarely used, but may be indicated if there are coexisting gynecologic problems. (Based on consensus; RCTs unlikely to be conducted.)

Laparoscopic Bilateral Oophorectomy. We found no systematic review or RCT of laparoscopic bilateral oophorectomy in women with PMS. Cohort studies have found almost complete eradication of the symptoms of PMS after hysterectomy plus bilateral oophorectomy and continuous estrogen therapy, and there is consensus that it is effective. Surgery is rarely used, but may be indicated if there are coexisting gynecologic problems. (Based on consensus; RCTs unlikely to be conducted.)

UNKNOWN EFFECTIVENESS

Endometrial Ablation. We found no systematic review or RCT of endometrial ablation in women with PMS.

Definition

A woman has PMS if she complains of recurrent psychological or physical symptoms occurring specifically during the luteal phase of the menstrual cycle, and often resolving by the end of menstruation.¹ The symptoms can also persist during the bleeding phase.

The definition of severe PMS varies among RCTs, but in recent studies, standardized criteria have been used to diagnose one variant of severe PMS—premenstrual dysphoric disorder. These criteria are based on at least five symptoms, including one of four core psychological symptoms (from a list of 17 physical and psychological symptoms), being severe before menstruation starts and mild or absent after menstruation.^2,3 The symptoms are: depression; feeling hopeless or guilty; anxiety or tension; mood swings; irritability or persistent anger; decreased interest; poor concentration; fatigue; food craving or increased appetite; sleep disturbance; feeling out of control or overwhelmed; poor coordination; headache; aches; swelling, bloating, and weight gain; cramps; and breast tenderness.

Incidence and Prevalence

Premenstrual symptoms occur in 95 percent of all women of reproductive age; severe, debilitating symptoms (PMS) occur in about 5 percent of those women.¹

Etiology

The cause is unknown, but hormonal and other factors (possibly neuroendocrine) probably contribute.^4,5

Prognosis

Except after oophorectomy, symptoms of PMS usually recur when treatment is stopped.

editor's note: Tibolone is not available in the United States.

search date: November 2006

Adapted with permission from Kwan I, Onwude JL. Premenstrual syndrome. Clin Evid Handbook.