82-84 However, estrogen must be cycled with progesterone to reduce the risk of uterine cancer, and the extent to which exogenous progesterone results in return of PMS symptoms remains unclear. Progesterone treatment, of PMS was advocated for many years, but numerous studies,

including three large randomized controlled trials, failed to show improvement significantly greater than placebo for the mood and behavioral symptoms of PMS.85-87 Anxiolytics Alprazolam and buspirone showed modest efficacy for PMS in some studies,87-91 but not others.92,93 The Inhibitors,research,lifescience,medical well-known risk of dependence with alprazolam must be considered, and this medication should be tried only when the patient, has symptoms clearly limited to the luteal phase (so that the medication is stopped for at least 2 weeks in each cycle) and no history of substance abuse. These medications offer an alternative to antidepressants, Inhibitors,research,lifescience,medical but the extent to which patients who fail to respond to antidepressants respond to these anxiolytics is not known. Nonpharmacologic approaches Numerous nonpharmacologic approaches have been

advocated for PMS, but few are supported by solid empirical Inhibitors,research,lifescience,medical evidence.94 A large study of calcium supplementation (600 mg twice daily) for PMS reduced premenstrual depression, fatigue, edema, and pain significantly more than the placebo. However, the severity of the dysphoric mood symptoms was not indicated, and further information is required to determine the efficacy of this treatment for premenstrual dysphorias.95 A meta-analysis showed that vitamin B6 was about twice as likely as placebo to improve PMS symptoms Inhibitors,research,lifescience,medical overall, with an odds ratio for improvement, in depressive symptoms of 1.69, but the researchers concluded that the quality of the studies was too poor to have confidence in the results.96 There was no significant dose response, indicating that the amount of

vitamin B6 did not affect improvement, and reports of peripheral neuropathies with doses exceeding 200 mg preclude the use Inhibitors,research,lifescience,medical of megadoses.96 Several reports of cognitive therapies show improvement of premenstrual symptoms.94 Other complementary and alternative therapies showed no convincing evidence of efficacy for PMS in a review of randomized controlled trials (dietary supplements, 13 trials; herbal medicines, 7 trials; biofeedback, 2 trials; homeopathy, most relaxation, massage, reflexology, and PI3K inhibitor chiropractic, 1 trial each).97 Emerging from a long history with little understanding and many treatments of doubtful effect, clinically significant PMS is now recognized as a chronic disorder that impairs functioning and personal relationships for a sizeable number of women. Serotonergic antidepressants are the first-line treatment at this time. Using these medications only in the symptomatic luteal phase is effective for women without, other comorbid disorders.