Premenstrual Syndrome and Premenstrual Dysphoric Disorder: Quality of Life and Burden of Illness

Andrea J. Rapkin; Sharon A. Winer

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2009;9(2):157-170. 

In This Article

Effective Treatments for PMS/PMDD

Antidepressants that increase synaptic serotonin such as selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) are effective in up to 80% of women with PMDD.[34] Three SSRIs, fluoxetine, sertraline and paroxetine received indications from the US FDA for PMDD. Some aspects of the biology of the premenstrual disorders make SSRI treatment particularly attractive. First, luteal daily dosing (starting ~14 days before the expected menses and discontinuing at the onset of menses) has been found to be almost as effective as daily continuous dosing. Unlike treatment of depression, symptoms respond within the first cycle of treatment and withdrawal symptoms do not occur when treatment is stopped.[35,36,37] Second, standard doses of these agents generally ameliorate the physical as well as the affective and behavioral symptoms of PMS/PMDD. Third, fewer days of therapy each month and positive treatment response at the lower end of the dosing regimen contribute to the reduction of side effects, in particular sexual dysfunction and weight gain and also help reduce cost of drug therapy. However, the utility of antidepressants for PMS/PMDD is diminished by the fact that many women elect not to start or to continue therapy or find the medications do not adequately control symptoms.[38] There is a social stigma of taking an antidepressant, especially for some professions such as airline pilots and government officials. SSRI side effects (i.e., gastrointestinal disturbance, sedation, insomnia, dizziness, headache and anxiety)[39] are usually transient. However, many women stop the medication due to these adverse effects. Possible long-term side effects of weight gain and decreased libido or orgasm also contribute to drug discontinuation. Long-term efficacy studies (>6 months) are also lacking, although one observational study did find continued benefit of SSRIs at 18 months.[40]

Shah et al. performed a meta-analysis of SSRIs for treatment of symptoms related to severe PMS and PMDD. Included in the review were 29 double-blind, randomized, controlled trials comparing a SSRI with placebo reporting a change in a score on a validated assessment tool for premenstrual symptomatology. The analysis demonstrated that SSRIs are effective for treating PMS and PMDD (OR: 0.40; 95% CI: 0.31-0.51). Intermittent, luteal phase dosing regimens were found to be less effective (OR: 0.55; 95% CI: 0.45-0.68) than continuous dosing regimens (OR: 0.28; 95% CI: 0.18-0.42). Fluoxetine, sertraline and paroxetine were the most common SSRIs studied for PMDD and no SSRI was demonstrably better than another.[41]

Until recently, many gynecologists and general practitioners typically prescribed combined oral contraceptives (OCs), containing both estrogen and progestin for PMS, as they recognized the link with ovulation and appreciated that many moliminal symptoms, premenstrual discomfort and menstrual pain responded to OCs. However, the traditional formulation and dosing regimen of OCs has not been found to have a major impact on the affective symptoms of PMS.[6] In the general population, OCs improved premenstrual symptoms in only 12.3%, and in 16% symptoms deteriorated, while 74% stated the OC had no effect on mood.[42] The reason for lack of efficacy is not really known but the endogenous hormones are not completely suppressed with the 21/7 OC regimens (21 days of active pills followed by 7 days of inactive pills).[43] The progestins in most hormonal contraceptives are derived from testosterone and these progestins and/or higher estrogen dose OCs may provoke symptoms similar to PMS (e.g., irritability, mood lability and fluid retention).[44]

A newer OC contains a progestin drospirenone that is not derived from testosterone but from spirolactone and has antiandrogenic and antimineralocorticoid properties.[45] Drospirenone also has a long half-life and that, in combination with the novel dosing regimen of 24 active followed by four inactive pills in each cycle, provides better hormone suppression and symptom control.[46] In two randomized, controlled pivotal trials, the OC containing a low dose of estrogen (20 µg of ethinyl estradiol) with 3 mg of drospirenone in a 24/4 regimen has been found to be effective for approximately 60% of women with PMDD[47,48] resulting in an indication by the FDA for PMDD for women who desire hormonal contraception. Side effects leading to discontinuation of OCs in up to 20% of women include breakthrough bleeding, nausea, moodiness, breast tenderness, headache, decreased libido and weight gain.[49] Some women with medical conditions, including but not limited to procoagulant conditions, hypertension, liver disease, renal or adrenal disease, epilepsy, complex migraines can not be safely prescribed OCs in general or OCs containing drospirenone and some discontinue OCs while attempting conception.

Continuous estrogen/progestin-containing OCs do reliably suppress endogenous hormones and have been under study for PMS/PMDD but favorable evidence has yet to be published. Physical PMS-like symptoms often accompany the bothersome breakthrough bleeding and spotting that occur in up to 60% of cycles within the first 6 months of treatment with continuous OC regimens.

Gonadotropin-releasing hormone agonists abolish ovarian cyclicity and create a 'medical oophorectomy' by downregulating the production of gonadotropins, estradiol and progesterone.[50] These agents have been found effective for the treatment of PMS but the side effects of estrogen deficiency and long-term adverse effects, even with the concomitant addition of estrogen and progesterone, render this approach third-line therapy.[51]

Calcium supplements were also found to be significantly better than placebo for the treatment of PMS, but PMDD was not studied and many of the subjects were taking oral contraceptives.[33] Calcium should be supplemented if the patient is not taking adequate dietary calcium, approximately 1200 mg per day in divided doses. Vitamin D requirements are 1000 units per day, if the subject is not exposed to adequate sunlight without sun block.

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