(Published June 2008)
More than 80 different therapies have been suggested for the treatment of PMS/PMDD, resulting in much conflicting information and many unwarranted claims of effectiveness. No single intervention is effective for all women, and there is a substantial placebo response with many therapies.1 It may take time and several attempts to determine the safest and most effective treatment for an individual patient.
Treatment of PMS/PMDD is best approached in a stepwise fashion, beginning with lifestyle modifications and progressing to nutritional supplementation, nonpharmacologic therapy, and nonprescription and prescription medications. Conservative treatment has proved beneficial in many women and should be considered first-line therapy in women with mild symptoms and adjunctive therapy in all others.
Table 2 shows a hierarchical approach to the treatment of PMS/PMDD that matches the aggressiveness of the approach to the severity of symptoms. Selection of therapy can also be matched to the nature of the symptoms. For instance, women with a PMS diagnosis presenting with bloating and breast tenderness as her key symptoms (Level 2) may be prescribed spironolactone, if there are no contraindications, to minimize this specific symptom.
|Table 2. Hierarchical Approach to the Treatment of PMS and PMDD2|
|Move to the next level if the chosen approach is ineffective for two to four cycles.Level 1. PMS, mild to moderate:
Level 2. PMS with physical problems predominating:
Level 3. PMS or PMDD with mood symptoms predominating:
Level 4. PMDD not responsive to therapy for Levels 1–3:
|* If initial SSRI is ineffective or not tolerated, try at least two additional types of SSRIs (including venlafaxine) before abandoning this type of agent.
GnRH = gonadotropin-releasing hormone; MPA = medroxyprogesterone acetate; DMPA = depo-medroxyprogesterone acetate; NSAID = nonsteroidal anti-inflammatory drug; OC = oral contraceptive; PMS = premenstrual syndrome; PMDD = premenstrual dysphoric disorder; SSRI = selective serotonin reuptake inhibitor.
Treatment must be individualized and often requires a combination of approaches. Long-term treatment of PMS/PMDD is typically required, as evidence indicates that symptoms return when treatment is discontinued.3
Treatment of mild premenstrual disorders begins with 2–3 months of lifestyle changes during the same time the woman is charting her symptoms. Based on medical history, the modifications listed in Table 3 can be suggested.
|Table 3. Lifestyle Modifications for Mild PMS4 – 21|
Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) should be considered first-line therapy for the pharmacologic treatment of severe premenstrual symptoms.22 An estimated 60% of women respond to this class of drugs.15 SSRIs have been shown to be effective for both PMS and PMDD9 and to be equally efficacious for the treatment of physical, behavioral, and psychological symptoms.23
Safety and Side Effects
The long-term safety of SSRIs has been demonstrated based on their widespread use in treating depression.1 More recently, this class of drugs has had labeling changes to reflect the increased risk of suicidal thinking and behavior in young adults.22,23
Side effects of SSRIs include the following:
- Decreased libido
- Gastrointestinal disturbances (including nausea and indigestion)
- Dry mouth
- Weight gain
These side effects are generally manageable and may be reduced or eliminated by dose modification and use during the luteal phase only. There is no addictive potential and no tolerance with extended use of SSRIs. SSRIs are classified as Pregnancy Category C.
Orgasmic dysfunction (normal libido and arousal with delayed or absent orgasm) is the most problematic side effect of this class of drugs, reported in up to 80% of patients taking SSRIs continuously and for long duration.24
Sexual dysfunction can be managed by the following:3
- Taking a watch and wait approach, as it may resolve on its own
- Reducing the dose
- Taking drug holidays
- Substituting another SSRI agent
- Augmenting treatment with various agents (such as bupropion)
Women who have been counseled to anticipate that it may be more difficult to achieve orgasm when using SSRIs and other serotonergic agents may be best equipped to manage this common side effect, often through communication with their partner. Many women experiencing relief of their PMS/PMDD symptoms may be so pleased with their improvement on SSRIs that they are willing to tolerate or adapt to the sexual dysfunction associated with use of this class of medications.
Unlike the use of SSRIs to treat depression, which may take 4–8 weeks to show efficacy, SSRIs used to treat PMS may reduce symptoms in a matter of days, and usually within 4 weeks after the start of treatment.23 For this reason, intermittent dosing with these medications can be used in some patients, thereby reducing prescription costs and side effects and increasing compliance. Other women prefer the simplicity of continuous daily dosing.
The doses of SSRIs needed to treat PMS are typically lower than those used to treat depression and anxiety.23 Table 4 shows the recommended doses of various SSRIs for the treatment of premenstrual disorders. Intermittent treatment is recommended, either during the luteal phase or on symptom days only.2
|Table 4. Serotonergic Agents: Dosage and Administration for Treating Premenstrual Disorders|
|* Consider starting women at lower doses to reduce side effects and improve adherence.
** Approved for the treatment of PMDD by the U.S. Food and Drug Administration.
Other Serotonergic Agents
Agents such as venlafaxine and clomipramine are also often used to treat PMDD.25 These agents inhibit the serotonin transporter as well as the uptake of norepinephrine and may be beneficial for some women who do not respond to or tolerate the “pure” SSRIs.2,15 Adding bupropion (a nonserotonergic agent) to a serotonergic antidepressant can boost antidepressant efficacy without increasing side effects such as orgasmic dysfunction. Nonserotonergic antidepressants, however, have not specifically been found to be effective in treating PMS.2
The use of oral contraceptives (OCs) reduces dysmenorrhea, intensity and duration of menstrual flow. Because premenstrual symptoms occur almost exclusively in ovulatory cycles, inhibiting ovulation could be expected to reduce or eliminate these symptoms.26 Hormonal contraceptives that suppress ovulation, including the pill, patch, vaginal ring, and depot-medroxyprogesterone acetate (DMPA) injections, offer effective relief from premenstrual symptoms for many women.
Because women using OCs for PMS often experience symptoms during the hormone-free interval, the selected treatment strategy should minimize or eliminate the hormone-free interval. Women may use monophasic OCs continuously, omitting the 7-day inert pills and starting a second pack immediately after the last active pill of their current pack. This regimen is safe and can be used indefinitely. Extended-regimen OCs, which are packaged with 84 days of active treatment with a 7-day pill-free interval (e.g., Seasonale®, Seasonique®), or continuous OC regimens (Lybrel®) may decrease hormone withdrawal symptoms, which include menstrually related headaches, cyclic mood swings, pelvic pain, and dysmenorrhea. Unscheduled bleeding is common during extended or continuous use of OCs. Provided that the patient has used OC tablets for a minimum of the last 21 days, taking a 3-day break from OC use and then resuming their use can reduce future episodes of unscheduled bleeding.27 Monthly OCs with a reduced hormone-free interval (Mircette®, LoEstrin 24®,YAZ®) may also have advantages over traditional 21/7 OC formulations in treating premenstrual symptoms.
Until recently, only limited data have assessed the efficacy of OCs in the treatment of PMS, and the few randomized trials have published conflicting results. However, two recently published multicenter randomized trials found that women’s PMDD symptoms were significantly reduced with a combination OC formulation (24 tablets containing drospirenone and ethinyl estradiol followed by 4 hormonally inert tablets).27,28 Drospirenone is a spironolactone antagonist that binds to the androgen receptor. This OC formulation had a greater impact on physical symptoms than placebo but also significantly improved mood symptoms. On the basis of these landmark trials, this 24/4 OC formulation with drospirenone (YAZ®), has received FDA approval for the treatment of PMDD, and also represents an OC formulation that clinicians and women may choose when PMS or other premenstrual symptoms are present.
If PMS or PMDD is diagnosed in a patient who is already using OCs, premenstrual symptoms may be reduced by switching to a formulation with a reduced hormone-free interval, to an extended continuous OC formulation, or to one that contains the progestin drospirenone.
Other Pharmacologic Agents
Other medications have been used to treat the symptoms of PMS/PMDD with various levels of success (Table 5).
|Table 5. Other Pharmacologic Agents for the Treatment of PMS/PMDD15|
|Agent||Type/Class||Effective for Symptoms||Notes|
|Alprazolam||GABA agonist; benzodiazepine
|Addictive and sedating. Should be reserved for intermittent use as a second-line agent.|
|Bromocriptine||Dopamine agonist; lowers prolactin levels||Breast tenderness||Side effects may include dizziness and nausea.|
|Buspirone||Partial serotonin agonist||Anxiety||No addictive potential.|
|Danazol||Weak synthetic androgen; inhibits LH and FSH, suppressing ovarian steroid production||Side effects limit use:
|GnRH agonists||Reduce LH and FSH
|Creates “pharmacologic menopause,” with associated menopause-like effects.
Should be reserved for women who do not respond to other treatments.
Add-back estrogen/progestin needed if continued >6 months.
|NSAIDs||Anti-inflammatory||Dysmenorrhea||Also reduce menstrual flow.|
|Spironolactone||Potassium-sparing diuretic; anti-mineralocorticoid and anti-androgenic properties||Bloating
|Not highly effective.
Monitor serum potassium levels.
|FSH = follicle-stimulating hormone; GABA = gamma-aminobutyric acid; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone.|
Patients should be advised not to take herbal preparations randomly or without consultation.
A few studies have examined the use of other forms of alternative therapies for the treatment of PMS/PMDD. Other alternative therapies women may want to explore include the following:15,30
- Acupressure and acupuncture
- Chiropractic and massage therapy
- Homeopathic remedies
- Light therapy
- Vaginal biofeedback34
|Table 6. Herbal Supplements Used for the Treatment of PMS/PMDD2,4,15,32|
|Evening primrose oil||500 mg per day to 1,000 mg t.i.d.
Most studied, but no safety data
|Chaste tree extract (Vitex agnus-castus)||30–40 mg/day
Few adverse effects, but no safety data
Shown to be inferior to fluoxetine
|St. John’s wort||No controlled trials evaluating use for PMS
Possible drug interactions
Long-term effects unknown
|Natural progesterone||Shown to be ineffective in controlled trials|
|Gingko||No controlled trials
Potential for drug interactions
|Kava||No controlled trials
Potential for hepatotoxicity
|Dong quai||No controlled trials
Unsafe in pregnancy
Contains coumarin derivative—should not be used by patients on anticoagulants
|Black cohosh||Stimulates estrogen receptors
Used to treat anxiety, breast pain
No controlled trials or safety data
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About Audrey Kelly, PharmD