PMDD: Breaking the Cycle

APRIL 01, 2007
Erin Raney, PharmD, BCPS

This is supported by Bayer HealthCare Pharma.

Physical and psychological symptoms associated with the menstrual cycle, commonly referred to as premenstrual syndrome (PMS), occur in up to 80% of women during their reproductive years. Symptoms generally manifest 7 to 10 days prior to menses, and although they vary widely, symptoms of PMS typically include fatigue, bloating, irritability, and depression.

Defining PMDD

Premenstrual dysphoric disorder (PMDD) is a more severe manifestation of PMS and is less common, occurring in 3% to 8% of women in their reproductive years. The symptoms develop during the luteal phase of the menstrual cycle, begin to improve in the early follicular phase, and subside in the week after menses. The DSM-IV criteria for the diagnosis of PMDD specify that 5 or more symptoms occur for most cycles over 1 year.1

Symptoms of PMDD

The symptoms can be categorized as behavioral (fatigue, insomnia, food cravings), psychological (irritability, anxiety, mood swings, anger), and physical (headache, breast tenderness, muscle pain, edema, bloating). At least 1 symptom must be psychological, ie, a marked mood change? either depressed mood, anxiety, labile affect, or anger. Finally, and perhaps most important, the symptoms must cause significant impairment of social and occupational functioning.1

The cause of PMDD is unknown, but symptoms appear to be triggered by fluctuating hormone levels during the menstrual cycle, which is associated with dysregulation of serotonin in susceptible women. The diagnosis of PMDD is based on documentation of the severity and pattern of symptoms in a symptom diary and the use of a history, physical examination, and laboratory testing to rule out other potential conditions that mimic PMDD, such as perimenopause, thyroid conditions, and mood and anxiety disorders.

Treatment Options for PMDD

Women with symptoms of PMS may benefit from lifestyle interventions, such as increased exercise and the limitation of sodium, caffeine, sugar, and alcohol in the diet; practicing good sleep hygiene; and supplementation with vitamin B6 (50 to 100 mg per day), calcium (1200 mg elemental per day), and vitamin E (400 IU per day).2

The frequency and severity of symptoms associated with PMDD, however, usually require pharmacotherapy for adequate management. Approaches can either target specific symptoms or provide more comprehensive relief of physical and psychological symptoms. For example, acetaminophen or anti-inflammatory agents can be used for the relief of headache and muscle pain, and the diuretic spironolactone may be helpful for symptoms associated with fluid retention.

Psychotropic Agents

Various psychotropic agents may provide relief of psychological and behavioral symptoms. Because of the link with serotonin, one approach is to administer a selective serotonin reuptake inhibitor (SSRI). Fluoxetine (Sarafem), sertraline (Zoloft), and paroxetine controlled-release (Paxil CR) have received FDA approval for the treatment of PMDD, although other agents are used clinically. These agents can provide symptom relief when administered daily or intermittently for the 14 days prior to the expected onset of menstruation. This allows patients to limit the length of medication use to only symptomatic intervals. The use of SSRIs may be associated with gastrointestinal side effects, insomnia, and sexual dysfunction.3 Earlier studies with tricyclic antidepressants such as nortriptyline and clomipramine have also demonstrated benefit, but lower tolerability due to anticholinergic effects and weight gain has limited their use.4 For patients with symptoms of anxiety, benzodiazepines such as alprazolam may be an option, but they are typically reserved for second-or third-line use due to concerns about tolerance and dependence. Buspirone may be preferred for the management of anxiety over the benzodiazepines due to this concern.4

Hormone Treatments

Another treatment approach involves the direct alteration of the hormone fluctuations of the menstrual cycle. The use of gonadotropin-releasing hormone agonists results in amenorrhea and a "pseudomenopause," but is often poorly tolerated because of symptoms of low estrogen such as hot flashes and vaginal dryness. Danazol also inhibits release of gonadotropins but is associated with treatment-limiting androgenic effects such as hirsutism. The use of combined mono-or biphasic oral contraceptives, which prevent ovulation and provide consistent levels of hormones across the treatment interval, is a more common approach and is especially beneficial for women desiring contraception. Although widely used, the benefits of combined oral contraceptives for the symptoms of PMDD have not been well-documented in the literature and have been primarily limited to relief of physical symptoms such as bloating, headaches, and breast tenderness.5 Combined oral contraceptives vary in estrogen content and type of progestin, and tolerability varies widely between individuals. In addition, certain patients are poor candidates for estrogen-containing contraceptives, such as those with a history of estrogen-dependent cancer, thromboembolic events, gallbladder disease, uncontrolled hypertension, and tobacco use.

A recent trend in hormonal contraception involves the shortening of the 7-day hormone- free interval of the typical "21/7" regimen to reduce symptoms of hormone withdrawal that some patients experience. Yaz (ethinyl estradiol and drospirenone) is an example of a "24/4" regimen that was recently approved for the treatment of PMDD and acne in women who choose oral contraceptives for contraception. Drospirenone is structurally related to spironolactone and exhibits antiandrogen and antimineralocorticoid effects, which may help reduce symptoms of bloating and counteract estrogen-induced fluid retention. As with spironolactone, patients who are predisposed to hyperkalemia are not appropriate candidates for this formulation. Clinical studies have demonstrated significant improvement in both physical and psychological symptoms of PMDD.5-7 Patients using a "24/4" regimen also report benefits of a shorter and lighter menstrual flow.

In summary, several treatment options for PMDD can be individually matched to a patient's needs. Oral contraceptives, especially those with a shorter hormone-free interval, may provide a suitable alternative to antidepressants for patients with PMDD who also desire contraception.

Dr. Raney is an associate professor of pharmacy practice at Midwestern University College of Pharmacy-Glendale, Glendale, Ariz.


1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:717-718.

2. American College of Obstetricians and Gynecologists. Premenstrual syndrome. Washington, DC: ACOG; 2000. ACOG Practice Bulletin no 15.

3. Wyatt KM, Dimmock PW, O'Brien PM. Selective serotonin reuptake inhibitors for premenstrual syndrome. Cochrane Database Syst Rev. 2002:3;Art. No.: CD001396. DOI: 10.1002/14651858.CD001396.

4. Kessel B. Premenstrual syndrome: advances in diagnosis and treatment. Obstet Gynecol Clin North Am. 2000;27:625-639.

5. Kroll R, Rapkin A. Treatment of premenstrual disorders. J Reprod Med. 2006;51(4 suppl 1):359-370.

6. Yonkers KA, Brown C, Pearlstein TB, Foegh M, Sampson-Landers C, Rapkin A. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol. 2005;106:492-501.

7. Pearlstein TB, Bachmann GA, Zacur HA, Yonkers KA. Treatment of premenstrual dysphoric disorder with a new drospirenone-containing contraceptive formulation. Contraception. 2005;72:414-421.