PMDD: Breaking the Cycle

This is supported by Bayer HealthCare Pharma.

Physical and psychologicalsymptoms associated withthe menstrual cycle, commonlyreferred to as premenstrualsyndrome (PMS), occur in up to 80%of women during their reproductiveyears. Symptoms generally manifest 7to 10 days prior to menses, andalthough they vary widely, symptomsof PMS typically include fatigue, bloating,irritability, and depression.

Defining PMDD

Premenstrual dysphoric disorder(PMDD) is a more severe manifestationof PMS and is less common,occurring in 3% to 8% of women intheir reproductive years. The symptomsdevelop during the luteal phaseof the menstrual cycle, begin toimprove in the early follicular phase,and subside in the week aftermenses. The DSM-IV criteria for thediagnosis of PMDD specify that 5 ormore symptoms occur for mostcycles over 1 year.¹

Symptoms of PMDD

The symptoms can be categorizedas behavioral (fatigue, insomnia, foodcravings), psychological (irritability,anxiety, mood swings, anger), andphysical (headache, breast tenderness,muscle pain, edema, bloating).At least 1 symptom must be psychological,ie, a marked mood change?either depressed mood, anxiety, labileaffect, or anger. Finally, and perhapsmost important, the symptoms mustcause significant impairment of socialand occupational functioning.¹

The cause of PMDD is unknown,but symptoms appear to be triggeredby fluctuating hormone levels duringthe menstrual cycle, which is associatedwith dysregulation of serotoninin susceptible women. The diagnosisof PMDD is based on documentationof the severity and pattern of symptomsin a symptom diary and the useof a history, physical examination, andlaboratory testing to rule out otherpotential conditions that mimicPMDD, such as perimenopause, thyroidconditions, and mood and anxietydisorders.

Treatment Options for PMDD

Women with symptoms of PMSmay benefit from lifestyle interventions,such as increased exercise andthe limitation of sodium, caffeine,sugar, and alcohol in the diet; practicinggood sleep hygiene; and supplementationwith vitamin B⁶ (50 to 100mg per day), calcium (1200 mg elementalper day), and vitamin E (400 IUper day).²

The frequency and severity ofsymptoms associated with PMDD,however, usually require pharmacotherapyfor adequate management.Approaches can either targetspecific symptoms or provide morecomprehensive relief of physical andpsychological symptoms. For example,acetaminophen or anti-inflammatoryagents can be used for the reliefof headache and muscle pain, and thediuretic spironolactone may be helpfulfor symptoms associated with fluidretention.

Psychotropic Agents

Various psychotropic agents mayprovide relief of psychological andbehavioral symptoms. Because of thelink with serotonin, one approach is toadminister a selective serotonin reuptakeinhibitor (SSRI). Fluoxetine(Sarafem), sertraline (Zoloft), andparoxetine controlled-release (PaxilCR) have received FDA approval forthe treatment of PMDD, althoughother agents are used clinically. Theseagents can provide symptom reliefwhen administered daily or intermittentlyfor the 14 days prior to theexpected onset of menstruation. Thisallows patients to limit the length ofmedication use to only symptomaticintervals. The use of SSRIs may beassociated with gastrointestinal sideeffects, insomnia, and sexual dysfunction.³ Earlier studies with tricyclic antidepressantssuch as nortriptyline andclomipramine have also demonstratedbenefit, but lower tolerability dueto anticholinergic effects and weightgain has limited their use.⁴ Forpatients with symptoms of anxiety,benzodiazepines such as alprazolammay be an option, but they are typicallyreserved for second-or third-lineuse due to concerns about toleranceand dependence. Buspirone may bepreferred for the management of anxietyover the benzodiazepines due tothis concern.⁴

Hormone Treatments

Another treatment approach involvesthe direct alteration of the hormonefluctuations of the menstrualcycle. The use of gonadotropin-releasinghormone agonists results inamenorrhea and a "pseudomenopause,"but is often poorly toleratedbecause of symptoms of low estrogensuch as hot flashes and vaginaldryness. Danazol also inhibits releaseof gonadotropins but is associatedwith treatment-limiting androgeniceffects such as hirsutism. The use ofcombined mono-or biphasic oral contraceptives,which prevent ovulationand provide consistent levels of hormonesacross the treatment interval,is a more common approach and isespecially beneficial for women desiringcontraception. Although widelyused, the benefits of combined oralcontraceptives for the symptoms ofPMDD have not been well-documentedin the literature and have been primarilylimited to relief of physicalsymptoms such as bloating, headaches,and breast tenderness.⁵Combined oral contraceptives vary inestrogen content and type of progestin,and tolerability varies widelybetween individuals. In addition, certainpatients are poor candidates forestrogen-containing contraceptives,such as those with a history of estrogen-dependent cancer, thromboembolicevents, gallbladder disease,uncontrolled hypertension, and tobaccouse.

A recent trend in hormonal contraceptioninvolves the shorteningof the 7-day hormone-free interval of thetypical "21/7" regimen toreduce symptoms of hormonewithdrawal thatsome patients experience.Yaz (ethinyl estradiol anddrospirenone) is an exampleof a "24/4" regimen thatwas recently approved forthe treatment of PMDD andacne in women whochoose oral contraceptivesfor contraception. Drospirenoneis structurally relatedto spironolactone andexhibits antiandrogen andantimineralocorticoid effects,which may helpreduce symptoms of bloatingand counteract estrogen-induced fluid retention.As with spironolactone, patientswho are predisposedto hyperkalemia are notappropriate candidates forthis formulation. Clinicalstudies have demonstratedsignificant improvement in both physicaland psychological symptoms ofPMDD.^5-7 Patients using a "24/4" regimenalso report benefits of a shorterand lighter menstrual flow.

In summary, several treatmentoptions for PMDD can be individuallymatched to a patient's needs. Oralcontraceptives, especially those witha shorter hormone-free interval, mayprovide a suitable alternative to antidepressantsfor patients with PMDDwho also desire contraception.

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

References

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 inhibitorsfor 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. ObstetGynecol 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 premenstrualdysphoric disorder. Obstet Gynecol. 2005;106:492-501.

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