New Treatment Approaches for Premenstrual Disorders

Supplements and Featured Publications, Managing the Spectrum of Premenstrual Symptoms, Volume 11, Issue 16 Suppl

Several approaches to alleviating the symptoms ofpremenstrual disorders are available to women andcan be tailored according to individual needs andpreferences. This article discusses methods that entailchanges to lifestyle and diet and managing life stresseswithout relying on drug therapy, as well as a varietyof medications that may be necessary in additionto or in place of recommended lifestyle modifications.New pharmacologic research is promising andis discussed along with the need to provide empatheticcounseling for patients to determine theapproach that will work best for each individual.

(Am J Manag Care. 2005;11:S480-

S491)

The term "premenstrual disorders"covers a spectrum of premenstrualsymptom combinations, from mildpremenstrual syndrome (PMS) to premenstrualdysphoric disorder (PMDD) that issevere enough to interfere with work andsocial functioning. Effective evaluation andtreatment of PMS were hampered until themid-1980s by the lack of established criteriafor diagnosing this common condition. TheAmerican College of Obstetricians andGynecologists (ACOG) published a practicebulletin in 2000 that included criteria forPMS, based on an earlier article by Mortolaand colleagues, as well as a discussion ofdifferent approaches for treating PMS,1,2including lifestyle modifications such as regularaerobic exercise and dietary changes.Pharmacologic options studied for treatingsevere PMS include selective serotonin reuptakeinhibitors (SSRIs), anxiolytic agents,gonadotropin-releasing hormone (GnRH)agonists, the diuretic spironolactone, andcombination oral contraceptives (OCs).

Diagnostic and

Statistical Manual of Mental Disorders

Fourth Edition, Text Revision (DSM-IV-TR)

PMDD is defined as a psychiatric disorderin Appendix B of the ,.3Currently, selected SSRIs are the only pharmacologicagents with a US Food and DrugAdministration (FDA) indication for PMDD.

DSM-III

Prior to the early 1990s when PMDD wasdefined as "late luteal dysphoric disorder" in, various severities of PMS andPMDD were often investigated and discussedwithout differentiation. Therefore, many ofthe early studies in which the term "PMS"was used probably included patients withPMDD as well. It is necessary to keep thisfact in mind when reviewing the literatureon premenstrual disorders.

In this article, a number of available nonpharmacologicand pharmacologic treatmentsare reviewed, as well as recentadvances in pharmacotherapy for premenstrualdisorders.

Lifestyle Modifications

Lifestyle modification rather than drugtherapy may be the most appropriate treatmentapproach for women with mild PMSsymptoms. Physicians should always informtheir female patients about lifestyle changesthat may ameliorate their premenstrualsymptoms and advise them to evaluate theeffect of various approaches during the 2months for which they keep a daily symptomdiary. (At least 2 months of prospectivedaily symptom recording are required for adiagnosis of PMS or PMDD.) Regular aerobicexercise, for example, eases premenstrualsymptoms for many women.4 The decline inendorphin levels that normally occurs in thelate luteal phase of the menstrual cycle hasbeen suggested to be an underlying mechanismfor premenstrual symptoms in somewomen. Because regular aerobic exerciseleads to the release of endorphins in the centralnervous system, physicians should recommendthat women perform at least 20 to30 minutes of aerobic exercise per day for atleast 3 days each week.5

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Dietary and nutritional modificationshave also been used over the years totreat premenstrual symptoms. One suchapproach, calcium supplementation, wasstudied by Thys-Jacobs and colleagues in466 evaluable women with moderate-to-severepremenstrual symptoms that hadbeen documented over 2 cycles.6 Participantswere randomized to receive 1200mg/day of elemental calcium or a placebo for3 cycles. Premenstrual symptoms were significantlylower in the calcium-treated groupthan in controls in the second (= .007) andthird (<.001) treatment cycles. Therefore,calcium supplementation appeared toreduce premenstrual symptoms in somewomen.

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Other studies have suggested that excessalcohol, salt, and caffeine intakes may actuallyworsen premenstrual symptoms bydecreasing magnesium levels.7 For example,Walker et al conducted a double-blind,placebo-controlled, crossover study inwhich 41 evaluable women were randomizedto 200 mg/day of magnesium or placebofor 2 cycles before being crossed over to thealternate treatment for 2 additional cycles.8Walker and colleagues observed that dailymagnesium supplementation significantlylowered mild symptoms of fluid retention(ie, weight gain, breast tenderness, swellingof extremities, and abdominal bloating)compared with placebo in the second cycleof administration (= .0009), but not in thefirst cycle.7

Another study conducted by Freemanand colleagues included 53 women with premenstrualsymptom rates that were 30%higher during the late luteal phase than inthe follicular phase.9 Patients were randomizedto a commercial carbohydrate-richbeverage or to an isocaloric placebo beveragetaken twice daily for 5 days before theanticipated onset of menses. Mood symptomswere decreased in approximately onethird of women consuming the carbohydrate-rich beverage, compared with 5% ofthe placebo group.

A study indicated that vitamin B6 hadsome clinical benefit in reducing premenstrualsymptoms,10 but doses in excess of100 mg/day can be harmful.1 Additionally,the herbal product evening primrose oil hasnot been shown to be effective in treatingpremenstrual symptoms11; however, theACOG practice bulletin indicated that itmay decrease breast tenderness.1 Finally,with regard to nutrition, reductions in salt,sugar, alcohol, and caffeine intake areoften suggested for relieving premenstrualsymptoms, but these approaches have notbeen investigated extensively in controlledstudies.12

Pharmacotherapeutic Options

Compared with the nonpharmacologicapproaches, pharmacotherapeutic optionsfor managing premenstrual disorders havebeen investigated in greater detail. However,the study techniques employed have variedwidely, including methods of diagnosis, outcomesanalyzed, and methods of outcomemeasurement. Studies should include proceduresfor recording improvements inpsychological symptoms and physical symptomsas well as overall improvement. Dailyself-report diaries constitute the primarymeasurement, but some clinician-ratedscales have also been validated. In addition,symptom assessment should include severalmonths of tracking to confirm the diagnosisbefore entry into the study and placebo runinperiods to exclude placebo responders.

Antidepressants.

Of numerous optionsavailable, antidepressants from the class ofthe SSRIs may be considered the therapyof choice for PMDD in many patients.Currently, the only agents with an FDAindication for PMDD are fluoxetine hydrochloride,sertraline hydrochloride, andparoxetine hydrochloride. Unlike tricyclicantidepressants, which interact with severalreceptors, the SSRIs interact minimally withreceptors other than the serotonin (5-HT)reuptake receptor.13 Fluoxetine has a recommended dose of 20 mg/day (Figure 1); inclinical studies, no added benefit wasobserved with increasing the dosage to 60mg/day. Sertraline is initiated at a dose of 50mg/day and can be increased up to 150mg/day for daily dosing or up to 100 mg/dayfor dosing only during the luteal phase of thecycle. Paroxetine is initiated at a dose of12.5 mg/day and can be increased to 25mg/day.14 Clinical trials that formed thebasis for approval of these 3 SSRIs for managingPMDD symptoms and additional trialswith other SSRIs are listed in Table 1.

Several adverse effects are associatedwith daily use of the SSRIs that have receivedan FDA indication for PMDD (Table 2).Individual response to these side effects maylead to poor adherence or discontinuation ofthese medications.

In a study to investigate compliance toantidepressant agents prescribed for PMS,Sundström-Poromaa and colleagues notedreasons given by these patients for discontinuingantidepressant use.15 A total of 170(84.2%) of the 202 women who were prescribedan SSRI or a tricyclic antidepressantfor PMS during a 4-year period completed awritten questionnaire. The 22 (12.9%)women who never started treatment listedtheir primary reasons as fear of negative sideeffects (54.5%) and not wishing to take thistype of drug (54.5%). (A woman could givemore than 1 reason for not initiating antidepressanttherapy.) Of the 148 (87.1%)women who did start therapy, 91 (61.5%)had discontinued the antidepressant by theend of 2 years. Table 3 lists the reasons fordiscontinuation of therapy.

Women who experience severe side effectscan be advised to switch to a different SSRI.Should they choose to switch to a differentdrug class, the SSRI dose must be taperedslowly to avoid discontinuation symptoms.In addition, the FDA recently revised thesafety labeling for SSRIs to advise againsttheir use in patients younger than 18 yearsand to warn patients with major depressivedisorder of the risk for worsening symptomsand/or for suicidal ideations.

Studies with non-SSRI/selective norepinephrineantidepressants have had lessfavorable results compared with SSRIs. Acomparative study of treatment with sertralineand desipramine (flexible dosage range50-150 mg/day) vs placebo in 189 subjectswith PMS/PMDD showed that sertraline wassignificantly more effective than placebo onthe Penn Daily Symptom Report (>50%symptom decrease in 65% of subjects in thesertraline groups), whereas desipraminewas not (symptom decrease in 36% ofsubjects in the sertraline group and 29%in the placebo group).16 Another comparativestudy investigated fluoxetine 20mg/day, bupropion 100 mg/day, andplacebo in 34 women with PMDD. Fluoxetinewas superior to both bupropion andplacebo in efficacy by Global ClinicalImpression ratings. Posttreatment HamiltonRating Scale for Depression andGlobal Assessment Scale rating scoreswere intermediate between but not significantlydifferent from fluoxetine orplacebo.17

On the whole, studies conducted withantidepressants in women with PMS andPMDD indicate that serotonergic activity isrequired for efficacy. The SSRIs have beeninvestigated for both continuous and lutealphase(intermittent) administration, and fluoxetine,paroxetine CR (controlled release),and sertraline are approved for use in PMDDwithout specification of the regimen, so canbe employed continuously or intermittently.Onset of efficacy is rapid: therapeutic benefitis seen in the first menstrual cycle afterinitiation of treatment with these agents.Patients on systemic hormonal contraceptiveswere excluded from many of the SSRItrials, so the efficacy of SSRIs in combinationwith systemic (including oral) hormonalcontraceptives for the continuous dailytreatment of PMDD is unknown.

Anxiolytics.

The anxiolytic agent alprazolamhas not shown consistent results instudies evaluating its effectiveness in alleviatingpremenstrual symptoms, according tothe ACOG practice bulletin.1 In a study conductedby Evans and colleagues, womenwith premenstrual symptoms were giveneither alprazolam (0.25, 0.50, or 0.75 mg) orplacebo during both the luteal and follicularphases of the cycle under controlled laboratoryconditions.18 It was observed that acutedoses of alprazolam did not improve negativepremenstrual mood and actually wereassociated with an increase in negativemood in the follicular phase.18 Also, alprazolamimpaired task performance in bothphases of the cycle. As a result, acute administrationof alprazolam was not deemed aclinically useful treatment for premenstrualsymptoms. In addition, continued use ofalprazolam can lead to dependency, andsome users develop a tolerance to this agent.

GnRH agonists.

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A third treatment optionis the class of GnRH agonists, which use ahormonal approach to suppress ovariansteroid hormone production and preventovulation, in effect by inducing medicaloophorectomy.4 These agents have demonstratedefficacy in alleviating several premenstrualsymptoms. For example, in a smallstudy conducted by Mortola and colleagues,19 GnRH monotherapy was associatedwith at least a 75% improvement frombaseline in the Calendar of PremenstrualExperiences (COPE) scores for behavioral(<.01), physical (<.05), and total (<.01)symptoms. However, because GnRH agonistsinduce medical menopause, estrogenand progestin must be added back to preventbone loss and potentially for cardioprotection.4 According to an additional, smallstudy, 10 women with PMS symptoms givenleuprolide acetate at 3.75 mg/mo for 3months had a significant decrease in symptomsmeasured using a Daily Rating Formand the observer form of the Rating Scale forPremenstrual Tension Syndrome. Additionof either progesterone vaginal suppositoriesor a 17&#946;-estradiol patch or the leuprolideregimen resulted in significant return ofsymptoms. No changes in mood occurred in15 normal women who received the sameregimen. The authors conclude that inwomen with PMS, the occurrence of symptomsrepresents an abnormal response tonormal hormonal changes.20

Synthetic androgens.

Danazol, a syntheticandrogen indicated in the United Statesfor the treatment of endometriosis, menorrhagia,fibrocystic breast disease, and hereditaryangioedema, has also been investigatedfor the management of PMS and premenstrualmastalgia, with moderate results.Luteal-phase-only danazol was not effectivefor treating the general symptoms (dailyanalogue scale scores) of premenstrual syndrome,but appeared highly effective forrelieving premenstrual mastalgia in a studyconducted on 100 women.21 A smaller study,conducted in 31 women meeting rigorouscriteria for a diagnosis of severe PMS, evaluatedeffects of danazol treatment using thePremenstrual Tension Self-Rating Scale, theBeck Depression Inventory, and a visualanalogue scale. Danazol 200 mg bid providedgreater symptom relief than did placebo.22 Potential adverse effects of danazol area cause for concern with this agent.23

Diuretics.

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Another therapeutic considerationis spironolactone, an aldosteronereceptor agonist derived from 17&#945;-spirolactone. According to the ACOGpractice bulletin, thiazide diuretics havenot been demonstrated to be beneficial inalleviating premenstrual fluid retention,but spironolactone has, in fact, beenshown to have benefit in PMS.1 Spironolactonealso has been shown to relieveother symptoms associated with the premenstrualphase of the cycle,4 as noted in adouble-blind, parallel-group study over 3cycles conducted by Vellacott and colleagues.24 Sixty-three women, aged 16 to 45,with a history of at least 6 months of cyclicsymptoms were randomized to spironolactone100 mg/day or to placebo, given fromday 12 of the menstrual cycle to the onset ofmenses. Spironolactone was significantlysuperior to placebo in relieving the generalfeeling of bloating (= .001). By cycle 3,more than half of the 26 women usingspironolactone also experienced improvementof abdominal swelling, swelling of thehands and feet, breast discomfort, irritability,depression, anxiety, tension, and increasein sexual interest.

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Spironolactone was also examined in adouble-blind, crossover study conducted byWang and colleagues in 35 women withPMS.25 Two pretreatment cycles were usedto diagnose PMS, after which the treatmentphase began, consisting of two 3-month periods.Women were randomized to 100 mg/dayof spironolactone or placebo administereddaily from day 14 of the menstrual cycleuntil the onset of menses. The primary outcomemeasure was the prospective dailyvisual analogue scale. During the intervalswhen women were taking spironolactone,they experienced significant improvementsin negative symptoms (ie, anxiety and tension,irritability, fatigue, and depression)and in physical symptoms (ie, headache,feelings of swelling, cravings for sweets, andbreast tenderness) compared with baselinevalues and with placebo (<.01 for all measures).Spironolactone treatment was alsoassociated with an improvement in positivesymptoms (cheerfulness, well-being, friendliness,feeling energetic) compared withbaseline values (<.01).

Oral contraceptives.

Another hormonaloption, combination OCs, is a popularchoice for helping to relieve several premenstrualsymptoms. In the United States, OCscontain estrogen as ethinyl estradiol (EE) incombination with a variety of progestins. EEcauses a rise in serum aldosterone levels,which lead to sodium and water retention,thereby contributing to bloating and breasttenderness.26 All progestins have progestogenicactivity, but they can differ in terms ofother pharmacologic effects. The pharmacologicprofiles of progesterone and variousprogestins used in OCs (as found in animalmodels) are demonstrated in the work ofKrattenmacher.27

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Until recently, very few controlled studieshad evaluated the efficacy of OCs in reducingpremenstrual symptoms, and those thathad been conducted yielded mixed results.For example, in 1992 Graham and Sherwinstudied 82 women with moderate-to-severepremenstrual symptoms in a double-blind,placebo-controlled trial.28 The women charteddaily symptoms for 1 cycle, after whichthey were randomly assigned to a triphasicOC containing EE 35 &#956;g and norethindrone(0.5 mg, 1.0 mg, and 0.5 mg) or to placebofor 3 cycles. A total of 23 women (28%)dropped out of the study (18 in the OCgroup and 5 in the placebo group). Compared with placebo, the OC significantlyreduced premenstrual breast pain and bloating(<.03) but did not have significantlybetter effects on mood symptoms.

Similarly, in a double-blind crossoverstudy of 3 OCs, 36 women aged 20 to 40 whoeither had PMS or experienced symptomsthroughout their entire menstrual cycle withpremenstrual aggravation were examined.29The study consisted of 2 treatment cycles followedby a crossover to the alternate preparationfor 2 additional treatment cycles.Nineteen women were randomly assignedto a monophasic OC containing EE combinedwith either desogestrel (DSG) or levonorgestrel(LNG), and 17 women wererandomized to treatment with either monophasicEE/DSG or a triphasic OC containingEE plus LNG. Mood scores improved frombaseline for all 3 OCs, but Bäckström andcolleagues concluded that the beneficialeffect observed in the study was no higherthan that reported for placebo in otherstudies. The monophasic DSG pill resultedin less change in mood parameters than didthe monophasic and triphasic LNG OCs.However, physical complaints were less frequentlyreported during the use of thetriphasic preparation as compared to themonophasic DSG preparation.29

Finally, a nested case-control study conductedby Joffe and colleagues examined acohort of 976 women, aged 36 to 45.30 Of the658 women who had previously used a varietyof OCs, 107 (16.3%) reported pill-relatedpremenstrual mood deterioration, 81(12.3%) reported premenstrual mood improvement,and 470 (71.4%) reported noeffect of OCs on premenstrual mood. Therefore,it was concluded that OCs do not affectpremenstrual mood in most women.30

All but one of the progestins being used inOCs in the United States are derived from19-nortestosterone. The exception is theprogestin drospirenone, which is derivedfrom 17&#945;-spirolactone and is an analogue ofspironolactone. The pharmacologic profileof drospirenone closely resembles that ofnatural progesterone in that it has potentprogestogenic, antiandrogenic, and antimineralocorticoidactivities, and no androgenicactivity.26 The antimineralocorticoidactivity of 3 mg of drospirenone is comparablewith 25 mg of spironolactone.31Drospirenone acts by binding to aldosteronereceptors, blocking aldosterone action in thekidneys, resulting in a substantial rise insodium and water excretion and some retentionof potassium (Figure 2).27

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In recent years, several studies haveexamined the efficacy of the OC formulationcontaining EE 30 &#956;g plus drospirenone 3 mg(30EE/drospirenone) on premenstrual symptoms.For example, a double-blind trialincluded 82 women with PMDD who wererandomized to 30EE/drospirenone (n = 42)or placebo (n = 40).32 The drospirenone-containingOC was observed to have a positiveeffect on symptoms of PMDD, with thebetween-group differences reaching statisticalsignificance in appetite, food cravings,and acne (= .03). In addition, Apter andcolleagues conducted an open, 6-cycle studyof 336 women to evaluate the actions of30EE/drospirenone on fluid-related symptomsduring the luteal phase of the cycle andthe effects of these symptoms on overall well-being.33 Use of 30EE/drospirenone was associatedwith a significant reduction in theincidence and severity of the abdominalbloating and breast tenderness (both <.001)associated with the menstrual cycle. Also, thesignificant beneficial effect of 30EE/drospirenoneon psychologic well-being (<.0001),as measured by the Psychological GeneralWell-Being Index, observed at cycle 3 wasmaintained at cycle 6.

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Further, an open-label, 26-cycle studywas conducted by Foidart and colleagues of627 evaluable women: 310 were randomizedto 30EE/drospirenone and 317 to EE 30 &#956;gplus DSG 150 &#956;g.34 Compared with theEE/DSG group, women who were given30EE/drospirenone experienced a greaterincidence of premenstrual symptoms beforethe study and a lesser incidence throughoutthe study. The between-group differenceswere not statistically significant. Morerecently, Sangthawan and Taneepanichskulconducted an open-label, 6-cycle study of 99evaluable women who were randomized toeither 30EE/drospirenone or EE 30 &#956;g plusLNG 150 &#956;g.35 The prevalence of premenstrualsymptoms was reduced from 58.0%at baseline to 32.0% at cycle 6 in the30EE/drospirenone group and rose from59.2% at baseline to 61.2% at cycle 6 in theEE/LNG group. The between-group differencewas statistically significant (= .005).

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Positive results with drospirenone werealso noted by Borenstein et al, who analyzedresponses of 858 women who completed asurvey when initiating 30EE/drospirenoneand again after 2 cycles of treatment.36Compared with baseline values, 30EE/drospirenoneuse was associated with significantreductions in premenstrual symptoms(<.001) and improvement in the women'ssense of well-being (<.05). Finally, Sillemand colleagues conducted an observationalstudy of 1433 women using 30EE/drospirenone,175 of whom continuously took thisOC between 42 and 126 days using anextended regimen.37 Although it was notdesigned specifically to evaluate premenstrualsymptoms, this study did monitorsome symptoms associated with PMS andPMDD. A reduction in edema was experiencedby 31% of new users and 40% of theswitchers and by 34% of the women receivingthe standard regimen compared with49% of the women receiving the extendedregimen (<.001). A decrease in breast tendernesswas reported by 40% of new usersand 42% of the switchers and by 40% of thewomen receiving the standard regimen comparedwith 50% of the women receiving theextended regimen (= .046). A reduction inbloating was experienced by 31% of newusers and 30% of the switchers and by 29% ofthe women receiving the standard regimencompared with 37% of the women receivingthe extended regimen. Table 4 summarizesthe results of the studies of OCs in womenwith premenstrual symptoms.

The beneficial results observed in thestudies cited should be considered in light ofpotential side effects associated with OCuse in some women, including nausea,breakthrough bleeding, weight gain, breasttenderness, and headache, as well as contraindicationswith certain coexisting medicalconditions. However, as with SSRIs,women can switch to a different OC if sideeffects make this necessary. Given theknown noncontraceptive health benefits ofOCs, especially their favorable effects onseveral premenstrual symptoms, they arestrong candidates for patient use.

Recent Research Findings for OCFormulations and Regimens

Recently, several studies have assessedthe efficacy of a new OC formulation containingEE 20 &#956;g and drospirenone 3 mg(20EE/drospirenone) administered for 24days, followed by a 4-day hormone-freeinterval (24/4), in the treatment of PMDD.Yonkers and Foegh reported on a double-blind,placebo-controlled, crossover studyof 20EE/drospirenone that consisted of two3-cycle treatment periods separated by awashout cycle.38 Of the 64 women, aged 18to 40 years, with PMDD symptoms whowere randomized, 34 women initiatedactive treatment with 20EE/drospirenonefollowed by placebo, and 30 women initiatedplacebo followed by the new OC formulation.The change from baseline withdrospirenone/20EE was significantly superiorto that with placebo in the DRSP, whichwas the primary outcome measure, and inthe secondary outcome measures (ie, theCGI-Efficacy and CGI-Severity indexes), theself-rated rating scale for premenstrualtension syndrome (PMTS), and the EndicottQuality of Life Enjoyment and SatisfactionQuestionnaire (Q-LES-Q) items 1 to 14 anditem 16 (Table 5).

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More recently, Yonkers and colleaguesconducted another double-blind, placebo-controlled,parallel-group study with20EE/drospirenone used in a 24/4 regimenin women with PMDD symptoms.39 Thestudy design consisted of 2 run-in menstrualcycles (the qualification phase) followed by3 treatment cycles. Of the 449 women whowere randomized, 231 were in the active-treatmentgroup and 218 received placebo.The primary outcome measure was the 21individual items in the DRSP. When theseindividual items were grouped into physical,mood, and behavioral symptoms, 20EE/drospirenonewas observed to be statisticallysuperior to placebo for all symptom groupings.Improvement occurred as early ascycle 1 and continued during all 3 cycles. Inaddition, 20EE/drospirenone was significantlymore effective than placebo in the observer-rated (= .023) and self-rated (= .004)rating scale for PMTS, the observer-rated(= .004) and self-rated (= .014) ClinicalGlobal Impression (CGI)-Improvement scales,the 3 functional items of the DRSP (productivityand enhanced enjoyment in socialactivities, both = .003; better quality ofrelationships, = .0003), and the Q-LES-Q,items 1 to 14 (= .05). (All values havenormality correction.)

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One means of assessing the effects of variousagents on premenstrual symptoms isto compare response rates using the samedefinition. For example, response rate wasdefined as a score of "much" or "verymuch" improved on the CGI-Improvementscale in 2 studies of the SSRI sertralineand in the crossover and parallel studies of20EE/drospirenone 24/4. In a double-blindstudy, women with PMDD were randomizedto a flexible daily dose (50-150mg/day) of sertraline (n = 121) or to placebo(n = 122).40 At end point, 62% of thewomen in the active-treatment group and34% of the women in the placebo groupwere classified as responders (<.001). Ina study of intermittent sertraline, theresponse rate was 58% in the womenreceiving active treatment and 45% inthe placebo group (= .036).41 Theresponse rates in these 4 studies are comparedin Figure 3.

Counseling Women WithPremenstrual Disorders

To provide effective counseling for awoman with bothersome or severe premenstrualsymptoms, physicians must be empatheticand caring communicators as well asknowledgeable about this complex area ofwomen's health. It is important to assure thepatient that her symptoms are real, with aphysiologic basis, and that she is not "crazy."42The clinician or other counselor shouldexplain the details of the menstrual cycle tothe patient, especially how premenstrualsymptoms occur on a cyclic basis. Becausepatients usually retain only part of the informationthey receive during a visit, physiciansshould provide them with interesting andpractical educational materials to reinforcewhat is discussed. Patients should keep a dailysymptom diary for at least 2 months toensure that an accurate diagnosis of PMS orPMDD is achieved. Clinicians or other counselorsshould provide the diary for prospectivelyrecording the patient's symptoms,making certain that she knows how to use itproperly.

Even before a diagnosis of PMS or PMDDhas been made, the physician or counselorcan help the patient identify ways to adjusther lifestyle to manage stress that can contributeto premenstrual symptoms. Patientsshould be encouraged to seek nonthreateningsupport from family and friends. In addition,they should be instructed about how toinitiate lifestyle modifications, such as exercise,dietary changes, appropriate use ofvitamin and mineral supplements, and stressmanagement, including relaxation and cognitivebehavioral approaches. Availablepharmacotherapeutic options should be discussed,keeping in mind the patient's personalpreferences, side effects, the cost ofthe treatments being considered, and herneeds. For example, use of an OC might bethe best first-line treatment choice for awoman who also has contraceptive needs,which can be reversed if so desired. OCs alsohave noncontraceptive health benefits ofwhich the patient should be informed.Finally, the patient should be assured thatshe can try different therapeutic optionsuntil she finds the one most suitable for her.

Conclusion

A variety of approaches have been used totreat premenstrual symptoms. Lifestylemodifications, such as regular physicalactivity and dietary/nutritional changes, canreduce premenstrual symptoms in somewomen. Nonpharmacologic options are theeasiest forms of treatment to implement,based on appropriate counseling, and can betried by any woman as she charts her symptomsin a daily symptom record for at least2 cycles to enable her physician to arrive ata correct diagnosis.

Several pharmacologic options have beenshown to be effective and should be evaluatedin light of the patient's individual needsand preferences. Some agents, such as particularSSRIs, are effective in many patientsbut also can be expensive and cause unwantedside effects. Other options, such as GnRHagonists, may be of limited use for similarreasons. Combination OCs are often used totreat premenstrual symptoms, even with alack of evidence-based support, althoughnew research is revealing more supportivedata. OC formulations containing progestindrospirenone have been shown to be effectivein treating symptoms of PMDD in controlledstudies.

Counseling women about the nature oftheir symptoms and the variety of treatmentpossibilities provides much-needed reassurancein many instances and makes it feasibleto individualize therapy based on thepatient's preferences, treatment cost, andthe most likely means of restoring patientcomfort, function, and overall health.

Address correspondence to: Andrea J. Rapkin, MD, David Geffen School of Medicine at UCLA, Department of Obstetrics and Gynecology, 10833 Le Conte, Room 27-165 CHS, Los Angeles, CA 90095-1740; arapkin@mednet.ucla.edu.