Simon, James A. MD, CCD, NCMP, IF, FACOG1; Portman, David J. MD2; Kaunitz, Andrew M. MD3; Mekonnen, Hana MA4; Kazempour, Kazem PhD4; Bhaskar, Sailaja PhD5; Lippman, Joel MD5
Vasomotor symptoms (VMS), encompassing hot flashes and night sweats,1 affect up to 80% of menopausal women in the United States.2,3 VMS are the most bothersome aspects of menopause,4 significantly affecting quality of life.5,6 To date, hormone therapy (HT) has been the only approved treatment for moderate to severe VMS due to menopause.7 However, women seeking treatment need safe and effective non-HT options. In the past few years, several clinical trials have demonstrated that selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may be efficacious in treating VMS due to menopause among nondepressed women,8 although tolerability of such agents may be a concern at doses indicated for psychiatric disorders.
Brisdelle (paroxetine 7.5 mg; previously called low-dose mesylate salt of paroxetine [LDMP]) is the first and only US Food and Drug Administration (FDA)–approved nonhormonal option for the treatment of moderate to severe VMS associated with menopause. This medication was specifically developed for the treatment of menopausal VMS at a dose lower than that indicated for psychiatric disorders. Paroxetine mesylate is an orally administered psychotropic drug similar to paroxetine hydrochloride, which contains mesylate salt instead of hydrochloride salt.9 Results of an 8-week phase 2 study in postmenopausal women (N = 102)10 showed that paroxetine 7.5 mg was efficacious in treating moderate to severe VMS and was well-tolerated. The mean difference in hot flash frequency reduction between paroxetine 7.5 mg and placebo was −1.4 hot flashes per day (P = 0.0177), with a mean reduction of 6.5 hot flashes per day for paroxetine 7.5 mg-treated women and 5.1 hot flashes per day for placebo-treated women. The discontinuation rate in the paroxetine 7.5 mg arm in the phase 2 study and the safety profile of paroxetine 7.5 mg were comparable with those of placebo.10
Reduced estrogen levels in menopause are hypothesized to modulate endorphin concentrations in the hypothalamus, leading to changes in norepinephrine and serotonin levels.11-13 These neurotransmitters lower the thermoregulatory set point in the hypothalamic neuroregulatory nucleus, triggering inappropriate heat loss.11-13 Paroxetine’s mechanism of action in reducing hot flashes is not clearly understood but is probably mediated by the activation of hypothalamic serotonin receptors.13
Herein, we report the results of two similarly designed, multicenter, double-blind, randomized, placebo-controlled, phase 3 studies of 12 and 24 weeks’ duration, respectively, conducted to evaluate the safety and efficacy of paroxetine 7.5 mg (once daily at bedtime) in postmenopausal women with moderate to severe VMS due to menopause.
Both studies included postmenopausal women 40 years or older who were required to meet one of the following criteria for menopause: spontaneous amenorrhea for 12 consecutive months or longer; amenorrhea for 6 months or more with follicle-stimulating hormone levels higher than 40 mIU/mL; or bilateral salpingo-oophorectomy, with or without hysterectomy, 6 weeks or more before screening. A key eligibility criterion was an average of more than 7 to 8 moderate to severe hot flashes per day, or 50 to 60 moderate to severe hot flashes per week, before screening. Moderate hot flashes were defined as a sensation of heat with sweating and ability to continue with activity, whereas severe hot flashes were defined as a sensation of heat with sweating causing cessation of activity. No concomitant estrogen/progestin–containing products were permitted during the study, and participants who were taking such products at the screening visit had to undergo washout periods: 1 week before the run-in visit for vaginal hormone products (rings, creams, and gels), 4 weeks for transdermal estrogen or estrogen/progestin products, and 8 weeks for oral estrogen or estrogen/progestin therapy.
The inclusion and exclusion criteria for these studies were consistent with the 2003 FDA guidance for the clinical evaluation of HT for VMS due to menopause.14 Concomitant use of psychotropic drugs during the study was limited. Participants who were taking such medications at the screening visit had to undergo washout periods: 2 weeks before the run-in visit for thioridazine, pimozide, tricyclic antidepressants, SSRIs (except for fluoxetine), SNRIs, lithium and oral neuroleptics, and all sedatives and hypnotics (except for zolpidem, zaleplon, eszopiclone, and diphenhydramine); 4 weeks before the run-in visit for fluoxetine, St John’s wort, and monoamine oxidase inhibitors; and 12 weeks before the run-in visit for depot neuroleptics. During the entire duration of the study, participants were not permitted to take the following: tamoxifen, select psychotropic drugs, thioridazine, pimozide, monoamine oxidase inhibitors, estrogen or estrogen/progestin–containing products, gabapentin and pregabalin, soy and soy-based products, isoflavone-containing substances, and alternative therapies for the treatment of VMS.
Key exclusion criteria were as follows: hypersensitivity to paroxetine; known nonresponse to previous SSRI or SNRI treatment of VMS; untreated hypertension; impaired liver or kidney function; unstable cardiac disease; pregnancy; a history of self-injurious behavior; a history of clinical diagnosis or treatment of any psychiatric disorder; and any other medical condition. Participants with any clinically significant abnormality at screening (physical examination, electrocardiogram [ECG], laboratory tests, or urine drug screening) were not eligible for inclusion. Use of an investigational study medication within 30 days before screening or during the study was also prohibited.
These multicenter, double-blind, randomized, placebo-controlled, phase 3 studies were conducted from June 2011 to January 2012 (12-wk study) and from March 2010 to September 2011 (24-wk study). Both studies were designed to meet the FDA guidance for VMS, which specifies that studies should be of 12 weeks’ duration.14 However, because VMS may persist for months or years after the onset of menopause, the 24-week study was designed to examine whether efficacy and safety outcomes were maintained for a longer duration. The studies were conducted according to the guidelines of Good Clinical Practice, the Declaration of Helsinki, and all applicable local regulations and were approved by each study center’s local or central institutional review board. Seventy research sites across the United States contributed to the 12-week study, and 65 US investigative sites contributed to the 24-week study. A written informed consent form for study participation was obtained from all participants.
After an initial screening period, eligible participants entered a single-blind, run-in period of up to 12 days, during which they received placebo once daily at bedtime and recorded the number and severity of hot flashes in electronic daily diaries (Fig. 1). This run-in period allowed participants to learn the definitions of mild, moderate, and severe hot flashes and to be trained on using the electronic diary system as they familiarized themselves with protocol requirements. At the end of the run-in period, participants who no longer met the eligibility criterion of more than 7 to 8 moderate to severe hot flashes per day or 50 to 60 moderate to severe hot flashes per week or who were noncompliant with dosing or daily diary recording of hot flashes were excluded from the study. This ensured that participants met the eligibility criteria and screened out high placebo responders who may not have benefited from pharmacological intervention while eliminating those who were unwilling or unable to complete the electronic diary. Participants compliant with electronic diary entry and dosing and met hot flash eligibility criteria were randomly assigned 1:1 to receive paroxetine 7.5 mg or an identical capsule of placebo once daily at bedtime. Randomization was applied centrally across all sites using an interactive voice response system. All personnel were blinded to medication until study completion and database lock. Treatment began at bedtime on the day of randomization (day 1) and continued until day 84 (end of 12-wk study) or day 168 (end of 24-wk study) or until early discontinuation. During the double-blind treatment period, participants in both studies were required to return to the clinic for assessment on days 14 and 28. Participants were also required to come to the clinic on day 85 (12-wk study) or day 169 (24-wk study) for all scheduled end-of-study evaluations. For participants who discontinued prematurely from the study, all scheduled end-of-study evaluations were performed at the time of early discontinuation.
The coprimary efficacy endpoints in this study were mean change from baseline in the frequency of moderate to severe hot flashes on weeks 4 and 12 and mean change from baseline in the severity of moderate to severe hot flashes on weeks 4 and 12.14 Persistence of treatment benefit, an additional efficacy endpoint, was also included in the 24-week study.
Treatment compliance was assessed by counting the number of capsules dispensed and the number of capsules returned. Compliance percentage was calculated and dichotomized into two groups: those taking 80% or more of the study drug (compliance) and those taking less than 80% of the study drug (noncompliance).
Daily hot flash data were collected using the electronic hot flash diary, which was completed daily by study participants. This validated, interactive, real-time system was available for use 24 hours per day for data entry, and daily compliance reports were generated for each participant.
Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, ECG, and clinical laboratory abnormalities. TEAEs were summarized by preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA), as is standard procedure for this type of investigation. Because the studies were not designed to detect statistical differences in adverse events between treatments, results are shown quantitatively by treatment arm. Adverse events of special interest (ie, linked to reports from studies using higher doses of paroxetine), including suicidality, abnormal bleeding, and bone fractures, were also assessed.
For assessment of potential discontinuation symptoms, participants were asked to complete a 27-symptom survey—the Discontinuation-Emergent Signs and Symptoms (DESS) scale—within 7 (3) [mean (SD)] days of the last dose of study medication, regardless of when they exited the study. The DESS scale has been shown to provide an accurate assessment of discontinuation symptoms when used in trials of antidepressants used to treat depression and anxiety disorders.15
Five hundred thirty-four participants (267 per treatment arm) were planned to be randomly assigned in each study; this included a conservative dropout rate of approximately 15% (based on the phase 2 trial, which had a dropout rate of 6%10). Sample size estimation using nQuery Advisor 6.01 (Statistical Solutions LLC, Overland Park, KS) indicated that, for VMS severity, 155 participants per treatment arm were required for 95% power based on a type I error rate of 0.05 (α = 0.05, two-sided), a clinically meaningful reduction in severity higher than 50% (mean difference, 0.17 − 0.08), and a common SD of 0.22. For the coprimary endpoint of VMS frequency, 227 participants per treatment arm were required to provide 85% statistical power to detect a mean difference between treatments of 1.41 hot flashes per day based on a type I error rate of 0.05 (α = 0.05, two-sided) and a common SD of 5. The aim, therefore, was to have 454 participants complete each study.
Prespecified analysis populations included modified intent-to-treat (mITT), per-protocol (PP), and safety populations. The mITT group, which served as the primary population for analysis, comprised all randomly assigned participants with valid baseline daily hot flash diary data who had taken one or more doses of study medication and had one or more days of on-treatment daily hot flash diary data. The PP population included all participants in the mITT population who were treated according to the protocol and fulfilled the following: (1) satisfied all inclusion and exclusion criteria without compromise of the blind; (2) had no significant protocol violations; and (3) demonstrated 80% or more compliance with assigned study treatment. The PP population was identified before database lock and was used to conduct supportive analysis. The safety population included all participants who had received one or more doses of study medication and had undergone one or more postdose safety measurements.
All analyses were performed using SAS for Windows, version 9.2 (SAS Institute Inc, Cary, NC). Descriptive statistics (n, mean, SD, median, and range) were calculated by treatment arm for continuous variables. Frequencies and percentages are presented by treatment arm for categorical variables.
Primary efficacy variables were measured at multiple time points during the study. Because the data were not normally distributed, treatment arms were compared using rank-transformed analysis of covariance with baseline values as covariates. For categorical variables, a logit model was used, with baseline as covariate. In the event of missing diary data, the average of hot flash diary data across entries in the previous 7 days was imputed. Sensitivity analysis was performed using the last observation carried forward (LOCF) principle for all missing data.
Total weekly moderate and severe hot flashes at baseline for each participant were calculated by a standard method as follows: [(x on day 1 + x on day 2 + ... + x on day n) / (n − 1)] × 7, where x is the number of moderate and severe hot flashes, and n is the number of days in the run-in period. This number was used for all analyses requiring a baseline hot flash count. Total weekly moderate and severe hot flashes during the double-blind treatment period were calculated as the sum of moderate and severe hot flashes recorded in the daily hot flash diary for seven calendar days in the specific treatment week. Weekly hot flash severity score was determined by (2Fm + 3Fs) / (Fm + Fs), where Fm and Fs are the frequencies of moderate and severe hot flashes, respectively, during the study week.
To calculate the persistence of treatment benefit (24-wk study only), we compared the paroxetine 7.5 mg and placebo arms on proportions of responders (defined as those participants who achieved a 50% or more reduction in moderate to severe hot flash frequency from baseline to week 24). Persistence of treatment benefit was demonstrated by a statistically significant difference in the proportion of responders on week 24 versus baseline between the paroxetine 7.5 mg arm and the placebo arm. For this analysis, a logit model was used, with the baseline number of hot flashes as covariate. Participants who discontinued from the study before week 24 were considered treatment failures.
In pooled analysis, data from both studies from baseline to week 12 were used to calculate the primary efficacy endpoints. Rank-transformed analysis of covariance was used to compare treatment arms for pooled results.
Six hundred fourteen postmenopausal women were randomly assigned to the 12-week study, and 570 postmenopausal women were randomly assigned to the 24-week study. In the 12-week study, the paroxetine 7.5 mg arm comprised 306 participants, and the placebo arm included 308 participants (Fig. 2A). Five participants randomly assigned to the paroxetine 7.5 mg arm and three participants randomly assigned to the placebo arm did not receive the study drug and were accordingly excluded from the mITT and safety populations (paroxetine 7.5 mg, 301; placebo, 305). The mITT population in this study was identical to the safety population. In the 24-week study, 285 women were randomly assigned to each treatment arm (Fig. 2B). One participant in the placebo arm did not receive the study medication and was excluded from the mITT and safety populations (paroxetine 7.5 mg, 285; placebo, 284). One additional participant in the paroxetine 7.5 mg arm did not have complete diary entries and was excluded from the mITT population (paroxetine 7.5 mg, 284; placebo, 284) but was included in the safety population.
Most study discontinuations occurred upon the participant’s request (12-wk study: paroxetine 7.5 mg, 2.6%; placebo, 3.9%; 24-wk study: paroxetine 7.5 mg, 5.3%; placebo, 12.3%). Twelve participants (2.0%) in the 12-week study and 30 participants (5.3%) in the 24-week study discontinued the study early because of an adverse event (Fig. 2). Most participants were 80% or more compliant with their assigned study drug (12-wk study: paroxetine 7.5 mg, 91.7%; placebo, 91.8%; 24-wk study: paroxetine 7.5 mg, 84.2%; placebo, 78.9%).
Baseline demographics and characteristics
Baseline demographics were similar between treatment arms (Table 1). All participants were postmenopausal women; most were white (70%) or black (27%), and 3% were of other races. The median age was 54 years. At baseline, the mean daily frequency of hot flashes was 11.3, and the mean hot flash severity score was 2.53.
Effect of treatment on VMS frequency
In the 12-week study, the mean weekly reductions in VMS frequency were significantly greater for paroxetine 7.5 mg than for placebo on week 4 (−33.0 and −23.5, respectively; P < 0.0001) and week 12 (−43.5 and −37.3, respectively; P = 0.0090; Fig. 3A). In the 24-week study, the mean weekly reductions in VMS frequency were significantly greater for paroxetine 7.5 mg than for placebo on week 4 (−28.9 and −19.0, respectively; P < 0.0001) and week 12 (−37.2 and −27.6, respectively; P = 0.0001; Fig. 3B). In the pooled analysis, paroxetine 7.5 mg significantly reduced the frequency of VMS versus placebo on weeks 4 and 12 (P < 0.0001; Fig. 3C).
Effect of treatment on VMS severity
In the 12-week study, the mean weekly reductions from baseline in VMS severity were significantly greater for paroxetine 7.5 mg than for placebo on week 4 (−0.09 and −0.05, respectively; P = 0.0048) but not on week 12 (−0.10 and −0.09, respectively; P = 0.2893; Fig. 3D). In the 24-week study, the mean weekly reductions in VMS severity were significantly greater for paroxetine 7.5 mg than for placebo on week 4 (−0.09 and −0.06, respectively; P = 0.0452) and week 12 (−0.12 and −0.07, respectively; P = 0.0114; Fig. 3E). In the pooled analysis, paroxetine 7.5 mg significantly reduced the severity of VMS versus placebo on week 4 (P = 0.0006) and week 12 (P = 0.0110; Fig. 3F).
Persistence of treatment benefit
Significantly more participants treated with paroxetine 7.5 mg than with placebo were responders on week 24 (47.5% vs 36.3%, respectively; P = 0.0066; Fig. 3G), thus demonstrating persistence of treatment benefit.
Results of sensitivity analyses that used the LOCF principle in handling missing data were similar to the results calculated without LOCF imputation (data not shown). Results of efficacy analyses using the PP population were supportive of data calculated using the mITT population (data not shown).
Overall, 295 of 586 (50.3%) participants in the paroxetine 7.5 mg arm and 275 of 589 (46.7%) participants in the placebo arm experienced one or more TEAEs; most were mild or moderate in severity (Table 2). Twenty-three participants (3.9%) in the paroxetine 7.5 mg arm and 18 participants (3.1%) in the placebo arm reported a severe TEAE.
Study drug discontinuations caused by TEAEs were reported for 26 of 586 (4.4%) participants in the paroxetine 7.5 mg arm and for 21 of 589 (3.6%) participants in the placebo arm. Twelve participants had study drug interruption because of an adverse event (paroxetine 7.5 mg, 6 of 586 [1.0%]; placebo, 6 of 589 [1.0%]). Twenty-two participants reported treatment-emergent serious adverse events (paroxetine 7.5 mg, 14 of 586 [2.4%] participants; placebo, 8 of 589 [1.4%] participants). One death was reported (12-wk study: acute respiratory failure with evidence of hypertension-mediated pulmonary edema and hypertensive cardiovascular disease) and was not considered by the investigator to be related to the study drug.
The TEAEs reported in 2% or more of participants in the paroxetine 7.5 mg arm and with twofold (or more) higher frequency than in the placebo arm were nausea (paroxetine 7.5 mg, 3.8%; placebo, 1.4%), fatigue (paroxetine 7.5 mg, 3.4%; placebo, 1.5%), and dizziness (paroxetine 7.5 mg, 2.0%; placebo, 0.8%; Table 2). No clinically significant changes in laboratory values, vital signs, or ECG were observed in either treatment arm during the course of the study.
A suicide attempt was spontaneously reported in the 24-week study. One participant in the paroxetine 7.5 mg arm took an overdose of nonstudy medications 1 week after receiving a prescription for clonazepam for newly reported anxiety. Investigators determined that the event was unrelated to paroxetine 7.5 mg treatment.
The incidences of gastrointestinal or other bleeding adverse events between treatment arms were similar. Vaginal or postmenopausal hemorrhage was the most commonly reported bleeding adverse event (six participants in each arm). No clinically important findings on gastrointestinal or bleeding adverse events were evident in the paroxetine 7.5 mg arm.
Five bone fractures were reported: four events in three participants in the placebo arm and one event in the paroxetine 7.5 mg arm. Three of the fractures in the placebo arm were reported as serious adverse events.
Finally, DESS scale results did not demonstrate any meaningful differences between the paroxetine 7.5 mg arm and the placebo arm. After treatment discontinuation without tapering, 17.2% of paroxetine 7.5 mg-treated participants and 13.6% of placebo-treated participants experienced one or more new symptoms, and 25.3% and 17.7%, respectively, reported worsening of a previously reported symptom. The new symptoms described in 2% or more of participants in the paroxetine 7.5 mg arm and with twofold (or more) higher frequency than in the placebo arm were muscle cramps, spasms, and twitching (paroxetine 7.5 mg, 3.4%; placebo, 1.5%); a restless feeling in the legs (paroxetine 7.5 mg, 2.6%; placebo, 1.2%); and insomnia (paroxetine 7.5 mg, 2.6%; placebo, 1.2%). No worsening of a previously reported symptom occurred in 2% or more of participants in the LDMP arm or with twofold (or more) higher frequency than in the placebo arm.
Paroxetine 7.5 mg, a once-daily nonhormonal agent specifically developed for the treatment of moderate to severe menopausal VMS, has been shown in these two phase 3 studies to be effective in reducing symptoms. In both studies, paroxetine 7.5 mg administration reduced the frequency and severity of moderate to severe VMS compared with placebo. The observed reduction in the frequency of moderate to severe VMS among participants treated with paroxetine 7.5 mg remained statistically significant versus placebo throughout the studies; in the 24-week study, the proportion of responders (defined as ≥50% reduction from baseline) was significantly greater in the paroxetine 7.5 mg arm than in the placebo arm, thereby demonstrating persistence of treatment benefit with paroxetine 7.5 mg up to 24 weeks.
Paroxetine 7.5 mg was also safe and well-tolerated in this population; most TEAEs were mild to moderate. The frequency of adverse events and the rate of discontinuations associated with adverse events were low, and the compliance rate was high. No clinically important findings on abnormal bleeding, bone fractures, or suicidality were evident in the paroxetine 7.5 mg arm. Moreover, no meaningful differences in discontinuation symptoms were observed between the paroxetine 7.5 mg arm and the placebo arm upon cessation of the study drug without down-titration. Results of the DESS scale indicate that paroxetine 7.5 mg does not cause an increase in discontinuation symptoms after treatment discontinuation. Tapering of higher-dose SSRI therapy, as opposed to abrupt discontinuation, has been recommended by prescribing information and several guidelines in the literature to diminish the occurrence of discontinuation symptoms (which may include flu-like symptoms, dizziness, fatigue, nausea, sensory disturbances, and paresthesias).16,17 In the present studies, participants did not report discontinuation symptoms typically observed with higher doses of SSRIs,16,17 and no discontinuation-emergent symptom was reported in 5% or more of paroxetine 7.5 mg-treated participants and at twice the incidence observed in the placebo arm. Collectively, these reassuring observations may be attributable to the low dose of paroxetine used in these studies.
The results of these studies are timely and important because, to date, there is an unmet need for FDA-approved nonhormonal treatments of VMS due to menopause. After the publication of the Women’s Health Initiative in 2002,18 many clinicians became reluctant to prescribe HT for symptomatic women, and many women discontinued or chose not to initiate HT because of risk concerns. HT prescriptions rapidly declined by 44% between 2001 and 2003.19 The National Health and Nutrition Examination Survey (1999-2010) reported a continued decline in HT use to the current level of 4.7% across a wide range of participant subgroups.20 It is clear that many women with symptoms do not seek treatment, and others desire treatment but prefer not to initiate or continue HT.4,21-23 Complementary and alternative therapies are often used to self-manage symptoms,21 but none has shown significant benefit in randomized controlled trials.7,23,24 Previously, no nonhormonal treatments were approved for the treatment of VMS due to menopause, and clinicians consequently may have prescribed antidepressants off-label.21 However, tolerability may be an issue if doses commonly used for psychiatric disorders are used to manage VMS, as is often the case. According to an estimate from IMS Health, more than 2.4 million SSRI prescriptions for the treatment of VMS were filled in 2012; in prescriptions for paroxetine, the most commonly prescribed doses were 20 and 40 mg.25
The mechanism of action for VMS improvement with SSRIs is complex and probably differs from the mechanisms involved in the treatment of psychiatric disorders. Two 5-HT receptor subtypes, 5-HT1a and 5-HT2a, have been associated with thermoregulation in mammals and seem to have opposite regulatory effects; a balance between the two probably maintains temperature homeostasis.26-28 Higher doses of SSRIs used for treating major depression, anxiety, and other indications may be unnecessary for treating menopausal VMS. Current off-label use of these medications for VMS is not supported by safety and efficacy data from adequate and well-controlled trials. Until more data are available, only agents specifically tested in randomized controlled studies at doses and formulations for postmenopausal women with VMS due to menopause should be considered as safe and effective treatments to relieve symptoms.
Some limitations of the current studies should be noted. First, consistent with guidance from the FDA, the studies had no HT arm serving as an active comparator, and the duration of the studies was limited to 12 or 24 weeks. Most participants (∼80%) had naturally occurring menopause. To date, only combined estrogen/progestin therapy has been approved for treating VMS in women with intact uterus and spontaneous menopause. Because the Women’s Health Initiative estrogen/progestin study demonstrated greater risks with combined therapy than with estrogen alone,18,29,30 alternative nonhormonal treatments are needed for this population of women. By using a low-dose paroxetine regimen that has not been used or indicated for psychiatric conditions, clinicians will be able to offer women a nonhormonal treatment specifically geared toward menopausal VMS and will avoid possible concerns about mental health stigmatization or minimization of VMS. Untoward adverse effects and withdrawal symptoms associated with higher paroxetine doses seem to be avoided with paroxetine 7.5 mg.
Paroxetine 7.5 mg is safe, well-tolerated, and efficacious in reducing the frequency and severity of moderate to severe VMS due to menopause and demonstrates persistence of treatment benefit throughout a 24-week treatment duration. Paroxetine 7.5 mg is a nonhormonal option for women seeking an alternative to estrogen-containing therapies for VMS due to menopause.
We acknowledge the editorial assistance provided by Maribeth Bogush, PhD, Lynn Brown, PhD, and Sally Mitchell, PhD, of ApotheCom LLC.
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© 2013 by The North American Menopause Society.