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ORIGINAL RESEARCH |
From the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; and University of California San Francisco Coordinating Center, Department of Medicine, Prevention Sciences Group, University of California, San Francisco, San Francisco, California.
Address reprint requests to: Francesmary Modugno, PhD, MPH, University of Pittsburgh, Graduate School of Public Health, Department of Epidemiology, 516A Parran Hall, 130 DeSoto Street, Pittsburgh, PA 15261; E-mail: fm{at}cs.cmu.edu.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: A subset (12%) of English-speaking women in the United States and Canada participating in the Multiple Outcomes of Raloxifene Evaluation Trial were asked to complete a sexual function questionnaire at baseline and after 36 months of treatment. The Multiple Outcomes of Raloxifene Evaluation Trial is a multicenter, randomized, blinded, placebo-controlled clinical trial, in which 7705 postmenopausal women with osteoporosis were randomly assigned to one of three groups: raloxifene hydrochloride 60 mg per day or 120 mg per day or placebo. In this substudy, 943 women completed the sexual function questionnaire at both visits. Because preliminary analyses showed no differences by raloxifene dose (n = 302 for 60 mg per day; n = 322 for 120 mg/day), the two groups were combined and compared with the placebo group (n = 319). For the given sample size, we had 80% power (
= .05, two-sided, ratio of raloxifene to placebo = 2:1) to detect a 10%–16% difference in the proportion of women experiencing no change in sexual function between placebo and treatment groups.
RESULTS: Overall, sexual function and changes in sexual function from baseline to study end between the raloxifene and placebo groups did not differ. In particular, there were no differences in sexual desire or frequency of sexual activity between the groups. Among sexually active women, there were no differences in enjoyment, satisfaction, orgasm, or reported sexual problems.
CONCLUSION: Sexual function in older postmenopausal women with osteoporosis is not affected by treatment with raloxifene.
The menopausal transition is marked by both physical and psychological changes, such as vaginal dryness, vaginal atrophy, dyspareunia, and decreased sexual function.1–6 It is often assumed that these changes result from the menopausal loss of estrogens. If this were true, estrogen replacement should improve both the physical and psychological symptoms of menopause. There is good evidence that estrogen replacement therapy alleviates physical symptoms7–12 and can restore vaginal cytology.13,14 The evidence that it improves psychological symptoms, and in particular, sexual dysfunction, is less clear. Estrogen replacement may benefit some aspects of sexual functioning, such as increasing sexual desire.8,15,16 However, these finding are inconsistent10,17–19 and may be limited to women using combined estrogen and testosterone therapies only.16,18–21
Raloxifene is a selective estrogen receptor modulator that has been approved for the treatment and prevention of postmenopausal osteoporosis.22 In addition, raloxifene has been shown to improve a woman’s lipid profile23–25 and possibly to reduce her risk of breast cancer.26
As a selective estrogen receptor modulator, raloxifene acts as an estrogen agonist in some tissue, such as bone, and as an estrogen antagonist in other tissues, such as the breast and uterus.27 Raloxifene’s effect on vaginal mucosa is unknown; however, evidence suggests an agonistic effect,28 supporting a potential positive role for the drug on sexual function in postmenopausal women. On the other hand, previous studies of raloxifene have noted an increase in hot flashes,29–31 with no effect on other menopausal symptoms, such as vaginal dryness.29,30,32,33 Together, these data suggest that raloxifene may negatively impact sexual function.
Given the mixed estrogen agonist/antagonist effects of raloxifene, clinicians and patients have raised concerns about the potential for an adverse impact of the drug on sexual function. In this article, we report an analysis of the effects of raloxifene on sexual function in older, postmenopausal women with osteoporosis. The women were a subset of individuals participating in a multicenter, randomized, clinical trial, whose primary end point was to evaluate the effects of 36 months of treatment with raloxifene compared with placebo on the rate of vertebral and nonvertebral fragility in postmenopausal women with osteoporosis.
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MATERIALS AND METHODS |
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To assess the effect of raloxifene on sexual function, subjects were administered the sexual function questionnaire at baseline and again after 36 months of treatment. The questionnaire was a modification of McCoy’s Sex Scale Questionnaire.2 Subjects were informed that for this study, sexual activity was defined as "any activity that is sexually arousing to you—masturbation, oral sex, intercourse, etc." All women were asked to report their frequency of sexual activity and desire during the last 6 months. For sexually inactive women, the reason for inactivity was reported. For sexually active women, additional questions evaluated feelings during sexual activity, intensity of orgasms, and sexual problems. Questions of sexual activity and desire, as well as the follow-up sexual activity questions, were answered on a 5- or 6-point Likert scale. For each participant and each sexual function question, we computed the absolute difference in response between follow-up and baseline. We then categorized each response as indicating an improvement, decline, or no change in that variable. For example, a woman reporting sexual activity 2–3 times per week at baseline and about once per month at follow-up was categorized as "decline" for the sexual activity variable. We further calculated a summary score to assess overall change in sexual feelings. To calculate this score, we added together the categorical answers to the sexual feeling questions to obtain a categorical summary score. We then used the difference between the follow-up score and baseline score to create a categorical variable. Each participant was assigned an increase, decrease, or no change in overall sexual feelings, depending on whether the difference between follow-up and baseline scores was positive, negative, or zero, respectively. A similar approach was used to evaluate overall change in sexual problems.
Because our preliminary comparison showed no evidence for a difference between the 60 mg per day (n = 302) and 120 mg per day (n = 322) doses of raloxifene on sexual function, we combined both treatment groups into a single category in this presentation. Baseline characteristics of the raloxifene and placebo groups were compared using t tests for continuous variables and 
2 or Fisher exact tests for categorical variables. To evaluate the differences in sexual function between the raloxifene and placebo groups, we compared the proportion of women in each group reporting an improvement, decline, or no change in each sexual function variable, using a 2 x 3 2 test. Based on a sample size of 943 women completing the sexual desire and activity questions at both visits, we had 80% power to detect a 10% difference in the proportion of women reporting no change in desire or activity between the raloxifene and placebo groups ( = .05, two-sided, ratio of raloxifene to placebo = 2:1). Among the 343 sexually active women, we had 80% power to detect a 16% difference in the proportion of women reporting no change between the raloxifene and placebo groups ( = .05, two-sided, ratio of raloxifene to placebo = 2:1) for each question relating to sexual feelings, experience, and problems. Both of these effect sizes are considered small,34 suggesting ample power to detect a difference in sexual activity, desire, feelings, orgasms, and problems between the raloxifene and placebo groups.
Cumulative logistic regression models with and without indicator variables for the clinical sites were used to determine whether baseline sexual function and changes in sexual function were significantly different between the clinical sites. Adding the clinical site variable to the models did not change the interpretation of the treatment effect for any of the outcomes. Thus the analyses presented here do not include adjustment for the clinical site.
All analyses reported here were done with the SAS statistical program (SAS Institute, Cary, NC), and all comparisons were tested at the .05 level of significance using two-sided tests.
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RESULTS |
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A total of 624 women in the raloxifene arm and 319 women in the placebo arm completed the same questions in the sexual function questionnaire at both baseline and follow-up. There were no significant differences in descriptive characteristics between the two groups, although a slightly larger percentage of women in the raloxifene group were married (58.2% compared with 54.7%), Table 1
. The mean age of women in both arms was 68 years, and the mean age at menopause was 48 years. The average body mass index was 25 kg/m2 in both groups.
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–5 summarize participants’ baseline sexual characteristics. A greater proportion of women in the raloxifene arm reported some sexual activity (47.4% compared with 44.5%) and some desire for sexual activity (58.8% compared with 56.0%), although the differences among the levels of activity between the two groups were not significant. A total of 229 women in the raloxifene group (36.7%) and 114 women in the placebo group (35.7%) reported sexual activity at both baseline and follow-up. Among these women, there were no differences between women on raloxifene and women on placebo in frequency of reported feelings during sexual activity, although more women in the raloxifene group initially reported some pain and discomfort during intercourse (28.4% compared with 21.0%). More women randomized to receive raloxifene also initially reported problems during sexual activity. In particular, a greater percentage of women assigned to the raloxifene arm initially reported problems with orgasm (44.2% compared with 38.2%) and with discomfort during intercourse (31.3% compared with 25.4%). However, the differences in reported problems between the two treatment groups were not statistically significant.
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lists the proportion of women in each group showing a decline, no change, or an improvement for each of the 12 sexual function questions. Only the 343 women reporting sexual activity at both visits were included in the analyses of sexual feelings, orgasms, and problems. A greater proportion of women in the placebo group reported an improvement in sexual feelings, especially with respect to frequency of pain during intercourse (27.2% in the placebo group compared with 18.8% in the raloxifene group). However, women in the placebo group also reported an increase in problems associated with sexual discomfort (26.4% compared with 24.2%). None of these differences, however, were statistically significant. In addition, there were no differences in the summary scores for overall sexual feelings and overall sexual problems between women on raloxifene and those in the placebo group.
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, the most common reasons for inactivity among women previously or subsequently reporting activity were disinterest, lack of a partner, or a partner’s problem. Again, no differences were found between the raloxifene and placebo groups.
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DISCUSSION |
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Only one previous study has investigated the effects of raloxifene on sexual function. Strickler et al28 conducted a double-blind trial, in which they randomly assigned 398 postmenopausal women to one of four treatment groups: raloxifene 60 mg per day, raloxifene 150 mg per day, conjugated equine estrogens 0.625 mg per day, or placebo. After 12 months of treatment, no differences in sexual desire or satisfaction among the four groups were found. In contrast with the subset of Multiple Outcomes of Raloxifene Evaluation study women analyzed here, the participants in the Strickler et al study were younger (average age, 54.7 years), and none were osteoporotic women. Moreover, the women were treated for only 12 months, compared with 36 months in the Multiple Outcomes of Raloxifene Evaluation study. Despite these differences, the results of the two studies are consistent.
There have been few studies of the effect of the selective estrogen receptor modulator tamoxifen on sexual function. Tamoxifen is currently used in the treatment of breast cancer35 and is approved as a chemopreventive agent in the disease.36,37 Vaginal smears taken before and after treatment with tamoxifen indicate that the drug has an estrogen agonist effect on vaginal mucosa,38,39 which would suggest that sexual function may be unaffected or improved in women taking the drug. However, in women undergoing treatment for breast cancer, tamoxifen was found to contribute to sexual dysfunction by increasing pain, burning, and discomfort during intercourse.40 Notably, the study design precluded assessing the individual contributions of tamoxifen versus chemotherapy to sexual dysfunction. In the National Surgical Adjuvant Breast and Bowel Project P-1 trial, women randomized to the tamoxifen intervention reported increased problems with sexual functioning compared with women receiving placebo.36 In particular, women in the tamoxifen group reported a decrease in sexual interest, more difficulty becoming aroused, and more difficulty having orgasm. However, in the British tamoxifen chemopreventive trial, there was no evidence of treatment-related side effects that impact sexual functioning.37 Vaginal dryness, painful intercourse, and reported pleasure from sexual activity were not associated with tamoxifen. Other psychosocial results from the British trial were comparable to the National Surgical Adjuvant Breast and Bowel Project results, despite differences in study populations, methodology, and instruments. Hence, the effect of tamoxifen on sexual function in women remains unclear, although the evidence suggests a potential negative impact.
The data from this study also present a picture of sexual activity in postmenopausal women. Approximately 47% of women reported some sexual activity at baseline, which is similar to the level reported in other populations.41 In general, the women in our study reported feelings of enjoyment and satisfaction during intercourse. They further reported few problems during sexual activity. Difficulty with orgasm and frequent pain during intercourse were the most commonly cited problems. These results are consistent with the general picture of sexual activity in postmenopausal women,2,41–45 although differences in study design, study populations, instruments, and data analyses make it difficult to compare directly the components of sexual functioning among different studies.
Partner problems, such as partner’s physical problems or lack of interest, were the most common reason for lack of sexual activity in women reporting activity at baseline or follow-up but not both visits. This is consistent with results reported by Dennerstein et al,3 in which "partner problems" was a significant determinant of sexual functioning. Again, differences in study design preclude a direct comparison of the two studies.
The greatest strength of this study was the large sample size, which provided ample power to determine whether raloxifene affects sexual function in older, postmenopausal women with osteoporosis. The use of a randomized clinical trial design and a standardized assessment of sexual function further add to the study strength. We are careful to note that the assessment of sexual activity was not a primary end point of the Multiple Outcomes of Raloxifene Evaluation trial; nor was the study designed to assess the treatment of sexual dysfunction in the study population. Rather, the data presented here address the question of the effect of raloxifene compared with placebo on sexual function, with no assessment of sexual dysfunction. Therefore, the sexual function questionnaire did not incorporate US Food and Drug Administration–recommended questions to evaluate sexual dysfunction, such as measures of personal distress and numbers of successful and satisfactory sexual encounters over a fixed time period.46 We are unable, therefore, to assess the level of sexual function (or dysfunction) in this study population. Moreover, we did note some differences in sexual function between women who completed the questionnaire at both visits and those who did not complete the questionnaire at follow-up. In particular, the "noncompleters" reported less activity and desire as well as greater trouble with orgasm. However, because the differences in percentage of noncompleters between raloxifene and placebo were not significant, it is unlikely that treatment influenced a woman’s decision not to complete the follow-up questionnaire. Nonetheless, no conclusions can be made about raloxifene and sexual dysfunction from these data.
Despite its strengths, the study has several weaknesses, including the fact that all women in the study had osteoporosis, defined as bone density at least 2.5 standard deviations below the mean for normal young women47 at either the lumbar spine or femoral neck, or had at least one moderate or two mild vertebral fractures that were detected by lateral spine radiography. Moreover, the Multiple Outcomes of Raloxifene Evaluation study was limited to older, postmenopausal women, and the data on sexual activity was obtained only on a small subset (12%) of English-speaking Multiple Outcomes of Raloxifene Evaluation study participants in the United States and Canada. In addition, women with significant menopausal symptoms who desired treatment for those symptoms were specifically excluded from the Multiple Outcomes of Raloxifene Evaluation trial. Therefore, our results apply only to older, postmenopausal women seeking therapy for the treatment of osteoporosis. Although our results suggest that treatment with raloxifene will not influence sexual function in older, postmenopausal women with osteoporosis, no conclusion can be made about the effect of raloxifene on sexual function in premenopausal women, in younger, postmenopausal women, or in women experiencing menopausal symptoms.
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Footnotes |
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This work was supported by Eli Lilly and Company, maker of raloxifene. The company provided salary support to SE and research support to JAC, who is also a member of the speaker’s bureau of Eli Lilly and Company.
Received May 15, 2002. Received in revised form July 17, 2002. Accepted August 8, 2002.
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