too many women are seeking help for their “normal state” is inaccurate. In the Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking (PRESIDE) survey of 31,581 women, 37% reported decreased desire and 9.5% met the diagnostic criteria of distress using the Female Sexual Distress Scale-Revised.1 We do not presume that the 37% who reported decreased desire had hypoactive sexual desire disorder or should seek treatment. Similarly, we do not presume that the 50% of postmenopausal women reporting decreased desire in West et al2 have hypoactive sexual desire disorder. The prevalence of hypoactive sexual desire disorder in that study was 8.3%, similar to PRESIDE. What is most relevant is that, of the 9.5% in PRESIDE who met the criteria for hypoactive sexual desire disorder, only 35% sought treatment. There are several reasons for this. Women do not always know where to seek help, and gynecologists do not always routinely assess sexual problems, forcing women to initiate the topic. Unfortunately, many will not. Also, some women are not aware that hypoactive sexual desire disorder is a medically recognized condition. As a result, many women suffer in silence, thinking they are the only ones experiencing their symptoms. Unfortunately, telling a woman with distressing low desire that this is normal and implying that it is not worthy of treatment happens much more frequently than Dr. Harris’s concern— women being pressured to be hypersexual. Women who present in our practices are very clear that they want their desire back. Women who have acquired hypoactive sexual desire disorder will report that the loss of desire is tremendously distressing, has negatively affected their satisfaction with life, and interferes with their relationship with a partner. We are concerned that Dr. Harris is placing asexuality on the same spectrum as hypoactive sexual desire disorder. They are unmistakably different. Women who present with no sexual desire and are satisfied with this state do not meet the criteria for hypoactive sexual desire disorder and represent an entirely different patient population. We are disappointed that Dr. Harris attempts to use a historical bias against homosexuality to justify her argument that treating women with distressing low desire is essentially the same as
trying to “cure” homosexuality. We cannot imagine this argument being used in the context of arguing against the right of men to seek treatment for erectile dysfunction. It is not our intention to convince women or their gynecologists to treat a lack of desire that is not causing distress. However, we do have a responsibility to educate women and their providers that hypoactive sexual desire disorder is a legitimate health condition that deserves evaluation and treatment. Financial Disclosure: Dr. Kingsberg is a consultant or sits on advisory boards for Sprout, Palatin, Pfizer, Shionogi, Trimel, Apricus, Strategic Solutions Technology, Nuelle, NovoNordisk, Metagenics, Emotional Brain, Endoceutics, Sermonix, and Teva. The other author did not report any potential conflicts of interest.
Sheryl A. Kingsberg, PhD University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio Terri Woodard, MD The University of Texas MD Anderson Cancer Center and Baylor College of Medicine, Houston, Texas
REFERENCES 1. Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: problems and correlates. Obstet Gynecol 2008;112:970–8. 2. West SL, D’Alosio AA, Agans RP, Kalsbeek WD, Borisov NN, Thorp JM. Prevalence of low sexual desire and hypoactive sexual desire disorder in a nationally representative sample of US women. Arch Intern Med 2008: 168:1441–9.
Time Interval Between Endometrial Biopsy and Surgical Staging for Type I Endometrial Cancer: Association Between Tumor Characteristics and Survival Outcome To the Editor:
The study by Matsuo et al1 showing no association between wait times for 435 women with stage 1 low-grade endometrial cancer and survival outcomes is in
contrast with our study results,2 which identified a relationship between longer wait times and poorer survival in 9,417 women and in a sub-analysis of 3,381 women with favorable prognostic factors (Elit LM, Pond G, Seow HY. Treatment delay in endometrial cancer [letter-reply]. J Clin Oncol 2014;32:2114). Tumor (grade, stage, and histology) and patient information (body mass index, diabetes, hypertension) available—strengths of their study— may have led to the different conclusions. There are also jurisdictional differences between California (private insurance) and Ontario, Canada (publicly funded insurance). For instance, 29% of women waited 6–12 weeks in Ontario compared with 58% in California, likely reflecting different patterns of selfselection by patients and physicians in the timing of surgery. However, there are also methodologic issues that may have contributed to the different conclusions. The Matsuo cohort included only 435 patients, of whom there were only 17 observed deaths and 25 recurrences with a median follow-up of 28.8 months. We disagree that there is sufficient power to detect differences in 5year survival between 82% and 72%, such as we observed. By our calculations, a two-group log-rank test would have less than 15% power based on these numbers. Notably, the observed confidence intervals for hazard ratios are extremely wide (eg, estimate of grade change from 1 to 3 ranges from 2.27 to 436), and the longest wait group (more than 85 days) had no observed deaths, which, combined with the survival plots, implies that waiting longer leads to better survival. A more plausible explanation for these results is limited power and self-selection. Moreover, their multivariable analysis is severely overfit, with 14 degrees of freedom given so few events. Additionally as a secondary aim, the investigators examine the effects of grade change on wait times; a more appropriate analysis would be to investigate the effect of wait times on grade changes. Ultimately it is important to note that Matsuo et al are correct to conclude only that they observed no statistical evidence of an association between wait times and survival outcomes, not that one does not exist. Financial Disclosure: The authors did not report any potential conflicts of interest.
VOL. 125, NO. 6, JUNE 2015
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Letters
1497
Laurie M. Elit, MD McMaster University, Hamilton, Ontario, Canada Greg Pond, PhD Hsien Seow, PhD Escarpment Research Institute, Hamilton, Ontario, Canada
REFERENCES 1. Matsuo K, Opper NR, Ciccone MA, Garcia J, Tierney KE, Baba T, et al. Time interval between endometrial biopsy and surgical staging for type 1 endometrial cancer: association between tumor characteristics and survival outcome. Obstet Gynecol 2015; 125:424–33. 2. Elit LM, O’Leary EM, Pond GR, Seow HY. Impact of wait times on survival for women with uterine cancer. J Clin Oncol 2013;32:27–33.
In Reply: We thank Dr. Elit and colleagues for their constructive comments on our recent study.1 Null studies are often difficult to interpret, and we welcome the opportunity to contextualize our results. There are certainly many factors contributing to our discrepant results (eg, different geographical locations, demographics, and study design). However, the most important difference is that our analysis was limited to grade 1–2 tumors1 and their analysis included both grade 1–2 and grade 3 tumors (Elit LM, Pond G, Seow HY. Treatment delay in endometrial cancer [letter-reply]. J Clin Oncol 2014;32:2114). Because grade 3 tumors are clinically and molecularly distinct2 and because detailed tumor information was not available to Dr. Elit and colleagues, our respective studies are difficult to compare directly. Dr. Elit and colleagues have additional methodologic concerns. First, to check their supposition that a lack of events in the 85 days or longer group was driving our null result, we reanalyzed our data by combining this group with those waiting 43–84 days. The results did not meaningfully differ (all P..05). Second, although we fully agree that longer follow-up would be valuable, most recurrences occur within 2 years, and the vast majority of our patients were
1498
Letters
followed for longer than 2 years.3 Third, their power analysis was based on their results (5-year overall survival 81.8% in those waiting 15–42 days compared with 71.9% in those waiting 85 days or longer).4 Although their methodology is reasonable, owing to the recognized differences in our study population described above, we powered our study using another method (0.20 correlation between wait time and survival time) and had more than sufficient power to detect a significant negative correlation (as reported in the original study). Given the potential effects of self-selection on any observational study, we felt thorough multivariable analyses to be important. However, this does leave open the possibility of overfitting or overadjusting. In response, we performed additional multivariable analyses with a Cox proportional hazard regression model using backward elimination. The results were similar to what we reported previously 1; wait time was not a significant predictor of recurrence or cancer-related death. Finally, there was no association between wait time and grade changes when wait time was used as the predicting variable. Collectively, we believe our findings to be relevant to low-grade tumors and plan to examine the effect of wait time on high-grade tumors in the future directions. Financial Disclosure: The authors did not report any potential conflicts of interest.
Koji Matsuo, MD, PhD Neisha R. Opper, MPH Lynda D. Roman, MD Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California
REFERENCES 1. Matsuo K, Opper NR, Ciccone MA, Garcia J, Tierney KE, Baba T, et al. Time interval between endometrial biopsy and surgical staging for type I endometrial cancer: association between tumor characteristics and survival outcome. Obstet Gynecol 2015; 125:424–33. 2. Voss MA, Ganesan R, Ludeman L, McCarthy K, Gornall R, Schaller G, et al. Should grade 3 endometrioid endometrial carcinoma be considered a type 2
cancer-a clinical and pathological evaluation. Gynecol Oncol 2012;124:15–20. 3. van Wijk FH, van der Burg ME, Burger CW, Vergote I, van Doorn HC. Management of recurrent endometrioid endometrial carcinoma: an overview. Int J Gynecol Cancer 2009;19:314–20. 4. Elit LM, O’Leary EM, Pond GR, Seow HY. Impact of wait times on survival for women with uterine cancer. J Clin Oncol 2014;32:27–33.
Influence of Endometriosis on Assisted Reproductive Technology Outcomes: A Systematic Review and Meta-analysis To the Editor: We read with interest the systematic review by Hamdan and colleagues1 examining the effects of endometriosis on in vitro fertilization (IVF) outcomes. The authors conclude that minor degrees of endometriosis have no effect on IVF pregnancy outcomes but that more severe grades of endometriosis appear to diminish IVF live birth rates. Although we agree with this conclusion, we feel that the discussion is incomplete because it fails to mention the possible role of adenomyosis. Adenomyosis recently has been linked with an increase in early pregnancy loss and a significant reduction in clinical pregnancy rates during IVF treatment. 2 Furthermore, studies have shown that adenomyosis is very commonly present in women with severe endometriosis3 and that adenomyosis is associated with multiple alterations in endometrial function. 4 Therefore, we believe that the reported reduction in IVF live birth rates seen in women with severe endometriosis is most likely related to the negative effects of adenomyosis on implantation. The authors also conclude that there is insufficient evidence to recommend routine surgery for severe endometriosis before IVF, because there is no evidence that this translates into improved live birth rates. Because it is generally impossible to surgically excise adenomyosis, this lack of improvement in pregnancy rates is not surprising. However, we would like to highlight that there is significant evidence that hormonal
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
trying to “cure” homosexuality. We cannot imagine this argument being used in the context of arguing against the right of men to seek treatment for erectile dysfunction. It is not our intention to convince women or their gynecologists to treat a lack of desire that is not causing distress. However, we do have a responsibility to educate women and their providers that hypoactive sexual desire disorder is a legitimate health condition that deserves evaluation and treatment. Financial Disclosure: Dr. Kingsberg is a consultant or sits on advisory boards for Sprout, Palatin, Pfizer, Shionogi, Trimel, Apricus, Strategic Solutions Technology, Nuelle, NovoNordisk, Metagenics, Emotional Brain, Endoceutics, Sermonix, and Teva. The other author did not report any potential conflicts of interest.
Sheryl A. Kingsberg, PhD University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio Terri Woodard, MD The University of Texas MD Anderson Cancer Center and Baylor College of Medicine, Houston, Texas
REFERENCES 1. Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: problems and correlates. Obstet Gynecol 2008;112:970–8. 2. West SL, D’Alosio AA, Agans RP, Kalsbeek WD, Borisov NN, Thorp JM. Prevalence of low sexual desire and hypoactive sexual desire disorder in a nationally representative sample of US women. Arch Intern Med 2008: 168:1441–9.
Time Interval Between Endometrial Biopsy and Surgical Staging for Type I Endometrial Cancer: Association Between Tumor Characteristics and Survival Outcome To the Editor:
The study by Matsuo et al1 showing no association between wait times for 435 women with stage 1 low-grade endometrial cancer and survival outcomes is in
contrast with our study results,2 which identified a relationship between longer wait times and poorer survival in 9,417 women and in a sub-analysis of 3,381 women with favorable prognostic factors (Elit LM, Pond G, Seow HY. Treatment delay in endometrial cancer [letter-reply]. J Clin Oncol 2014;32:2114). Tumor (grade, stage, and histology) and patient information (body mass index, diabetes, hypertension) available—strengths of their study— may have led to the different conclusions. There are also jurisdictional differences between California (private insurance) and Ontario, Canada (publicly funded insurance). For instance, 29% of women waited 6–12 weeks in Ontario compared with 58% in California, likely reflecting different patterns of selfselection by patients and physicians in the timing of surgery. However, there are also methodologic issues that may have contributed to the different conclusions. The Matsuo cohort included only 435 patients, of whom there were only 17 observed deaths and 25 recurrences with a median follow-up of 28.8 months. We disagree that there is sufficient power to detect differences in 5year survival between 82% and 72%, such as we observed. By our calculations, a two-group log-rank test would have less than 15% power based on these numbers. Notably, the observed confidence intervals for hazard ratios are extremely wide (eg, estimate of grade change from 1 to 3 ranges from 2.27 to 436), and the longest wait group (more than 85 days) had no observed deaths, which, combined with the survival plots, implies that waiting longer leads to better survival. A more plausible explanation for these results is limited power and self-selection. Moreover, their multivariable analysis is severely overfit, with 14 degrees of freedom given so few events. Additionally as a secondary aim, the investigators examine the effects of grade change on wait times; a more appropriate analysis would be to investigate the effect of wait times on grade changes. Ultimately it is important to note that Matsuo et al are correct to conclude only that they observed no statistical evidence of an association between wait times and survival outcomes, not that one does not exist. Financial Disclosure: The authors did not report any potential conflicts of interest.
VOL. 125, NO. 6, JUNE 2015
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Letters
1497
Laurie M. Elit, MD McMaster University, Hamilton, Ontario, Canada Greg Pond, PhD Hsien Seow, PhD Escarpment Research Institute, Hamilton, Ontario, Canada
REFERENCES 1. Matsuo K, Opper NR, Ciccone MA, Garcia J, Tierney KE, Baba T, et al. Time interval between endometrial biopsy and surgical staging for type 1 endometrial cancer: association between tumor characteristics and survival outcome. Obstet Gynecol 2015; 125:424–33. 2. Elit LM, O’Leary EM, Pond GR, Seow HY. Impact of wait times on survival for women with uterine cancer. J Clin Oncol 2013;32:27–33.
In Reply: We thank Dr. Elit and colleagues for their constructive comments on our recent study.1 Null studies are often difficult to interpret, and we welcome the opportunity to contextualize our results. There are certainly many factors contributing to our discrepant results (eg, different geographical locations, demographics, and study design). However, the most important difference is that our analysis was limited to grade 1–2 tumors1 and their analysis included both grade 1–2 and grade 3 tumors (Elit LM, Pond G, Seow HY. Treatment delay in endometrial cancer [letter-reply]. J Clin Oncol 2014;32:2114). Because grade 3 tumors are clinically and molecularly distinct2 and because detailed tumor information was not available to Dr. Elit and colleagues, our respective studies are difficult to compare directly. Dr. Elit and colleagues have additional methodologic concerns. First, to check their supposition that a lack of events in the 85 days or longer group was driving our null result, we reanalyzed our data by combining this group with those waiting 43–84 days. The results did not meaningfully differ (all P..05). Second, although we fully agree that longer follow-up would be valuable, most recurrences occur within 2 years, and the vast majority of our patients were
1498
Letters
followed for longer than 2 years.3 Third, their power analysis was based on their results (5-year overall survival 81.8% in those waiting 15–42 days compared with 71.9% in those waiting 85 days or longer).4 Although their methodology is reasonable, owing to the recognized differences in our study population described above, we powered our study using another method (0.20 correlation between wait time and survival time) and had more than sufficient power to detect a significant negative correlation (as reported in the original study). Given the potential effects of self-selection on any observational study, we felt thorough multivariable analyses to be important. However, this does leave open the possibility of overfitting or overadjusting. In response, we performed additional multivariable analyses with a Cox proportional hazard regression model using backward elimination. The results were similar to what we reported previously 1; wait time was not a significant predictor of recurrence or cancer-related death. Finally, there was no association between wait time and grade changes when wait time was used as the predicting variable. Collectively, we believe our findings to be relevant to low-grade tumors and plan to examine the effect of wait time on high-grade tumors in the future directions. Financial Disclosure: The authors did not report any potential conflicts of interest.
Koji Matsuo, MD, PhD Neisha R. Opper, MPH Lynda D. Roman, MD Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California
REFERENCES 1. Matsuo K, Opper NR, Ciccone MA, Garcia J, Tierney KE, Baba T, et al. Time interval between endometrial biopsy and surgical staging for type I endometrial cancer: association between tumor characteristics and survival outcome. Obstet Gynecol 2015; 125:424–33. 2. Voss MA, Ganesan R, Ludeman L, McCarthy K, Gornall R, Schaller G, et al. Should grade 3 endometrioid endometrial carcinoma be considered a type 2
cancer-a clinical and pathological evaluation. Gynecol Oncol 2012;124:15–20. 3. van Wijk FH, van der Burg ME, Burger CW, Vergote I, van Doorn HC. Management of recurrent endometrioid endometrial carcinoma: an overview. Int J Gynecol Cancer 2009;19:314–20. 4. Elit LM, O’Leary EM, Pond GR, Seow HY. Impact of wait times on survival for women with uterine cancer. J Clin Oncol 2014;32:27–33.
Influence of Endometriosis on Assisted Reproductive Technology Outcomes: A Systematic Review and Meta-analysis To the Editor: We read with interest the systematic review by Hamdan and colleagues1 examining the effects of endometriosis on in vitro fertilization (IVF) outcomes. The authors conclude that minor degrees of endometriosis have no effect on IVF pregnancy outcomes but that more severe grades of endometriosis appear to diminish IVF live birth rates. Although we agree with this conclusion, we feel that the discussion is incomplete because it fails to mention the possible role of adenomyosis. Adenomyosis recently has been linked with an increase in early pregnancy loss and a significant reduction in clinical pregnancy rates during IVF treatment. 2 Furthermore, studies have shown that adenomyosis is very commonly present in women with severe endometriosis3 and that adenomyosis is associated with multiple alterations in endometrial function. 4 Therefore, we believe that the reported reduction in IVF live birth rates seen in women with severe endometriosis is most likely related to the negative effects of adenomyosis on implantation. The authors also conclude that there is insufficient evidence to recommend routine surgery for severe endometriosis before IVF, because there is no evidence that this translates into improved live birth rates. Because it is generally impossible to surgically excise adenomyosis, this lack of improvement in pregnancy rates is not surprising. However, we would like to highlight that there is significant evidence that hormonal
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
