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Journal of Clinical Oncology, Vol 24, No 22 (August 1), 2006: pp. 3576-3582 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.1896 The Impact of Hormone Replacement Therapy on Menopausal Symptoms in Younger High-Risk Women After Prophylactic Salpingo-Oophorectomy
From the Division of Psychosocial Research and Epidemiology, and Department of Gynecology, the Netherlands Cancer Institute; Department of Gynecology, Vrije Universiteit University Medical Center; Department of Gynecology, Academic Medical Center, Amsterdam; Department of Gynecology, University Medical Center Nijmegen, Nijmegen; Department of Gynecology, Leiden University Medical Center, Leiden; Department of Gynecology, University Medical Center Groningen, University of Groningen; Department of Gynecology, University Medical Center Utrecht, Utrecht; Department of Gynecology, Academic Hospital Maastricht, Maastricht, the Netherlands; and Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY Address reprint requests to Neil K. Aaronson, PhD, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Division of Psychosocial Research and Epidemiology, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: n.aaronson{at}nki.nl
PURPOSE: Preventive health strategies for women at increased hereditary risk of ovarian cancer include gynecologic screening (GS) and/or prophylactic oophorectomy (PBSO). Hormone replacement therapy (HRT) is often prescribed to compensate for postsurgical endocrine deficiencies. This study examined the impact of HRT use on levels of endocrine symptoms and sexual functioning among premenopausal women who have undergone PBSO. Comparisons were made with similar women undergoing GS. PATIENTS AND METHODS: Questionnaire data on endocrine symptoms and sexual functioning were obtained from 450 premenopausal, high-risk women who had participated in this nationwide, cross-sectional, observational study. RESULTS: Thirty-six percent of women had undergone PBSO and 64% had opted for GS. In the PBSO group, 47% of the women were current HRT users. They reported significantly fewer vasomotor symptoms than nonusers (P < .05). However, compared with premenopausal women undergoing GS, oophorectomized HRT users were more likely to report vasomotor symptoms (P < .01). HRT users and nonusers reported comparable levels of sexual functioning. Compared with women in the GS group, oophorectomized HRT users reported significantly more sexual discomfort due to vaginal dryness and dyspareunia (P < .01). CONCLUSION: Although HRT has a positive impact on surgically induced vasomotor symptoms, it may be less effective than is often assumed. Symptom levels remain well above those of premenopausal women undergoing screening, and sexual discomfort is not alleviated by HRT. Physicians need to provide younger high-risk women considering PBSO with realistic information about both benefits and drawbacks of this preventive strategy, including information about premature menopause and HRT.
Preventive health care recommendations for women at increased hereditary risk of ovarian cancer include periodic gynecologic screening (GS) and/or prophylactic bilateral salpingo-oophorectomy (PBSO). In the face of uncertain efficacy of the currently available screening techniques, including transvaginal ultrasonography and CA-125 serology,1 and the established risk-reducing benefit of PBSO for ovarian and breast cancers,2,3 carriers of BRCA1/BRCA2 gene mutations are usually advised to undergo PBSO after the age of 35 years or after the completion of childbearing.4 Adverse effects associated with PBSO in premenopausal women include loss of fertility, immediate onset of menopause with vasomotor and urogenital symptoms,5,6 and a decline in sexual interest and activity.7 The management of surgically induced menopause requires strategies for alleviating the climacteric symptoms, and improving women's functioning and quality of life. Hormone-replacement therapy (HRT) is often prescribed at the time of surgery.8 HRT has proven to be highly effective in alleviating vasomotor symptoms (eg, hot flushes, sweats) and urogenital atrophy in women undergoing natural menopause.8,9 Because of its androgenic properties, tibolone has shown to have additional beneficial effects on sexual functioning.10-12 Recent studies,13-17 however, indicate that HRT use by healthy menopausal women is associated with increased risks of breast cancer and cardiovascular complications, and that these risks may overshadow the potentially beneficial effects on osteoporosis and colon cancer. Current recommendations call for short-duration HRT treatment for severe symptoms, and avoidance of long-term use for prevention of chronic health conditions.18,19 Only two studies have investigated post-PBSO menopausal symptoms and sexual functioning as part of a larger investigation of the psychosocial impact of prophylactic surgery.20,21 In both studies, PBSO was found to be associated with the occurrence of menopausal symptoms. The results with regard to sexual functioning were inconsistent, with some evidence of sexual impairment in the study of Elit et al,20 but not in the study of Fry et al.21 Neither of these studies investigated endocrine symptoms and sexual functioning explicitly in relation to post-PBSO HRT use. The primary focus of this report is on the impact of HRT use on the levels of endocrine symptoms and sexual functioning among premenopausal women who have undergone PBSO. Comparisons are made with premenopausal high-risk women undergoing GS.
Participants and Procedures This investigation was part of a larger, cross-sectional, observational study of psychosocial issues surrounding ovarian cancer prevention among high-risk women in the Netherlands. Study participants were recruited from the gynecology departments of eight hospitals. Women were eligible for the larger study if they were between 30 and 75 years of age, came from a hereditary breast/ovarian cancer family, and had sought gynecologic advice on preventive measures at one of the clinics between 1996 and 2001. Patients were excluded from participation if they had undergone oophorectomy as treatment for a medical condition, or had metastatic cancer or any other severe comorbidity. The current analysis was restricted to data of women who were premenopausal at the time of PBSO or were currently premenopausal (GS group). Premenopause was defined as having regular menses during the last 6 months or before PBSO. After surgery, women were prescribed standard doses of HRT (estrogen/progesterone or tibolone) administered either orally or transdermally. Eligible women who had undergone PBSO or GS received an invitation letter by mail, an informed consent form, a questionnaire, and a postage-paid return envelope. If no response was received after 2 weeks, reminders by mail and telephone were used. Patients were classified as nonrespondents if they actively declined to participate, or if they could not be reached after multiple attempts. The study was approved by the institutional review boards of all participating hospitals.
Measures The Sexual Activity Questionnaire23 was used to measure sexual functioning. It consists of three scales: pleasure (six items on desire, enjoyment, satisfaction, and current frequency of activities); discomfort (two items on vaginal dryness, pain and discomfort during penetration); and habit (frequency of sexual activity compared with the usual level). Lower scores represent poorer sexual functioning.
Medical and Sociodemographic Data
Statistical Analysis The study sample was divided into three groups according to the type of prevention and the current hormonal status: oophorectomized, current users and nonusers of HRT (PBSO HRT users and PBSO HRT nonusers), and premenopausal women undergoing GS. One-way analysis of covariance was used to test for group differences in endocrine symptoms and sexual functioning, controlling for possible confounders (age, DNA status, history of breast cancer, tamoxifen use, and prophylactic mastectomy). Among HRT users, the effect of the type of medication (estrogen/progesterone v tibolone) was also investigated. In addition, individual symptoms of the FACT-ES scale were dichotomized (symptom present was considered to be a response in either of the two highest categories, "very much" and "quite a bit"). For each symptom, a multivariate logistic regression analysis was conducted to determine the significance of between-group differences, when controlling for potential confounders.
Study Sample Of 1,205 high-risk women in the hospitals' databases, 1,084 were eligible for study participation (Fig 1). The reasons for ineligibility were oophorectomy carried out as treatment for a medical condition (n = 94), death (n = 23), metastatic cancer (n = 3), and severe psychiatric problems (n = 1). In total, 858 (79%) women returned completed questionnaires. Lack of interest (n = 137), poor health (n = 8), and emotional problems (n = 8) were the main reasons for nonparticipation. The data of 12 women had to be excluded: five women reported that the questionnaire was not applicable to their present situation, given that their cancer risk was found not to be increased based on DNA testing; five women had a high percentage (> 50%) of missing values; and two women had undergone an oophorectomy before 1996. There were no statistically significant differences between the respondents and nonrespondents in the type of ovarian cancer prevention and mean age (data not shown). Among the respondents, 450 premenopausal women were identified, of whom 164 (36%) had undergone PBSO. Data on menopausal status of nonrespondents were not available.
The background characteristics of the sample are shown in Table 1. Compared with the GS group, the PBSO group was significantly older, more likely to have been diagnosed with breast cancer, to be BRCA1/2 mutation carriers, and to have undergone prophylactic mastectomy (all P < .001). At the time of assessment, 47% of the PBSO group reported current use of HRT, with the largest percentage taking estrogen/progesterone medications. HRT users were younger (45 v 47 years; P < .05) and had undergone PBSO at a younger age (41 v 44 years; P < .01), were less likely to have a history of breast cancer (17% v 47%; P < .001), and were more likely to have undergone prophylactic mastectomy (62% v 41%; P < .01) than nonusers. One fourth of the latter group reported having used HRT at some time postsurgery. Data on the reasons for HRT discontinuation were not available. The majority of current HRT users (82%) received a prescription for HRT at the time of PBSO, and reported having started HRT directly after surgery (72%) and being (highly) compliant with HRT use (99%; Table 1).
Endocrine Symptoms Table 2 presents the mean FACT-ES scale scores and the individual symptom frequencies. As indicated by the mean scores, the PBSO HRT users group reported significantly fewer symptoms overall than the PBSO HRT nonusers group (P < .05). At the individual endocrine symptom level, significant between-group differences were found only for hot flushes, and cold and night sweats (all P < .05).
The PBSO HRT users group reported significantly more endocrine symptoms overall (FACT-ES scale scores) than the GS group (P < .05). Significant group differences were found in the frequency of all vasomotor symptoms, vaginal dryness, pain/discomfort during intercourse, and loss of interest in sex, with the PBSO HRT users group experiencing more problems (all P < .01).
Sexual Functioning
The PBSO HRT users and PBSO HRT nonusers groups reported comparable levels of sexual functioning, as measured by the pleasure, discomfort, and habit scales of the Sexual Activity Questionnaire. Compared with the GS group, the PBSO HRT users group reported significantly more discomfort during sexual activities (P < .01). Although the numbers were small (Table 1), we examined whether the type of HRT used differentially affected levels of endocrine symptoms and sexual functioning. No statistically significant differences were found between those who used estrogen/progesterone versus tibolone (data not shown in the table).
Many women from hereditary breast/ovarian cancer families consider PBSO or GS as a strategy for managing their increased risk of developing ovarian cancer. Although the risk reduction attributed to PBSO is largest in premenopausal women,2,3,24 the resulting postoperative endocrine imbalance may affect functioning in several health domains. This report presents the results of a study that investigated the impact of PBSO on endocrine symptoms and sexuality among premenopausal, high-risk women, and the effect of HRT in alleviating these symptoms. In the Netherlands, HRT is recommended as a means of alleviating vasomotor and sexual symptoms only to high-risk women who are premenopausal at the time of surgery. In clinical practice, it is generally recommended that HRT use begin immediately after PBSO, and be discontinued at the time of expected natural menopause (ie, at approximately 50 years of age).4 There is currently no consensus about whether HRT use after oophorectomy contributes additionally to the already increased risk of breast cancer resulting from BRCA1 or BRCA2 mutation carriership.25 Recent studies4,26 have suggested that decisions regarding HRT use should be based on quality-of-life considerations, rather than on life expectancy. Moreover, short-term HRT use does not negate the protective effect of PBSO on subsequent breast cancer risk in BRCA1/2 mutation carriers.26 When deciding to undergo PBSO, younger women may expect that postsurgical HRT use will minimize if not entirely prevent menopausal symptoms, and that their functioning will return approximately to the presurgery level. In our study, 47% of oophorectomized women were currently using HRT. The results indicated that current HRT use significantly reduced vasomotor symptoms, with prevalence rates being 14% to 21% lower among HRT users versus nonusers. Although these reductions are not trivial, previous studies of HRT use among women experiencing natural menopause have demonstrated larger reductions in vasomotor symptoms.9 In addition, contrary to expectations based on clinical experience, no significant differences in the frequency of other endocrine symptoms (eg, vaginal dryness) were observed between HRT users and nonusers after controlling for possible confounders and type of medication. Surgical menopause may entail symptoms of higher severity for which commonly applied HRT may be less effective, given that it was originally designed to compensate for gradual endocrine losses in naturally menopausal women. This issue, however, needs to be addressed empirically. Although HRT use does have a salutary effect on vasomotor symptoms in women with surgically induced menopause, it does not alleviate these symptoms entirely, as evidenced by the comparison with premenopausal women undergoing GS. It is commonly assumed that HRT use will virtually eliminate hot flushes.27 The current findings indicate that oophorectomized HRT users continue to report significantly more vasomotor and other endocrine symptoms than the group of premenopausal women undergoing screening. The only previous study21 that has compared the physical and psychosocial functioning of women undergoing PBSO versus GS found an overall trend for the surgical group (n = 29) to report more menopausal symptoms than the nonsurgical group (n = 28). However, it is unclear if that study adjusted statistically for current HRT use. In addition, the observed group differences were with regard to aches and pains, weight gain, and menstrual problems, but not vasomotor symptoms. The majority of women in the current study reported being sexually active, and no significant differences were found in the level of activity between the oophorectomized HRT users, oophorectomized HRT nonusers, and women undergoing screening. However, oophorectomized women who were not sexually active attributed their inactivity significantly more frequently to decreased libido and bodily problems than did women in the screening group. HRT users and nonusers reported similar levels of sexual functioning, and HRT users reported significantly more discomfort (eg, vaginal dryness, dyspareunia) than women undergoing screening. These results are in line with other studies6,20,28,29 that have reported impairments in sexual functioning due to surgically induced menopause, and sustained problems with libido, lubrication, and dyspareunia despite HRT use.6,28 However, these studies included a more heterogeneous sample of women, including those who had undergone oophorectomy as a medical treatment. Two other studies of high-risk women who had undergone PBSO have reported that HRT may mitigate potential sexual problems.21,30 However, these were single-center studies, the results of which were based on (qualitative) data derived from small samples. Decreased androgen concentrations after PBSO may underlie sexual problems.31 Some studies have reported that use of transdermal testosterone32 or tibolone improves sexual function.10,12,33 In our sample, none of the women were treated with testosterone. We did not observe any significant differences in sexual functioning among women using tibolone versus estrogen/progesterone. However, the sample size for this specific comparison was limited, with small numbers of tibolone users. The strength of our study lies in its multicenter design, the large sample size, and the high response rate. We believe that the study sample is representative of high-risk women in the Netherlands. The main limitation of the study is its cross-sectional design, which does not allow for interpretation of causal relationships or detection of changes in endocrine symptom levels or sexual functioning over time due to the absence of a baseline (ie, presurgical) assessment. We are currently conducting a prospective, multicenter study with presurgical and follow-up assessment. In addition, although we controlled for possible confounders in our statistical analyses, statistical adjustments cannot entirely rule out the possibility of indication bias, given that the study design was nonrandomized. Indication bias would suggest that the severity of menopausal symptoms would be decisive in whether or not to use HRT following PBSO. In clinical practice, the gynecologists from the participating hospitals typically prescribe standard doses of HRT preoperatively and recommend that women commence HRT use directly after PBSO, rather than waiting until menopausal symptoms occur. The majority of HRT users in our sample began using HRT directly after PBSO, and they were highly compliant with its use. Nevertheless, there are several reasons why one cannot entirely rule out the possibility of indication bias. First, for those women who were current HRT users, no information was available on whether their use had been continuous or intermittent during the period after surgery. Second, no data were available about the reasons why some women had discontinued postsurgical use of HRT. We would emphasize, however, that although indication bias may play some role in the comparisons made between HRT users and nonusers, it does not when comparing symptoms of oophorectomized HRT users with those of women undergoing gynecologic screening. Ultimately, one would want to investigate these issues in a randomized clinical trial. However, the feasibility of such a randomized clinical trial is questionable because it is likely that many eligible women would not want to be randomly assigned to HRT use or nonuse, or to a placebo group. In conclusion, this study has documented relatively high levels of endocrine symptoms and impaired sexual functioning associated with PBSO. Although the efficacy of HRT in alleviating symptoms of natural menopause has been established in numerous randomized studies, our observational data suggest that HRT may be less effective in the case of surgically induced symptoms. Randomized studies are needed to determine the efficacy of HRT and testosterone supplementation in alleviating menopausal symptoms after PBSO, including dose-response issues. In addition, the role of nonhormonal medical treatments and psychosocial interventions in alleviating climacteric complaints merits further study. Ganz et al34 have demonstrated that psychosocial interventions in combination with nonhormonal medications are a viable alternative to HRT among older breast cancer survivors suffering from menopausal symptoms. Possibly, younger oophorectomized women may also benefit from such interventions. Physicians need to provide younger high-risk women considering PBSO with realistic and balanced information about both the benefits and possible drawbacks of this preventive strategy, including information about ovarian function, menopause, HRT, and psychosocial effects (eg, reduced cancer worries and lower risk perceptions).30,35,36 Such balanced information will help women in making informed decisions about the optimal preventive health strategy.
The authors indicated no potential conflicts of interest.
We thank the women who participated in this research, Miranda Gerritsma and Esther Janssen for their administrative support, the staff of the participating hospitals for assistance in recruiting patients, and Matti Rookus, PhD, for her valuable comments on an earlier version of the manuscript.
Supported by Grant No. NKI 2001-2382 from the Dutch Cancer Society. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Hogg R, Friedlander M: Biology of epithelial ovarian cancer: Implications for screening women at high genetic risk. J Clin Oncol 22:1315-1327, 2004 2. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616-1622, 2002 3. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609-1615, 2002 4. Armstrong K, Schwartz JS, Randall T, et al: Hormone replacement therapy and life expectancy after prophylactic oophorectomy in women with BRCA1/2 mutations: A decision analysis. J Clin Oncol 22:1045-1054, 2004 5. Bachmann GA: Vasomotor flushes in menopausal women. Am J Obstet Gynecol 180:S312-S316, 1999 (suppl)[CrossRef][Medline] 6. Shifren JL, Nahum R, Mazer NA: Incidence of sexual dysfunction in surgically menopausal women. Menopause 5:189-190, 1998[Medline] 7. Taylor M: Psychological consequences of surgical menopause. J Reprod Med 46:317-324, 2001[Medline] 8. Nelson HD: Commonly used types of postmenopausal estrogen for treatment of hot flashes: Scientific review. JAMA 291:1610-1620, 2004 9. McLennan A, Broadbent J, Lester S, et al: Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Oxford, United Kingdom, Cochrane Library, CD002978, 4, 2004 10. Egarter C, Topcuoglu A, Vogl S, et al: Hormone replacement therapy with tibolone: Effects on sexual functioning in postmenopausal women. Acta Obstet Gynecol Scand 81:649-653, 2002[CrossRef][Medline] 11. Wu MH, Pan HA, Wang ST, et al: Quality of life and sexuality changes in postmenopausal women receiving tibolone therapy. Climacteric 4:314-319, 2001[Medline] 12. Nathorst-Boos J, Hammar M: Effect on sexual life: A comparison between tibolone and a continuous estradiol-norethisterone acetate regimen. Maturitas 26:15-20, 1997[CrossRef][Medline] 13. Beral V: Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419-427, 2003[CrossRef][Medline] 14. Manson JE, Hsia J, Johnson KC, et al: Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 349:523-534, 2003 15. Stahlberg C, Pedersen AT, Lynge E, et al: Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe. Int J Cancer 109:721-727, 2004[CrossRef][Medline] 16. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al: Effect of estrogen plus progestin on stroke in postmenopausal women: The Women's Health Initiative—A randomized trial. JAMA 289:2673-2684, 2003 17. Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative Randomized Controlled Trial. JAMA 288:321-333, 2002 18. Stephenson J: FDA orders estrogen safety warnings: Agency offers guidance for HRT use. JAMA 289:537-538, 2003 19. Nelson HD: Postmenopausal estrogen for treatment of hot flashes: Clinical applications. JAMA 291:1621-1625, 2004 20. Elit L, Esplen MJ, Butler K, et al: Quality of life and psychosexual adjustment after prophylactic oophorectomy for a family history of ovarian cancer. Fam Cancer 1:149-156, 2001[CrossRef][Medline] 21. Fry A, Busby-Earle C, Rush R, et al: Prophylactic oophorectomy versus screening: Psychosocial outcomes in women at increased risk of ovarian cancer. Psychooncology 10:231-241, 2001[CrossRef][Medline] 22. Fallowfield LJ, Leaity SK, Howell A, et al: Assessment of quality of life in women undergoing hormonal therapy for breast cancer: Validation of an endocrine symptom subscale for the FACT-B. Breast Cancer Res Treat 55:189-199, 1999[Medline] 23. Thirlaway K, Fallowfield L, Cuzick J: The Sexual Activity Questionnaire: A measure of women's sexual functioning. Qual Life Res 5:81-90, 1996[CrossRef][Medline] 24. Kramer JL, Velazquez IA, Chen BE, et al: Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol 23:8629-8635, 2005 25. Garber J, Hartman A: Prophylactic oophorectomy and hormone replacement therapy: Protection at what price? J Clin Oncol 22:978-980, 2004 26. Rebbeck TR, Friebel T, Wagner T, et al: Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group. J Clin Oncol 23:7804-7810, 2005 27. Lobo RA, Kelsey J, Marcus R (eds): Menopause: Biology and Pathobiology. New York, NY, Academic Press, 2000 28. Nathorst-Boos J, von Schoultz B, Carlstrom K: Elective ovarian removal and estrogen replacement therapy: Effects on sexual life, psychological well-being and androgen status. J Psychosom Obstet Gynaecol 14:283-293, 1993[Medline] 29. Robson M, Hensley M, Barakat R, et al: Quality of life in women at risk for ovarian cancer who have undergone risk-reducing oophorectomy. Gynecol Oncol 89:281-287, 2003[CrossRef][Medline] 30. Meiser B, Tiller K, Gleeson MA, et al: Psychological impact of prophylactic oophorectomy in women at increased risk for ovarian cancer. Psychooncology 9:496-503, 2000[CrossRef][Medline] 31. Shifren JL: Androgen deficiency in the oophorectomized woman. Fertil Steril 77:S60-S62, 2002 (suppl 4) 32. Shifren J, Braunstein G, Simon J, et al: Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 343:682-688, 2000 33. Egarter C, Huber J, Leikermoser R, et al: Tibolone versus conjugated estrogens and sequential progestogen in the treatment of climacteric complaints. Maturitas 23:55-62, 1996[CrossRef][Medline] 34. Ganz PA, Greendale GA, Petersen L, et al: Managing menopausal symptoms in breast cancer survivors: Results of a randomized controlled trial. J Natl Cancer Inst 92:1054-1064, 2000 35. Hallowell N: A qualitative study of the information needs of high-risk women undergoing prophylactic oophorectomy. Psychooncology 9:486-495, 2000[CrossRef][Medline] 36. Madalinska JB, Hollenstein J, Bleiker EMA, et al: The quality of life effects of prophylactic salpingo-oophorectomy versus gynecologic screening among women at increased risk of hereditary ovarian cancer. J Clin Oncol 23:6890-6898, 2005 Submitted December 8, 2005; accepted March 2, 2006. Related Editorial
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests were used to examine potential differences in the background characteristics of women who had undergone PBSO versus GS. 
