- Email: [email protected]
Comparison of hCG-stimulated androgen production in women with polycystic ovary syndrome and normal women
CONCLUSIONS: We observed a decrease in implantation rate for patients with a BMIR30. Obese patients do not show any increased risks of spontaneous miscarriage. Age plays a preponderant role in relation to BMI. BMI affects prognosis for younger women; beyond the age of 38, the negative impact lessens.
P-53 Tuesday, October 20, 2009 THE INFLUENCE OF BODY MASS INDEX (BMI) ON PREGNANCY RATES AND OUTCOMES AMONG INFERTILE JAPANESE WOMEN. M. Funabiki, S. Taguchi, T. Hayashi, H. Ujino, Y. Nakamura. Oak Clinic, Osaka, Japan. OBJECTIVE: The World Health Organization defines obesity as BMI R 30 kg/m. The Japan Society for the Study of Obesity (JASSO) defines obesity as BMI R 25 kg/m. The objective of this study was to examine the effect of BMI on infertility treatment in Japanese women based on JASSO criteria. DESIGN: Retrospective study MATERIALS AND METHODS: 616 patients undergoing infertility treatment from June 2006 to June 2007 were allocated into 3 main groups according to the JASSO criteria: low (n¼ 112), normal (n¼ 460), and high (n¼ 44) BMI. They were further subdivided by treatment into 2 subgroups: no in vitro fertilization (IVF) (n¼ 302) and IVF (n¼ 314). The main outcome measures were pregnancy rate (PR), ongoing pregnancy rate (OPR), and miscarriage rate (MR). Statistical testing included Student’s t-test, Pearson’s chi square test, and Fisher’s exact test. RESULTS: PR was significantly lower in the high BMI group (22/44, 50%) than in the normal BMI group (318/460, 69.1%; P<0.05). Low BMI had no significant impact on fertility. Compared to IVF patients with normal BMI (n¼ 238), IVF patients with high BMI (n ¼ 25) had: a tendency towards lower PR (5/25, 20% vs. 55/238, 23.1%), OPR (3/5, 60% vs. 41/55, 74.5%.), MR (2/5, 40% vs. 14/55, 25.5%), and fertilization rate (115/219, 52.5% vs. 1658/2832, 58.5%); a significant reduction in the number of oocytes retrieved (8.85.7 vs. 11.98.8; P<0.05) and the number of good quality embryos (33/90, 36.7% vs. 656/1118, 58.7%; P<0.05); and a significant increase in the cancellation rate due to poor response or lack of fertilization (5/25, 20% vs. 18/238, 7.6%; p<0.05). CONCLUSIONS: Obesity has a deleterious effect on fertility. This is clearly obvious among high BMI women seeking IVF, who showed fewer retrieved oocytes, a deterioration in embryo quality. No significant difference was observed in the implantation rate between normal BMI and high BMI women. However, the low fertilization and cleavage rates, possibly due to the bad quality embryos, may explain the poor outcomes in high BMI women.
P-54 Tuesday, October 20, 2009 SOCIAL APPEARANCE ANXIETY IS ASSOCIATED WITH PERCEIVED BARRIERS TO EXERCISE IN WEIGHT LOSS SURGERY PATIENTS. M. Aubuchon, L. Martin-Hawver, T. Sonnanstine, D. Williams, M. Thomas. Obstetrics and Gynecology, University of Cincinnati, Cincinnati, OH; General Surgery, University of Cincinnati, Cincinnati, OH; Tri State Weight Loss, St Luke Hospital, Florence, KY. OBJECTIVE: To determine whether social appearance anxiety influences perceived barriers to exercise in women considering or having undergone weight-loss surgery. DESIGN: Cross-sectional study. MATERIALS AND METHODS: Women age 18-45 in the offices of weight-loss surgeons completed a brief anonymous survey between 20082009. Information was obtained for age, height, weight, menstrual cyclicity, and pre/post surgery status. As a possible contributor to social anxiety, respondents were asked whether hyperandrogenic symptoms, specifically bothersome hair growth or acne, were present. The following validated instruments were also included: Center for Epidemiologic Studies Depression Scale, Exercise Barriers and Benefits Scale (EBBS), and Social Appearance Anxiety Scale (SAAS). Respondents were first categorized as depressed/nondepressed and then further described as hyperandrogenic/non-hyperandrogenic. Statistical analysis employed Student t test and Pearson correlation for continuous and chi square for categorical variables, with significance assessed at 2 tailed p<0.05. RESULTS: Forty-two questionnaires were returned, of which 16 were incomplete or ineligible. For the remaining 26, 16 were noted to be depressed and 10 were not depressed. Of this group of women, 7 of 16 depressed and 5 of 10 non-depressed responders noted hyperandrogenic symptoms. Four of
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26 respondents noted oligomenorrhea. When depressed and non-depressed were analyzed separately, no significant differences were noted in terms of age, body mass index, EBBS scores, or SAAS scores between hyperandrogenic and nonhyperandrogenic responders. Also, there was no significant difference for affirmative response to embarrassment with exercise on EBBS between hyperandrogenic and non-hyperandrogenic responders. For non-depressed responders, EBBS barrier score was significantly correlated with SAAS score (r¼0.83, p¼0.003). CONCLUSIONS: Social appearance anxiety is associated with perceived barriers to exercise among non-depressed female weight loss surgery patients.
POLYCYSTIC OVARY SYNDROME P-55 Tuesday, October 20, 2009 PIOGLITAZONE TREATMENT DECREASES FOLLICULAR FLUID LEVELS OF TNF-ALPHA AND IL-6, AND IMPROVES OVARIAN RESPONSE TO FSH AND IVF OUTCOME IN PATIENTS WITH POLYCYSTIC OVARY SYNDROME UNDERGOING IVF. C.-H. Kim, K.-H. Cheon, E.-H. Park, Y.-H. Koo, K.-S. Jung, B.-M. Kang. Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Obstetrics and Gynecology, Jang’s Women’s Hospital, Seoul, Republic of Korea; Obstetrics and Gynecology, Haesung Hospital, Cheonan-City, Chungnam-Do, Republic of Korea. OBJECTIVE: To investigate the effects of pioglitazone on controlled ovarian stimulation (COS), IVF outcome, and intrafollicular cytokines levels in polycystic ovary syndrome (PCOS) patients. DESIGN: Prospective, randomized controlled trial MATERIALS AND METHODS: Eighty-six infertile patients with PCOS who were resistant to clomiphene citrate were recruited in this study and they were randomized into pioglitazone treatment group (n¼43) or control group (n¼43). All patients were pretreated for 3 weeks with monophasic oral contraceptives (OCs) before COS with recombinant human FSH (rhFSH) and GnRH antagonist. In treatment group, pioglitazone of 30 mg once daily was started on the starting day of OCs and continued to the day of hCG injection. Oocyte retrieval was performed 35-36 h after hCG injection. Tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) levels were assayed in the follicular fluids obtained at oocyte retrieval. RESULTS: There were no significant differences in age, body mass index (BMI), infertility duration, endocrine profile between two groups. Total dose and days of rFSH administered were significantly lower in treatment group (P¼0.002, P<0.001, respectively). The numbers of follicle R 14mm and follicle with diameter of 11-13mm on the day of hCG injection were significantly lower (P¼0.002, P<0.001, respectively). The numbers of retrieved oocytes and MII oocytes were also significantly lower in treatment group (P<0.001, P<0.001). Follicular fluid TNF-a and IL-6 levels were significantly lower in women treated with pioglitazone than in controls (P¼0.003, P¼0.001, respectively). The clinical pregnancy rate was higher and incidence of severe ovarian hyperstimulation syndrome (OHSS) was lower in treatment group but statistical significance was not found. CONCLUSIONS: Pioglitazone therapy could reduce the follicular fluid TNF-a and IL-6 levels, and might be beneficial in improving ovarian response to COS and IVF outcomes in PCOS patients.
P-56 Tuesday, October 20, 2009 COMPARISON OF HCG-STIMULATED ANDROGEN PRODUCTION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME AND NORMAL WOMEN. M. A. Rosencrantz, M. S. Coffler, A. S. Park, R. Shayya, A. Ramos-Haggan, R. J. Chang. Reproductive Medicine, UCSD, La Jolla, CA. OBJECTIVE: We have previously reported that 17-OHP exhibits significant increased dose-responsiveness to recombinant human chorionic gonadotropin (r-hCG) in PCOS women compared to normal women (2008 Endo Society). To further examine androgen responsiveness to hCG stimulation, we measured serum levels of androstenedione (A) and testosterone (T) following iv r-hCG in both groups. DESIGN: Prospective study at a general clinical research center in a tertiary academic medical center. MATERIALS AND METHODS: 10 PCOS subjects and 10 normal women received r-hCG iv at doses of 1, 10, 25, 100 and 250 micrograms on separate
Vol. 92., No. 3, Supplement, September 2009
occasions in a randomized manner. Blood was obtained prior to and at 24 hours after r-hCG administration for hormone measurements. A subset of 5 PCOS subjects and 4 normal women had blood samples obtained before and at 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 hours after iv administration of 25 micrograms r-hCG. RESULTS: In PCOS women, 17-OHP exhibited a progressive increasing dose-responsiveness to r-hCG that was significantly greater than that of normal women. Peak responses were achieved with the 100 microgram dose in both groups. In PCOS women, serum A and T exhibited a marked rise at the 10 microgram dose which appeared to be maximal as further increases were not observed at higher doses. In contrast, in normal women, increases of serum A and T were not seen at any dose of r-hCG. Time course studies indicated that, for all androgens, peak responses occurred at 24 hours. CONCLUSIONS: Consistent with our previous findings, theca cell sensitivity was greater in PCOS women compared to normal women. In PCOS women, A and T exhibited maximal dose responses that were 10-fold greater than that of 17-OHP. In normal women, A and T appeared to be non-responsive to r-hCG at the doses administered. Supported by: Eunice Kennedy Shriver NICHD/NIH (U54 HD12303-28) as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research and NIH grant MO1 RR00827.
P-57 Tuesday, October 20, 2009 PROLONGED ANOVULATION CAUSES ABERRANT ENDOMETRIAL GENE PROMOTER METHYLATION CHANGES IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. C. P. Montville, W.-Y. Tang, S.-M. Ho. Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH; Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH. OBJECTIVE: Abnormal expression of steroid hormone receptors in the endometrium of women with polycystic ovary syndrome (PCOS) has been suggested to adversely affect endometrial function. Although aberrant epigenetic regulation of endometrial gene expression has been demonstrated in endometriosis and endometrial adenocarcinoma, epigenetic regulation of endometrial gene expression in PCOS has not been evaluated. We hypothesize that abnormal endometrial gene expression in PCOS may be associated with epigenetic modification of gene promoter sites. DESIGN: Laboratory comparison study. MATERIALS AND METHODS: Endometrial specimens were collected in PCOS (n¼3) and control (n¼3) subjects. The subjects with PCOS had a proliferative phase that ranged from 5-120 days. Endometrial stromal cells were isolated and grown in culture with subsequent isolation of RNA and DNA. Expression levels of AR, ERb, and HOXA10 were determined by real time RT-PCR. Results for individual PCOS patients were compared to averaged control results. Differences in methylation patterns at CpG island sites of the promoters for AR, ERb, and HOXA10 were determined by EpiTyper. Unpaired student t test and one way ANOVAwere used for statistical analysis. RESULTS: Compared to controls, PCOS was associated with increased expression of AR and ERb and decreased expression of HOXA10. Longer proliferative phase duration in PCOS patients was positively associated with the observed changes in gene expression. AR and ERb promoters were found to be demethylated at specific CpG sites in PCOS patients. No difference was noted in HOXA10 promoter methylation between control and PCOS groups. CONCLUSIONS: Aberrant steroid hormone receptor expression in endometrial stromal cells of women with PCOS is associated with changes in gene promoter methylation. This expression appears to be more pronounced in those subjects who have demonstrated proliferative changes over a longer period of time. Supported by: University of Cincinnati internal training grant (Dept OB/GYN).
P-58 Tuesday, October 20, 2009 A RANDOMIZED, PLACEBO-CONTROLLED STUDY OF THE INFLUENCE OF INSTANT-RELEASE METFORMIN ON RESPONSE TO CLOMIPHENE CITRATE AND TIME TO CONCEPTION IN POLYCYSTIC OVARY SYNDROME. C. D. Williams, L. M. Pastore, W. B. Shelly, A. P. Bailey, D. C. Baras, B. G. Bateman. Reproductive Medicine and Surgery Center of Virginia, PLC, Charlottesville, VA; Departnent of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA. OBJECTIVE: To evaluate the influence of instant-release metformin hydrochloride on the response to clomiphene citrate in women with polycystic ovary syndrome who are attempting to conceive.
FERTILITY & STERILITYÒ
DESIGN: A randomized, triple blind, placebo-controlled design. MATERIALS AND METHODS: Group 1 received clomiphene citrate þ placebo(CC þ P); group 2 received clomiphene citrate þ metformin hydrochloride(CC þ M) in 500mg doses three times daily. Clomiphene citrate was progressively increased by 50 mg increments until mid-luteal phase serum progesterone was R 15ng/mL. Participants remained in the study until six ovulatory cycles, as defined by serum progesterone R5ng/mL, were completed or conception occurred. Partipants who did not respond to 200mg of CC on cycle days 5-9 were unblinded and those in the placebo group were crossed over to CC þ M group. Statistical methods included Wilcoxan tests and survival analyses. RESULTS: 55 women completed at least one treatment cycle for a total of 187 blinded study cycles. In Group 1, 26 women underwent 99 blinded cycles, 20 of whom (76.9%; 95% CI: 58.0%-89.0%) ovulated, and 8 of 26 (30.8%; 95% CI: 16.5%-50%) conceived from blinded cycles. In Group 2, 29 women underwent 88 blinded cycles 17 of whom (58.6%; 95% CI: 40.7%-74.5%) ovulated, and 12 of 29 (41.4%; 95% CI: 25.5-59.3%) conceived from blinded cycles. There were no significant differences in median number of cycles to ovulation or conception. There was a higher chance of conceiving once ovulatory in CC þ M (12/17, 70.6%) compared to CC þ P (8/20, 40%) (log rank p<0.028), with conception occurring on average 1 month earlier in CC þ M (mean 2.4 cycles) compared to CC þ P (mean 3.5 cycles). CONCLUSIONS: There were no significant differences in frequency of ovulation or pregnancy rates when metformin was added to clomiphene citrate compared to clomiphene citrate alone. Among ovulatory women there was a shorter time to conception if metformin was administered in combination wtih clomiphene citrate. Supported by: Supported by a grant from the Berlex Foundation.
P-59 Tuesday, October 20, 2009 FURTHER REFINEMENT IN DEFINING THE EFFECT OF HETEROZYGOUS-ABNORMAL CGG COUNTS ON THE FMR1 (FRAGILE X) GENE: DEFINITION OF A DISTINCT SUBGROUP OF PCOS PATIENTS, BASED ON NORMA/LOW GENOTYPE. D. H. Barad, A. Weghofer, A. Goyal, N. Gleicher. Center for Human Reproduction (CHR) – New York and Foundation for Reproductive Medicine, New York, NY; Departments of Epidemiology and Social Medicine as well as Department of Obstetrics, Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, NY; Department of Obstetrics and Gynecology, Vienna University School of Medicine, Innere Stadt, Wien, Austria; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT. OBJECTIVE: We report elsewhere that normal and heterozygous (het) or homozygous (hom) abnormal counts on the FMR1 gene reflect distinct ovarian aging curves. Het abnormal can, however, be normal/low or normal/high, which may affect ovarian reserve (OR) differently. DESIGN: Cohort study. MATERIALS AND METHODS: Triple CGG counts on FMR1 gene were investigated in 339 consecutive women. A normal count was 26-32 and FMR1 was considered normal (norm) with both alleles in normal range, het if 1, and hom if both alleles were abnormal. Het could be low/normal (het-1) or high/normal (het-2). Whether OR, reflected by anti-Mu¨llerian hormone (AMH) and oocytes yield (phenotype), differs depending on FMR1 genotype, was investigated in 4 groups (norm, het-1, het-2, hom) for groups as a whole, and stratified for age < 35 and R 35 years. Mean ranks between groups were compared with KruskalWallis or Mann Whitney tests. RESULTS: Among participants in all 4 groups was no difference in AMH (p¼0.24) and oocytes (p¼ 0.054). Age-stratified, women < 35 years demonstrated, however, significant difference between norm and het-2 and hom and het-1 AMH (Z ¼ -2.22, p ¼ 0.027) and oocytes (Z ¼ -3.194, p ¼ 0001), not noted above age 35. Het-1 genotype at young age expresses the highest AMH, decreasing rapidly in the early 30s. Het-2, in contrast, presents already at young age with 2nd lowest AMH after hom. CONCLUSIONS: Refinement in CGG count analysis of het abnormal women demonstrates distinct differences in ovarian aging patterns between het-1 and het-2 genotypes. Based on initially very high AMH in het-1 and observed habitues, the het-1 genotype appears to represent (normal weight) women with non-typical PCOS, who at young age unusually rapidly lose OR. Supported by: The Foundation for Reproductive Medicine and intramural CHR funds.
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P-53 Tuesday, October 20, 2009 THE INFLUENCE OF BODY MASS INDEX (BMI) ON PREGNANCY RATES AND OUTCOMES AMONG INFERTILE JAPANESE WOMEN. M. Funabiki, S. Taguchi, T. Hayashi, H. Ujino, Y. Nakamura. Oak Clinic, Osaka, Japan. OBJECTIVE: The World Health Organization defines obesity as BMI R 30 kg/m. The Japan Society for the Study of Obesity (JASSO) defines obesity as BMI R 25 kg/m. The objective of this study was to examine the effect of BMI on infertility treatment in Japanese women based on JASSO criteria. DESIGN: Retrospective study MATERIALS AND METHODS: 616 patients undergoing infertility treatment from June 2006 to June 2007 were allocated into 3 main groups according to the JASSO criteria: low (n¼ 112), normal (n¼ 460), and high (n¼ 44) BMI. They were further subdivided by treatment into 2 subgroups: no in vitro fertilization (IVF) (n¼ 302) and IVF (n¼ 314). The main outcome measures were pregnancy rate (PR), ongoing pregnancy rate (OPR), and miscarriage rate (MR). Statistical testing included Student’s t-test, Pearson’s chi square test, and Fisher’s exact test. RESULTS: PR was significantly lower in the high BMI group (22/44, 50%) than in the normal BMI group (318/460, 69.1%; P<0.05). Low BMI had no significant impact on fertility. Compared to IVF patients with normal BMI (n¼ 238), IVF patients with high BMI (n ¼ 25) had: a tendency towards lower PR (5/25, 20% vs. 55/238, 23.1%), OPR (3/5, 60% vs. 41/55, 74.5%.), MR (2/5, 40% vs. 14/55, 25.5%), and fertilization rate (115/219, 52.5% vs. 1658/2832, 58.5%); a significant reduction in the number of oocytes retrieved (8.85.7 vs. 11.98.8; P<0.05) and the number of good quality embryos (33/90, 36.7% vs. 656/1118, 58.7%; P<0.05); and a significant increase in the cancellation rate due to poor response or lack of fertilization (5/25, 20% vs. 18/238, 7.6%; p<0.05). CONCLUSIONS: Obesity has a deleterious effect on fertility. This is clearly obvious among high BMI women seeking IVF, who showed fewer retrieved oocytes, a deterioration in embryo quality. No significant difference was observed in the implantation rate between normal BMI and high BMI women. However, the low fertilization and cleavage rates, possibly due to the bad quality embryos, may explain the poor outcomes in high BMI women.
P-54 Tuesday, October 20, 2009 SOCIAL APPEARANCE ANXIETY IS ASSOCIATED WITH PERCEIVED BARRIERS TO EXERCISE IN WEIGHT LOSS SURGERY PATIENTS. M. Aubuchon, L. Martin-Hawver, T. Sonnanstine, D. Williams, M. Thomas. Obstetrics and Gynecology, University of Cincinnati, Cincinnati, OH; General Surgery, University of Cincinnati, Cincinnati, OH; Tri State Weight Loss, St Luke Hospital, Florence, KY. OBJECTIVE: To determine whether social appearance anxiety influences perceived barriers to exercise in women considering or having undergone weight-loss surgery. DESIGN: Cross-sectional study. MATERIALS AND METHODS: Women age 18-45 in the offices of weight-loss surgeons completed a brief anonymous survey between 20082009. Information was obtained for age, height, weight, menstrual cyclicity, and pre/post surgery status. As a possible contributor to social anxiety, respondents were asked whether hyperandrogenic symptoms, specifically bothersome hair growth or acne, were present. The following validated instruments were also included: Center for Epidemiologic Studies Depression Scale, Exercise Barriers and Benefits Scale (EBBS), and Social Appearance Anxiety Scale (SAAS). Respondents were first categorized as depressed/nondepressed and then further described as hyperandrogenic/non-hyperandrogenic. Statistical analysis employed Student t test and Pearson correlation for continuous and chi square for categorical variables, with significance assessed at 2 tailed p<0.05. RESULTS: Forty-two questionnaires were returned, of which 16 were incomplete or ineligible. For the remaining 26, 16 were noted to be depressed and 10 were not depressed. Of this group of women, 7 of 16 depressed and 5 of 10 non-depressed responders noted hyperandrogenic symptoms. Four of
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26 respondents noted oligomenorrhea. When depressed and non-depressed were analyzed separately, no significant differences were noted in terms of age, body mass index, EBBS scores, or SAAS scores between hyperandrogenic and nonhyperandrogenic responders. Also, there was no significant difference for affirmative response to embarrassment with exercise on EBBS between hyperandrogenic and non-hyperandrogenic responders. For non-depressed responders, EBBS barrier score was significantly correlated with SAAS score (r¼0.83, p¼0.003). CONCLUSIONS: Social appearance anxiety is associated with perceived barriers to exercise among non-depressed female weight loss surgery patients.
POLYCYSTIC OVARY SYNDROME P-55 Tuesday, October 20, 2009 PIOGLITAZONE TREATMENT DECREASES FOLLICULAR FLUID LEVELS OF TNF-ALPHA AND IL-6, AND IMPROVES OVARIAN RESPONSE TO FSH AND IVF OUTCOME IN PATIENTS WITH POLYCYSTIC OVARY SYNDROME UNDERGOING IVF. C.-H. Kim, K.-H. Cheon, E.-H. Park, Y.-H. Koo, K.-S. Jung, B.-M. Kang. Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Obstetrics and Gynecology, Jang’s Women’s Hospital, Seoul, Republic of Korea; Obstetrics and Gynecology, Haesung Hospital, Cheonan-City, Chungnam-Do, Republic of Korea. OBJECTIVE: To investigate the effects of pioglitazone on controlled ovarian stimulation (COS), IVF outcome, and intrafollicular cytokines levels in polycystic ovary syndrome (PCOS) patients. DESIGN: Prospective, randomized controlled trial MATERIALS AND METHODS: Eighty-six infertile patients with PCOS who were resistant to clomiphene citrate were recruited in this study and they were randomized into pioglitazone treatment group (n¼43) or control group (n¼43). All patients were pretreated for 3 weeks with monophasic oral contraceptives (OCs) before COS with recombinant human FSH (rhFSH) and GnRH antagonist. In treatment group, pioglitazone of 30 mg once daily was started on the starting day of OCs and continued to the day of hCG injection. Oocyte retrieval was performed 35-36 h after hCG injection. Tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) levels were assayed in the follicular fluids obtained at oocyte retrieval. RESULTS: There were no significant differences in age, body mass index (BMI), infertility duration, endocrine profile between two groups. Total dose and days of rFSH administered were significantly lower in treatment group (P¼0.002, P<0.001, respectively). The numbers of follicle R 14mm and follicle with diameter of 11-13mm on the day of hCG injection were significantly lower (P¼0.002, P<0.001, respectively). The numbers of retrieved oocytes and MII oocytes were also significantly lower in treatment group (P<0.001, P<0.001). Follicular fluid TNF-a and IL-6 levels were significantly lower in women treated with pioglitazone than in controls (P¼0.003, P¼0.001, respectively). The clinical pregnancy rate was higher and incidence of severe ovarian hyperstimulation syndrome (OHSS) was lower in treatment group but statistical significance was not found. CONCLUSIONS: Pioglitazone therapy could reduce the follicular fluid TNF-a and IL-6 levels, and might be beneficial in improving ovarian response to COS and IVF outcomes in PCOS patients.
P-56 Tuesday, October 20, 2009 COMPARISON OF HCG-STIMULATED ANDROGEN PRODUCTION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME AND NORMAL WOMEN. M. A. Rosencrantz, M. S. Coffler, A. S. Park, R. Shayya, A. Ramos-Haggan, R. J. Chang. Reproductive Medicine, UCSD, La Jolla, CA. OBJECTIVE: We have previously reported that 17-OHP exhibits significant increased dose-responsiveness to recombinant human chorionic gonadotropin (r-hCG) in PCOS women compared to normal women (2008 Endo Society). To further examine androgen responsiveness to hCG stimulation, we measured serum levels of androstenedione (A) and testosterone (T) following iv r-hCG in both groups. DESIGN: Prospective study at a general clinical research center in a tertiary academic medical center. MATERIALS AND METHODS: 10 PCOS subjects and 10 normal women received r-hCG iv at doses of 1, 10, 25, 100 and 250 micrograms on separate
Vol. 92., No. 3, Supplement, September 2009
occasions in a randomized manner. Blood was obtained prior to and at 24 hours after r-hCG administration for hormone measurements. A subset of 5 PCOS subjects and 4 normal women had blood samples obtained before and at 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 hours after iv administration of 25 micrograms r-hCG. RESULTS: In PCOS women, 17-OHP exhibited a progressive increasing dose-responsiveness to r-hCG that was significantly greater than that of normal women. Peak responses were achieved with the 100 microgram dose in both groups. In PCOS women, serum A and T exhibited a marked rise at the 10 microgram dose which appeared to be maximal as further increases were not observed at higher doses. In contrast, in normal women, increases of serum A and T were not seen at any dose of r-hCG. Time course studies indicated that, for all androgens, peak responses occurred at 24 hours. CONCLUSIONS: Consistent with our previous findings, theca cell sensitivity was greater in PCOS women compared to normal women. In PCOS women, A and T exhibited maximal dose responses that were 10-fold greater than that of 17-OHP. In normal women, A and T appeared to be non-responsive to r-hCG at the doses administered. Supported by: Eunice Kennedy Shriver NICHD/NIH (U54 HD12303-28) as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research and NIH grant MO1 RR00827.
P-57 Tuesday, October 20, 2009 PROLONGED ANOVULATION CAUSES ABERRANT ENDOMETRIAL GENE PROMOTER METHYLATION CHANGES IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. C. P. Montville, W.-Y. Tang, S.-M. Ho. Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH; Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH. OBJECTIVE: Abnormal expression of steroid hormone receptors in the endometrium of women with polycystic ovary syndrome (PCOS) has been suggested to adversely affect endometrial function. Although aberrant epigenetic regulation of endometrial gene expression has been demonstrated in endometriosis and endometrial adenocarcinoma, epigenetic regulation of endometrial gene expression in PCOS has not been evaluated. We hypothesize that abnormal endometrial gene expression in PCOS may be associated with epigenetic modification of gene promoter sites. DESIGN: Laboratory comparison study. MATERIALS AND METHODS: Endometrial specimens were collected in PCOS (n¼3) and control (n¼3) subjects. The subjects with PCOS had a proliferative phase that ranged from 5-120 days. Endometrial stromal cells were isolated and grown in culture with subsequent isolation of RNA and DNA. Expression levels of AR, ERb, and HOXA10 were determined by real time RT-PCR. Results for individual PCOS patients were compared to averaged control results. Differences in methylation patterns at CpG island sites of the promoters for AR, ERb, and HOXA10 were determined by EpiTyper. Unpaired student t test and one way ANOVAwere used for statistical analysis. RESULTS: Compared to controls, PCOS was associated with increased expression of AR and ERb and decreased expression of HOXA10. Longer proliferative phase duration in PCOS patients was positively associated with the observed changes in gene expression. AR and ERb promoters were found to be demethylated at specific CpG sites in PCOS patients. No difference was noted in HOXA10 promoter methylation between control and PCOS groups. CONCLUSIONS: Aberrant steroid hormone receptor expression in endometrial stromal cells of women with PCOS is associated with changes in gene promoter methylation. This expression appears to be more pronounced in those subjects who have demonstrated proliferative changes over a longer period of time. Supported by: University of Cincinnati internal training grant (Dept OB/GYN).
P-58 Tuesday, October 20, 2009 A RANDOMIZED, PLACEBO-CONTROLLED STUDY OF THE INFLUENCE OF INSTANT-RELEASE METFORMIN ON RESPONSE TO CLOMIPHENE CITRATE AND TIME TO CONCEPTION IN POLYCYSTIC OVARY SYNDROME. C. D. Williams, L. M. Pastore, W. B. Shelly, A. P. Bailey, D. C. Baras, B. G. Bateman. Reproductive Medicine and Surgery Center of Virginia, PLC, Charlottesville, VA; Departnent of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA. OBJECTIVE: To evaluate the influence of instant-release metformin hydrochloride on the response to clomiphene citrate in women with polycystic ovary syndrome who are attempting to conceive.
FERTILITY & STERILITYÒ
DESIGN: A randomized, triple blind, placebo-controlled design. MATERIALS AND METHODS: Group 1 received clomiphene citrate þ placebo(CC þ P); group 2 received clomiphene citrate þ metformin hydrochloride(CC þ M) in 500mg doses three times daily. Clomiphene citrate was progressively increased by 50 mg increments until mid-luteal phase serum progesterone was R 15ng/mL. Participants remained in the study until six ovulatory cycles, as defined by serum progesterone R5ng/mL, were completed or conception occurred. Partipants who did not respond to 200mg of CC on cycle days 5-9 were unblinded and those in the placebo group were crossed over to CC þ M group. Statistical methods included Wilcoxan tests and survival analyses. RESULTS: 55 women completed at least one treatment cycle for a total of 187 blinded study cycles. In Group 1, 26 women underwent 99 blinded cycles, 20 of whom (76.9%; 95% CI: 58.0%-89.0%) ovulated, and 8 of 26 (30.8%; 95% CI: 16.5%-50%) conceived from blinded cycles. In Group 2, 29 women underwent 88 blinded cycles 17 of whom (58.6%; 95% CI: 40.7%-74.5%) ovulated, and 12 of 29 (41.4%; 95% CI: 25.5-59.3%) conceived from blinded cycles. There were no significant differences in median number of cycles to ovulation or conception. There was a higher chance of conceiving once ovulatory in CC þ M (12/17, 70.6%) compared to CC þ P (8/20, 40%) (log rank p<0.028), with conception occurring on average 1 month earlier in CC þ M (mean 2.4 cycles) compared to CC þ P (mean 3.5 cycles). CONCLUSIONS: There were no significant differences in frequency of ovulation or pregnancy rates when metformin was added to clomiphene citrate compared to clomiphene citrate alone. Among ovulatory women there was a shorter time to conception if metformin was administered in combination wtih clomiphene citrate. Supported by: Supported by a grant from the Berlex Foundation.
P-59 Tuesday, October 20, 2009 FURTHER REFINEMENT IN DEFINING THE EFFECT OF HETEROZYGOUS-ABNORMAL CGG COUNTS ON THE FMR1 (FRAGILE X) GENE: DEFINITION OF A DISTINCT SUBGROUP OF PCOS PATIENTS, BASED ON NORMA/LOW GENOTYPE. D. H. Barad, A. Weghofer, A. Goyal, N. Gleicher. Center for Human Reproduction (CHR) – New York and Foundation for Reproductive Medicine, New York, NY; Departments of Epidemiology and Social Medicine as well as Department of Obstetrics, Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, NY; Department of Obstetrics and Gynecology, Vienna University School of Medicine, Innere Stadt, Wien, Austria; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT. OBJECTIVE: We report elsewhere that normal and heterozygous (het) or homozygous (hom) abnormal counts on the FMR1 gene reflect distinct ovarian aging curves. Het abnormal can, however, be normal/low or normal/high, which may affect ovarian reserve (OR) differently. DESIGN: Cohort study. MATERIALS AND METHODS: Triple CGG counts on FMR1 gene were investigated in 339 consecutive women. A normal count was 26-32 and FMR1 was considered normal (norm) with both alleles in normal range, het if 1, and hom if both alleles were abnormal. Het could be low/normal (het-1) or high/normal (het-2). Whether OR, reflected by anti-Mu¨llerian hormone (AMH) and oocytes yield (phenotype), differs depending on FMR1 genotype, was investigated in 4 groups (norm, het-1, het-2, hom) for groups as a whole, and stratified for age < 35 and R 35 years. Mean ranks between groups were compared with KruskalWallis or Mann Whitney tests. RESULTS: Among participants in all 4 groups was no difference in AMH (p¼0.24) and oocytes (p¼ 0.054). Age-stratified, women < 35 years demonstrated, however, significant difference between norm and het-2 and hom and het-1 AMH (Z ¼ -2.22, p ¼ 0.027) and oocytes (Z ¼ -3.194, p ¼ 0001), not noted above age 35. Het-1 genotype at young age expresses the highest AMH, decreasing rapidly in the early 30s. Het-2, in contrast, presents already at young age with 2nd lowest AMH after hom. CONCLUSIONS: Refinement in CGG count analysis of het abnormal women demonstrates distinct differences in ovarian aging patterns between het-1 and het-2 genotypes. Based on initially very high AMH in het-1 and observed habitues, the het-1 genotype appears to represent (normal weight) women with non-typical PCOS, who at young age unusually rapidly lose OR. Supported by: The Foundation for Reproductive Medicine and intramural CHR funds.
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