- Email: [email protected]
Contribution of endogenous LH secretion to hCG-stimulated androgen production in women with polycystic ovary syndrome
POLYCYSTIC OVARY SYNDROME P-339 Wednesday, October 27, 2010 MITOCHONTRIAL DNA COPY NUMBER IN PERIPHERAL BLOOD IN POLYCYSTIC OVARIAN SYNDROME. J. W. Lee, S. H. Lee, D. J. Chung, E. S. Kim, C. S. Ryu, S. M. Kang. Department of Family Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; Department of Obstetrics and Gynecology, Seoul Women’s Hospital, Incheon, Korea; Department of Obstetrics and Gynecology, MizMedi Hospital, Seoul, Korea. OBJECTIVE: Insulin resistance is known to be related to PCOS even thought the mechanism is not fully understood. Recently, mitochondrial function has been associated with glucose metabolism and the maintenance of mitochondrial DNA (mtDNA) copy number is essential for the preservation of mitochondrial function. The aim of this study was to investigate the potential role of mtDNA copy number in women with PCOS. DESIGN: Cross-sectional study. MATERIALS AND METHODS: 51 women with PCOS and 58 healthy women, all of whom were age- and weight-matched, were studied. Blood was obtained to determine mtDNA copy number as well as metabolic and hormonal parameters and indices of IR (fasting insulin, and the homeostasis model assessment of insulin resistance [HOMA-IR]), indices of insulin sensitivity (IS) (fasting glucose/fasting insulin [GF/IF], and the quantitative insulin sensitivity check index [QUICKI]) were calculated for each subject. RESULTS: The mtDNA copy number were lower (P <0.01) in women with PCOS after adjusting for age, body mass index (BMI), mean blood pressure, triglyceride (TG), high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, fasting glucose, fasting insulin, LH/FSH, total testosterone and SHBG levels. PCOS status was the strongest predictor of lower mtDNA copy number. In both the PCOS and control groups, mtDNA copy number was negatively correlated with IR and positively correlated with IS indices. In addition, mtDNA copy number was significantly correlated with triglyceride and SHBG in PCOS (P ¼0.01 and P¼ 0.01, respectively). CONCLUSION: Lower mtDNA copy number in the PCOS group, when compared to the non-PCOS group, was observed, and this difference may play a role in the pathophysiology observed in women with PCOS. Further studies are needed to clarify the role of mitochondrial function in these women. Supported by: The National Research Foundation of Korea(NRF) grant funded by the Korea government(MEST).(2009-0075404).
P-340 Wednesday, October 27, 2010 CONTRIBUTION OF ENDOGENOUS LH SECRETION TO hCGSTIMULATED ANDROGEN PRODUCTION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. M. A. Rosencrantz, H. I. Su, A. Ramos-Haggan, R. J. Chang. Reproductive Medicine, UC San Diego, La Jolla, CA. OBJECTIVE: In polycystic ovary syndrome (PCOS), hyperandrogenemia is a result of enhanced theca cell androgen production driven by abnormally increased LH secretion. To determine the extent to which endogenous gonadotropin secretion may contribute to ovarian androgen overproduction in PCOS women, we measured basal and stimulated serum androgen levels following intravenous (iv) injection of r-hCG before and after administration of a GnRH antagonist. DESIGN: Prospective study at a general clinical research center in a tertiary academic medical center. MATERIALS AND METHODS: 12 PCOS and 11 normal controls received iv r-hCG, 25 micrograms. Blood samples were obtained before and 24hrs after r-hCG. One month later, each subject was given GnRH antagonist (Cetrotide, 3mg) and r-hCG stimulation repeated 48hrs later. RESULTS: Before receiving GnRH antagonist, baseline and 24hr stimulated levels of 17-hydroxyprogesterone, androstenedione, and testosterone in PCOS women were higher than those of normal controls. After GnRH antagonist, basal gonadotropin and androgen levels decreased in both groups as did stimulated androgen responses. However, the pattern of responsiveness to hCG stimulation remained similar in both groups. CONCLUSION: In PCOS women, basal and stimulated theca cell androgen responses were greater than those of normal women. After GnRH antag-
S192
Abstracts
onist, androgen responses to hCG were reduced in both groups but remained higher in PCOS women. These findings suggest that endogenous gonadotropins influence basal androgen secretion whereas an effect on stimulated theca cell androgen production was minimal. This is consistent with a primary defect of theca cell activity in PCOS women. 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-341 Wednesday, October 27, 2010 EXPRESSION OF GLUCOSE TRANSPORTERS (GLUTS) IN GRANULOSA CELLS ACCORDING TO INSULIN RESISTANCE AND METABOLIC SYNDROME IN PCOS PATEINTS. E. Kim, H. H. Seok, D.-R. Lee, T.-K. Yoon, W.-S. Lee, K.-A. Lee. Department of Biomedical Science, CHA University, Seoul, Korea; Fertility Center, CHA Gangnam Medical Center, Seoul, Korea. OBJECTIVE: Women with PCOS often have insulin resistance. Glucose is initially uptaken via various glucose transporters (GLUTs) with or without insulin signaling, and insulin resistance is possibly linked with GLUTs expression. The aim of the study is to investigate the relationship between expression of GLUTs and clinical features of PCOS women, especially insulin resistance. DESIGN: Thirty-eight PCOS women were divided into with insulin resistance group (n¼9) and without insulin resistance (n¼29) according to HOMA-IR score. Transcript expression of GLUT family was assessed. MATERIALS AND METHODS: Granulosa cells (GCs) were obtained from follicular aspirates after the cumulus-oocyte-complexes were collected for in vitro fertilization (IVF), and purified by Percoll gradient and incubation with CD45+ magnetic beads. From purified GCs, total RNA was extracted, cDNA was synthesized, and PCR was performed. Various characteristics related to PCOS, insulin resistance, and metabolic disease, and related hormone profiles were measured. RESULTS: Our results showed that GLUT 1, 3, 5, 8, and 13 were constitutively expressed, but GLUT 2 and 7 were not expressed at all in human GCs. GLUT 4, 6, 9, 10, 11, and 12 were expressed differently in two groups. Apparently more insulin resistant PCOS patients expressed GLUT6 (77.8%) than metabolically normal PCOS patients (41.4%). Factors showing significant differences were HOMA, BMI, waist/hip ratio, arterial blood pressure, triglycerides, and DHEA-S. CONCLUSION: This is the first report on the expression of GLUTs in the human GCs, especially in the PCOS patients. In addition, it is the first finding that the GLUT 6, not GLUT 4 may be related with insulin resistance and metabolic syndrome. We believe this will be a new approach to understand the relationships existing between metabolism and cell-to-cell communication on oocyte maturation. Supported by: Grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A084923).
P-342 Wednesday, October 27, 2010 OVULATION INDUCTION WITH CLOMIPHENE, METFORMIN, OR A COMBINATION OF THE TWO DOES NOT AFFECT HIRSUTISM SCORE OVER A STANDARD COURSE OF TREATMENT IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. W. D. Schlaff, R. S. Legro, M. P. Diamond, C. Coutifaris, H. Zhang. Reproductive Medicine Network. Obstetrics and Gynecology, University of Colorado, Aurora, CO; Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA; Obstetrics and Gynecology, Wayne State University, Detroit, MI; Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA; Epidemiology and Public Health, Yale University, New Haven, CT; Data Coordinating Center, NICHD, New Haven, CT. OBJECTIVE: Analyze whether ovulation induction with clomiphene (CC), metformin (MET) or a combination of the two reduces the hirsutism score in PCOS patients over a standard course of treatment. DESIGN: Prospective, randomized, double-blind, multicenter trial. MATERIALS AND METHODS: The Pregnancy in Polycystic Ovary Syndrome trial was undertaken by the Reproductive Medicine Network and enrolled 628 anovulatory, infertile women to a 3-armed trial of CC (50-150 mg x 5d), metformin XR (1000 mg BID) or a combination of the two for up to 6 cycles. Participation was discontinued when the subject conceived, completed 6 cycles without pregnancy, or left the study. A Ferriman-Galway hirsutism assessment and hormonal testing were performed at baseline and
Vol. 94., No. 4, Supplement, September 2010
P-340 Wednesday, October 27, 2010 CONTRIBUTION OF ENDOGENOUS LH SECRETION TO hCGSTIMULATED ANDROGEN PRODUCTION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. M. A. Rosencrantz, H. I. Su, A. Ramos-Haggan, R. J. Chang. Reproductive Medicine, UC San Diego, La Jolla, CA. OBJECTIVE: In polycystic ovary syndrome (PCOS), hyperandrogenemia is a result of enhanced theca cell androgen production driven by abnormally increased LH secretion. To determine the extent to which endogenous gonadotropin secretion may contribute to ovarian androgen overproduction in PCOS women, we measured basal and stimulated serum androgen levels following intravenous (iv) injection of r-hCG before and after administration of a GnRH antagonist. DESIGN: Prospective study at a general clinical research center in a tertiary academic medical center. MATERIALS AND METHODS: 12 PCOS and 11 normal controls received iv r-hCG, 25 micrograms. Blood samples were obtained before and 24hrs after r-hCG. One month later, each subject was given GnRH antagonist (Cetrotide, 3mg) and r-hCG stimulation repeated 48hrs later. RESULTS: Before receiving GnRH antagonist, baseline and 24hr stimulated levels of 17-hydroxyprogesterone, androstenedione, and testosterone in PCOS women were higher than those of normal controls. After GnRH antagonist, basal gonadotropin and androgen levels decreased in both groups as did stimulated androgen responses. However, the pattern of responsiveness to hCG stimulation remained similar in both groups. CONCLUSION: In PCOS women, basal and stimulated theca cell androgen responses were greater than those of normal women. After GnRH antag-
S192
Abstracts
onist, androgen responses to hCG were reduced in both groups but remained higher in PCOS women. These findings suggest that endogenous gonadotropins influence basal androgen secretion whereas an effect on stimulated theca cell androgen production was minimal. This is consistent with a primary defect of theca cell activity in PCOS women. 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-341 Wednesday, October 27, 2010 EXPRESSION OF GLUCOSE TRANSPORTERS (GLUTS) IN GRANULOSA CELLS ACCORDING TO INSULIN RESISTANCE AND METABOLIC SYNDROME IN PCOS PATEINTS. E. Kim, H. H. Seok, D.-R. Lee, T.-K. Yoon, W.-S. Lee, K.-A. Lee. Department of Biomedical Science, CHA University, Seoul, Korea; Fertility Center, CHA Gangnam Medical Center, Seoul, Korea. OBJECTIVE: Women with PCOS often have insulin resistance. Glucose is initially uptaken via various glucose transporters (GLUTs) with or without insulin signaling, and insulin resistance is possibly linked with GLUTs expression. The aim of the study is to investigate the relationship between expression of GLUTs and clinical features of PCOS women, especially insulin resistance. DESIGN: Thirty-eight PCOS women were divided into with insulin resistance group (n¼9) and without insulin resistance (n¼29) according to HOMA-IR score. Transcript expression of GLUT family was assessed. MATERIALS AND METHODS: Granulosa cells (GCs) were obtained from follicular aspirates after the cumulus-oocyte-complexes were collected for in vitro fertilization (IVF), and purified by Percoll gradient and incubation with CD45+ magnetic beads. From purified GCs, total RNA was extracted, cDNA was synthesized, and PCR was performed. Various characteristics related to PCOS, insulin resistance, and metabolic disease, and related hormone profiles were measured. RESULTS: Our results showed that GLUT 1, 3, 5, 8, and 13 were constitutively expressed, but GLUT 2 and 7 were not expressed at all in human GCs. GLUT 4, 6, 9, 10, 11, and 12 were expressed differently in two groups. Apparently more insulin resistant PCOS patients expressed GLUT6 (77.8%) than metabolically normal PCOS patients (41.4%). Factors showing significant differences were HOMA, BMI, waist/hip ratio, arterial blood pressure, triglycerides, and DHEA-S. CONCLUSION: This is the first report on the expression of GLUTs in the human GCs, especially in the PCOS patients. In addition, it is the first finding that the GLUT 6, not GLUT 4 may be related with insulin resistance and metabolic syndrome. We believe this will be a new approach to understand the relationships existing between metabolism and cell-to-cell communication on oocyte maturation. Supported by: Grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A084923).
P-342 Wednesday, October 27, 2010 OVULATION INDUCTION WITH CLOMIPHENE, METFORMIN, OR A COMBINATION OF THE TWO DOES NOT AFFECT HIRSUTISM SCORE OVER A STANDARD COURSE OF TREATMENT IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. W. D. Schlaff, R. S. Legro, M. P. Diamond, C. Coutifaris, H. Zhang. Reproductive Medicine Network. Obstetrics and Gynecology, University of Colorado, Aurora, CO; Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA; Obstetrics and Gynecology, Wayne State University, Detroit, MI; Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA; Epidemiology and Public Health, Yale University, New Haven, CT; Data Coordinating Center, NICHD, New Haven, CT. OBJECTIVE: Analyze whether ovulation induction with clomiphene (CC), metformin (MET) or a combination of the two reduces the hirsutism score in PCOS patients over a standard course of treatment. DESIGN: Prospective, randomized, double-blind, multicenter trial. MATERIALS AND METHODS: The Pregnancy in Polycystic Ovary Syndrome trial was undertaken by the Reproductive Medicine Network and enrolled 628 anovulatory, infertile women to a 3-armed trial of CC (50-150 mg x 5d), metformin XR (1000 mg BID) or a combination of the two for up to 6 cycles. Participation was discontinued when the subject conceived, completed 6 cycles without pregnancy, or left the study. A Ferriman-Galway hirsutism assessment and hormonal testing were performed at baseline and
Vol. 94., No. 4, Supplement, September 2010