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Comparison of effects of simvastatin and metformin in women with PCOS: a randomized trial
and 150 mg in subsequent cycles if the previous cycle’s dose failed to induce ovulation; or (c) both drugs, begun and given in parallel fashion. CC was not given at doses >150 mg. Ovulation was determined by weekly serum progesterone and confirmed if PR5 ng/mL. There were 209 women enrolled in each CC-containing treatment group. Data on the CC dose which first induced ovulation were available for 150 of 157 ovulators in the CC-only group and 164 of 174 ovulators in the CCþMetformin group. TABLE
Number (%) who ovulated after CC dose 50 mg 100 mg 150 mg
CC-only
CCþMetformin
95 (45.5%) 38 (18.1%) 17 (8.1%)
109 (52.2%) 43 (20.6%) 12 (5.7%)
RESULTS: There were no baseline differences in age, BMI, or metabolic parameters [fasting insulin and insulin resistance (HOMA-IR)] between treatment groups. The numbers of women who achieved first ovulation on each CC dose and the percent of all enrolled subjects in that group who ovulated on that dose are shown below for the CC-only group and the CCþMetformin group. There was no significant difference in the frequency distribution (chi-square test). CONCLUSIONS: Metformin does not reduce the lowest dose of clomiphene which induces ovulation in women with PCOS. Although higher CC doses have been associated with adverse effects on fecundity, the concomitant use of metformin was not shown to have a ‘‘clomiphene-sparing’’ effect. In this study, since metabolic parameters were not improved by metformin (ref. 1), no conclusion can be reached about the role of metabolic improvement in reducing CC threshold dose for ovulation. Reference (1): Legro RS et al., New Engl J Med 356:551–66 (2007). Supported by: NICHD Cooperative Multicenter Reproductive Medicine Network, U of Virginia Ligand Assay and Analysis Core Laboratory. Details in Ref. 1.
Wednesday, October 17, 2007 4:00 pm O-196 COMPARISON OF EFFECTS OF SIMVASTATIN AND METFORMIN IN WOMEN WITH PCOS: A RANDOMIZED TRIAL. B. Banaszewska, L. Pawelczyk, R. Z. Spaczynski, A. J. Duleba. Gyn/Ob, Poznan University of Medical Sciences, Poznan, Poland; OB/GYN, UC Davis, Sacramento, CA. OBJECTIVE: Statins are HMG-Co-A reductase inhibitors with pleiotropic effects including decreased cholesterol synthesis and reduction of oxidative stress. In ovarian theca cell cultures, statins inhibit proliferation, promote apoptosis and lower steroidogenesis reducing expression of CYP11 and 3ßHSD. Statins may also decrease oxidative stress inhibiting expression of NADPH subunits. Recently, we have evaluated the effects of simvastatin on women with polycystic ovary syndrome (PCOS), randomizing the subjects to the use of oral contraceptive pill (OCP) alone or in combination with simvastatin. In the presence of OCP, simvastatin reduced hyperandrogenism and improved lipid profile. This is the first trial comparing the use of simvastatin with metformin in women with PCOS not using any hormonal treatment. DESIGN: Prospective, randomized trial. MATERIALS AND METHODS: Forty-one women with PCOS were enrolled and 34 completed the trial. Age of the women was 25.5 4.3 (mean SD) and BMI was 23.6 4.1. Patients were randomized to: simvastatin (S) alone (20 mg/day), metformin (M) alone (1,700 mg/day), and simvastatinþmetformin (SþM). Evaluations were performed at baseline and after 3 months of treatment. All subjects were using barrier contraception. Data were analyzed using Student’s t-test and Wilcoxon SignRank test. RESULTS: S reduced total testosterone by 14% (P¼0.005); M had no effect (decrease by 0.3%; P¼0.9) while S þ M decreased testosterone by 11% (P¼0.02). Similarly, S decreased free testosterone by 12% (P¼0.005) while M or M þ S had no effect. In parallel, acne score im-
S74
Abstracts
proved following treatment with S by 46% (P¼0.02); M or S þ M had no effect. S also decreased total cholesterol by 22% while M had no effect (decrease by 2%). S þ M reduced total cholesterol by 32%; this effect was greater than that of S alone (P<0.05). Similar effects of S were observed on LDL and triglycerides. Body mass index decreased minimally (by 2.5– 3%) following each treatment (P<0.05). Insulin sensitivity index determined by a 2-hour glucose tolerance test increased following M (by 19%, P<0.05). CONCLUSIONS: This is the first study demonstrating that statin used alone significantly lowers hyperandrogenism and hyperandrogenemia in women with PCOS. Furthermore, as anticipated, simvastatin improves lipid profile. The effects of simvastatin are likely mediated by mechanisms distinctly different than those of metformin. We propose that statins use may represent a novel treatment of PCOS-related hyperandrogenism. Supported by: NIH R01 HD40207.
Wednesday, October 17, 2007 4:15 pm O-197 TRANSVAGINAL ULTRASOUND-GUIDED OVARIAN INTERSTITIAL LASER TREATMENT IN ANOVULATORY WOMEN WITH CLOMIFENE CITRATE-RESISTANT POLYCYSTIC OVARY SYNDROME. W. Zhu, X. Li, X. Chen, Z. Lin, L. Zhang. Department of Reproductive Medical Centre, ShenZhen Maternity and Child Healthcare Hospital, ShenZhen, Guangdong, China. OBJECTIVE: To assess the effectiveness of transvaginal ultrasoundguided ovarian interstitial laser-coagulation treatment in anovulatory women with polycystic ovary syndrome (PCOS). DESIGN: A pilot study. MATERIALS AND METHODS: Twenty-three anovulatory women with clomifene citrate-resistant PCOS. underwent the ultrasound-guided transvaginal ovarian interstitial YAG-laser treatment. A fibre-optic cable of 400 um in diameter was stripped of its outer insulation layer for a length of 10 mm at the end. The optical fibre was marked from this tip at a distance equal to the length of a 17-gauge, 35-cm long needle. The operator then punctured the fornix with the long needle into the intraovarian point. The assistant cut the soft tube connected to the end of the needle and inserted the fibre-optic cable into the needle up to the marked point. The electrical laser was activated for 1–2 minutes with a power of 3–5 W, until a 10 mm light spot appeared on the ovarian plane. This procedure was repeated and 2 to 3 points were accomplished for each ovary, only with one puncture site on the ovarian surface. Serum LH, FSH, testosterone (T), Prolactin (PRL), and Estradiol (E2) levels, spontaneous ovulation rate and pregnancy rate were measured over six months follow up. RESULTS: Regular ovulation occurred in 19 out of 22 (86.4%) in the six months following ovarian treatment (1 case failure to follow). On the postoperative 2nd, 4th and 6th month , the mean serum LH were 4.54 1.21IU/L, 4.90 2.18IU/L and 4.42 1.03IU/L, and significantly (P<0.001, P<0.001, P<0.001) lower than preoperative level of 13.89 3.62IU/L; the mean serum testosterone levels were 2.69 1.83 nmol/L, 2.42 1.11 nmol/L and 2.28 1.96 nmol/L, and significantly (P<0.001, P<0.001, P<0.001) lower than the preoperative baseline value of 5.37 3.09 nmol/L; the mean LH/ FSH ratios of 0.93 0.26, 0.88 0.17 and 0.81 0.14, were also significantly lower than the preoperative value of 2.78 1.21 (P<0.001). Pregnancy occurred in 8 women and there was a cumulative pregnancy rate at 6 months of 36% (8/22) among the subjects. There were no significant operative complications. CONCLUSIONS: Ultrasound-guided transvaginal ovarian interstitial laser treatment appears effective in improving hormonal profiles and inducing ovulation and successful pregnancy in women with clomifene-resistant PCOS. Supported by: This work was supported by a grant for scientific research from the ShenZhen Bureau of Science and Technology (No. 200304167).
Vol. 88, Suppl 1, September 2007
Number (%) who ovulated after CC dose 50 mg 100 mg 150 mg
CC-only
CCþMetformin
95 (45.5%) 38 (18.1%) 17 (8.1%)
109 (52.2%) 43 (20.6%) 12 (5.7%)
RESULTS: There were no baseline differences in age, BMI, or metabolic parameters [fasting insulin and insulin resistance (HOMA-IR)] between treatment groups. The numbers of women who achieved first ovulation on each CC dose and the percent of all enrolled subjects in that group who ovulated on that dose are shown below for the CC-only group and the CCþMetformin group. There was no significant difference in the frequency distribution (chi-square test). CONCLUSIONS: Metformin does not reduce the lowest dose of clomiphene which induces ovulation in women with PCOS. Although higher CC doses have been associated with adverse effects on fecundity, the concomitant use of metformin was not shown to have a ‘‘clomiphene-sparing’’ effect. In this study, since metabolic parameters were not improved by metformin (ref. 1), no conclusion can be reached about the role of metabolic improvement in reducing CC threshold dose for ovulation. Reference (1): Legro RS et al., New Engl J Med 356:551–66 (2007). Supported by: NICHD Cooperative Multicenter Reproductive Medicine Network, U of Virginia Ligand Assay and Analysis Core Laboratory. Details in Ref. 1.
Wednesday, October 17, 2007 4:00 pm O-196 COMPARISON OF EFFECTS OF SIMVASTATIN AND METFORMIN IN WOMEN WITH PCOS: A RANDOMIZED TRIAL. B. Banaszewska, L. Pawelczyk, R. Z. Spaczynski, A. J. Duleba. Gyn/Ob, Poznan University of Medical Sciences, Poznan, Poland; OB/GYN, UC Davis, Sacramento, CA. OBJECTIVE: Statins are HMG-Co-A reductase inhibitors with pleiotropic effects including decreased cholesterol synthesis and reduction of oxidative stress. In ovarian theca cell cultures, statins inhibit proliferation, promote apoptosis and lower steroidogenesis reducing expression of CYP11 and 3ßHSD. Statins may also decrease oxidative stress inhibiting expression of NADPH subunits. Recently, we have evaluated the effects of simvastatin on women with polycystic ovary syndrome (PCOS), randomizing the subjects to the use of oral contraceptive pill (OCP) alone or in combination with simvastatin. In the presence of OCP, simvastatin reduced hyperandrogenism and improved lipid profile. This is the first trial comparing the use of simvastatin with metformin in women with PCOS not using any hormonal treatment. DESIGN: Prospective, randomized trial. MATERIALS AND METHODS: Forty-one women with PCOS were enrolled and 34 completed the trial. Age of the women was 25.5 4.3 (mean SD) and BMI was 23.6 4.1. Patients were randomized to: simvastatin (S) alone (20 mg/day), metformin (M) alone (1,700 mg/day), and simvastatinþmetformin (SþM). Evaluations were performed at baseline and after 3 months of treatment. All subjects were using barrier contraception. Data were analyzed using Student’s t-test and Wilcoxon SignRank test. RESULTS: S reduced total testosterone by 14% (P¼0.005); M had no effect (decrease by 0.3%; P¼0.9) while S þ M decreased testosterone by 11% (P¼0.02). Similarly, S decreased free testosterone by 12% (P¼0.005) while M or M þ S had no effect. In parallel, acne score im-
S74
Abstracts
proved following treatment with S by 46% (P¼0.02); M or S þ M had no effect. S also decreased total cholesterol by 22% while M had no effect (decrease by 2%). S þ M reduced total cholesterol by 32%; this effect was greater than that of S alone (P<0.05). Similar effects of S were observed on LDL and triglycerides. Body mass index decreased minimally (by 2.5– 3%) following each treatment (P<0.05). Insulin sensitivity index determined by a 2-hour glucose tolerance test increased following M (by 19%, P<0.05). CONCLUSIONS: This is the first study demonstrating that statin used alone significantly lowers hyperandrogenism and hyperandrogenemia in women with PCOS. Furthermore, as anticipated, simvastatin improves lipid profile. The effects of simvastatin are likely mediated by mechanisms distinctly different than those of metformin. We propose that statins use may represent a novel treatment of PCOS-related hyperandrogenism. Supported by: NIH R01 HD40207.
Wednesday, October 17, 2007 4:15 pm O-197 TRANSVAGINAL ULTRASOUND-GUIDED OVARIAN INTERSTITIAL LASER TREATMENT IN ANOVULATORY WOMEN WITH CLOMIFENE CITRATE-RESISTANT POLYCYSTIC OVARY SYNDROME. W. Zhu, X. Li, X. Chen, Z. Lin, L. Zhang. Department of Reproductive Medical Centre, ShenZhen Maternity and Child Healthcare Hospital, ShenZhen, Guangdong, China. OBJECTIVE: To assess the effectiveness of transvaginal ultrasoundguided ovarian interstitial laser-coagulation treatment in anovulatory women with polycystic ovary syndrome (PCOS). DESIGN: A pilot study. MATERIALS AND METHODS: Twenty-three anovulatory women with clomifene citrate-resistant PCOS. underwent the ultrasound-guided transvaginal ovarian interstitial YAG-laser treatment. A fibre-optic cable of 400 um in diameter was stripped of its outer insulation layer for a length of 10 mm at the end. The optical fibre was marked from this tip at a distance equal to the length of a 17-gauge, 35-cm long needle. The operator then punctured the fornix with the long needle into the intraovarian point. The assistant cut the soft tube connected to the end of the needle and inserted the fibre-optic cable into the needle up to the marked point. The electrical laser was activated for 1–2 minutes with a power of 3–5 W, until a 10 mm light spot appeared on the ovarian plane. This procedure was repeated and 2 to 3 points were accomplished for each ovary, only with one puncture site on the ovarian surface. Serum LH, FSH, testosterone (T), Prolactin (PRL), and Estradiol (E2) levels, spontaneous ovulation rate and pregnancy rate were measured over six months follow up. RESULTS: Regular ovulation occurred in 19 out of 22 (86.4%) in the six months following ovarian treatment (1 case failure to follow). On the postoperative 2nd, 4th and 6th month , the mean serum LH were 4.54 1.21IU/L, 4.90 2.18IU/L and 4.42 1.03IU/L, and significantly (P<0.001, P<0.001, P<0.001) lower than preoperative level of 13.89 3.62IU/L; the mean serum testosterone levels were 2.69 1.83 nmol/L, 2.42 1.11 nmol/L and 2.28 1.96 nmol/L, and significantly (P<0.001, P<0.001, P<0.001) lower than the preoperative baseline value of 5.37 3.09 nmol/L; the mean LH/ FSH ratios of 0.93 0.26, 0.88 0.17 and 0.81 0.14, were also significantly lower than the preoperative value of 2.78 1.21 (P<0.001). Pregnancy occurred in 8 women and there was a cumulative pregnancy rate at 6 months of 36% (8/22) among the subjects. There were no significant operative complications. CONCLUSIONS: Ultrasound-guided transvaginal ovarian interstitial laser treatment appears effective in improving hormonal profiles and inducing ovulation and successful pregnancy in women with clomifene-resistant PCOS. Supported by: This work was supported by a grant for scientific research from the ShenZhen Bureau of Science and Technology (No. 200304167).
Vol. 88, Suppl 1, September 2007