Comparison of the effects of acarbose and metformin use on ovulation rates in clomiphene citrate-resistant polycystic ovary syndrome

BACKGROUND: The aim of this study was to evaluate the effects of metformin and acarbose on insulin resistance, hormone profiles and ovulation rates in patients with clomiphene citrate-resistant polycystic ovary syndrome (PCOS). METHODS: Thirty clomiphene citrate-resistant patients were selected randomly and divided into two groups. Group I was treated with 100 mg/day clomiphene citrate and 300 mg/day acarbose 100 mg/day orally, for 3 months. Group II was treated with clomiphene citrate 100 mg/day and metformin 1700 mg/day orally, for 3 months. Serum fasting insulin and glucose, FSH, LH, estradiol, progesterone, prolactin and total testosterone levels plus body mass index (BMI) were measured before and after treatment. Follicle growth was followed by transvaginal ultrasonography. RESULTS: LH:FSH ratio and total testosterone concentrations decreased (P<0.05) and ovulation rates increased in both groups. Reduction in weight and BMI was only significant in the acarbose group. CONCLUSIONS: Both treatment modalities were effective in the treatment of insulin resistance and improving ovulation rates. Increase in the number of eumenorrhoeic and normoinsulinaemic cases and decrease in the number of insulin-resistant cases were significant in both groups (P<0.05). Ovulation rate was greater in the metformin group in the second month of therapy (P<0.05). Acarbose was found to be a safe and effective agent that could be used in cases with clomiphene-resistant PCOS.     

Recombinant FSH in alternative doses or versus urinary gonadotrophins for ovulation induction in subfertility associated with polycystic ovary syndrome: a systematic review based on a Cochrane review

This paper is based on a Cochrane review published in The Cochrane Library, issue 2, 2001 (see www.CochraneLibrary. net for information) with permission from The Cochrane Collaboration and Update Software. Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the review. This systematic review was performed to study the efficacy and safety of recombinant FSH (rFSH) versus urinary FSH (uFSH) and to compare different dose regimens of rFSH for ovulation induction in women with clomiphene-resistant polycystic ovary syndrome (PCOS). Six randomized controlled trials were included in the review, according to the principles of the Cochrane Menstrual Disorders and Subfertility Group. Three trials compared rFSH with uFSH and three trials compared two different treatment regimens of rFSH. Participants were women with clomiphene citrate-resistant PCOS. Main outcome measures were ovulation, clinical pregnancy, miscarriage, multiple pregnancy, ovarian stimulation syndrome (OSS), total gonadotrophin dose used and total duration of stimulation. Summary statistics were expressed as odds ratios. Data from the trials comparing rFSH and uFSH could be pooled. There was no evidence of a difference between rFSH and uFSH in any of the outcomes. Data from the trials comparing different dose regimens of rFSH could not be combined, and for each comparison there was insufficient evidence of a difference. More randomized clinical trials with sufficient power are necessary to estimate the difference, if one exists, between rFSH and uFSH and between different dose regimens of rFSH.     

Similar ovulation rates, but different follicular development with highly purified menotrophin compared with recombinant FSH in WHO Group II anovulatory infertility: a randomized controlled study

BACKGROUND: The contribution of the LH activity in menotrophin preparations for ovulation induction has been investigated in small trials conducted versus FSH preparations. The objective of this study was to demonstrate non-inferiority of highly purified urinary menotrophin (HP-HMG) versus recombinant FSH (rFSH) with respect to the primary outcome measure, ovulation rate. METHODS: This was a randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized (computer-generated list) to stimulation with HP-HMG (n=91) or rFSH (n=93) using a low-dose step-up protocol. RESULTS: The ovulation rate was 85.7% with HP-HMG and 85.5% with rFSH (per-protocol population), and non-inferiority was demonstrated. Significantly fewer intermediate-sized follicles were observed in the HP-HMG group (P<0.05). The singleton live birth rate was comparable between the two groups. The frequency of ovarian hyperstimulation syndrome and/or cancellation due to excessive response was 2.2% with HP-HMG and 9.8% with rFSH (P=0.058). CONCLUSIONS: Stimulation with HP-HMG is associated with ovulation rates at least as good as a rFSH in anovulatory WHO Group II women. LH activity modifies follicular development so that fewer intermediate-sized follicles develop. This could have a positive impact on the safety of ovulation induction protocols.     

An economic comparison of a laparoscopic electrocautery strategy and ovulation induction with recombinant FSH in women with clomiphene citrate-resistant polycystic ovary syndrome

BACKGROUND: Recombinant FSH (rFSH) is the current standard treatment for ovulation induction in women with polycystic ovary syndrome (PCOS) that do not respond to clomiphene citrate. Ovulation induction with rFSH is known to be costly due to the necessity of daily injections and intensive monitoring. An alternative strategy, starting with electrocautery of the ovaries, may be a less costly option. METHODS: An economic evaluation was set up alongside a multicentre randomized clinical trial comparing laparoscopic electrocautery of the ovaries, followed by clomiphene citrate and rFSH when anovulation persisted, and treatment with rFSH in 168 women with clomiphene citrate-resistant PCOS. Data on resources used for treatment and productivity loss were collected prospectively up to an eventual ongoing pregnancy with a time horizon of 12 months. RESULTS: At 12 months the ongoing pregnancy rates were 67% for both the electrocautery strategy and rFSH treatment. Mean total costs per woman were 5308 euros for the electrocautery strategy and 5925 euros for treatment with rFSH, resulting in a mean difference of 617 (95% CI: -382 euros to 1614 euros). CONCLUSIONS: The total treatment costs up to an ongoing pregnancy are comparable for rFSH treatment and an alternative strategy starting with electrocautery. Due to a lower number of multiple pregnancies, the electrocautery strategy can be expected to result in lower total costs when costs of the delivery are included.     

In-vivo ovarian androgen responses to recombinant FSH with and without recombinant LH in polycystic ovarian syndrome

BACKGROUND: Effects of exogenous LH on ovarian androgen secretion during ovulation induction have not been clearly characterized in polycystic ovarian syndrome (PCOS). The purpose of this study was to compare androgen secretion in PCOS women during ovarian stimulation with either recombinant FSH (rFSH) alone or combined with recombinant LH (rLH). METHODS: Clomiphene-resistant women with PCOS were allocated, in a factorial study design, to receive either daily injections of rFSH (n = 24) or rFSH + rLH (n = 24) in a 1:1 ratio starting: (i) on day 2-3 of progestogen-induced menses (n = 8); (ii) after 6 weeks of GnRH agonist treatment (nafarelin, 400 micro g twice daily; n = 8); or (iii) after nafarelin treatment as in (ii) plus dexamethasone (n = 8). The effects of rFSH with rFSH + rLH under these three hormone conditions on serum LH, 17alpha-hydroxyprogesterone (17-OHP), androstenedione (DeltaDelta(4)) and testosterone were contrasted by analysis of variance with specific treatment days as a repeated measures factor. RESULTS: Pre-study hormone levels were similar for all groupings. Nafarelin significantly suppressed LH levels, which remained at the lower limit of assay sensitivity (0.5 IU/l) during stimulation with rFSH but increased significantly to >1 but <2 IU/l when rLH was added. As expected, 17-OHP, DeltaDelta(4) and testosterone levels fell following nafarelin treatment. Dexamethasone further suppressed 17-OHP, DeltaDelta(4) and testosterone levels and unmasked a small but significant rise in these ovarian steroids 24 h following the first dose of rFSH + rLH, a rise that was absent with rFSH alone. Secretion of these steroids then appeared to 'catch-up' after 5 days of rFSH stimulation. CONCLUSIONS: Despite profound LH, 17-OHP, DeltaDelta(4) and testosterone suppression, comparable E(2) response, follicle development and successful pregnancies in PCOS subjects receiving rFSH alone to those receiving rFSH + rLH would argue that circulating LH at levels as low as 0.5 IU/l are sufficient to sustain adequate follicle development and function when FSH is present in abundance. Whether the observed dichotomy between rFSH and rFSH + rLH treatment in temporal secretion patterns reflects a greater reliance on evolving paracrine mechanisms as the follicles mature under profound LH suppression remains to be explored but may influence the optimal LH threshold for ovulation induction in PCOS.     

Sequential treatment of metformin and clomiphene citrate in clomiphene-resistant women with polycystic ovary syndrome: a randomized,controlled trial

BACKGROUND: Recognition of the importance of insulin resistance in clomiphene-resistant women with polycystic ovary syndrome (PCOS) has led to the use of insulin sensitizers. METHODS: A randomized, controlled trial was conducted to compare efficacy of sequential treatment with metformin and clomiphene citrate with conventional gonadotrophins. Sixty clomiphene-resistant women with PCOS were randomized to two groups (n = 30 each), using computer-generated tables. Group I received metformin for 6 months, followed by ovulation induction with clomiphene citrate; group II received hMG for ovulation induction. Hormonal profiles were evaluated at the onset and after completion of treatment. RESULTS: There was no significant difference in pregnancy rates between the two groups (16.7 versus 23.3%). In group I, there was a significant improvement in menstrual function and ovulation after treatment (40%, P < 0.001; and 46.7%, P < 0.001), with a significant decrease in fasting insulin levels (P < 0.05). There were no changes in other biochemical parameters. The ovulation rate in group II was 43.3%, with a high drop-out rate. The cost-effective analysis for medications per pregnancy in group I was US$ 71 +/- 3 versus US$ 277 +/- 171 in group II. CONCLUSIONS: Sequential treatment with metformin and clomiphene citrate is an effective and safe option for clomiphene-resistant women with PCOS.     

Predicting ongoing pregnancy following ovulation induction with recombinant FSH in women with polycystic ovary syndrome

BACKGROUND: Ovulation induction with recombinant FSH (rFSH) is common in women with polycystic ovary syndrome (PCOS) not responding to clomiphene citrate treatment, despite the associated risk of multiple pregnancies. We analysed clinical, ultrasonographic and endocrine parameters during initial screening of women with clomiphene citrate-resistant PCOS as predictors of ongoing pregnancy within 12 months of treatment following ovulation induction with rFSH. METHODS: Eighty-five women were allocated to receive rFSH as part of a multicentre clinical trial. rFSH was administered in a chronic low-dose step-up protocol. The primary end-point was an ongoing pregnancy within 12 months. A logistic model was built using clinical, ultrasonographic and endocrine parameters to predict the response to rFSH treatment, adjusted for the number of cycles performed. RESULTS: In total, 85 women underwent 272 treatment cycles with rFSH, of which 57 women (67%) achieved an ongoing pregnancy. Oligomenorrhoea, shorter duration of infertility and a lower free androgen index (FAI) were associated with higher chances of an ongoing pregnancy, resulting in a predictive model with a modest discriminative power (area under the curve 0.72, 95% confidence interval 0.64-0.79) that allowed us to distinguish between women with a probability of <5% of attaining an ongoing pregnancy and women with a probability of >25% of doing so. CONCLUSION: A model consisting of oligo/amenorrhoea, duration of infertility and FAI level allowed a distinction to be made between women with a poor chance and women with a good chance of achieving an ongoing pregnancy.     

The use of metformin for women with PCOS undergoing IVF treatment

BACKGROUND: Metformin appears to improve reproductive function in some women with polycystic ovary syndrome (PCOS). We wished to explore the effect of metformin in women with PCOS undergoing IVF. METHODS: A randomized, placebo-controlled, double-blind study was carried out between 2001 and 2004. Patients with PCOS undergoing IVF/ICSI treatment using a long GnRH agonist protocol were randomized to receive metformin (MET), 850 mg, or placebo (PLA) tablets twice daily from the start of the down-regulation process until the day of oocyte collection. The primary outcome was to be an improvement in the overall fertilization rate. RESULTS: One-hundred and one IVF/ICSI cycles were randomized to receive metformin (52) or to receive placebo (49). There was no difference in the total dose of rFSH required per cycle (median dose: MET = 1200 U, PLA = 1300 U; P = 0.937). The median number of oocytes retrieved per cycle (MET = 17.2, PLA = 16.2; P = 0.459) and the overall fertilization rates (MET = 52.9%, PLA = 54.9%; P = 0.641) did not differ. However, both the clinical pregnancy rates beyond 12 weeks gestation per cycle (MET = 38.5%, PLA = 16.3%; P = 0.023) and per embryo transfer (MET = 44.4%, PLA = 19.1%; P = 0.022) were significantly higher in those treated with metformin. Furthermore, a significant decrease in the incidence of severe ovarian hyperstimulation syndrome (OHSS) was observed (MET = 3.8%, PLA = 20.4%; P = 0.023), and this was still significant after adjustment for BMI, total rFSH dose and age (OR = 0.15; 95% CI: 0.03, 0.76; P = 0.022). CONCLUSION: Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS.     

A randomized controlled trial evaluating metformin pre-treatment and co-administration in non-obese insulin-resistant women with polycystic ovary syndrome treated with controlled ovarian stimulation plus timed intercourse or intrauterine insemination

BACKGROUND: There are few data in the literature regarding the utility of metfomin before and during gonadotrophin administration in women with polycystic ovary syndrome (PCOS). The aim of the present study was to assess the effect of the pre-treatment and co-administration of metformin in infertile PCOS women treated with controlled ovarian stimulation (COS) followed by timed intercourse (TI) or intrauterine insemination (IUI). METHODS: Seventy insulin-resistant primary infertile women with PCOS were randomized to receive metformin cloridrate (850 mg twice daily; group A) or placebo tablets (two tablets daily; group B) for 3 months. Three trials of COS using highly purified urinary FSH (hpFSH) plus TI/IUI were performed. Number of ampoules of gonadotrophin used, duration of the ovarian stimulation, cycle cancellation, ovulation, pregnancy, abortion, live birth, mono-ovulatory cycles, multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) rates were assessed. RESULTS: No difference between groups was detected in ovulation, cycle cancellation, pregnancy, abortion, live birth, multiple pregnancies and OHSS rates. The mono-ovulatory cycle rates were significantly (P = 0.002) more frequent in group A than in group B, whereas the days of stimulation for non-cancelled cycles and the number of vials of gonadotrophins used were significantly (P < 0.001) higher in group A than in group B. CONCLUSION: In insulin-resistant women with PCOS, metformin pre-treatment and co-administration with hpFSH increases the mono-ovulatory cycles.     

Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease

BACKGROUND: Adding metformin to clomiphene citrate in clomiphene-resistant polycystic ovary syndrome (PCOS) patients increases ovulatory response. However, because of anti-estrogenic effects of clomiphene it may be associated with lower pregnancy rate, offsetting the ovulation rate benefit. Letrozole is an aromatase inhibitor which induces ovulation without anti-estrogenic effects. METHODS: Infertile women with PCOS were randomly divided into metformin-letrozole (29 patients) and metformin-clomiphene groups (30 patients). After an initial 6-8 weeks of metformin, they received either letrozole (2.5 mg) or clomiphene (100 mg) from day 3-7 of their menstrual cycle. Estradiol (E2) levels, number of follicles, pregnancy rates and endometrial thickness were measured on the day of HCG administration. RESULTS: Mean total E2 and E2 per mature follicle were significantly higher in clomiphene group without a difference in mean number of mature follicles >18 mm and ovulation rate. Endometrial thickness was significantly higher in letrozole group. The pregnancy rate in letrozole group (10 patients, 34.50%) as compared with clomiphene group (5 patients, 16.67%) did not show significant difference, whereas full-term pregnancies were higher in letrozole group [10 patients (34.50%) versus 3 patients (10%)]. CONCLUSION: In clomiphene-resistant PCOS patients, the combination of letrozole and metformin leads to higher full-term pregnancies.     

Highly purified FSH is as efficacious as recombinant FSH for ovulation induction in women with WHO Group II anovulatory infertility: a randomized controlled non-inferiority trial

BACKGROUND: The objective of this study was to demonstrate non-inferiority of a highly purified urinary follicle stimulating hormone (HP-FSH) preparation compared with a recombinant (rFSH) preparation with respect to ovulation rate (primary end-point). METHODS: This was a randomized, open-label, assessor-blind, multinational study. Women with anovulatory infertility WHO Group II and resistant to clomiphene citrate were randomized (computer-generated list) to stimulation with HP-FSH (n=73) or rFSH (n=78) using a low-dose step-up protocol. The non-inferiority limit was prespecified at -20%. RESULTS: The ovulation rate was 85.2% (51/62) with HP-FSH and 90.9% (60/66) with rFSH (per-protocol population), and non-inferiority was demonstrated [95% confidence interval: -16.9; 5.6]. No differences were noted between groups in number of follicles>or=12 mm, >or=15 mm or >or=18 mm, mono-follicular development, pregnancy rates, endometrial thickness, number of ovarian stimulation syndrome cases or frequency of injection site reactions/pain. The singleton live birth rate was 15% in both groups (11/73 with HP-FSH and 12/78 with rFSH). CONCLUSIONS: This urinary HP-FSH preparation is non-inferior compared with a rFSH preparation with respect to ovulation rate in anovulatory WHO Group II women failing to ovulate or conceive on clomiphene citrate.     

Laparoscopic electrocautery of the ovaries versus recombinant FSH in clomiphene citrate-resistant polycystic ovary syndrome. Impact on women's health-related quality of life

BACKGROUND: Ovulation induction with gonadotrophins is the standard treatment strategy for women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). Laparoscopic electrocautery of the ovaries is an alternative treatment modality, leading to a comparable cumulative pregnancy rate. In deciding which treatment to opt for, women's health-related quality of life (HRQoL) should be taken into account. METHODS: A total of 168 CC-resistant women with PCOS were randomly assigned to receive either the electrocautery strategy, entailing laparoscopic electrocautery of the ovaries followed by CC and recombinant FSH (rFSH) if anovulation persisted, or ovulation induction with rFSH. We assessed women's HRQoL with the standard questionnaires Short Form-36, Rotterdam Symptom Checklist and Center for Epidemiological Studies Depression Scale, administered before randomization and 2, 12 and 24 weeks thereafter. RESULTS: The intention to treat analysis revealed no significant differences between the treatment groups on any of the scales at any point during follow-up. In women without an ongoing pregnancy, those treated with rFSH showed significantly more depressive symptoms than women allocated to the electrocautery strategy, with or without CC, although differences were small. CONCLUSIONS: Overall, HRQoL was not affected in both groups. In women still under treatment, rFSH was slightly more burdensome for women's HRQoL than electrocautery with or without CC.     

二甲双胍和罗格列酮对肥胖型PCOS治疗作用的对照性研究

目的观察罗格列酮和二甲双胍联合氯米芬治疗肥胖型多囊卵巢综合征患者的内分泌改善及生殖功能的临床疗效。方法50例肥胖型PCOS患者分别给予罗格列酮4mg/d和二甲双胍1500mg/d联合氯米芬100mg/d,治疗3个月,比较治疗前后体重指数、内分泌参数、腰臀比和Hom a IR的变化。结果用罗格列酮治疗后排卵率为88%,周期排卵率为64.29%,优势卵泡平均个数为1.8±0.8个,妊娠率为56%,而用二甲双胍治疗后分别为72%、54.84%、1.1±0.6个、48%。两者治疗后能使LH、LH/FSH、T的血清浓度明显下降,SHBG的浓度明显上升,Hom a IR明显改善。结论罗格列酮和二甲双胍联合氯米芬治疗肥胖型多囊卵巢综合征疗效可靠。二甲双胍有降低体重作用、价格便宜,适用于肥胖型P-COS伴胰岛素抵抗不严重者;罗格列酮在胰岛素增敏作用优于二甲双胍,适用于胰岛素抵抗较严重的PCOS患者。     

Clomiphene citrate increases insulin-like growth factor binding protein-1 and reduces insulin-like growth factor-I without correcting insulin resistance associated with polycystic ovarian syndrome

The induction of ovulation by clomiphene could be the result of interaction of the drug at various levels: hypothalamus, pituitary and ovary. It was demonstrated that administration of clomiphene to women with polycystic ovarian syndrome (PCOS) is accompanied by a reduction in plasma concentrations of insulin-like growth factor-I (IGF-I). IGF-I seems to have an overall negative effect on normal folliculogenesis and ovulation. The aim of the present study was to evaluate the effect of clomiphene on plasma concentrations of IGF-I and IGF binding protein (IGFBP)-1 and on insulin resistance associated with PCOS. Fifteen patients diagnosed with PCOS were recruited. Clinical diagnosis was based on chronic oligomenorrhoea or amenorrhoea and hyperandrogenaemia. Clomiphene citrate was administered at a dose of 100mg/day to all women from day 5 to day 9 of the spontaneous or medroxyprogesterone acetate (MAP)-induced menstrual cycle. Blood sampling and a 2 h oral glucose loading test (75 g) were performed the day before and after the course of clomiphene. Ovulation was confirmed in 13/15 PCOS patients. Plasma concentrations of IGF-I decreased by 31.5% (434 +/- 84 versus 297 +/- 71 ng/ml; P: < 0.05) after 5 days of clomiphene therapy, whereas plasma concentrations of IGFBP-1 increased by approximately 28.1% (26.3 +/- 4 versus 36.6 +/- 7 ng/ml; P: < 0.05). This gave a 56.5% reduction in the IGF-I:IGFBP-1 ratio (21.9 versus 9.53). No significant changes in basal plasma concentrations of fasting insulin or area under the insulin curve were observed in response to oral loading. The present results show that clomiphene does not cause changes in insulin resistance associated with PCOS but reduces plasma concentrations of IGF-I and increases those of IGFBP-1, with a consequent marked reduction in the IGF-I:IGFBP-1 ratio.     

Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study

BACKGROUND: Our aim was to investigate the effect of pre-treatment with metformin in women with polycystic ovary syndrome (PCOS) scheduled for IVF stimulation. METHODS: Seventy-three oligo/amenorrhoeic women with polycystic ovaries and at least one of the following criteria: hyperandrogenaemia, elevated LH/FSH ratio, hyperinsulinism, decreased SHBG levels or hirsutism, were studied. Normal weight and overweight patients were randomized separately in a prospective, randomized, double blind study. All patients were treated for at least 16 weeks with metformin (1000 mg bid) or placebo ending on the day of HCG injection. RESULTS: No differences were found in the primary end-points: duration of FSH stimulation 14.4 (13.1-15.7) versus 14.2 (12.6-15.7) days or estradiol on the day of HCG injection 6.8 (5.3-8.2) versus 7.6 (5.6-9.6) nmol/l in the metformin and placebo groups, respectively. The secondary end-points number of oocytes, fertilization rates, embryo quality, pregnancy rates and clinical pregnancy rates were equal. However, in the normal weight subgroup (BMI <28 kg/m(2), n = 27), pregnancy rates following IVF were 0.71 (0.63-0.79) versus 0.23 (0.15-0.31) in the metformin and placebo groups, respectively (P = 0.04). Overall clinical pregnancy rates were equal: 0.51 (0.34-0.68) versus 0.44 (0.27-0.62) in the metformin and placebo groups, respectively. However, in the normal weight subgroup, clinical pregnancy rates were 0.67 (0.43-0.91) and 0.33 (0.06-0.60), respectively (P = 0.06). CONCLUSIONS: Pre-treatment with metformin prior to conventional IVF/ICSI in women with PCOS does not improve stimulation or clinical outcome. However, among normal weight PCOS women, pre-treatment with metformin tends to improve pregnancy rates. Further studies in subgroups of PCOS women are required.     

Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome

BACKGROUND: This paper is a systematic review of metformin versus clomiphene citrate (CC) in women with polycystic ovary syndrome (PCOS). METHODS: Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and QUality Of Reporting Of Meta-analyses (QUOROM) guidelines were followed. A systematic computerized literature search was done of seven bibliographic databases. Inclusion criteria included cohort and randomized controlled trials (RCT) of women with PCOS and the following medications: metformin versus placebo; metformin versus CC; metformin plus CC versus placebo plus CC. Rev-man 4.1 and Metaview 4.0 were used to analyse data. Relative risk (RR) estimates were presented. A chi2-test determined the significance of the association. Heterogeneity was determined by the Cochran Q-test. RESULTS: Metformin was 50% better than placebo for ovulation induction in infertile PCOS patients [RR 1.50; 95% confidence interval (CI) 1.13, 1.99]. Metformin was also of benefit in non-infertile (i.e. patients with PCOS who were not complaining of infertility) PCOS patients for cycle regulation compared to placebo (RR 1.45; CI 1.11, 1.90). Metformin was not of confirmed benefit versus placebo for achievement of pregnancy (RR 1.07; CI 0.20, 5.74). Metformin plus CC may be 3-4-fold superior to CC alone for ovulation induction (RR 3.04; CI 1.77, 5.24) and pregnancy (RR 3.65; CI 1.11, 11.99) in women with PCOS. CONCLUSIONS: Metformin is effective for ovulation induction and cycle regulation in this group of patients. Metformin plus CC appears to be very effective for achievement of pregnancy compared to CC alone. No RCTs directly compare metformin to CC but the need for such a trial exists.     

Infertility: Late low-dose pure follicle stimulating hormone for ovarian stimulation in intra-uterine insemination cycles

At present, there is general agreement that ovarian stimulationimproves pregnancy rates after intra-uterine insemination (IUI).Also, ovulation induction with gonadotrophins is associatedwith higher success rates than clomiphene citrate in IUI cycles.However, the drawbacks to the use of gonadotrophin stimulationbefore IUI include the risks of ovarian hyperstimulation andmultiple gestation, and the relative cost of a treatment cyclein view of the medication costs and the need for increased monitoringby hormone assays and ultrasonographic measurements. In thepresent prospective randomized trial, the efficacy and safetyof ovarian stimulation with clomiphene citrate (50 mg/day for5 days) and IUI (clomiphene/IUI group) were compared with thoseof late low-dose pure follicle stimulating hormone (FSH, 75IU/day from day cycle 7 until the leading follicle reached >17mm in diameter) and IUI (FSH/IUI group) in ovulatory women whowere infertile because of unexplained infertility (n=40)or malesubfertility (n =60). The mean length of treatment in the FSHgroup was 6.4±2.5 days. Multiple follicular developmentwas seen in 25% of clomiphene-stimulated cycles but only in8% of those treated with FSH. Pregnancy rate per cycle in clomiphene/IUIand FSH/IUI groups was 4% (4/98) and 13% (12/94) respectively(P=0.02). All pregnancies obtained were singleton. There weretwo and one clinical abortions in the clomiphene/IUI (50%) andFSH/IUI (8%) groups respectively. No patient developed ovarianhyperstimulation syndrome. Use of our therapeutic scheme, whichproved to be efficacious, safe and economic for ovarian stimulationin IUI cycles, is advocated before the institution of in-vitrofertilization (IVF) or gamete intra-Fallopian transfer (GIFT)therapy in infertile patients with patent Fallopian tubes. Thislate low-dose technique of administering pure FSH is suitablefor use in offices without immediate access to oestradiol results.     

The use of metformin as first line treatment in polycystic ovary syndrome

This study evaluated the use of metformin as first line treatment for patients with polycystic ovary syndrome. A retrospective review of patients' files diagnosed with PCOS over 16 months in Department of obstetrics and gynaecology of a Regional hospital. The outcome was the response to metformin treatment regardless of the main complaint. Treatment response was measured by change in LH/FSH ratio, fasting insulin, testosterone, day 21 progesterone and/or pregnancy. A day 21 progesterone greater than 25.5 nmol/l and/or pregnancy were the parameter of ovulation. Thirty-four patients were diagnosed with PCOS. Twenty-five complained of infertility (14 primary and 11 secondary), six patients had oligomenorrhoea or amenorrhoea and three presented with hirsutism. Seventeen patients received metformin as first line treatment. Eight received it with other treatment (5 clomiphene citrate and 3 ant androgens). Nine patients did not receive metformin. This study justifies the use of metformin as an appropriate first line treatment for PCOS.     

High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome.

This preliminary report reviews our experience with 18 infertile patients with clomiphene-resistant polycystic ovary syndrome (PCOS). In the first treatment cycle, troglitazone was administered alone. During cycles 2-5, clomiphene was added with increments of 50 mg (up to 200 mg/day) if the previous cycle was anovulatory. Basal body temperature charts and serum progesterone were obtained to confirm ovulation. In a total of 66 treatment cycles, ovulation occurred in 44 (67%) and pregnancy in seven (11%). There were no significant changes in body weight, waist:hip ratio or liver enzymes during treatment. Troglitazone, alone or with clomiphene, induced ovulation in 15 of 18 patients (83%) and seven (39%) of them achieved pregnancy. This is the first report on ovulatory rates in clomiphene-resistant women with PCOS when troglitazone was used alone or with clomiphene. Recently, metformin and clomiphene were successfully used in women with PCOS. However, our patients represent a more resistant population of women with PCOS, with each patient serving as her own historical control by previous resistance to clomiphene. Although the pregnancy rate (39%) was promising for clomiphene-resistant women with polycystic ovary syndrome, it does not seem to have a definite advantage over gonadotrophins.     

A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome

BACKGROUND: The aim of the study was to evaluate follicular development and ovulation comparing the low-dose step-up and the step-down protocols, in women with clomiphene citrate (CC)-resistant polycystic ovaries. METHODS: Eighty-three women were randomized, and treated with recombinant (r) FSH (Puregon) using either the step-up (n=44) or step-down (n=39) protocol. They were followed up for three cycles unless pregnancy occurred. RESULTS: Monofollicular development occurred in 68.2% of the 85 cycles in the step-up group, as compared with 32% of the 72 cycles in the step-down group (P<0.0001). Hyperstimulation was statistically less frequent using the step-up procedure (4.7 versus 36%, P<0.0001). Both protocols used the same number of FSH units per cycle (951+/-586 versus 967+/-458 in step-up and step-down respectively, P=not significant). However, the duration of ovarian stimulation was statistically different (15.2+/-7.0 days in step-up versus 9.7+/-3.1 in step-down, P<0.001). Ovulation was observed in 70.3% of the cycles using the step-up procedure as compared with 51.3% using the step-down procedure (P<0.01). The cumulative rate of clinical gestations during the study did not differ between the two groups (38.6% in the step-up versus 30.8% in the step-down procedure). CONCLUSIONS: The step-up protocol using rFSH (Puregon), is more efficient in obtaining a monofollicular development and ovulation than the step-down protocol, in women with CC-resistant polycystic ovaries. Although the duration of stimulation is longer, the rate of ovarian hyperstimulation is much lower using the step-up protocol.