Pulsatile gonadotrophin releasing hormone stimulation after medium-term pituitary suppression in polycystic ovary syndrome. A randomized controlled study comparing the endocrine effects of pulsatile intravenous gonadotropin-releasing hormone after gonadotropin-releasing hormone agonist pretreatment versus clomiphene citrate in patients with polycystic ovary syndrome. Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization-embryo transfer. Use of combined exogenous gonadotropins and pulsatile gonadotropin-releasing hormone in patients with polycystic ovarian disease. Ovarian stimulation by concomitant administration of cetrorelix acetate and HMG following Diane-35 pre-treatment for patients with polycystic ovary syndrome: a prospective randomized study. Ovulation induction in polycystic ovarian disease by pure FSH (Metrodin). A comparison between chronic low-dose pulsatile administration and i.m. injections. Comparison of GnRH antagonist with long GnRH agonist protocol after OCP pretreatment in PCOs patients. Use of a GnRH antagonist in controlled ovarian hyperstimulation for assisted conception in women with polycystic ovary disease: a randomized, prospective, pilot study. The effect of metformin plus clomiphene citrate on ovulation and pregnancy rates in clomiphene-resistant women with polycystic ovary syndrome. A randomized controlled trial of laparoscopic ovarian diathermy versus gonadotropin therapy for women with clomiphene citrate-resistant polycystic ovary syndrome. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.
Ovulation induction in the polycystic ovary syndrome with pulsatile gonadotrophin releasing hormone (GnRH) in the recovery phase after treatment with a GnRH agonist (GnRHa) during 6-8 weeks has been reported to improve ovulation and pregnancy rates and to normalize follicular phase luteinizing hormone (LH) levels. We studied the results of stimulation with pulsatile GnRH after a shorter 'medium-term' period of 3 weeks of treatment with a GnRHa by comparing a cycle without GnRHa pre-treatment with a cycle with GnRHa (post-GnRHa) pre-treatment in 12 patients. We could prove no significant clinical improvement in post-GnRHa cycles. Ovulation rates were similar. However, in the post-GnRHa cycles, two ongoing pregnancies were observed versus one spontaneous abortion in the cycles without GnRHa pre-treatment. This observation might be explained by the fact that follicular phase LH levels in post-GnRHa cycles were significantly decreased. OBJECTIVE: To compare the endocrine changes in the follicular phase in infertile patients with polycystic ovary syndrome (PCOS) treated with either pulsatile IV GnRH after GnRH-agonist (GnRH-a) down-regulation or clomiphene citrate (CC). DESIGN: Subgroup analysis within a randomized, controlled, multicenter study. SETTING: Women referred to the Infertility Clinic, Catharina Hospital Eindhoven, The Netherlands. PATIENT(s): Twenty-eight infertile patients with PCOS. INTERVENTIONs): Patients were randomly assigned to pulsatile IV GnRH (10-20 microgram/90 min) after GnRH-a down-regulation or CC (50-150 mg; cycle days 3-7). Patients were monitored on alternate days with ovarian sonography and serum concentrations of E(2), LH, and FSH. Serum P and sonography confirmed ovulation. MAIN OUTCOME MEASURE(s): Serum concentrations of E(2), LH, and FSH were assessed before treatment was started and after each ovarian sonography. RESULT(s): In ovulatory cycles, no statistically significant differences were observed during the follicular phase comparing serum concentrations of E(2), LH, and FSH between the treatments. However, a significant increase in LH occurred in the GnRH group. CONCLUSION(s): No significant endocrine differences were observed between GnRH and CC treatment. However, there was a significant increase in the serum LH concentration during the follicular phase in the GnRH group. Increments of LH in the GnRH group may be due to recovery of endogenous LH secretion. The combination of gonadotropin-releasing hormone (GnRH) antagonist and gonadotropin represents a valid alternative to the classical protocol with GnRH agonist for ovulation induction in patients with polycystic ovary syndrome (PCOS). The use of metformin is of benefit to women with PCOS. The aim of the present study was to compare the stimulation characteristics and in vitro fertilization (IVF)-embryo transfer (ET) outcomes of the standard short GnRH antagonist protocol for ovarian stimulation with or without metformin.
                We recruited 40 PCOS patients. The population studied was divided into two groups (A and B). Group A was pretreated for 2 months with metformin 1.5 g/day (Glucophage(R); Merck Pharm), and then stimulated with recombinant follicle-stimulating hormone (rFSH) 150 UI/day (Gonal F(R) 75 UI; Serono). GnRH antagonist, cetrorelix acetate 0.25 mg/day (Cetrotide(R); Serono), was started when the leading follicle reached 14 mm diameter on ultrasound scan. Group B was treated only with rFSH 150 UI/day and GnRH antagonist 0.25 mg/day when the leading follicle was >or=14 mm in diameter.
                In group A we found a statistically significant (p < 0.05) decrease in the number of ampoules of rFSH (A vs. B: 18+/-6 vs. 24+/-8) and estradiol levels (A vs. B: 2400+/-600 vs. 3370+/-900 pg/ml) (all values mean+/-standard deviation). Group A had significantly fewer cancelled cycles (A vs. B: 1 vs. 3; p < 0.05). The incidence of ovarian hyperstimulation syndrome was 5% in group A and 15% in group B (p < 0.05). In patients treated with metformin, the total number of follicles on the day of human chorionic gonadotropin treatment (23+/-1.2 vs. 33+/-2.6) was decreased with no change in the number of follicles >or=14 mm in diameter (A vs. B: 18+/-1.2 vs. 19+/-1.7). However, the mean number of mature oocytes (A vs. B: 8.4+/-1.5 vs. 5.0+/-1.5) was increased with metformin treatment (p < 0.05). No difference was found in the number of cleaved embryos (A vs. B: 2.5+/-0.5 vs. 2.2+/-0.3).
                The use of metformin with GnRH antagonist improves the outcome of ovarian stimulation in IVF-ET cycles in PCOS patients. We previously tested a combined regimen based on the administration of gonadotropin in the early follicular phase followed by pulsatile gonadotropin-releasing hormone (GnRH) until complete follicular maturation in patients suffering from polycystic ovarian disease. Despite good clinical results, a high rate of premature luteinization was observed with this approach. We therefore evaluated in this study whether starting pulsatile GnRH therapy before gonadotropin administration might reduce premature luteinization. Eight women underwent induction of ovulation with both combined therapy and pure exogenous follicle-stimulating hormone alone using a crossover scheme. No premature luteinization and a single follicular growth were recorded with the modified combined regimen. Clinical results (8/8 versus 3/7 ovulatory cycles; 3/8 versus 1/7 pregnancies) favor the combined approach over gonadotropin alone. Patients with polycystic ovary syndrome (PCOS) may need a longer period of pituitary downregulation to suppress the elevated serum LH and androgen levels effectively during IVF treatment using the GnRH agonist long protocol. We proposed a stimulation protocol incorporating Diane-35 and GnRH antagonist (Diane/cetrorelix protocol) and compared it with the GnRH agonist long protocol for PCOS patients.
                Part I of the study was an observational pilot study to evaluate the hormonal change as a result of the Diane/cetrorelix protocol (n = 26). Part II of the study was a prospective randomized study comparing the Diane/cetrorelix protocol (n = 25) and the GnRH agonist long protocol (n = 24). In the Diane/cetrorelix protocol, patients were pre-treated with three cycles of Diane-35, followed by 0.25 mg of cetrorelix on cycle day 3. From day 4, cetrorelix and gonadotrophin were administered concomitantly until the day of HCG injection.
                Serum LH, estradiol and testosterone levels were suppressed comparably in both protocols at the start of gonadotrophin administration. Serum LH was suppressed at constant levels without a premature LH surge in the Diane/cetrorelix protocol. The clinical results for both protocols were comparable, with significantly fewer days of injection, lower amounts of gonadotrophin used and lower estradiol levels on the day of HCG injection following the Diane/cetrorelix protocol. Furthermore, there was no significant difference in clinical pregnancy outcome between the two stimulation protocols.
                The Diane/cetrorelix protocol has a similar pregnancy outcome to the GnRH agonist long protocol for women with PCOS undergoing IVF treatment. A randomized cross-over study was performed to assess the value of pulsatile versus i.m. administration of pure FSH in polycystic ovarian disease. All patients admitted to the study had failed to respond to treatment with clomiphene citrate, while four had also been unsuccessfully treated with i.m. Pergonal. Sixteen cycles with i.m. FSH and 15 cycles with pulsatile s.c. FSH were analysed. The results showed no statistically significant differences in the dosage, the rate of ovulation or pregnancy rate. Hyperstimulation occurred in 30% of both the treatment groups. It is concluded that chronic low-dose pulsatile administration of pure FSH (Metrodin, Serono) has no advantage over chronic low-dose i.m. administration. To evaluate the efficacy of GnRH antagonist in comparison with the GnRH agonist protocol in OCP pretreated polycystic ovary syndrome (PCOs) patients undergoing their first ART cycle.
                Prospective randomized controlled trial. University-based tertiary fertility center. Ninety-five PCOs patients under 35 years of age, with primary infertility were randomized to an ovarian stimulation protocol consisting of either. GnRh antagonist (study group) or GnRH agonist (control group) after pretreatment with OCP. Coasting or GnRH agonist Trigger was used when estradiol level > or =3,000 pgr/ml in the control and study group, respectively. Both groups received 800 mg vaginal progesterone and 4 mg oral estradiol valerate for luteal phase support.
                There was no statistically significant difference in the age, body mass index, basal FSH, duration of infertility, the number of oocytes retrieved, the number of embryos transferred, Serum E2 levels on day of trigger, fertilization rate, chemical and clinical pregnancy rates between the two groups. None of the patients in the study group developed ovarian hyperstimulation syndrome (OHSS) compared with 22.2% of patients in the control group. Total duration of treatment and the number of HMG ampoules used were lower in the study group.
                Antagonist protocol and GnRH agonist trigger for ovulation whenever necessary has a similar cycle outcome to the GnRH-agonist protocol in OCP pretreated PCOs patients, with significantly reduced risk of OHSS. To compare the outcome of using gonadotropin-releasing hormone (GnRH) antagonists versus agonists in women with polycystic ovary disease (PCOD) who underwent controlled ovarian hyperstimulation (COH) for assisted reproductive techniques (ART).
                A total of 129 patients with PCOD were randomly allocated to undergo COH with a GnRH antagonist (59 patients) and GnRH agonist (leuprolide acetate) (70 patients) to prevent a premature luteinizing hormone (LH) surge. Assisted fertilization following oocyte retrieval and embryo transfer was performed.
                None of the cycles were cancelled due to a premature LH surge. There was no significant difference between the antagonist and agonist arms in the number of gonadotropin ampules consumed per cycle. However, in the antagonist arm a shorter duration of ovarian stimulation was recorded as compared to the agonist arm. Although similar numbers of oocytes was retrieved from both groups of patients, the quality of the oocytes, as measured by metaphase 2/total oocyte ratio, was lower in the antagonist arm as compared to the agonist arm. Pregnancy rates were 57.6% and 58.5% in the antagonist and agonist arms, respectively (p > 0.05). Implantation rates were not different (34.0% and 34.6%, respectively). The frequency of ovarian hyperstimulation syndrome also did not differ between the treatment groups (5% and 7.1%, respectively).
                The size of our study, on a specific subgroup of patients, does not allow a reliable conclusion regarding ART outcomefollowing the use of a GnRH antagonist versus agonist. Nevertheless, the protocol with the antagonist gave results that were as good as those of the protocol with the agonist in this PCOD patient population. To study the effect of metformin in combination with clomiphene citrate, as compared with placebo plus clomiphene citrate, on the ovulation and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome.
                This study was carried out at King Hussein Medical Center, Amman, Jordan, during the period January 2001 through to July 2001. Twenty-eight clomiphene citrate-resistant polycystic ovary syndrome women were evaluated prospectively for 6 treatment cycles by receiving metformin, 850mg twice daily throughout the cycle along with 50 mg clomiphene citrate, starting on day 5-9 of the same cycle (N=16), or by taking placebo with clomiphene citrate (N=12). During cycles 2-6, clomiphene citrate was added with increments of 50mg (up to 200 mg/day) for both groups. Progesterone level on day 21 and 28 >5ng/dl was indicative of ovulation.
                A statistically significant increase in the rates of ovulation (68.6% versus 25%, p<0.05) and pregnancy (56.3% versus 16.6%, p<0.05) were observed in the metformin-clomiphene citrate group as compared with the placebo-clomiphene citrate controls. Insignificant increase in the rate of ovarian hyperstimulation was noted in the placebo-clomiphene citrate group.
                Metformin-clomiphene citrate regimen in resistant-clomiphene citrate polycystic ovary syndrome women significantly increases the ovulation and pregnancy rates, and decreases the occurrence of ovarian hyperstimulation syndrome. To compare the effectiveness of laparoscopic ovarian diathermy with gonadotropin ovulation induction for women with clomiphene citrate-resistant polycystic ovary syndrome.
                Randomized controlled trial.
                A tertiary referral fertility clinic.
                Women with anovulatory infertility secondary to clomiphene-resistant polycystic ovary syndrome. Inclusion criteria were age of <39 years, body mass index of <35 kg/m(2), failure to ovulate with 150 mg of clomiphene citrate for 5 days in the early follicular phase, >12 months of infertility, and no other causes of infertility.
                Laparoscopic ovarian diathermy versus three cycles of urinary or recombinant gonadotropins.
                Cumulative pregnancy and miscarriage rates.
                Cumulative pregnancy rates were 28% at 6 months for laparoscopic ovarian diathermy and 33% for three cycles of ovulation induction with gonadotropins. There were three miscarriages in each group. Women in the laparoscopic ovarian diathermy arm of the study had four additional spontaneous pregnancies 6 to 12 months after surgery.
                There was no statistically significant difference in pregnancy or miscarriage rates during the 6-month follow-up period or the three cycles. Laparoscopic ovarian diathermy is a safe and effective alternative to ovulation induction with gonadotropins. In the last few years some studies assessed the effects of attenuation of hyperinsulinemia and insulin resistance, obtained by insulin sensitizing agents, in women with polycystic ovary syndrome (PCOS), suggesting potential scope for these drugs in treating the whole spectrum of reproductive, endocrine, and metabolic abnormalities found in such subjects. However, the results of these studies, mostly uncontrolled and short-term, are still inconclusive, and there is no long-term follow-up. In the present study, 23 PCOS subjects [mean (+/- SE) body mass index 30.0+/-1.1 kg/m2] were randomly assigned to double-blind treatment with metformin (500 mg tid) or placebo for 6 months, while maintaining their usual eating habits. Before and after treatment, menstrual history, endocrine and metabolic profiles, serum 17-hydroxyprogesterone response to GnRH-agonist testing, and insulin sensitivity measured by the glucose clamp technique were assessed. Eighteen of these women, as well as 14 additional PCOS patients, were subsequently given metformin in an open trial for 11.0+/-1.3 months (range 4-26), to assess long-term effects of treatment and baseline predictors of metformin efficacy on reproductive abnormalities. After metformin treatment, mean frequency of menstruation improved (P = 0.002), due to striking amelioration of menstrual abnormalities in about 50% of subjects. Women given metformin showed reduced plasma insulin (at fasting: P = 0.057; during the clamp studies: P<0.01) and increased insulin sensitivity (P<0.05). Concurrently, ovarian hyperandrogenism was attenuated, as indicated by significant reductions in serum free testosterone (P<0.05) and in the 17-hydroxyprogesterone response to GnRH-agonist testing (P<0.05). No changes were found in the placebo group. Only comparable minor changes in body mass index were found both in the metformin group and in the placebo group. In the open, long-term trial 17 women (54.8%) showed striking improvements of their menstrual abnormalities and were considered as responders. Logistic regression analysis of baseline characteristics in responders and nonresponders showed that plasma insulin, serum androstenedione, and menstrual history were independent predictors of the treatment's clinical efficacy. In 10 subjects whose menses proved regular after treatment, the great majority of cycles became ovulatory (32 out of 39 assessed, 79%). In conclusion, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin.
The four trials describing four different comparisons with a short follow up (1 to 3 cycles) were too small to either prove or discard the value of pulsatile GnRH treatment in patients with polycystic ovary syndrome.