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Study Question: Is the treatment with recombinant FSH (rFSH) plus recombinant LH (rLH) more effective than highly purified (HP)-hMG in terms of ongoing pregnancy rate (PR) in women ≥35 years of age undergoing intrauterine insemination (IUI) cycles?, Summary Answer: The ongoing PR was not significantly different in women treated with rFSH plus rLH or with HP-hMG., What Is Known Already: Although previous studies have shown beneficial effects of the addition of LH activity to FSH, in terms of PR in patients aged over 34 years having ovulation induction, no studies have compared two different gonadotrophin preparations containing LH activity in women ≥35 years of age in IUI cycles., Study Design, Size, Duration: A single-centre RCT was performed between May 2012 and September 2013 with 579 women ≥35 years of age undergoing IUI cycles. The patients were randomly assigned to one of the two groups, rFSH in combination with rLH group or HP-hMG (Meropur) group, by giving them a code number from a computer generated randomization list, in order of enrolment. The randomization visit took place on the first day of ovarian stimulation., Participants/materials, Setting, Methods: Five hundred and seventy-nine patients with unexplained infertility or mild male factor undergoing IUI cycles were recruited in a university hospital setting. All women were enrolled in this study only for one cycle of treatment. Five hundred and seventy-nine cycles were included in the final analysis. Two hundred and ninety patients were treated with rFSH in combination with rLH and 289 patients were treated with HP-hMG. The ovarian stimulation cycle started on the third day of the menstrual cycle and the starting gonadotrophin doses used were 150 IU/day of rFSH plus 150 IU/day of rLH or 150 IU/day of HP-hMG. The drug dose was adjusted according to the individual follicular response. A single IUI per cycle was performed 34-36 h after hCG injection., Main Results and the Role of Chance: The main outcome measures were ongoing PR and number of interrupted cycles for high risk of ovarian hyperstimulation syndrome (OHSS). Ongoing pregnancy rates were 48/290 (17.3%) in the recombinant group versus 35/289 (12.2%) in the HP-hMG group [(odds ratio (OR) 1.50, 95% CI 0.94-2.41, P = 0.09]. The number of interrupted cycles for high risk of OHSS was 13/290 (4.5%) in the rFSH plus rLH group and 2/289 (0.7%) in the HP-hMG group (OR 6.73, 95% CI 1.51-30.12, P = 0.013)., Limitations, Reasons for Caution: One of the limitations of this study was the early closure and the ongoing PR could be overestimated. Both patient and gynaecologist were informed of the assigned treatment., Wider Implications of the Findings: Our results demonstrated the lack of differences in terms of ongoing PR between recombinant product and HP-hMG, in women ≥35 years undergoing controlled ovarian stimulation for IUI cycles. HP-hMG was safer than recombinant gonadotrophin concerning the risk of OHSS., Study Funding/competing Interests: None., Trial Registration Number: NCT01604044., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To demonstrate the noninferiority of highly purified menotropin (HP-hMG) compared with recombinant FSH (rFSH) regarding clinical pregnancy rate (PR) in intrauterine insemination (IUI) cycles., Design: Prospective randomized noninferiority trial., Setting: Unit of physiopathology of human reproduction, university hospital., Patient(s): Five hundred twenty-three patients with unexplained infertility or mild male infertility undergoing controlled ovarian hyperstimulation for IUI., Intervention(s): Patients were randomized for treatment with rFSH (262 patients) or HP-hMG (261 patients). Insemination was performed 34-36 hours after hCG injection., Main Outcome Measure(s): The primary outcome was clinical pregnancy rate (PR). The secondary outcome was the number of interrupted cycles for high risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy., Result(s): The clinical PR was 19.7% (95% confidence interval [CI] 15.3%-25.1%) in the HP-hMG group and 21.4% (95% CI 16.9%-26.8%) in the rFSH group [absolute difference -1.7% (95% CI -8.6%-5.2%)]; therefore, the noninferiority was demonstrated. The number of interrupted cycles for OHSS risk and multiple pregnancy was significantLy higher in the rFSH group, 8.4% (95% CI 5.6%-12.4%) than in the HP-hMG group 1.2% (95% CI 0.4%-3.3%) [absolute difference -7.27% (95% CI -11.3 to -3.7)]., Conclusion(s): HP-hMG is not inferior compared with rFSH regarding clinical PR., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effects of the GnRH antagonist cetrorelix on the gonadal axis in patients with polycystic ovary syndrome (PCOS)., Design: Observational clinical study., Setting: Academic research center., Patient(s): Ten patients with PCOS and 10 controls with normal ovulation., Intervention(s): Patients received a daily cetrorelix injection (0.25 mg SC at 9:00 am) for 6 days, starting from day 3 of the menstrual cycle., Main Outcome Measure(s): Serum gonadotropin, E(2), T, 17-OH-P, and androstenedione plasma levels were evaluated at baseline and at 12 and 24 hours after each daily injection. These hormones were also assayed at days 10, 12, and 14 of the menstrual cycle., Result(s): We observed in patients with PCOS a significantly higher suppression of FSH and LH for the entire length of therapy; LH recovery secretion was significantly higher in the PCOS group. Regarding androgens, we found a greater suppression of T. Androstenedione and 17-OH-P showed a trend toward a higher suppression in PCOS., Conclusion(s): Gonadotropin and androgen suppression by GnRH antagonist is more effective in PCOS than in controls, suggesting a higher sensitivity of GnRH receptors in PCOS to this drug.

Recent studies have proposed that, in women affected by the polycystic ovary syndrome (PCOS), aging is able to regularize the menstrual cyclicity. To evaluate the ovarian response in PCOS patients according to their age, we studied 33 PCOS patients, 20 of whom with an age ranging from 28 to 34 years (younger PCOS) and 13 ranging from 35 to 45 years (older PCOS). All patients underwent an ovulation induction therapeutic protocol with low-dose recombinant follicle stimulating hormone, for a total of 80 cycles (44 cycles for the younger PCOS group and 36 cycles for the older PCOS group). No significant difference was found between the days of therapy (12.3 +/- 5.4 vs. 13.5 +/- 5.6 days), total amount of drugs (980.7 +/- 568.9 IU vs. 1063.9 +/- 469.5 IU) or ovulation rate (93% vs. 89%) in the two groups. The two groups showed a significant difference in the maximum estradiol level (2053.5 +/- 1497.2 vs. 1269.0 +/- 911.5 pmol/l, p < 0.01), the number of the recruited and preovulatory follicles (1.7 +/- 2.5 vs. 0.64 +/- 0.9, p < 0.05 and 1.7 +/- 1.1 vs. 1.2 +/- 0.5, p < 0.01, respectively) and the pregnancy rate (36% vs. 14%, p < 0.05). In conclusion, our data clearly showed that, also in PCOS, advanced age is a negative prognostic factor in the ovarian response to ovulation induction therapies.

Background: We studied polycystic ovarian syndrome (PCOS) in fifty 25- to 37-year-old women who failed to conceive with clomiphene citrate treatment., Methods: Twenty patients were submitted to treatment with low-dose (75 IU) urinary FSH (uFSH) in order to achieve ovulation and 30 patients were treated with recombinant FSH (rFSH) according to the same protocol., Results: Ovulation was achieved in 75 and 97% of the cycles after uFSH and rFSH, respectively (p < 0.02). The length of treatment needed to achieve ovulation, the number of ampules given and dose per kilogram were significantly lower in the rFSH group. Mild ovarian hyperstimulation syndrome (OHSS) was observed in 9 uFSH cycles, whereas only 1 of the women treated with rFSH developed an OHSS (1/38 vs. 9/36; p < 0.01)., Conclusion: rFSH is more efficient than uFSH in inducing ovulation in PCOS patients. The high prevalence of ovulatory cycles using a lower dose guaranteed greater safety of treatment and significantly reduced the incidence of OHSS., (Copyright 2001 S. Karger AG, Basel)

The aim of the study was to evaluate the influence of insulin level on the ovarian response to FSH when inducing ovulation in patients affected by polycystic ovarian syndrome (PCOS). To evaluate the presence of hyperinsulinemia, 34 patients affected by PCOS were studied by an oral glucose tolerance test, then patients were stimulated for 52 cycles using FSH to induce ovulation. The ovarian response to therapy was evaluated by ultrasounds and as estradiol (E2) and androstenedione (A) plasma level determinations. On the basis of the insulinemic response to the glucose challenge, 20 patients were considered to be hyperinsulinemic and 14 normoinsulinemic. The hormonal features of each group were similar. The ovulation rate was similar in hyperinsulinemic and normoinsulinemic subjects, whereas the incidence of ovarian hyperstimulation was significantly higher in the hyperinsulinemic group. The increase in ovarian dimensions observed in hyperinsulinemic subjects after gonadotropin stimulation was more marked than that observed in normoinsulinemic ones. This was caused by the development of a larger number of immature follicles. E2 levels gradually increased after gonadotropin stimulation in both groups of subjects; however, higher levels were observed in hyperinsulinemic patients. During stimulation, the higher E2/A ratio suggests the presence of a greater aromatization activity in hyper-insulinemic patients. In conclusion, the present study suggests that, in PCOS, the insulinemic pattern may influence the ovarian response to gonadotropin administration; thus, hyperinsulinemic subjects may be at greater risk of ovarian hyperstimulation syndrome than normoinsulinemic subjects.

Five women (group A) with polycystic ovarian disease (PCOD) and sterility for at least 3 yr were treated for 1 cycle for ovulation induction with a combined regimen of GnRH agonist (GnRH-A) plus highly purified FSH. The patients received GnRH-A (Buserelin; 200 micrograms, sc, twice a day) for 6 weeks and then GnRH-A combined with FSH highly purified (2 ampules a day; 75 IU FSH and less than 0.11 IU LH in each ampule). Ovarian response was evaluated by plasma estradiol (E2) assay and ultrasound examination, performed daily. Furthermore, plasma FSH and LH levels were assayed 3 times a week. Once a follicle was considered sufficiently developed, the combined regimen was withheld, and 24-48 h later hCG (5000 IU, im) was given. The results are compared with those of 31 ovulatory cycles induced by im FSH highly purified (group B) in PCOD patients with the same FSH administration, clinical, and monitoring protocols. Ovulation was achieved in all cycles treated by GnRH-A plus FSH. Two singleton and a twin pregnancy resulted. Multiple follicular development occurred in all cycles. Plasma E2 levels were generally in the normal range. Echographic and endocrine features in the 2 groups were as follows. 1) basal ovarian volume and ovarian enlargement were similar. 2) Group A had a greater number of follicles than did group B (P less than 0.01), while E2 to number of follicles and E2 to ovarian volume ratios were greater (P less than 0.01) in group B. 3) The linear correlations between plasma E2 levels and ovarian volume were markedly different in groups A and B (P less than 0.01). The regression line for group B had a steeper slope than that for group A. This finding indicates that at a fixed ovarian volume plasma E2 levels were significantly lower in group A than in group B. We conclude that the combined GnRH-A and FSH regimen may constitute an alternative and promising tool for the induction of ovulation in patients with PCOD.

IIV FSH was administered to eight women with PCOD to induce ovulation. These patients had been previously treated unsuccessfully with CC or IM gonadotropins. The drug was administered by a pump at 120-minute intervals. Dosage was 1 ampule Metrodin (75 IU of FSH less than 0.11 IU of LH)/day. Eight cycles of treatment were effected. With the IIV regimen, ovulation rate was 75% (six cycles). Two multiple pregnancies and one abortion (mola vescicularis) were observed. Preovulatory E2 plasma levels and the number of follicles recruited per cycle varied from 530 to 3800 pg/ml and from 4 to 15, respectively. Maximal follicular diameter was between 16 and 28 mm. LH levels significantly decreased, while FSH levels were unchanged, resulting in a decrease of LH/FSH ratio. It is concluded that the IIV FSH regimen offers an additional modality for the induction of ovulation in PCOD patients. Further clinical trials with alternative regimens are needed, however, to identify the optimal dosage and frequency of administration of the drug.

Sixteen patients with polycystic ovarian disease (PCOD) were treated for 39 cycles with pure follicle-stimulating hormone (FSH) for the induction of ovulation. At ovulation time human chorionic gonadotropin (hCG) was administered. Twenty-one cycles were ovulatory. Twenty-three were classified as normostimulated (N): six pregnancies and three abortions were observed. In the remaining eight hyperstimulated (H) cycles there were four full-term pregnancies. Dosage and length of treatment were greater in patients with excess body weight (P less than 0.01). H cycles were characterized in respect to N cycles by: (1) higher baseline values of 17-hydroxy progesterone (17-OHP) plasma levels and LH/FSH ratios; (2) higher plasma concentrations and rate of increase of 17-OHP periovulatory levels. E2 plasma levels did not permit a clear differentiation between H and N cycles, and it was not useful for the timely recognition of hyperstimulation. Our data show that a slight controlled degree of ovarian hyperstimulation is beneficial to pregnancy rate and outcome.