REVIEW - Gonadotrophins for idiopathic male factor subfertility: a Cochrane systematic review

Objectives: To determine the effectiveness of gonadotrophins administration to men with idiopathic subfertility on spontaneous pregnancy rate and in assisted reproductive techniques. Search strategy: We searched the all relevant databases. Searches were not limited by language. The bibliographies of included, excluded trials and abstracts of major meetings were searched for additional trials. Authors and pharmaceutical companies were contacted for missing and unpublished data. Selection criteria: Truly randomized controlled trials where gonadotrophins were administered for the treatment of idiopathic male subfertility with reporting of pregnancy rates were included in the review. Data collection and analysis: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. Main results: Five RCTs with 426 participants were included in the analysis. Compared to placebo or no treatment FSH showed a significantly higher overall pregnancy rate per couple randomized during treatment period (OR 1.8, 95% CI 1.03 to 3.17, NNT 14, 95% CI 8 to 100). Follow up of patients up to three months post-treatment also showed a significant difference in favor of FSH treatment (OR 1.92, 95% CI 1.15 to 3.20, NNT 11, 95% CI 6 to 50. However when patients were followed up for extended period over three months post-treatment results showed a non-significant overall pregnancy rate difference in favor of FSH treatment (OR 1.52, 95% CI 0.99 to 2.33). Compared to placebo or no treatment there was non-significant difference in pregnancy rates after IUI/IVF/ICSI per couple randomized either during the treatment period, during treatment and up to three months follow-up, when the follow-up period was extended to more than three months post-treatment. The spontaneous pregnancy rate per couple randomized showed a favorable and significant difference in the FSH group over placebo or no treatment. OR was 3.99, 95% CI 1.80 to 8.82, NNT 11, 95% CI 7 to 25. Reviewers' conclusions: The number of trials and participants is not enough to draw final conclusions. However, analysis of the five included trials showed that in men with idiopathic subfertility treated with FSH there is a significant increase in the overall and spontaneous pregnancy rates per couple. This increased pregnancy rate is evident during the treatment period and within three months post-treatment. This increase is not significant in couples who undergo assisted conception

Clomiphene-acetyl cysteine combination as a new protocol to a friendly IVF cycle

Objective: N-acetyl-cysteine (NAC) has been shown to enhance the action of clomiphene citrate in ovulation induction. The objective of this study was to examine the use of NAC with clomiphene citrate for ovarian stimulation in assisted conception as a model for "Friendly IVF" Design: pilot study Materials and methods: Twenty infertile patients undergoing IVF/ICSI cycles were offered NAC, 1,200 mg/day from day 3-7 of the menstrual cycle with CC (100 mg /day) starting on day 3-7. hCG (10,000 IU) was given when leading follicle(s) were ≥ 18mm followed by ICSI. Main outcome measure(s): clinical pregnancy rate was the primary outcome and implantation rate, number of oocytes retrieved, fertilization rate were secondary outcomes Result(s): response to CC stimulation with NAC co-treatment was evident by a number of mature follicles ranging from 2-7 at the time of hCG administration. Clinical pregnancy was achieved in 4 cycles (20%). Conclusion(s): In this preliminary report, a potential benefit of NAC co-treatment with CC in young women undergoing IVF/ICSI cycles was demonstrated. This combination provides a cheap, effective way for ovulation induction in an IVF setting compatible with the concept of friendly IV

The effect of intramural fibroids on the outcome of IVF

Objective: To evaluate the effect of fibroids on outcome of IVF and study value of myomectomy prior to IVF. Design: Prospective controlled study. Setting: Private IVF center, The Egyptian IVF ET Center, Maadi, Cairo. Materials and methods: One hundred and eighty four patients were included. Sixty three patients with intramural fibroids were counseled for either myomectomy or no treatment prior to IVF and decision left to the patient. Group A, N=19 were treated by myomectomy, Group B, N=44 had no myomectomy. Group B were subdivided into B1, N=11 with fibroid at a distance < 5 mm from the endometrial lining and B2, N=33 at a distance of > 5 mm. Group C, N= 100 were an age-matched group of infertility patients. Group D included 11 submucous fibroids and 10 fibroid polyps that were all treated by hysteroscopic resection. Main outcome Measures: Size and distance of intramural fibroid to endometrial lining were recorded. Outcome of IVF was compared between fibroids at a distance > 5 mm and < 5 mm from endometrial lining. As well as outcome between group that performed myomectomy and that which did not undergo myomectomy. Results: Pregnancy rates achieved in the three groups A, B and C were; 50%, 27.5% and 36% respectively. This was found to be non significant. In subgroup B1 there was one pregnancy (9%) as compared to 10 pregnancies in subgroup B2 (30%). The difference was non significant. Following hysteroscopic resection 2 out of 6 patients with submucous fibroids and 6 out of 10 patients with fibroid polyps became pregnant after IVF. Conclusions: The distance between the intramural myomas and the endometrial lining did not affect the IVF outcome. An insignificant tendency towards improvement of IVF outcome was found in myomas at more than 5 mm from endometrial lining

Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

Background: Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists directly and rapidly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors. This property allows their use at any time during the follicular phase. Several different regimens have been described including multiple-dose fixed (0.25 mg daily from day six to seven of stimulation), multiple-dose flexible (0.25 mg daily when leading follicle is 14 to 15 mm), and single-dose (single administration of 3 mg on day 7 to 8 of stimulation) protocols, with or without the addition of an oral contraceptive pill. Further, women receiving antagonists have been shown to have a lower incidence of ovarian hyperstimulation syndrome (OHSS). Assuming comparable clinical outcomes for the antagonist and agonist protocols, these benefits would justify a change from the standard long agonist protocol to antagonist regimens. This is an update of a Cochrane review first published in 2001, and previously updated in 2006 and 2011. Objectives: To evaluate the effectiveness and safety of gonadotrophin-releasing hormone (GnRH) antagonists compared with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception cycles. Search methods: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched from inception to May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, inception to 28 April 2015), Ovid MEDLINE (1966 to 28 April 2015), EMBASE (1980 to 28 April 2015), PsycINFO (1806 to 28 April 2015), CINAHL (to 28 April 2015) and trial registers to 28 April 2015, and handsearched bibliographies of relevant publications and reviews, and abstracts of major scientific meetings, for example the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM). We contacted the authors of eligible studies for missing or unpublished data. The evidence is current to 28 April 2015. Selection criteria: Two review authors independently screened the relevant citations for randomised controlled trials (RCTs) comparing different GnRH agonist versus GnRH antagonist protocols in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). Data collection and analysis: Two review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary review outcomes were live birth and ovarian hyperstimulation syndrome (OHSS). Other adverse effects (miscarriage and cycle cancellation) were secondary outcomes. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I2 statistic. We assessed the overall quality of the evidence for each comparison using GRADE methods. Main results: We included 73 RCTs, with 12,212 participants, comparing GnRH antagonist to long-course GnRH agonist protocols. The quality of the evidence was moderate: limitations were poor reporting of study methods. Live birth There was no conclusive evidence of a difference in live birth rate between GnRH antagonist and long course GnRH agonist (OR 1.02, 95% CI 0.85 to 1.23; 12 RCTs, n = 2303, I2= 27%, moderate quality evidence). The evidence suggested that if the chance of live birth following GnRH agonist is assumed to be 29%, the chance following GnRH antagonist would be between 25% and 33%. OHSS GnRH antagonist was associated with lower incidence of any grade of OHSS than GnRH agonist (OR 0.61, 95% C 0.51 to 0.72; 36 RCTs, n = 7944, I2 = 31%, moderate quality evidence). The evidence suggested that if the risk of OHSS following GnRH agonist is assumed to be 11%, the risk following GnRH antagonist would be between 6% and 9%. Other adverse effects There was no evidence of a difference in miscarriage rate per woman randomised between GnRH antagonist group and GnRH agonist group (OR 1.04, 95% CI 0.82 to 1.30; 33 RCTs, n = 7022, I2 = 0%, moderate quality evidence). With respect to cycle cancellation, GnRH antagonist was associated with a lower incidence of cycle cancellation due to high risk of OHSS (OR 0.47, 95% CI 0.32 to 0.69; 19 RCTs, n = 4256, I2 = 0%). However cycle cancellation due to poor ovarian response was higher in women who received GnRH antagonist than those who were treated with GnRH agonist (OR 1.32, 95% CI 1.06 to 1.65; 25 RCTs, n = 5230, I2 = 68%; moderate quality evidence). Authors' conclusions: There is moderate quality evidence that the use of GnRH antagonist compared with long-course GnRH agonist protocols is associated with a substantial reduction in OHSS without reducing the likelihood of achieving live birth

Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles.

Background Several systematic reviews compared recombinant gonadotrophin with urinary gonadotrophins (HMG, purified FSH, highly purified FSH) for ovarian hyperstimulation in IVF and ICSI cycles and these reported conflicting results. Each of these reviews used different inclusion and exclusion criteria for trials. Our aim in producing this review is to bring together all randomised studies in this field under common inclusion criteria with consistent and valid statistical methods. Objectives To compare the effectiveness of recombinant gonadotrophin (rFSH) with the three main types of urinary gonadotrophins (i.e. HMG, FSH-P and FSH-HP) for ovarian stimulation in women undergoing IVF or ICSI treatment cycles. Search strategy An extended search was done according to Cochrane guidelines including the Menstrual Disorders & Subfertility Group's Specialised Register of controlled trials, The Cochrane Central Register of Controlled Trials, MEDLINE (1966 to May 2010), EMBASE (1980 to May 2010), CINAHL (1982 to May 2010), National Research Register, and Current Controlled Trials. Selection criteria All randomised controlled trials reporting data comparing clinical outcomes for women undergoing IVF/ICSI cycles and using recombinant FSH in comparison with HMG or highly purified HMG, purified urinary FSH (FSH-P), and highly purified urinary FSH (FSH-HP) for ovarian hyperstimulation in IVF or ICSI cycles were included. Data collection and analysis Primary outcome measure was live birth rate and OHSS per randomised woman. Binary outcomes were analysed using odds ratios and also reported in absolute terms. Grouped analyses were carried out for all outcomes to explore whether relative effects differed due to key features of the trials. Main results We included 42 trials with a total of 9606 couples. Comparing rFSH to any of the other gonadotrophins irrespective of the down-regulation protocol used, did not result in any evidence of a statistically significant difference in live birth rate (28 trials, 7339 couples, odds ratio 0.97, 95% CI 0.87 to 1.08). This suggests that for a group with a 25% live birth rate using urinary gonadotrophins the rate would be between 22.5% and 26.5% using rFSH. There was also no evidence of a difference in the OHSS rate (32 trials, 7740 couples, OR 1.18, 95% CI 0.86 to 1.61). This means that for a group with 2% risk of OHSS using urinary gonadotrophins, the risk would be between 1.7% and 3.2% using rFSH. Authors' conclusions Clinical choice of gonadotrophin should depend on availability, convenience and costs. Further research on these comparisons is unlikely to identify substantive differences in effectiveness or safet

Difficult embryo transfer: the impact of propofol anesthesia

Background: Difficult embryo transfers (ET) requiring general anesthesia are occasionally encountered in clinical practice. Little evidence is present in the literature as to the success rates when compared with difficult transfers not requiring anesthesia. Objective: To evaluate the impact of using Propofol anesthesia during difficult embryo transfers on the implantation and clinical pregnancy rates. Design: Retrospective patient chart review. Materials and methods: Women undergoing ICSI cycles in the Egyptian IVF-ET center, from January 2000 December 2002, and having difficult ET requiring general anesthesia (Group I = 99 women) were included. A matching group of women with difficult ET, without anesthesia (Group II = 99 women) were used as a control. Results: There were no significant differences in the patient demographics (e.g. age, period of infertility, number of oocytes retrieved, fertilization rate, embryo quality, number of embryos transferred. Moreover, there was no significant differences in implantation (Group I = 19.15%, Group II = 20.86%) or clinical pregnancy rates (Group I = 36.36%, Group II = 33.33%). Conclusion: The use of propofol general anesthesia during difficult embryo transfer does not seem to improve the implantation and pregnancy rates. Even though, prospective randomized trials are needed to confirm these findings