Article

FSH replaced by low-dose hCG in the late follicular phase versus continued FSH for assisted reproductive techniques

Department of Obstetrics and Gynecology, Medical School of Ribeirao Preto, University of Sao Paulo, Hospital das Clinicas da FMRP-USP, 8 andar, Campus Universitario da USP, Ribeirao Preto, Sao Paulo, Brazil, 14048-900.
Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 03/2013; 3(3):CD010042. DOI: 10.1002/14651858.CD010042.pub2
Source: PubMed

ABSTRACT

During controlled ovarian hyperstimulation (COH) follicle-stimulating hormone (FSH) is frequently used for several days to achieve follicular development. FSH is a relatively expensive drug, substantially contributing to the total expenses of assisted reproductive techniques (ART). When follicles achieve a diameter greater than 10 mm they start expressing luteinising hormone (LH) receptors. At this point, FSH might be replaced by low-dose human chorionic gonadotropin (hCG), which is less expensive. In addition to cost reduction, replacing FSH by low-dose hCG has a theoretical potential to reduce the incidence of ovarian hyperstimulation syndrome (OHSS).
To evaluate the effectiveness and safety of using low-dose hCG to replace FSH during the late follicular phase in women undergoing COH for assisted reproduction, compared to the use of a conventional COH protocol.
We searched for randomised controlled trials (RCT) in electronic databases (Menstrual Disorders and Subfertility Group Specialized Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), trials registers (ClinicalTrials.gov, Current Controlled Trials, World Health Organization International Clinical Trials Registry Platform), conference abstracts (ISI Web of knowledge), and grey literature (OpenGrey); additionally we handsearched the reference list of included studies and similar reviews. The last electronic search was performed in February 2013..
Only true RCTs comparing the replacement of FSH by low-dose hCG during late follicular phase of COH were considered eligible; quasi or pseudo-randomised trials were not included. Cross-over trials would be included only if data regarding the first treatment of each participant were available; trials that included the same participant more than once would be included only if each participant was always allocated to the same intervention and follow-up periods were the same in both/all arms, or if data regarding the first treatment of each participant were available. We excluded trials that sustained FSH after starting low-dose hCG and those that started FSH and low-dose hCG at the same time.
Study eligibility, data extraction, and assessment of the risk of bias were performed independently by two review authors, and disagreements were solved by consulting a third review author. We corresponded with study investigators in order to solve any query, as required. The overall quality of the evidence was assessed in a GRADE summary of findings table.
The search retrieved 1585 records; from those five studies were eligible, including 351 women (intervention = 166; control = 185). All studies were judged to be at high risk of bias. All reported per-woman rather than per-cycle data.When use of low-dose hCG to replace FSH was compared with conventional COH for the outcome of live birth, confidence intervals were very wide and findings were compatible with appreciable benefit, no effect or appreciable harm for the intervention (RR 1.56, 95% CI 0.75 to 3.25, 2 studies, 130 women, I² = 0%, very-low-quality evidence). This suggests that for women with a 14% chance of achieving live birth using conventional COH, the chance of achieving live birth using low-dose hCG would be between 10% and 45%.Similarly confidence intervals were very wide for the outcome of OHSS and findings were compatible with benefit, no effect or harm for the intervention (OR 0.30, 95% CI 0.06 to 1.59, 5 studies, 351 women, I² = 59%, very-low-quality evidence). This suggests that for women with a 3% risk of OHSS using conventional COH, the risk using low-dose hCG would be between 0% and 4%.The confidence intervals were wide for the outcome of ongoing pregnancy and findings were compatible with benefit or no effect for the intervention (RR 1.14, 95% CI 0.81 to 1.60, 3 studies, 252 women, I² = 0%, low-quality evidence). This suggests that for women with a 32% chance of achieving ongoing pregnancy using conventional COH, the chance using low-dose hCG would be between 27% and 53%.The confidence intervals were wide for the outcome of clinical pregnancy and findings were compatible with benefit or no effect for the intervention (RR 1.19, 95% CI 0.92 to 1.55, 5 studies, 351 women, I² = 0%, low-quality evidence). This suggests that for women with a 35% chance of achieving clinical pregnancy using conventional COH, the chance using low-dose hCG would be between 32% and 54%.The confidence intervals were very wide for the outcome of miscarriage and findings were compatible with benefit, no effect or harm for the intervention (RR 1.08, 95% CI 0.50 to 2.31, 3 studies, 127 pregnant women, I² = 0%, very-low-quality evidence). This suggests that for pregnant women with a 16% risk of miscarriage using conventional COH, the risk using low-dose hCG would be between 8% and 36%.The findings for the outcome of FSH consumption were compatible with benefit for the intervention (MD -639 IU, 95% CI -893 to -385, 5 studies, 333 women, I² = 88%, moderate-quality evidence).The findings for the outcome of number of oocytes retrieved were compatible with no effect for the intervention (MD -0.12 oocytes, 95% CI -1.0 to 0.8 oocytes, 5 studies, 351 women, I² = 0%, moderate-quality evidence).
We are very uncertain of the effect on live birth, OHSS and miscarriage of using low-dose hCG to replace FSH during the late follicular phase of COH in women undergoing ART, compared to the use of conventional COH. The current evidence suggests that this intervention does not reduce the chance of ongoing and clinical pregnancy; and that it is likely to result in an equivalent number of oocytes retrieved expending less FSH. More studies are needed to strengthen the evidence regarding the effect of this intervention on important reproductive outcomes.

Download full-text

Full-text

Available from: Wellington P Martins, Nov 01, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background As many as one in six couples encounter problems with fertility, defined as failure to achieve a clinical pregnancy after regular intercourse for 12 months. Increasingly, couples are turning to assisted reproductive technology (ART) for help with conceiving and ultimately giving birth to a healthy live baby of their own. Fertility treatments are complex and costly, and each assisted reproduction cycle consists of several steps. If one of the steps is incorrectly applied, the stakes are high as conception may not occur. With this in mind, it is important that each step involved in ART is supported by good evidence from well-designed studies. Cochrane reviewers examined the evidence from Cochrane systematic reviews on ART published in The Cochrane Library. Study characteristics We included 58 Cochrane systematic reviews on various stages in the ART cycle. All were high quality. Reviews of in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) were included in the overview. Reviews of intrauterine insemination and ovulation induction were not included. This overview provides the most up to date evidence from truly randomised controlled trials for ART cycles. Key results Thirty-two reviews identified interventions that were effective or promising, 14 reviews identified interventions that were ineffective or possibly ineffective, and 12 reviews were unable to draw conclusions due to lack of evidence. Use of the evidence from this overview to guide clinical practice should help to improve live birth rates and reduce rates of multiple pregnancy, cycle cancellation and ovarian hyperstimulation syndrome.
    No preview · Article · Aug 2013 · Cochrane database of systematic reviews (Online)
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To assess the potential pharmacogenetic use of FSH for infertility treatment. Review of the literature and genomic databases. SNP assessed: rs6166 (c.2039A>G, p.N680S), rs6165 (c.919A>G, p.T307A), rs1394205 (c.-29G>A) in FSHR and rs10835638 (c.-211G>T) in FSHB. Literature search via PubMed. Blast analysis of genomic information available in the NCBI nucleotide database. Comparison of allele frequency and haplotype distribution using the http://spsmart.cesga.es tool. All these SNPs appear first in Homo sapiens, result in reduced FSH action and are present with variable frequencies and combinations worldwide. Stringent clinical studies demonstrate that the FSHR genotype influences serum FSH levels and gonadal response in both sexes. Serum FSH levels depend on the -211G>T SNP, influencing transcriptional activity of the FSHB promoter. Genotypes reducing FSH action are overrepresented in infertile subjects. While the clinical relevance of the FSHR polymorphisms alone is limited, the combination of FSHR and FSHB genotypes has a much stronger impact than either one alone in both sexes. About 30% of people are carrier of the genotypes apparently less favorable for reproduction. Prospective studies need to investigate whether stratification of infertile patients according to their FSHR-FSHB genotypes improves clinical efficacy of FSH treatment compared to the current, naïve approach. A relative enrichment of less favorable FSHR-FSHB genotypes may be related to changes in human reproductive strategies and be a marker of some health-related advantage at the costs of reduced fertility.
    Preview · Article · Nov 2013 · European Journal of Endocrinology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the efficacy and safety of using cabergoline for reducing the risk of ovarian hyperstimulation syndrome (OHSS). Systematic review and meta-analysis of randomized clinical trials (RCTs). Women submitted to controlled ovarian stimulation (COS) for assisted reproduction. Cabergoline. Fertility centers. Moderate-severe OHSS, live birth, clinical pregnancy, number of retrieved oocytes, miscarriage, congenital abnormalities. Comparisons were performed with the use of risk ratios (RRs) or mean differences (MDs) and their respective 95% confidence intervals (CIs). Eight RCTs were considered to be eligible; data from seven studies could be extracted and included in the meta-analysis. Cabergoline reduces the risk of moderate-severe OHSS (RR 0.38, 95% CI 0.29-0.51, 7 studies, 858 women) and probably has no clinically relevant negative impact on clinical pregnancy (RR 1.02, 95% CI 0.78-1.34, 4 studies, 561 women) or on the number of retrieved oocytes (MD 1.15, 95% CI -0.76 to 3.07, 5 studies, 628 women). However, our estimates were imprecise for distinguishing between substantial harm, no effect, and substantial benefit considering live birth (RR 1.03, 95% CI 0.71-1.48, 1 study, 200 women), and miscarriage (RR 0.69, 95% CI 0.27 to 1.76, 3 studies, 194 pregnant women). No studies reported congenital abnormalities. Cabergoline reduces the occurrence of moderate-severe OHSS. Cabergoline is unlikely to have a clinically relevant negative impact on clinical pregnancy or on the number of retrieved oocytes. However, we are still uncertain of its impact on live birth, miscarriage, and congenital abnormalities.
    Full-text · Article · Dec 2013 · Fertility and sterility
Show more