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

BACKGROUND: 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). OBJECTIVES: 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. SEARCH METHODS: 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.. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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). AUTHORS' CONCLUSIONS: 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.

Hormone therapy for sexual function in perimenopausal and postmenopausal women.

BACKGROUND: The perimenopausal and postmenopausal periods are associated with many symptoms, including sexual complaints. OBJECTIVES: To assess the effect of hormone therapy (HT) on sexual function in perimenopausal and postmenopausal women. SEARCH METHODS: We searched for articles in the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform, ISI Web of Knowledge and OpenGrey. The last search was performed in December 2012. SELECTION CRITERIA: We included randomised controlled trials comparing HT to either placebo or no intervention (control). We considered as HT estrogens alone; estrogens in combination with progestogens; synthetic steroids (for example tibolone); or selective estrogen receptor modulators (SERMs) (for example raloxifene, bazedoxifene). Studies of other drugs possibly used in the relief of menopausal symptoms were excluded. We included studies that evaluated sexual function using any validated assessment tool. The primary outcome was a composite score for sexual function and the scores for individual domains (arousal and sexual interest, orgasm, and pain) were secondary outcomes. Studies were selected by two authors independently. DATA COLLECTION AND ANALYSIS: Data were independently extracted by two authors and checked by a third. Risk of bias assessment was performed independently by two authors. We contacted study investigators as required. Data were analysed using standardized mean difference (SMD) and relative risk (RR). We stratified the analysis by participant characteristics with regard to menopausal symptoms. The overall quality of the evidence for the primary outcome was evaluated using the GRADE criteria. MAIN RESULTS: The search retrieved 2351 records from which 27 studies (16,393 women) were included. The 'symptomatic or early post-menopausal' subgroup included nine studies: perimenopausal women (one study), up to 36 months postmenopause (one study), up to five years postmenopause (one study), experiencing vasomotor or other menopausal symptoms (five studies), or experiencing hot flushes and sexual dysfunction (one study). The 'unselected postmenopausal women' subgroup included 18 studies, which included women regardless of menopausal symptoms and permitted the inclusion of women with more than five years since the final menstrual period. No studies were restricted to women with sexual dysfunction. Only five studies evaluated sexual function as a primary outcome. Eighteen studies were deemed at high risk of bias, and the other nine studies were at unclear risk of bias. Twenty studies received commercial funding.Findings for sexual function (measured by composite score):For estrogens alone versus control, in symptomatic or early postmenopausal women the SMD and 95% CI were compatible with a small to moderate benefit in sexual function for the HT group (SMD 0.38, 95% CI 0.23 to 0.54, P < 0.00001, 3 studies, 699 women, I² = 55%, high-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with no effect to a small benefit (SMD 0.16, 95% CI -0.02 to 0.34, P = 0.08, 2 studies, 478 women, I² = 44%, low-quality evidence). The subgroups were not pooled because of considerable heterogeneity.For estrogens combined with progestogens versus control, in symptomatic or early postmenopausal women the 95% CI was compatible with a small to moderate benefit for sexual function in the HT group (SMD 0.42, 95% CI 0.19 to 0.64, P = 0.0003, 1 study, 335 women, moderate-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with no effect to a small benefit (SMD 0.09, 95% CI -0.02 to 0.20, P = 0.10, 3 studies, 1314 women, I² = 0%, moderate-quality evidence). The subgroups were not pooled because of considerable heterogeneity.For tibolone versus control, in symptomatic or early postmenopausal women the 95% CI was compatible with no effect to a small benefit for sexual function in the HT group (SMD 0.13, 95% CI 0.00 to 0.26, P = 0.05, 1 study, 883 women, low-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit (SMD 0.38, 95% CI 0.04 to 0.71, P = 0.03, 2 studies, 142 women, I² = 0%, low-quality evidence). In the combined analysis, the 95% CI was compatible with no effect to a small benefit (SMD 0.17, 95% CI 0.04 to 0.29, P = 0.008, 3 studies, 1025 women, I² = 20%).For SERMs versus control, in symptomatic or early postmenopausal women the 95% CI was compatible with no effect to a moderate benefit for sexual function in the HT group (SMD 0.23, 95% CI -0.04 to 0.50, P = 0.09, 1 study, 215 women, low-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with small harm to a small benefit (SMD 0.04, 95% CI -0.20 to 0.29, P = 0.72, 1 study, 283 women, low-quality evidence). In the combined analysis, the 95% CI was compatible with no effect to a small benefit (SMD 0.13, 95% CI -0.05 to 0.31, P = 0.16, 2 studies, 498 women, I² = 2%).A comparison of SERMs combined with estrogens versus control was only evaluated in symptomatic or early postmenopausal women. The 95% CI was compatible with no effect to a small benefit for sexual function in the HT group (SMD 0.21, 95% CI 0.00 to 0.43, P = 0.05, 1 study, 542 women, moderate-quality evidence). AUTHORS' CONCLUSIONS: HT treatment with estrogens alone or in combination with progestogens was associated with a small to moderate improvement in sexual function, particularly in pain, when used in women with menopausal symptoms or in early postmenopause (within five years of amenorrhoea), but not in unselected postmenopausal women. Evidence regarding other HTs (synthetic steroids and SERMs) is of low quality and we are uncertain of their effect on sexual function. The current evidence does not suggest an important effect of tibolone or of SERMs alone or combined with estrogens on sexual function. More studies evaluating the effect of synthetic steroids, SERMS and the association of SERM + estrogens would improve the quality of the evidence for the effect of these treatments on sexual function in peri and postmenopausal women. Future studies should also evaluate the effect of HT solely among women with sexual complaints.