FSH treatment of male idiopathic infertility improves pregnancy rate: a meta-analysis

INTRODUCTION: The aim of this study is to comprehensively evaluate whether FSH administration to the male partner of infertile couples improves pregnancy rate, spontaneously and/or after assisted reproductive techniques (ART). METHODS: Meta-analysis of controlled clinical trials in which FSH was administered for male idiopathic infertility, compared with placebo or no treatment. Randomization was not considered as an inclusion criterion. RESULTS: We found 15 controlled clinical studies (614 men treated with FSH and 661 treated with placebo or untreated). Concerning the type of FSH, eight studies used recombinant FSH, whereas seven studies used purified FSH. Nine studies evaluated spontaneous pregnancy rate, resulting in an overall odds ratio (OR) of about 4.5 (CI: 2.17-9.33). Eight studies evaluated pregnancy rate after ART, showing a significant OR of 1.60 (CI: 1.08-2.37). Sub-dividing studies according to the FSH preparations (purified/recombinant), pregnancy rate improvement remained significant for each preparation. Eleven studies considered sperm quality after FSH treatment, finding a significant improvement of sperm concentration (2.66×10(6)/ml, CI: 0.47-4.84), but not of concentration of sperm with progressive motility (1.22×10(6)/ml, CI: -0.07 to 2.52). Three trials evaluated testicular volume, showing a non-significant increase in men treated (1.35 ml, CI: -0.44 to 3.14). CONCLUSION: The results of controlled clinical trials available in the literature indicate an improvement of pregnancy rate after FSH administration to the male partner of infertile couples, both spontaneously and after ART. However, the heterogeneity of studies, the high risk of bias and the lack of precise criteria to guide FSH administration limit the strength of these results. Future studies should be designed to identify the markers of FSH response which are helpful in the decision-making process. Meanwhile, the use of FSH in the treatment of male infertility should be cautious

Sperm DNA fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management

10.1530/endoabs.56.GP21

Efficacy of follicle-stimulating hormone treatment in male idiopathic infertility: a meta-analysis

Study question: To comprehensively evaluate whether follicle stimulating hor- mone (FSH) administration to the male partner of idiopathic infertile couples improves pregnancy rate, both spontaneous and after assisted reproductive tech- nique (ART), using a meta-analytic approach and including controlled clinical trial. Summary answer: The administration of FSH to infertile men is reported in the literature since 1991, improving fertilisation and pregnancy rate. A significant increase in pregnancy rate after ART and male treatment with FSH was already shown in several studies, since FSH improves the sperm quality. FSH treatment could improve sperm quality and pregnancy rate in idiopathic infertile men. What is known already: The Cochrane Collaboration recently estimated the overall effect of FSH treatment of the man in couples attending ART, enrolled in randomised, controlled, clinical-trials. That meta-analysis demonstrated that FSH treatment significantly improves spontaneous pregnancy rate, whereas no improvement of pregnancy rate was observed after ART, using fixed and strict inclusion criteria. They excluded all trials in which the randomization was not provided leading to potential loss of useful information that could help clini- cians in their routinely practice. Study design, size, duration: We conducted a comprehensive literature search for controlled clinical trials in which FSH was administered for male idiopathic infertility, compared with placebo or no treatment. The randomization was not considered as inclusion criterion. We considered studies in which men with idiopathic infertility or subfertility were enrolled, chronicallty treated with any type of FSH, compared with placebo or no treatment. Participants/materials, setting, methods: We found 15 controlled clinical stud- ies. Concerning the type of FSH, eight studies included in the meta-analysis used recombinant FSH, whereas seven studies used purified FSH. Pregnancy rate, when evaluated, was considered spontaneous or after ART. Selected trials gave details about 1275 infertile-men, 614 treated with FSH and 661 not-treated. Main results and the role of chance: Among the 15 studies included, nine studies evaluated the spontaneous pregnancy rate, resulting in an overall im- provement of about 4.5 (CI 2.17–9.33 and I2 = 0%) (p < 0.001). Eight stud- ies evaluated pregnancy rate after ART, showing a significant improvement of about 1.60 (CI 1.08–2.37 and I2 = 43%) (p = 0.002). Sub-dividing studies ac- cording to the FSH preparations (purified or recombinant), the pregnancy rate improvement remained significant (p = 0.007 and p = 0.002, respectively). Elev- en studies considered sperm quality after FSH treatment, finding a significant improvement of sperm concentration (mean improvement of 2.66x106 millions/ mL, with CI 0.47–4.84, p = 0.02), but not of sperm motility (mean improvement of 1.22x106 millions/mL, with CI -0.07–2.52, p = 0.06). Finally, three trials evaluated testicular volume, showing a non-significant increase in men treated (mean increase of 1.35 mL, with CI -0.44–3.14, p = 0,14). Limitations, reason for caution: The heterogeneity of studies, together with the high risk of biases in this field of research could limit the strength of these results. Wider implications of the findings: The results of controlled clinical trials available in literature indicate an improvement of pregnancy rate after FSH ad- ministration to the male partner of infertile couples, both spontaneous and after ART. Study funding/competing interest(s): Funding by University(ies) – University of Modena and Reggio Emilia. Trial registration number: NA. Keywords: FSH, idiopathic male infertility, reproductio

Two hormones for one receptor: evolution, biochemistry, actions and pathophysiology of LH and hCG

Luteinizing hormone (LH) and chorionic gonadotropin (CG) are glycoproteins fundamental for sexual development and reproduction. Since they act on the same receptor (LHCGR), there is a general consensus that LH and hCG are equivalent. However, separate evolution of LHβ and hCGβ subunits occurred in primates, resulting in two molecules sharing ∼85% identity and regulating different physiological events. Pituitary, pulsatile LH production results in a ∼90 min half-life molecule targeting the gonads, to regulate gametogenesis and androgen synthesis. Trophoblast hCG, the "pregnancy hormone", exists in several isoforms and glycosylation variants with long half-lives (hours), angiogenic potential, and acts on luteinized ovarian cells as a progestational. The different molecular features of LH and hCG lead to hormone-specific LHCGR binding and intracellular signaling cascades. In ovarian cells, LH action is preferentially exerted through kinases, pERK1/2 and pAKT, resulting in irreplaceable proliferative/anti-apoptotic signals and partial agonism on progesterone production in vitro. In contrast, hCG displays notable cAMP/PKA-mediated steroidogenic and pro-apoptotic potential, which is masked by estrogen action in vivo. In vitro data are confirmed by large dataset from assisted reproduction, since the steroidogenic potential of hCG positively impacts on the number of retrieved oocytes, while LH impacts pregnancy rate (per oocyte number). Interestingly, Leydig cell in vitro exposure to hCG results in qualitatively similar cAMP/PKA and pERK1/2 activation as compared to LH, as well as testosterone. The supposed equivalence of LH and hCG is debunked by such data highlighting their sex-specific functions, thus deeming it an oversight caused by incomplete understanding of clinical data

Response: Commentary: Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + luteinizing hormone, human menopausal gonadotropin or FSH + human chorionic gonadotropin on assisted reproductive technology outcomes in the "Personalized" Medicine Era: A meta-analysis

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Efficacy of follicle-stimulating hormone (FSH) alone, FSH + luteinizing hormone, human menopausal gonadotropin or FSH + human chorionic gonadotropin on assisted reproductive technology outcomes in the "personalized" medicine era: A meta-analysis

Setting: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) act on the same receptor, activating different signal transduction pathways. The role of LH or hCG addition to follicle-stimulating hormone (FSH) as well as menopausal gonadotropins (human menopausal gonadotropin; hMG) in controlled ovarian stimulation (COS) is debated. Objective: To compare FSH + LH, or FSH + hCG or hMG vs. FSH alone on COS outcomes. Design: A meta-analysis according to PRISMA statement and Cochrane Collaboration was performed, including prospective, controlled clinical trials published until July 2016, enrolling women treated with FSH alone or combined with other gonadotropins. Trials enrolling women with polycystic ovarian syndrome were excluded (PROSPERO registration no. CRD42016048404). Results: Considering 70 studies, the administration of FSH alone resulted in higher number of oocytes retrieved than FSH + LH or hMG. The MII oocytes number did not change when FSH alone was compared to FSH + LH, FSH + hCG, or hMG. Embryo number and implantation rate were higher when hMG was used instead of FSH alone. Pregnancy rate was significantly higher in FSH + LH-treated group vs. others. Only 12 studies reported live birth rate, not providing protocol-dependent differences. Patients' stratification by GnRH agonist/antagonist identified patient subgroups benefiting from specific drug combinations. Conclusion: In COS, FSH alone results in higher oocyte number. HMG improves the collection of mature oocytes, embryos, and increases implantation rate. On the other hand, LH addition leads to higher pregnancy rate. This study supports the concept of a different clinical action of gonadotropins in COS, reflecting previous in vitro data

Effect of the Glucagon-Like Peptide-1 Receptor Agonists on Autonomic Function in Subjects with Diabetes: A Systematic Review and Meta-Analysis

Background: In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR). However, the GLP-1R actions on the autonomic nervous system (ANS) in diabetes remain debated. Therefore, this meta-analysis evaluates the effect of GLP-1R agonist on measures of ANS function in diabetes. Methods: According to the Cochrane Collaboration and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, we conducted a meta-analysis considering clinical trials in which the autonomic function was evaluated in diabetic subjects chronically treated with GLP-1R agonists. The outcomes were the change of ANS function measured by heart rate variability (HRV) and cardiac autonomic reflex tests (CARTs). Results: In the studies enrolled, HR significantly increased after treatment (P&lt;0.001), whereas low frequency/high frequency ratio did not differ (P=0.410); no changes in other measures of HRV were detected. Considering CARTs, only the 30:15 value derived from lying-to-standing test was significantly lower after treatment (P=0.002), but only two studies reported this measurement. No differences in other CARTs outcome were observed. Conclusion: The meta-analysis confirms the HR increase but seems to exclude an alteration of the sympatho-vagal balance due to chronic treatment with GLP-1R agonists in diabetes, considering the available measures of ANS function

First Year Metabolic and Hormonal Behavior Define two Different Populations of SGA Newborn for Weight or Height

Context: Small-for-gestational-age (SGA) children have a particular metabolic and hormonal pattern at birth that changes rapidly.Objective: To evaluate the linear and weight growth in the first year of life in SGA children.Design: Prospective, monocentric cohort study.Setting: Real-world data collected from April 2012 to January 2016.Patients: SGA newborns uniformly defined by either growth or length lower than -2 SDs for gestational age.Interventions: All children were evaluated for 1 year after birth, at 3 days of life, then 3, 6, and 12 months after birth.Main outcome measures: Anthropometric parameters and biochemical variables, such as blood glucose, insulin, leptin, IGF-1, IGF binding protein-3 (IGFBP-3), and homeostasis model assessment - insulin resistance (HOMA-IR) index.Results: A total of 133 SGA children were enrolled. Length significantly improved 1 month after birth, whereas weight significantly increased only at 3 months after birth. Biochemical variables increased during the first year of life, showing a prediction by IGFBP-3 and HOMA-IR index. Then, the variables were divided considering either weight, length, or both, showing a different incidence. The biochemical variable changes recorded in the first step were maintained considering SGA children for weight or length, whereas they disappeared when weight and length were considered together.Conclusions: Our study shows a specific catchup growth for weight and length in SGA children. Moreover, we highlight that weight and length should be considered as independent parameters in SGA children, defining 2 different metabolic-hormonal populations with different conceivable predictive role in early catchup growth and in later growth and metabolic status