Diseases are complex systems that can be studied through the integration of data derived from different disciplines to obtain a global and reliable picture of the biological phenomenon under investigation. Based on the recent observations that the metabolomics profiling of follicular fluids reflects the ovarian microenvironment of women and that endometriosis represents an example of complex diseases, clearly diagnosed by laparoscopy, we thought that the follicular fluids of endometriosis patients can represent a study model to evaluate the possibility of integrating data obtained by different approaches. Hence, the aim of this work was to analyze and integrate different clinical chemistry parameters with specific reference to the metabolic profile, inflammatory state and cell damage by a H-NMR approach and biochemical analysis in the follicular fluids of women with different stages of endometriosis (I-II and III-IV) subjected to the In Vitro Fertilization (IVF) cycle. Our analysis evidenced that in the follicular fluids of endometriosis patients the levels of phospholipids, lactate, insulin, PTX3, CXCL8, CXCL10, CCL11 and VEGF were higher whereas those of some fatty acids, lysine, choline, glucose, aspartate, alanine, leucine, valine, proline, phosphocholine, total LDH as well its LDH-3 isoform were lower in comparison to the control group. The levels of LDHB, PTX3 and insulin receptor were also confirmed by RT-PCR applied on cumulus cells surrounding oocytes retrieved from the patients. The reduced oocyte quality observed in patients with endometriosis can be certainly correlated to the different levels of these molecules. These data represent how the integration of different experimental approaches may be useful for understanding the underlying mechanisms of a complex disease and can lead to a better clinical management of endometriosis.

It has been reported that 10% to 15% of young normogonadotrophic women show suboptimal response to standard gonadotropin-releasing hormone-a long protocol. These patients require higher doses of exogenous follicle-stimulating hormone (FSH). This phenomenon could be associated with genetic characteristics. In this study, FSH receptor polymorphism was retrospectively evaluated in 42 normoresponder young women undergoing an in vitro fertilization/intracytoplasmic sperm injection cycle; patients were stratified according to recombinant human FSH (r-hFSH) consumption. We selected 17 normoresponder young patients who required a cumulative dose of recombinant FSH (rFSH) >2500 UI (group A). A control group was randomly selected among patients who required a cumulative dose of rFSH <2500 UI (group B). Follicle-stimulating hormone receptor (FSH-R) 307Ala and 680Ser variants were analyzed in all our patients. Our results show that the mean number of rFSH vials (36.3 ± 7.5 vs 28.6 ± 4.5, P = .0001) and days of stimulation (12.7 ± 2.4 vs 10.8 ± 2.8, P = .03) were significantly lower in group B, whereas the number of oocytes retrieved (7.1 ± 1.5 vs 9.6 ± 2.4; P = .0005) and the average number of embryos transferred (2.1 ± 0.7 vs 2.7 ± 0.4; P = .001) were significantly lower in group A. Estradiol serum levels on the human chorionic gonadotrophin day were significantly lower in group A (997.8 ± 384.9 pg/mL vs 1749.1 ± 644.4; P = .0001). The incidence of the Ser/Ser genotype was higher in patients with higher r-hFSH consumption (group A; P = .02). Based on our results, we hypothesize an association between the FSH-R polymorphisms and a "hyporesponse" to exogenous FSH.

Background and objectives: Male infertility is a global health dilemma and Follicle-Stimulating Hormone (FSH) administration has shown promising results. Several studies showed that infertile men with normal semen parameters have low levels of DNA damage while infertile men with abnormal semen parameters have more damage at the DNA level. Sperm DNA damage may affect the reproductive outcome and has been associated with failure in the achievement of competent embryos and pregnancy fulfillment. The aim of this study was to evaluate whether the administration of recombinant FSH (Gonal-f® PEN 900 IU) could improve sperm DNA fragmentation in men with infertility. The secondary endpoints of this study were to evaluate the FSH effects on sperm parameters and hormonal assets.Methods: A longitudinal, prospective, multicenter, open-label clinical trial was carried out. Infertile couples were recruited from six Italian Reproductive Medical Centers and 115 infertile men were enrolled for this study. All participants were treated with subcutaneous injections of Gonal-f® 150 IU every other day, within a 3 month-time frame. The semen samples were examined in accordance to the 2010 World Health Organization criteria. Sperm DNA Fragmentation (DFI) was determined by fluorescence microscopy using terminal deoxynucleotidyl transferase-mediated d-UTP Nick-end Labeling (TUNEL) assay. Statistical analysis was performed using both the t-test for paired samples and the Wilcoxon signed-rank test.Results: FSH administration improved DFI in 67% of patients, with an average decrease of 35.4% compared to the baseline. This improvement is more evident in men with basal DFI lower than 17% and in those with FSH basal levels between 2.16 and 4.27 IU/L. In addition, FSH enhanced the gonadal function, increasing the hormones AMH and Inhibin B and semen parameters. Limitation of these results are represented by the absence of a placebo group and of FSHR genotype stratification sub-analysis.Conclusion: Recombinant FSH 150 IU is well tolerated and effective in eliciting a significant DFI reduction as well as in improving gonadal function.Trial Registration: EUDRACT Number 2010-020196-23. Registred 14 April 2011.

Correction for ‘Metabolomic profiling and biochemical evaluation of the follicular fluid of endometriosis patients’ by Marianna Santonastaso et al., Mol. BioSyst., 2017, DOI: 10.1039/c7mb00181a.

Infertility treatment is a stressful process and factors like anxiety and preoccupation could affect the success of In Vitro Fertilization (IVF) or other assisted reproductive techniques. Moreover, luteal phase support (LPS) in IVF cycles is recommended. Our aim was to analyze the effects of LPS with intramuscular and subcutaneous progesterone on stress hormones (cortisol and prolactin). We analyzed one hundred-thirty women undergoing their first IVF cycle and then randomized in two groups: group A (65 patients) received 33 mg/day of intramuscular in oil-progesterone from pick-up and 50mg/day from embryo transfer, group B (65 patients), instead, received 25 mg of subcutaneous water soluble-progesterone from pick-up. Cortisol and prolactin serum levels were obtained at day+7 from oocyte retrieval. Our results showed that the values of prolactin and cortisol were statistically significantly higher in group A compared to the group B. Subcutaneous progesterone treatment, in fact, is associated with lower cortisol and prolactin levels, suggesting new therapeutic opportunities in IVF cycles to reduce patients' distress and improve quality of life. SOMMARIOIl trattamento dell'infertilità è un processo stressante e fattori come l'ansia e la preoccupazione potrebbero influenzare il successo della fecondazione in vitro (IVF) o di altre tecniche di riproduzione assistita. Inoltre, il supporto alla fase luteale (LPS) è raccomandato nei cicli di IVF. Il nostro obiettivo è stato quello di analizzare gli effetti sugli ormoni dello stress (cortisolo e prolattina), della LPS con progesterone intramuscolare e sottocutaneo. Abbiamo analizzato centotrenta donne sottoposte al primo ciclo di IVF e le abbiamo randomizzate in due gruppi: il gruppo A (65 pazienti) ha ricevuto 33 mg/die di progesterone intramuscolare dal giorno del pick-up e 50 mg/die dal giorno del trasferimento dell'embrione, il gruppo B (65 pazienti), invece, ha ricevuto 25 mg di progesterone, solubile in acqua, per via sottocutanea dal giorno del pick-up. I livelli sierici di cortisolo e prolattina sono stati valutati dopo sette giorni dal pick-up. I nostri risultati hanno mostrato che i valori di prolattina e cortisolo erano statisticamente più alti nel gruppo A rispetto al gruppo B. Il trattamento sottocutaneo di progesterone, infatti, è associato a livelli più bassi di cortisolo e prolattina, suggerendo nuove opportunità terapeutiche nei cicli di IVF per ridurre lo stress dei pazienti e migliorare la qualità della vita.

Implantation failure is considered as a major cause of infertility in women with recurrent pregnancy loss (RPL) and in otherwise healthy women with unexplained infertility. Preliminary data in primates suggested that relaxin (RLX) is involved in endometrial preparation for implantation. In a prospective observational study, the endometrial RLX receptor (LGR7) expression was assessed in three groups of patients with regular ovulatory cycle and normal uterine cavity: 23 with RPL (Group A), 23 with unexplained infertility undergone at least three cycles of failed in vitro fertilization (IVF) reporting good oocyte and embryo quality (Group B), 23 with proven fertility (Group C). Assessment of LGR7 expression was performed with both polymerase chain reaction (PCR) analysis and immunohistochemistry on endometrial samples obtained with hysteroscopic biopsy performed in the secretory phase of the menstrual cycle. Endometrial LGR7 was less expressed in group A and B versus C, both by PCR analysis (p = 0.024) and immunohistochemistry. The decreased expression of the endometrial RLX receptor in women with implantation failures, both in vitro fertilization failure and recurrent pregnancy loss, suggests that RLX may play a crucial role in the structural and functional changes of the endometrium during the window of implantation.

SUMMARYA prospective study was designed to investigate the effects of recombinant human follicle-stimulating hormone (rhFSH) on seminal anti-M€ ullerian hormone (AMH) levels in men with idiopathic oligoasthenoteratozoospermia (iOAT), researching possible relationships between the seminal AMH behavior and the response to the treatment. Thirty-nine men who were candidates for intracytoplasmic sperm injection (ICSI) because of iOAT were enrolled. Patients were treated on alternately days with 150 IU of rhFSH for at least 3 months before assisted reproduction cycles. Main outcome measures were seminal AMH concentrations before and after rhFSH therapy. After treatment, 16 subjects (responders) showed an improvement in their sperm count compared to baseline (7.6 AE 2.9 vs. 19.3 AE 7.7, p < 0.01) whereas 23 men (non-responders) experienced no sperm modifications. Baseline seminal AMH concentrations were significantly higher in responders than in non-responders (53.0 AE 30.6 vs. 34.6 AE 18.5, p < 0.025). Following therapy, a greater increase in AMH levels was observed in responders compared to non-responders (D = 24.8 AE 36.4 vs. D = 6.4 AE 11.2, p < 0.028). Seminal AMH levels significantly and positively correlated with sperm count (after rhFSH treatment rho = 0.647, p < 0.001). Our study suggests that rhFSH improves sperm count in a quota of iOAT men, and the subjects who respond to the treatment have higher baseline seminal AMH concentrations than the patients who are not responsive. Seminal AMH could be helpful to select those infertile men who may benefit from rhFSH treatment.

Background Venous thromboembolism (VTE) is a multifactorial disorder, accounting for high morbidity and mortality rates, due to a complex interplay of several variables classifiable as inherited (mutated Leiden V factor, prothrombin, protein C, protein S and antithrombin) and acquired (lupus anticoagulants, pregnancy, major surgery procedures, cancer and inflammatory diseases) risk factors. The association of VTE with the nephrotic syndrome, particularly deep vein and renal vein thrombosis (DVT and RVT, respectively) is tightly established. This risk is particularly high in patients with idiopathic membranous nephropathy. In fact, thromboembolic events occur with a frequency between &lt;10% and 45% in this disease. The reason(s) underlying the hypercoagulable status in nephrotic patients are not clearly understood. Multiple hemostatic abnormalities have been described, including decreased levels of antithrombin and plasminogen (due to urinary losses), increased platelet activation, reduced plasminogen activation, overproduction of fibrinogen and factors V and VIII as a compensatory response to hypoalbuminemia. The risk of thrombosis seems to be related to the severity and duration of the nephrotic status and seems to be particularly increased with serum albumin concentrations ≤2.0 g/dl (20 g/L). Case report We report the case of a 28 year-old male with nephrotic syndrome due to membranous nephropathy positive for serum anti-phospholipase-A2 receptor antibody. The patient was asymptomatic for VTE, but abdominal ultrasound showed endoluminal obstruction of both renal veins. Abdominal Computer Tomography confirmed the extensive bilateral renal vein thrombosis and also revealed an extension of the thrombosis to the inferior cava vein and the left common iliac vein. He was treated with low-molecular weight heparin for six months. According to our internal protocol, a complete Thrombophilia Molecular Study was performed and showed a normal Leiden V factor, but a rare homozygous mutation of the G20210A gene encoding for prothrombin. The prevalence of this is less than 5% in the general population, but is highly variable with ethnicity. The G20210A mutation confers a mildly increased thrombotic risk that is amplified by the presence of other risk factors, such as nephrotic syndrome. Conclusions In our case report, the association of a nephrotic syndrome secondary to a primitive membranous glomerulonephritis and the mutation in homozygous of the G20210A prothrombin, a rare mutation associated with a high thrombotic risk, led to a severe VTE in an still asymptomatic 28-year-old patient. Based on this experience, we would highlight the importance of the genetic screening for polymorphisms associated with inherited thrombophilia in nephrotic patients complicated with VTE.