Francesca Caprio

The pattern of expression of Notch protein members in normal and pathological endometrium.

The objective of this study was to investigate the pattern of expression and the localization of Notch‐1, Notch‐4 and Jagged‐1 in physiological and pathological human endometrium and to evaluate the expression levels of two major regulators of the G1 checkpoint, namely cyclin D1 and p21. Sixty samples of physiological endometrium and 60 samples of pathological endometrium were used for the study. Evaluation of the expression level and the distribution of Notch pathway members and cell‐cycle proteins was performed by immunohistochemistry. In the physiological endometrium we observed an increase of Notch‐1 and Jagged‐1 from proliferative to secretory phase and an opposite trend for Notch‐4. In menopause, the level of expression of all three members of the Notch pathway decreased. We also observed a cyclin D1 increase from proliferative to secretory phase. By contrast, p21 showed a slight increase from proliferative to secretory phase. In the pathological endometrium, we observed an increase of Notch‐1 expression from polyps to carcinoma and decrease for Notch‐4 and Jagged‐1. Moreover, we observed a higher expression of cyclin D1 in all the endometrial pathologies. By contrast, the expression level of p21 slightly increased from polyps to carcinoma. We concluded that in human endometrium Notch‐4 seems to be more involved in controlling proliferation, whereas Notch‐1 seems to be more involved in differentiation programming. Deregulation of these functions may induce the onset of several endometrial pathologies from polyps to cancer.

In Estimated Good Prognosis Patients Could Unexpected “Hyporesponse” to Controlled Ovarian Stimulation be Related to Genetic Polymorphisms of FSH Receptor?

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.

Sequential protocol with urinary-FSH/recombinant-FSH versus standard protocol with recombinant-FSH in women of advanced age undergoing IVF

Abstract A stimulation protocol mimicking the physiological pattern of FSH release may improve IVF outcome in women of advanced age. Urinary-FSH delivers a wider range of isoforms including the most acidic produced during the early follicular phase when oestradiol level is low, a common condition in women of advanced reproductive age. We hypothesized that a stimulation protocol using urinary-FSH during the early follicular phase and then shifting toward recombinant-FSH may improve oocyte quality and pregnancy rate in 35–40 years old patients in IVF program. A retrospective study was performed: after a standard down-regulation with GnRH-analogue, 115 women underwent stimulation with urinary-FSH for 6 days according to a step-down approach and then shifting to recombinant-FSH (group A), 115 women underwent a stimulation protocol with only recombinant-FSH (group B). Days of stimulation were lower in group A than in group B, a higher proportion of MII oocytes and of grade 1 embryos, higher implantation rate and pregnancy rate were observed in group A versus group B. We conclude that a sequential protocol using urinary-FSH in the early days of stimulation and subsequently recombinant-FSH may improve the IVF outcome in patients of advanced reproductive age. Chinese abstract 刺激方案通过模拟人体内FSH释放的生理学特性可能会提高高龄妇女IVF的妊娠结局。尿源性FSH提供了更多的亚型，包括酸性最强的亚型，该亚型只在雌二醇水平很低的早卵泡期产生。这种情况在高生育年龄患者中常见。假设对30-40岁患者行IVF促排卵过程中早卵泡期应用尿源性FSH而后转为应用重组FSH，该方案可能会提高卵子质量和妊娠率。一项回顾性研究显示：通过标准的GnRH-a降调节方案，115名患者前6天接受尿源性FSH刺激而后转为重组FSH刺激（A组），另外115名患者仅接受重组FSH刺激方案（B组）。与B组相比，A组刺激天数更少、MII卵细胞和一级胚胎比例较多且有更高的移植率和妊娠率。因而我们得出结论：在早期应用尿源性FSH而后转用重组FSH刺激的序贯方案可以提高高龄妇女的IVF结局。

Seminal anti-Müllerian hormone levels during recombinant human follicle-stimulating hormone treatment in men with idiopathic infertility undergoing assisted reproduction cycles

A prospective study was designed to investigate the effects of recombinant human follicle‐stimulating hormone (rhFSH) on seminal anti‐Müllerian 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 ± 2.9 vs. 19.3 ± 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 ± 30.6 vs. 34.6 ± 18.5, p < 0.025). Following therapy, a greater increase in AMH levels was observed in responders compared to non‐responders (Δ = 24.8 ± 36.4 vs. Δ = 6.4 ± 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.

Endometrial LGR7 expression and implantation failure.

Abstract 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.

Hormonal contraceptives and venous thromboembolism: Are inflammatory bowel disease patients at increased risk? A retrospective study on a prospective database

Recent studies showed an increased risk of venous thromboembolism (VTE) in patients receiving oral hormonal contraceptives. Inflammatory bowel diseases (IBD) often affect young patients and represent a pro-coagulant condition. This could result from active inflammation, but a potential role for genetic and molecular factors has been suggested. Hormonal contraceptives have also been associated with increased risk of VTE and the risk may be greater in IBD patients that already are in a pro-coagulant status, but no definitive data are available in this population. The purpose of our study was to seek for differences of the risk of VTE in IBD patients receiving hormonal contraceptives compared with controls. This is a retrospective study. We interrogated a prospectively maintained database of IBD patients observed at our outpatient clinic between 2000 and 2014. All female patients managed conservatively, with no active disease, who were taking oral hormone contraceptives in the study period, were included. Patients observed for other-than-IBD conditions at our Unit and at the Unit of Gynaecology and Obstetrics, receiving contraceptives, served as controls (ratio 1:2). Patients with cancer, those receiving hormonal therapy, and those with known genetic predisposition to VTE were excluded. We included 146 six IBD patients and 290 controls. One patient in each group developed VTE. Overall, the incidence of VTE associated with oral contraceptives was 0.5%. IBD was associated with increased risk of VTE (OR 1.9, 95% CI 0.12–32.12, p > 0.99). Active smokers since 10 years (17.2%) had higher risks of VTE (OR 8.6, 95% CI 1.16–19.25, p = 0.03). Our data show that patients with IBD in remission are not at higher risk of VTE due to oral oestrogen-containing contraceptives compared with non-IBD controls. Smokers are at increased risk, irrespective of the baseline disease.