Gonadotropin Activity during Early Folliculogenesis and Implications for Polycystic Ovarian Syndrome and Premature Ovarian Insufficiency: A Narrative Review.

Female fertility depends on the ovarian reserve of follicles, which is determined at birth. Primordial follicle development and oocyte maturation are regulated by multiple factors and pathways and classified into gonadotropin-independent and gonadotropin-dependent phases, according to the response to gonadotropins. Folliculogenesis has always been considered to be gonadotropin-dependent only from the antral stage, but evidence from the literature highlights the role of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) during early folliculogenesis with a potential role in the progression of the pool of primordial follicles. Hormonal and molecular pathway alterations during the very earliest stages of folliculogenesis may be the root cause of anovulation in polycystic ovary syndrome (PCOS) and in PCOS-like phenotypes related to antiepileptic treatment. Excessive induction of primordial follicle activation can also lead to premature ovarian insufficiency (POI), a condition characterized by menopause in women before 40 years of age. Future treatments aiming to suppress initial recruitment or prevent the growth of resting follicles could help in prolonging female fertility, especially in women with PCOS or POI. This review will briefly introduce the impact of gonadotropins on early folliculogenesis. We will discuss the influence of LH on ovarian reserve and its potential role in PCOS and POI infertility.

The Role of ß1 Integrin/CD29 as a Potential Prognostic Factor for the Risk of Progression to Cervical Carcinoma in HPV-Associated Lesions.

Background and Objectives: Available evidence reports the overexpression of ß1 integrin in dysplastic rather than normal cervical tissue. We aimed to evaluate the involvement of ß1 (CD29) integrin in the progressive pathogenesis of cervical intraepithelial neoplasia (CIN). Materials and Methods: From January 2019 to December 2021, we prospectively enrolled women undergoing a colposcopy with a cervical biopsy for abnormal cervical cytology and/or undefined cytology with a positive HPV DNA test and women with relapsing cervical inflammatory disorders. Based on the histopathological results, women were divided into four groups: group A (CIN1), group B (CIN2), group C (CIN3), and group D (no CIN diagnosis) as a control group. Subsequently, cytofluorimetry and immunohistochemical analysis (based on the identified positive cell ratios as follows: ≤10%, negative; 10-25%, 1+ (weak); 25-50%, 2+ (medium); ≥50%, and 3+ (high)) for ß1 integrin were carried out. Results: In total, 154 women were included. The average fluorescence intensity in the four groups was 2.35 ± 1.37, 2.73 ± 1.56, 3.09 ± 1.56, and 2.13 ± 1.25 UA from groups A to D, respectively; this figure was significantly different for CIN3 (group C) women relative to the other groups (p = 0.0132). Higher ß1 integrin/CD29 concentrations in the CIN groups with HR-HPV 16 and 18 were also detected (p = 0.0292, 0.0367, and 0.0357 respectively for CIN3, CIN2, and CIN1). Immunohistochemistry analysis showed higher results for the CIN3 group compared to controls and all the other groups (p < 0.001). Conclusions: ß1/CD29 integrin expression increased with CIN grade, and it was significantly higher in CIN3 lesions. This could be used as a promising screening tool to identify women prone to developing high-grade cervical lesions. However, additional evidence is needed to strengthen these findings.

Inhibition of Galectins and the P2X7 Purinergic Receptor as a Therapeutic Approach in the Neurovascular Inflammation of Diabetic Retinopathy.

Diabetic retinopathy (DR) is the most frequent microvascular retinal complication of diabetic patients, contributing to loss of vision. Recently, retinal neuroinflammation and neurodegeneration have emerged as key players in DR progression, and therefore, this review examines the neuroinflammatory molecular basis of DR. We focus on four important aspects of retinal neuroinflammation: (i) the exacerbation of endoplasmic reticulum (ER) stress; (ii) the activation of the NLRP3 inflammasome; (iii) the role of galectins; and (iv) the activation of purinergic 2X7 receptor (P2X7R). Moreover, this review proposes the selective inhibition of galectins and the P2X7R as a potential pharmacological approach to prevent the progression of DR.

Does Intrauterine Injection of hCG Improve IVF Outcome? A Systematic Review and a Meta-Analysis.

Various interventions have been proposed to improve embryo implantation in IVF. Among these, intrauterine injections of human chorionic gonadotropin seem to have promising results. Consequently, we conducted a review and meta-analysis to assess IVF outcomes by comparing couples who underwent intrauterine hCG injection transfer versus those who underwent embryo transfer with intrauterine injection of placebo, or without any additional intervention. The primary outcome was the clinical pregnancy rate. Secondary outcomes were the implantation rate, miscarriage rate, and live birth rate. A meta-analysis was conducted using the random effects model, while bias within studies was detected using the Cochrane risk of bias tool. Ectopic pregnancies and stillbirths were also assessed. The clinical pregnancy (RR 1.38, 95% CI 1.17−1.62, p < 0.0001) and implantation rate (RR 1.40, 95% CI 1.12−1.75, p = 0.003) were significantly higher in women who underwent hCG injection than in the control group. These significant effects persisted only in women who underwent cleavage-stage embryo transfer. No significant differences between groups were observed in the other secondary outcomes. In conclusion, our systematic review and meta-analysis demonstrate that intrauterine injection of hCG could be a valuable approach in women who undergo cleavage-stage embryo transfer. Given the lack of data about the live birth rate, caution should be exercised in interpreting these data.

Endometrial LGR7 expression and implantation failure.

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.

Immune Checkpoint Inhibitors and Scleroderma: Data from the European Pharmacovigilance Database.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can be commonly associated with the occurrence of immune-related adverse drug reactions (irADRs), which can involve any tissue and organ. ICI-induced skin toxicities are common irADRs and they can be a consequence of a rheumatologic ADR, such as in the case of scleroderma. A recent literature review reported that scleroderma and scleroderma mimics represent a group of disorders with significant morbidity that have been described during ICIs' use. OBJECTIVE AND METHODS: Considering the clinical significance of scleroderma cases, the present study aimed to analyze the occurrence of these events in patients receiving ICIs by describing data from individual case safety reports (ICSRs) retrieved from the European spontaneous reporting system, EudraVigilance (EV). RESULTS: Until February 2023, 70 ICSRs with at least one ICI as the suspected drug and at least one preferred term (PT) related to scleroderma cases were retrieved from the EV. Pembrolizumab was reported as suspected in 41 ICSRs, nivolumab in 25 ICSRs, ipilimumab in 8 ICSRs and atezolizumab in 3 ICSRs. Patients who experienced scleroderma cases were adults, and no differences were found in terms of sex distribution. Scleroderma cases were mainly classified as serious, while the outcome was mainly reported as favorable. The most reported PTs were scleroderma and morphea. CONCLUSIONS: Considering the seriousness of ICI-induced scleroderma cases and the recent marketing authorization of some ICIs, we believe that further high-quality clinical studies should be conducted on this topic to better estimate the impact of these events in patients with cancer.

Long-Term Outcomes of Tension-Free Vaginal Tape Obturator: Efficacy and Safety at Long-Term Follow-Up.

Background/Objectives: The use of tension-free vaginal tape obturator (TVT-O) for the treatment of stress urinary incontinence (SUI) has been widely debated over the last decade due to the lack of evidence on its long-term outcomes. The aim of this prospective study is to assess, for the first time in the available literature, the efficacy and safety of TVT-O implantation in women with pure SUI over a 17-year follow-up period. Methods: We included all women who complained of pure SUI symptoms (confirmed urodynamically) and underwent the TVT-O procedure. An objective cure was defined as the absence of urine leakage during the stress test, while subjective outcomes were assessed by means of the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), the Patient Global Impression of Improvement (PGI-I) scale, and a Visual Analogue Scale (VAS). Results: A total of 70 patients who met the inclusion criteria underwent the TVT-O procedure. During the study period, no patients were lost to follow-up, and all women completed the last evaluation at the 17-year mark. At the 17-year mark of follow-up, 62 out of 70 patients (81.4%) were subjectively cured, and 56 out of 70 (80%) patients were objectively cured. These data do not reveal any significant variation in the surgical outcomes over the follow-up period. We recorded seven (10%) tape exposure (three occurred after 10 years and four after 17 years). Among these, one woman was symptomatic for dyspareunia and "hispareunia". All patients with mesh exposure were treated with partial removal and re-suture of the vagina, but only one developed the recurrence of SUI that required a second treatment with a urethral bulking agent (UBA). In all other cases, women reported a complete resolution of symptoms without any worsening of the urinary continence. No significant bladder or urethral erosion was recorded. Conclusions: The 17-year evaluation of the TVT-O procedure has shown that it is a highly effective and safe option for the treatment of female SUI. Although there was an increased risk of tape exposure 17 years after implantation, no serious complications were reported, and no patient required the total removal of the sling.

Urethral Bulking Agents for the Treatment of Urinary Incontinence: Efficacy, Safety, and Impact on the Overactive Bladder Symptoms with an Underlying Detrusor Overactivity.

Background: Mixed urinary incontinence (MUI) has always represented a major therapeutic challenge and the management of this type of incontinence is often complicated by uncertain outcomes. Surgical options include interventions targeting both stress urinary incontinence (SUI) and urge urinary incontinence (UUI), although there are no international published guidelines that dictate whether it is better to start with surgical management to address the SUI or UUI component after the failure of conservative treatment. The aim of the present study is to evaluate the effectiveness of the Macroplastique (MPQ) procedure on overactive bladder (OAB) symptoms in women with MUI with a minimum follow-up of 1 year. Methods: A retrospective analysis of prospectively collected data was performed in two tertiary reference centers. We enrolled all women complaining of symptoms of SUI and OAB, dry or wet, with a urodynamically confirmed diagnosis of MUI [urodynamic stress incontinence (USI) with detrusor overactivity (DO)], who took a previous ineffective antimuscarinic treatment and underwent the MPQ procedure. We considered as objectively cured women who did not leak urine during the stress test and with a 1 h pad-test negative, while International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), ICIQ-OAB, Patient Global Impression of Improvement (PGI-I) scale, and a Visual Analogue Scale (VAS) were used to assess subjective outcomes. Results: A total of forty-six patients who met the inclusion criteria and who underwent the MPQ procedure were considered for the analysis. At the 1-year mark of follow-up, 72% of patients were objectively cured at stress test and 65% were objectively cured at pad-test, while 72% of women declared themselves subjectively cured. OAB symptoms significantly improved after MPQ and a complete resolution of OAB was recorded in 35% of patients. Conclusions: This study demonstrated that MPQ is a safe and effective option for the treatment of female MUI. Furthermore, MPQ significantly improves the symptoms of OAB and is able to completely cure this condition in a relevant percentage of women with MUI when pharmacological treatment fails.

Determination of Fertility Hormones and Adipokines by LC-MRM/MS Analysis.

Due to the increase in the rate of male and female infertility, assisted fertilization practices are currently adopted as valid support for couples unable to get pregnant. Analytical approaches for fertility hormone dosages are constantly being developed, following the technological progress of fertilization methods that have evolved for more than a century. Indeed, the analysis of fertility hormones in serum samples is a common clinical practice to check the fertility state, but absolute quantification of these hormones is a great challenge due to biological variability and low serum concentrations. Currently, ELISA (enzyme-linked immunosorbent assay) based methods are the most used analytical techniques to quantify hormones in blood in clinical settings. The current Article discusses the development of a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) to monitor multiple fertility hormones of a protein nature in a single chromatographic run, i.e., LH (luteinizing hormone), FSH (follicle-stimulating hormone), TSH (thyroid-stimulating hormone), AMH (anti-Müllerian hormone), adiponectin, ghrelin, leptin, glucagon, and obestatin. Particular attention has been paid to the AMH hormone, whose ELISA-based quantification is known to be controversial due to the poor reproducibility between the various kits used. For AMH, the internal standard method was used for the quantitative determination to compare mass spectrometry data to the ELISA assays performed by an accredited analysis laboratory on a cohort of samples from women aged between 18 and 60 years. The ability to monitor multiple transitions by LC-MRM/MS ensured both high specificity and high selectivity, which is necessary for the quantification of protein and steroid hormones, besides improvements in data reproducibility and reduced analysis times and costs.

Pregnancy Recommendations Solely Based on Preclinical Evidence Should Be Integrated with Real-World Evidence: A Disproportionality Analysis of Certolizumab and Other TNF-Alpha Inhibitors Used in Pregnant Patients with Psoriasis.

Treatment for pregnant women with psoriasis is limited by the lack of information typically related to clinical trials. While anti-tumor necrosis factor (TNF) drugs offer therapeutic benefits, their safety during pregnancy is a concern. Notably, certolizumab is comparatively safer than adalimumab, etanercept, infliximab, and golimumab according to the current recommendations. Thus, this study aimed to conduct a pharmacovigilance comparative analysis of maternal and neonatal outcomes associated with certolizumab versus other anti-TNF drugs by using data from EudraVigilance. A descriptive analysis was performed of Individual Case Safety Reports (ICSRs) associated with an anti-TNF drug and related to the pregnant patients with psoriasis from 2009 and 2023, focusing our analysis on the specific pregnancy outcomes and fetal/neonatal disorders. The most common pregnancy-related adverse event was spontaneous abortion, predominantly related to adalimumab and certolizumab. Certolizumab was also reported in cases of caesarean section, gestational diabetes, abortion, fetal death, fetal distress syndrome, pre-eclampsia, and premature separation of placenta. Generally, the findings from our study depicted a safety profile that overlapped for each anti-TNF drug, both in maternal/neonatal outcomes and other adverse events, suggesting no substantial differences between treatments. We advocate for further investigations before making concrete recommendations.

Macroplastique Is a Safe and Effective Long-term Surgical Treatment for Stress Urinary Incontinence: Prospective Study with 10-Year Follow-up.

BACKGROUND AND OBJECTIVE: Until a few years ago, a midurethral sling was considered the gold standard for the treatment of female stress urinary incontinence (SUI) after failure of conservative therapies. However, criticisms regarding the rate of mesh exposure and lack of long-term efficacy have led to reconsideration of other surgical procedures. Our aim was to investigate long-term subjective and objective outcomes after injection of Macroplastique, a urethral bulking agent. METHODS: We prospectively enrolled all consecutive women complaining of pure SUI symptoms with urodynamically proven SUI who received a Macroplastique injection. We investigated patient-reported subjective outcomes using International Consultation on Incontinence Questionnaire-Short Form, Urogenital Distress Inventory, Patient Global Impression of Improvement, and Visual Analog Scale (VAS) questionnaires, and the cough stress test to assess objective outcomes. Adverse events were recorded during follow-up. KEY FINDINGS AND LIMITATIONS: At 10 yr after Macroplastique injection, the objective cure rate was 56% and 71% of patients reported that they were satisfied. Long-term data revealed no significant decline in subjective or objective cure rates. No serious complications were reported. Study limitations include the small sample size and the lack of pad tests and bladder diaries for postoperative evaluations. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study shows that Macroplastique injection can be an effective and safe option for the treatment of female SUI in the long term, even when used in the first-line setting. PATIENT SUMMARY: We evaluated outcomes for women with stress urinary incontinence (SUI) who were treated with an injection of Macroplastique gel into the wall of the urethra to prevent leakage of urine. We found that this is a safe option for treatment of female SUI that is effective in the long term.

Racial and ethnic disparities in non-invasive prenatal testing adherence: a retrospective cohort study.

BACKGROUND: Fetal aneuploidies, including trisomies 21, 13, and 18, represent a significant issue in prenatal care. The advent of non-invasive prenatal testing (NIPT) through the detection of cell-free DNA (cf-DNA) in maternal blood has modified screening for chromosomal abnormalities. This study evaluates NIPT adherence among pregnant of different ethnicities, addressing potential disparities in prenatal care. METHODS: This was a retrospective, single-center study conducted at a tertiary care university hospital in Italy between March 31, 2021, and September 30, 2022. Participants were categorized by ethnicity (Asian/Pacific islander, Black, Latina, White, Middle Eastern). Maternal demographic characteristics and prenatal test data were recorded. Comparative analyses were executed utilizing a One-Way Analysis of Variance (ANOVA) Test, augmented by Tukey's honestly significant difference test for post-hoc evaluation. Statistical significance was denoted by a P value (P)<0.05. A multivariate analysis through a multinomial regression model was conducted for the results to detect potential bias. RESULTS: Six hundred seventeen pregnancies were included: 418 White, 105 Asian/Pacific islander, 46 Black, 40 Latina, and 8 Middle Eastern. Maternal age showed no significant variation. Black ethnicity had higher prepregnancy Body Mass Index (BMI; mean: 27.5 kg/m2±SD: 5.92, P=0.02), while Asian and White pregnancies had higher nulliparity rates (63.8% and 70.8%). Black ethnicity had no NIPT uptake (0.00%). Asian/Pacific islander and Latina pregnant had lower NIPT utilization (9.5% and 7.5%, P<0.001). White ethnicity had a higher NIPT rate (27.5%). In the NIPT group, 8.9% of White and 12.5% of Middle Eastern pregnancies chose cf-DNA without a prior first-trimester ultrasound test. Considering the first-trimester screening, 30.4% of Black pregnancies had nuchal translucency, while 17.4% combined it with beta-human chorionic gonadotrophin (ß-hCG) and associated plasma protein-A (PAPP-A; P<0.001). White pregnancies had high adherence: 74.6% had nuchal translucency and 53.8% had a first-trimester combined test. Overall, 69.6% of Black pregnancies skipped both tests versus 16.5% in the White group (P<0.001). CONCLUSIONS: Significant disparities in prenatal care and NIPT adherence were observed among pregnant women of diverse ethnic backgrounds. Lower cf-DNA adhesion and limited adherence to first-trimester screening were observed among any ethnicities. These findings highlight the critical need for targeted interventions and policies to reduce barriers and facilitate access to prenatal care for all women.

Real-World Safety Data of the Orphan Drug Onasemnogene Abeparvovec (Zolgensma®) for the SMA Rare Disease: A Pharmacovigilance Study Based on the EMA Adverse Event Reporting System.

The recent introduction of the innovative therapy, onasemnogene abeparvovec (Zolgensma®), has revolutionized the spinal muscular atrophy (SMA) therapeutic landscape. Although Zolgensma® therapy has proven to lead to functional improvements in SMA children, some gaps in its safety profile still need to be investigated. To better characterize the Zolgensma® safety profile, we conducted a retrospective observational study, analyzing all the Individual Case Safety Reports (ICSRs) referred to it and collected in the European pharmacovigilance database between 1 January 2019 and 22 September 2023. We found 661 ICSRs related to Zolgensma®, with a growing trend in the annual reporting. The majority of the reports were sent by healthcare professionals and referred to infant females. In more than 90% of the cases, Zolgensma® was the only reported suspected drug. Out of a total of 2744 reported ADRs, increased hepatic enzymes, pyrexia, vomiting, and thrombocytopenia were the most commonly reported adverse reactions. Of these adverse reactions (ADRs), 56.9% were serious, causing or prolonging the patient's hospitalization. A total of 39 ICSRs related to cases with a fatal outcome. Alterations in the heart rhythm, acute hepatic failure, and hepatic cytolysis emerged among the cardiac and hepatic disorders, respectively.

Therapeutic management in women with a diminished ovarian reserve: a systematic review and meta-analysis of randomized controlled trials.

IMPORTANCE: The clinical management of women with diminished ovarian reserve (DOR) is a challenge in the field of medically assisted reproduction. Several therapeutic strategies have been proposed, but with mixed results, mainly because the definition of DOR used was inconsistent among trials. OBJECTIVE: To investigate adjuvant treatments and protocols involving only women with DOR according to POSEIDON criteria. DATA SOURCES: We conducted a systematic search using the MEDLINE (PubMed), EMBASE, and ISI Web of Knowledge databases to identify relevant studies published up to June 2024. The review protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42022346117). STUDY SELECTION AND SYNTHESIS: After duplication removal, the titles and abstracts of 4,806 articles were scrutinized, and 124 full-text articles were assessed for eligibility. In total, 38 randomized controlled trials were included in the qualitative/quantitative analysis. The following interventions were evaluated: dehydroepiandrosterone (n = 1,336), testosterone (n = 418), high- versus low-dose gonadotropin (n = 957), delayed-start protocol with GnRH antagonist (n = 398), letrozole (n = 612), clomiphene citrate (1,113), growth hormone (311), luteal phase stimulation (n = 57), dual triggering (n = 139), dual stimulation (168), luteinizing hormone (979), oestradiol pre-treatment (n = 552), and corifollitropin alfa (n = 561). RESULTS: Testosterone supplementation is associated with higher live birth rates compared with non-supplemented women among all interventions evaluated (OR 2.19, 95% CI 1.11-4.32, 4 studies, 368 patients; p = 0.02). Testosterone (WMD 0.88, 95% CI 0.03-1.72; 4 studies, n = 368 patients; p = 0.04), DHEA (WMD 0.60, 95% CI 0.07-1.13; 4 studies, n = 418 patients; p = 0.03), high-dose gonadotropin regimen (WMD -1.57, 95% CI -2.12 to -1.17; 2 studies, n = 905 patients; p < 0.0001) and delayed started protocol (WMD 1.32, 95% CI 0.74 to 1.89; 3 studies, n = 398 patients; p < 0.00001) significantly improved the total number of eggs collected. The other interventions did not produce significant improvements. CONCLUSION AND RELEVANCE: Specific interventions such as testosterone seem to correlate with a better live birth rate in women with diminished ovarian reserve; these findings should be further explored in randomized trials.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and the reporting of falls and fractures: an european pharmacovigilance analysis.

Background: The risk of falls and bone fractures with sodium-glucose co-transporter-2 (SGLT2) inhibitors has been characterized by conflicting evidence. Therefore, we decided to investigate the reporting probability of falls and fractures by comparing SGLT2 inhibitors with DPP4 inhibitors. Methods A retrospective, pharmacovigilance study of the European database of Individual Case Safety Reports (ICSRs) was conducted. Disproportionality analyses (Reporting Odds Ratio, ROR) were conducted to compare the reporting probability of falls or fracture between treatments. Results A total of 507 ICSRs reporting at least one fall or fracture with SGLT2 inhibitors were identified. The most reported SGLT2 inhibitor was canagliflozin (N = 188; 36.9%), followed by empagliflozin (N = 176; 34.5%), and dapagliflozin (N = 143; 28.0%). A total of 653 events related to fall or bone fracture were reported. Fall was the most reported event (N = 333; 51.0%). Among fractures (N = 320; 49.0%), the most reported were foot fractures (N = 40; 6.1%) and hip fractures (N = 32; 4.9%). SGLT2 inhibitors were associated with a lower reporting probability of fall than DPP4 inhibitors (ROR, 0.66; 95%CI, 0.57-0.78). The lower reporting probability of fall was also observed when the single SGLT2 inhibitor was compared to DPP4 inhibitors: dapagliflozin (ROR, 0.67; 95%CI, 0.53-0.83), canagliflozin (ROR, 0.56; 95%CI, 0.45-0.70), and empagliflozin (ROR, 0.77; 95%CI, 0.63-0.94). For fractures, canagliflozin showed a slightly significant increased reporting when compared with DPP4 inhibitors (not confirmed in the sensitivity analysis), whereas all other comparison showed no statistically significant difference. Conclusion SGLT2 inhibitors were associated with a lower reporting probability of fall than DPP4 inhibitors, in accordance with the reassuring evidence about the safety profile of these drugs. Future researches will help to confirm their long-term safety profile.

The impact of epigenetic landscape on ovarian cells in infertile older women undergoing IVF procedures.

The constant decline in fertility and older reproductive age is the major cause of low clinical pregnancy rates in industrialised countries. Epigenetic mechanisms impact on proper embryonic development in women undergoing in vitro fertilisation (IVF) protocols. Here, we describe the main epigenetic modifications that may influence female reproduction and could affect IVF success.

Skin Toxicities Associated with Botulin Toxin Injection for Aesthetic Procedures: Data from the European Spontaneous Reporting System.

Botulinum toxin is a protein deriving from the bacteria Clostridium botulinum and it is widely used for the treatment of a variety of muscle hyperactivity syndromes and for cosmetic indications. Having a long-lasting effect, Botulinum toxin type A (BTA) is one of the most botulin toxin products used. Even if BTA has shown benefits in reducing the vertical lines between the eyebrows, Adverse Drug Reactions (ADRs) have been experienced as well, of which the most common ones are headache and drooping eyelids. In addition, since other local and systemic risks have been identified, a non-interventional post-authorization safety study (PASS) has been started. The aim of the present study was to report cases of skin toxicity associated with this drug, considering Individual Case Safety Reports (ICSRs) existing on the Eudravigilance website. Among 1464 ICSRs sent to the EV database, 718 ICSRs, including 5154 PTs, reported BTA as a suspected drug associated with cutaneous toxicity. The majority of patients experiencing BTA-induced skin toxicity were female (92.1%) belonging mostly to the age group of 18-64 years. The most serious criteria, when reported, were "Other Medically Important Condition" and "Caused/prolonged hospitalization", although the outcome was mainly reported as "Unknown". The most reported PTs, related to skin disorders, were: "Erythema", "Rash", "Pruritus", "Urticaria", "Swelling face", "Brow ptosis", "Eyelid ptosis", "Injection site pain", and "Angioedema". Considering that in most ICSRs, ADRs related to skin disorders were symptoms of hypersensitivity reactions which in some conditions could be life-threatening, further studies are required to better define the safety profile of BTA used for aesthetic procedures.

Genetic Variants of Gonadotropins and Their Receptors Could Influence Controlled Ovarian Stimulation: IVF Data from a Prospective Multicenter Study.

BACKGROUND: Specific polymorphisms might influence controlled ovarian stimulation in women undergoing assisted reproductive technologies (ARTs). Data regarding possible interactions of these polymorphisms are still scanty. The aim of this analysis was to evaluate the effect of polymorphisms of gonadotropins and their receptors in women undergoing ART. METHODS: A total of 94 normogonadotropic patients from three public ART units were enrolled. Patients underwent a gonadotropin releasing hormone (GnRH) long down-regulation protocol with a starting dose of 150 IU of recombinant follicular stimulating hormone (FSH) daily. Eight polymorphisms were genotyped. RESULTS: A total of 94 women (mean age 30.71 ± 2.61) were recruited. Fewer fertilized and mature oocytes were retrieved in homozygous carriers of luteinizing hormone/choriogonadotropin receptor (LHCGR) 291 (T/T) than in heterozygous C/T carriers (p = 0.035 and p = 0.05, respectively). In FSH receptor (FSHR) rs6165 and FSHR rs6166 carriers, the ratio between total gonadotropin consumption and number of oocytes retrieved differed significantly among three genotypes (p = 0.050), and the ratio was lower in homozygous A/A carriers than in homozygous G/G and heterozygous carriers. Women who co-expressed allele G in FSHR-29 rs1394205 and FSHR rs6166 and allele C LHCGR 291 rs12470652 are characterized by an increased ratio between total FSH dosage and number of oocytes collected after ovarian stimulation (risk ratio: 5.44, CI 95%: 3.18-7.71, p < 0.001). CONCLUSIONS: Our study demonstrated that specific polymorphisms affect the response to ovarian stimulation. Despite this finding, more robust studies are required to establish the clinical utility of genotype analysis before ovarian stimulation.

Expression of melatonin (MT1, MT2) and melatonin-related receptors in the adult rat testes and during development.

It is well known that melatonin provokes reproductive alterations in response to changes in hours of daylight in seasonally breeding mammals, exerting a regulatory role at different levels of the hypothalamic-pituitary-gonadal axis. Although it has also been demonstrated that melatonin may affect testicular activity in vertebrates, until now, very few data support the hypothesis of a local action of melatonin in the male gonads. The aim of this study was to investigate whether MT1, MT2 melatonin receptors and the H9 melatonin-related receptor, are expressed in the adult rat testes and during development. A semi-quantitative RT-PCR method was used to analyse the expression of MT1, MT2 and H9 receptors mRNAs in several rat tissues, mainly focusing on testes during development and adult life. Our results provide molecular evidences of the presence of both MT1 and, for the first time, MT2 melatonin receptors as well as of the H9 melatonin-related receptor in the examined tissues, including adult testes. During development MT1 and MT2 transcripts are expressed at lower levels in testes of rats from 1 day to 1 week of age, lightly increased at 2 weeks of age and remained permanently expressed throughout development until 6 months. These data strongly support the hypothesis that melatonin acts directly in male vertebrate gonads suggesting that rat testes may be a suitable model to verify the role of indolamine in vertebrate testicular activity.

Myo-inositol therapy for poor-responders during IVF: a prospective controlled observational trial.

BACKGROUND: The overall incidence of poor ovarian response in IVF cycles has been reported to be between 9 and 24%. The management of these patients remains a significant challenge in assisted reproduction. The aim of the present study was to evaluate the effect of myo-inositol (MI) on ovarian function in poor responders undergoing ICSI. METHODS: The study is a prospective controlled observational trial, that involved 72 poor responders included in an ICSI program and divided into two groups; group A: 38 patients who have been assuming MI (4 g) + folic acid (FA) (400 µg) for the previous 3 months before the enrollment day; group B: 38 patients assuming FA (400 µg) alone for the same period. COH was carried out in the same manner in the two groups. The main goal was the assessment of oocytes retrieved number and quality; secondary endpoints were the Ovarian Sensitivity Index (OSI: n° oocytes retrieved/total Gonadotropins units × 1000), oestradiol levels on the day of hGC, fertilization rate, implantation rate, ongoing pregnancy rate. RESULTS: There was no significant difference between the two groups regarding oestradiol level, but total rec-FSH units were significantly lower (p = 0.004) and M2 oocytes rate significantly higer (p = 0.01) in group A. The ovarian sensitivity index was higher, reaching a statistical significance (p < 0.05), in the group of patients pre-treated with MI, showing an improvement in ovarian sensibility to gonadotropin. CONCLUSIONS: Our results suggest that MI therapy in poor responders results in an increased of the number of oocytes recovered in MII and of the gonadotropin Ovarian Sensitivity Index (OSI), suggesting a MI role in improving ovarian response to gonadotropins. Therefore MI seems to be helpful in "poor responders" undergoing IVF cycles.