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Background: Intrahepatic cholestasis of pregnancy (ICP) in the first trimester occurring after ovarian hyperstimulation syndrome (OHSS) is a rare condition and few cases are reported in the literature. Hyperestrogenism may explain this problem in genetically predisposed women. The objective of this article is to report one of these rare cases and offer an overview of the other published cases., Case Presentation: We report a case of severe OHSS followed by ICP in the first trimester. The patient was admitted to the intensive care unit and was treated according to the guidelines for the management of OHSS. Moreover, the patient also received ursodeoxycholic acid for ICP, which brought to an improvement of her clinical conditions. The pregnancy continued without other complications until the 36 th week of gestation, when the patient developed ICP in the third trimester and underwent cesarean section for increased bile acid levels and cardiotocographic (CTG) pathologic alterations. The newborn was a healthy baby weighing 2500 gr. We also reviewed other case reports published by other authors about this clinical condition. We present what is, to our knowledge, the first case of ICP developed in the first trimester of pregnancy after OHSS in which genetic polymorphisms of ABCB4 (MDR3) have been investigated., Conclusions: ICP in the first trimester might be induced by elevated serum estrogen levels after OHSS in genetically predisposed women. In these women, it might be useful to check for genetic polymorphisms to know if they have a predisposition for ICP recurrence in the third trimester of pregnancy., (© 2023. The Author(s).)

Background: Restrictive measures imposed to prevent COVID-19 contagion have caused an increase in waiting times for other health procedures. During the pandemic, utilization of telemedicine has increased to ensure patient care safely. The aim of this study was to evaluate the perspective of infertile patients who underwent virtual consultations for infertility. Materials and Methods: This was an observational study. A survey was submitted to patients who attended a virtual consultation at a single in vitro fertilization (IVF) unit between March 2020 and July 2021. The survey concerned their experience with telemedicine assessing the experience of video consulting and the software characteristics. Results: The survey response rate was 50.3% ( n  = 159). In total, 98.8% of patients positively rated the experience of telemedicine. Regarding the software itself, it was defined as intuitive and easy to use by 87.4% of patients. A majority (92.5%) of interviewed patients reported that they were able to receive the information and clear any doubts they had and 85.5% of interviewed patients would repeat the experience of video consultation. Conclusions: The acceptance of telemedicine was very high among infertile patients. However, IVF treatments have a strong emotional component and face-to-face consultation with medical staff might help to create the right climate of trust, and the empathy that can be demonstrated during a vis-à-vis meeting cannot be achieved through a screen. The use of telemedicine should be considered in those situations where it is not possible to attend an in-person consultation or when couples prefer it.

Objective: Hyperandrogenic skin disorders, such as hirsutism, acne and alopecia, affect approximately 10-20% of women of reproductive age, reducing quality of life and causing psychological impairment. Spironolactone is a commonly used antiandrogen, especially in women who are not sexually active or have contraindications to hormonal contraceptives. The aim of this study was to evaluate the effects of spironolactone, especially after its withdrawal, in patients with hyperandrogenic skin disorders., Methods: Retrospective analysis of 63 women with hyperandrogenic skin symptoms due to polycystic ovary syndrome (PCOS), treated with spironolactone for at least 6 months as first-line treatment., Results: After a mean time of treatment of 25.7 months, all patients reported a significant improvement in hyperandrogenic skin disorders; only 5 patients were dissatisfied and required the addition of an oral contraceptive. The therapy was well tolerated and the most frequent side-effect was intermestrual bleeding in 68.2% of cases, affecting mainly classic PCOS phenotype. Thirthyeight patients showed prolonged effects 33.7 months after spironolactone withdrawal, whereas 20 relapsed 17.5 months after discontinuation. No significant difference in clinical and biochemical parameters was observed between these two groups both at baseline and after spironolactone treatment. Ovulatory PCOS patients were treated for a shorter time and reported earlier relapse than classic PCOS patients., Conclusion: Spironolactone is an effective and safe treatment for hyperandrogenic skin disorders, showing long-lasting effects even several months after its discontinuation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Endometriosis is a chronic inflammatory disease associated with pelvic pain, infertility, and increased cardiovascular risk. Recent studies suggest a possible role of aldosterone as a pro-inflammatory hormone in the pathogenesis of the disease. Cortisol is also an important mediator of stress reaction, but its role is controversial in endometriosis. The aim of this study was to evaluate aldosterone and cortisol levels and blood pressure values in women with endometriosis. We measured blood pressure, plasma aldosterone, renin, cortisol, and dehydroepiandrosterone sulfate (DHEAS) in 20 women with untreated minimal or mild pelvic endometriosis compared with 20 healthy controls matched for age and body mass index. Aldosterone values were similar in the two groups, while renin was significantly lower and the aldosterone to renin ratio was significantly higher in patients with endometriosis than in controls. Systolic blood pressure was in the normal range, but significantly higher in patients with endometriosis. Morning plasma cortisol was normal, but significantly lower in patients with endometriosis compared with controls, while DHEAS to cortisol ratio was similar in the two groups. These preliminary results are evidence of increased biological aldosterone activity and dysregulation of the hypothalamic-pituitary-adrenal axis in early stages of endometriosis. These alterations could play a role in disease development, suggesting new therapeutic targets for aldosterone receptor blockers.

Objective: we performed a systematic review/meta-analysis to evaluate the impact of septate uterus and hysteroscopic metroplasty on pregnancy rate-(PR), live birth rate-(LBR), spontaneous abortion-(SA) and preterm labor (PL) in infertile/recurrent miscarriage-(RM) patients. Data sources: a literature search of relevant papers was conducted using electronic bibliographic databases (Medline, Scopus, Embase, Science direct). Study eligibility criteria: we included in this meta-analysis all types of observational studies that evaluated the clinical impact of the uterine septum and its resection (hysteroscopic metroplasty) on reproductive and obstetrics outcomes. The population included were patients with a diagnosis of infertility or recurrent pregnancy loss. Study appraisal and synthesis methods: outcomes were evaluated according to three subgroups: (i) Women with untreated uterine septum versus women without septum (controls); (ii) Women with treated uterine septum versus women with untreated septum (controls); (iii) Women before and after septum removal. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for the outcome measures. A p-value < 0.05 was considered statistically significant. Subgroup analysis was performed according to the depth of the septum. Sources of heterogeneity were explored by meta-regression analysis according to specific features: assisted reproductive technology/spontaneous conception, study design and quality of papers included Results: data from 38 studies were extracted. (i) septum versus no septum: a lower PR and LBR were associated with septate uterus vs. controls (OR 0.45, 95% CI 0.27−0.76; p < 0.0001; and OR 0.21, 95% CI 0.12−0.39; p < 0.0001); a higher proportion of SA and PL was associated with septate uterus vs. controls (OR 4.29, 95% CI 2.90−6.36; p < 0.0001; OR 2.56, 95% CI 1.52−4.31; p = 0.0004). (ii) treated versus untreated septum: PR and PL were not different in removed vs. unremoved septum(OR 1.10, 95% CI 0.49−2.49; p = 0.82 and OR 0.81, 95% CI 0.35−1.86; p = 0.62); a lower proportion of SA was associated with removed vs. unremoved septum (OR 0.47, 95% CI 0.21−1.04; p = 0.001); (iii) before-after septum removal: the proportion of LBR was higher after the removal of septum (OR 49.58, 95% CI 29.93−82.13; p < 0.0001) and the proportion of SA and PL was lower after the removal of the septum (OR 0.02, 95% CI 0.02−0.04; p < 0.000 and OR 0.05, 95% CI 0.03−0.08; p < 0.0001) Conclusions: the results show the detrimental effect of the uterine septum on PR, LBR, SA and PL. Its treatment reduces the rate of SA.

GnRH agonists (GnRHa) are a useful tool for pretreatment before artificial endometrial preparation for frozen-thawed embryo-transfer (FET). Their prolonged administration has been associated with thyroid dysfunction, both hyper and hypothyroidism. The aim of this study is to investigate the impact of GnRHa administration on thyroid function in women undergoing artificial endometrial preparation. Seventy-eight euthyroid women undergoing endometrial preparation with hormone replacement for FET were retrospectively reviewed. They were divided into two groups according to pretreatment with GnRHa (group A, 42 women) or with an oral contraceptive (group B, 36 women). Group A was subsequently divided into two subgroups according to thyroid autoimmunity presence. Thyroid function has been evaluated and compared among groups and subgroups. Our results did not show any statistically significant differences in age, body mass index, and basal thyroid stimulating hormone (TSH). Total estradiol dosage, duration of treatment, and endometrial thickness were comparable among groups. When TSH was measured 14 days after embryo transfer, no significant differences between the two groups were reported. Among women of group A, TSH was significantly higher only in women with thyroid autoimmunity. GnRHa seems to be associated with thyroid dysfunction in women with thyroid autoimmunity undergoing hormone replacement therapy for FET., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Loris Marin et al.)

Epigenetics is the branch of genetics that studies the different mechanisms that influence gene expression without direct modification of the DNA sequence. An ever-increasing amount of evidence suggests that such regulatory processes may play a pivotal role both in the initiation of pregnancy and in the later processes of embryonic and fetal development, thus determining long-term effects even in adult life. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of epigenetic regulation, such as the role of ncRNAs and the effects of the gestational environment on fetal brain development. Epigenetic mechanisms in pregnancy are a dynamic phenomenon that responds both to maternal-fetal and environmental factors, which can influence and modify the embryo-fetal development during the various gestational phases. Therefore, we also recapitulate the effects of the most notable environmental factors that can affect pregnancy and prenatal development, such as maternal nutrition, stress hormones, microbiome, and teratogens, focusing on their ability to cause epigenetic modifications in the gestational environment and ultimately in the fetus. Despite the promising advancements in the knowledge of epigenetics in pregnancy, more experience and data on this topic are still needed. A better understanding of epigenetic regulation in pregnancy could in fact prove valuable towards a better management of both physiological pregnancies and assisted reproduction treatments, other than allowing to better comprehend the origin of multifactorial pathological conditions such as neurodevelopmental disorders., (© 2022. The Author(s).)

Purpose: The current gold standard for chronic endometritis (CE) diagnosis is immunohistochemistry (IHC) for CD-138. However, IHC for CD-138 is not exempt from diagnostic limitations. The aim of our study was to evaluate the reliability and accuracy of MUM-1 IHC, as compared with CD-138., Methods: This is a multi-centre, retrospective, observational study, which included three tertiary hysteroscopic centres in university teaching hospitals. One hundred ninety-three consecutive women of reproductive age were referred to our hysteroscopy services due to infertility, recurrent miscarriage, abnormal uterine bleeding, endometrial polyps or myomas. All women underwent hysteroscopy plus endometrial biopsy. Endometrial samples were analysed through histology, CD138 and MUM-1 IHC. The primary outcome was to evaluate the diagnostic accuracy of MUM-1 IHC for CE, as compared with CD-138 IHC., Results: Sensitivity and specificity of CD-138 and MUM-1 IHC were respectively 89.13%, 79.59% versus 93.48% and 85.03%. The overall diagnostic accuracy of MUM-1 and CD-138 IHC were similar (AUC = 0.893 vs AUC = 0.844). The intercorrelation coefficient for single measurements was high between the two techniques (ICC = 0.831, 0.761-0.881 95%CI). However, among CE positive women, MUM-1 allowed the identification of higher number of plasma cells/hpf than CD-138 (6.50 [SD 4.80] vs 5.05 [SD 3.37]; p = 0.017). Additionally, MUM-1 showed a higher inter-observer agreement as compared to CD-138., Conclusion: IHC for MUM-1 and CD-138 showed a similar accuracy for detecting endometrial stromal plasma cells. Notably, MUM-1 showed higher reliability in the paired comparison of the individual samples than CD-138. Thus, MUM-1 may represent a novel, promising add-on technique for the diagnosis of CE., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This meta-analysis aimed to assess the reproductive competence of blastocysts developed on day 7 compared with blastocysts developed on day 5/6. A systematic search was carried out to select relevant studies published before January 2020. Ten retrospective observational cohort studies were included. The primary outcome was the clinical pregnancy rate (CPR). Secondary outcomes were live birth rate (LBR), euploid rate, and survival rates after thawing. Frozen-thawed day 7 blastocyst transfer was associated with a significant reduction in CPR compared to day 5/6 (OR 0.36 95% CI 0.21 to 0.62, p = 0.0002, I 2  = 71% and OR 0.43, 95% CI 0.32 to 0.58, p < 0.0001, I 2  = 17% respectively). A significantly lower proportion of LBR was found comparing blastocysts transfers in day 7 to those in day 5/6 (OR 0.21, 95% CI 0.16-0.27, p < 0.0001, I 2  = 0% and OR 0.34, 95% CI 0.26-0.45, p < 0.0001, I 2  = 0% respectively). These findings were confirmed in a subgroup of Preimplantation Genetic Testing for Aneuploidies (PGT-A)-screened blastocysts. Blastocysts biopsied in day 7 was associated with a significant decrease of euploid rate compared with day 5/6 (OR 0.47, 95% CI 0.39-0.57, p < 0.0001, I 2  = 69% and OR 0.68, 95% CI 0.61-0.75, p < 0.0001, I 2  = 19% respectively). The survival rate after thawing was not statistically different. Sensitivity analyses were also performed. This study shows an association between delayed blastulation and a poorer prognosis in terms of euploid rate and pregnancy outcomes following frozen-thawed transfers. On the other hand, the results do not support the discharge of slow-blastulation embryos., (© 2021. Society for Reproductive Investigation.)

The aim of this systematic review and meta-analysis is to summarize data on the effectiveness of Sildenafil supplementation for women undergoing assisted reproduction techniques. This meta-analysis of randomized controlled trials (RCTs) evaluates the effects of Sildenafil administration during infertility treatments compared with a control group in infertile women. Outcomes evaluated were endometrial thickness (ETh) and the clinical pregnancy rate (CPR). The chemical pregnancy rate (ChPR) was also evaluated. Pooled results were expressed as the risk ratio (RR) or mean differences (MD) with a 95% confidence interval (95% CI). Women undergoing ovulation induction who received Sildenafil showed higher ETh and a higher CPR in comparison to controls. In this group, both the ETh and ChPR resulted in significantly higher values only with delayed start administration. Women undergoing fresh or frozen embryo transfer who received Sildenafil showed no significant advantages regarding ETh and CPR in comparison to controls. In this group, we found a significantly higher ChPR in women receiving Sildenafil. A subgroup analysis revealed significant advantages regarding ETh with oral administration for women undergoing fresh or frozen embryo transfer. Sildenafil therapy appears to improve endometrial thickness and pregnancy rate in women undergoing timed intercourses but it resulted not effective in IUI and IVF treatments. Further RCTs with rigorous methodology are still mandatory.

Endometriosis, an estrogen-dependent chronic gynecological disease, is characterized by a systemic inflammation that affects circulating red blood cells (RBC), by reducing anti-oxidant defenses. The aim of this study was to investigate the potential beneficial effects of licorice intake to protect RBCs from dapsone hydroxylamine (DDS-NHOH), a harmful metabolite of dapsone, commonly used in the treatment of many diseases. A control group (CG, n = 12) and a patient group (PG, n = 18) were treated with licorice extract (25 mg/day), for a week. Blood samples before (T 0 ) and after (T 1 ) treatment were analyzed for: i) band 3 tyrosine phosphorylation and high molecular weight aggregates; and ii) glutathionylation and carbonic anhydrase activity, in the presence or absence of adjunctive oxidative stress induced by DDS-NHOH. Results were correlated with plasma glycyrrhetinic acid (GA) concentrations, measured by HPLC-MS. Results showed that licorice intake decreased the level of DDS-NHOH-related oxidative alterations in RBCs, and the reduction was directly correlated with plasma GA concentration. In conclusion, in PG, the inability to counteract oxidative stress is a serious concern in the evaluation of therapeutic approaches. GA, by protecting RBC from oxidative assault, as in dapsone therapy, might be considered as a new potential tool for preventing further switching into severe endometriosis.

Introduction : To study the impact of biosimilars in assisted reproductive treatments, we performed a review of the literature. Biosimilars are a bioequivalent chemical drug referred to the original. Their production is strongly requested in order to reduce drug cost and reduce health economic impact on national health system. In assisted reproductive treatments different gonadotropin biosimilars are being produced. Areas covered : For this reason, we performed a review of the literature on follitropin alfa Gonal-F biosimilar, Ovaleap and Bemfola, to assess their cost efficacy in national health system. Cost effective (CE) analysis and incremental cost-effectiveness ratio (ICER) were used as parameters for biosimilar impact evaluation in the national health system economy. In particular, they had only slight impact on cost reduction of recombinant follitropin alfa products in Europe. Expert opinion : considering cost-effective analysis, Gonal-F remains the first choice for national health systems. However, well-designed powered methods are strongly needed to assess biosimilars cost-effectiveness.

Purpose: Chronic endometritis (CE) is a frequent hysteroscopic and histological finding which affects embryo transfer implantation during IVF-ICSI cycles. In particular, CE impairs proper decidualization and, subsequently, implantation. Although this correlation has been clearly clarified, a pathophysiological explanation assembling all the studies performed has not been elucidated yet. For this reason, we have structured a systematic review considering all the original articles that evaluated a pathological element involved in CE and implantation impairment., Methods: The authors searched electronic databases and, after screening, collected 15 original articles. These were fully scanned and used to create a summary pathway., Results: CE is primarily caused by infections, which lead to a specific cytokine and leukocyte pattern in order to prepare the uterus to fight the noxa. In particular, the immunosuppression requested for a proper semi-allogenic embryo transfer implantation is converted into an immunoreaction, which hampers correct embryo implantation. Moreover, endometrial vascularization is affected and both irregular vessel density and luminal thickening and thrombosis reduce what we have first identified as endometrial flow reserve. Finally, incorrect uterine wave propagation could affect embryo contact with decidua., Conclusion: This is the first summary of evidence on CE pathophysiology and its relationship with infertility. Understanding the CE pathophysiology could improve our knowledge in embryo transfer success.

Importance: To date, a comprehensive review on the safety and effectiveness of hysteroscopic metroplasty for T-shaped uterus is still missing., Objective: To provide a robust synthesis of the available studies investigating reproductive outcomes after hysteroscopic metroplasty for T-shaped uterus., Evidence Acquisition: We performed a systematic review and meta-analysis (CRD42019143291), using the proportion method with 95% confidence interval (CI). Statistical heterogeneity was assessed by Higgins test ( I 2 )., Results: We included 11 cohort studies embedding 937 women who underwent hysteroscopic metroplasty. After surgery, the pooled percentage of live birth was 44.54% (95% CI, 36.12%-53.12%; I 2 = 46.22%) and 56.88% (95% CI, 46.48%-66.98%; I 2 = 36.38%) in women with primary infertility and recurrent miscarriage, respectively. In women with recurrent miscarriage, the pooled proportion of miscarriage was 21.46% (95% CI, 15.09%-28.61%; I 2 = 30.18%). The pooled clinical pregnancy proportion in women with primary infertility was 57.19% (95% CI, 43.83%-70.03%; I 2 = 77.81%). The pooled rate of surgical complications was 0.65% (95% CI, 0.20%-1.33%; I 2 = 11.44%)., Conclusions: The hysteroscopic correction of T-shaped uteri was associated with high live birth rate and low miscarriage rate, both in case of primary infertility and recurrent miscarriage., Relevance: Hysteroscopic metroplasty can be considered a safe and effective strategy to improve reproductive outcomes in case of T-shaped uterus.

Bicarbonate uptake is one of the early steps of capacitation, but the identification of proteins regulating anion fluxes remains elusive. The aim of this study is to investigate the role of sperm solute carrier 4 (SLC4) A1 (spAE1) in the capacitation process. The expression, location, and tyrosine-phosphorylation (Tyr-P) level of spAE1 were assessed. Thereby, it was found that 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), an SLC4 family channel blocker, inhibited capacitation in a dose-dependent manner by decreasing acrosome reaction (ARC% 24.5 ± 3.3 vs 64.9 ± 4.3, p < 0.05) and increasing the percentage of not viable cells (NVC%), comparable to the inhibition by I-172, a cystic fibrosis transmembrane conductance regulator (CFTR) blocker (AR% 30.5 ± 4.4 and NVC% 18.6 ± 2.2). When used in combination, a synergistic inhibitory effect was observed with a remarkable increase of the percentage of NVC (45.3 ± 4.1, p < 0.001). spAE1 was identified in sperm membrane as a substrate for Tyr-protein kinases Lyn and Syk, which were identified as both soluble and membrane-bound pools. spAE1-Tyr-P level increased in the apical region of sperm under capacitating conditions and was negatively affected by I-172 or DIDS, and, to a far greater extent, by a combination of both. In conclusion, we demonstrated that spAE1 is expressed in sperm membranes and it is phosphorylated by Syk, but above all by Lyn on Tyr359, which are involved in sperm viability and capacitation.

Infertility, defined as the absence of spontaneous conception after 12 months of unprotected sexual intercourses, is a major public health issue. It is estimated that up to 15% of couples suffer from infertility and that most of them will refer for counselling to infertility specialists. Concurrently, the demands for assisted reproduction techniques are steadily increasing worldwide. Endometrial scratching is an intentional endometrial injury offered to infertile women with the purpose of enhancing endometrial receptivity before intrauterine insemination or embryo transfer. Endometrial scratching is a simple and low-cost procedure that consists in a voluntary mechanical disruption of endometrial lining, with minor patients' discomfort. Whilst the data about the effectiveness of endometrial scratching in intrauterine insemination is low but coherent, there is a great deal of confusion about the role of endometrial scratching before IVF-embryo transfer cycles. The aim of this commentary is to summarize the current evidence about the effectiveness of endometrial scratching before assisted reproduction techniques and future perspectives about the use of this technique in infertile women., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

To evaluate the effectiveness of delay start protocol in improving the success of in vitro fertilization (IVF) in poor responders according to Bologna's criteria. Only randomized controlled trial (RCT) of infertile women undergoing a single IVF/ICSI cycle with ovarian stimulation protocol based on daily injections with delay start protocol or a conventional antagonist protocol were included in this systematic review and meta-analysis. The review protocol was registered in PROSPERO before starting the data extraction (CRD42019128284). Primary outcome was clinical pregnancy rate. Ongoing pregnancy rate, miscarriage rate, number of oocytes, number of MII oocytes, stimulation length, gonadotropin amount and cancellation rate were considered as secondary outcomes. Four randomized controlled trials were included with a total number of 380 participants. 189 patients were included in the delayed start protocol and 191 were allocated to the comparison group. The results showed a significant higher clinical pregnancy rate (CPR) in patients allocated to the intervention. Data from all studies failed to detect a statistical difference between groups in terms of ongoing pregnancy rate (OPR), miscarriage rate (MR), Total-Oocyte, MII-Oocyte and Total-Embryos. Gonadotropin amount (GA) was significantly lower in the intervention group in comparison to controls, with no difference in stimulation length (SL) and cancelled cycle (CC). Delayed start GnRH-antagonist protocol may reduce GA and improve CPR in poor ovarian responder according to Bologna criteria., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Iodine supplementation during pregnancy in areas with mild-to-moderate iodine deficiency is still debated., Methods: A single-center, randomized, single-blind and placebo-controlled (3:2) trial was conducted. We enrolled 90 women before 12 weeks of gestation. From enrollment up until 8 weeks after delivery, 52 women were given an iodine supplement (225 ug/day, potassium iodide tablets) and 38 were given placebo. At recruitment (T0), in the second (T1) and third trimesters (T2), and 8 weeks after delivery (T3), we measured participants' urinary iodine-to-creatinine ratio (UI/Creat), thyroid function parameters (thyroglobulin (Tg), TSH, FT3, and FT4), and thyroid volume (TV). The newborns' urinary iodine concentrations were evaluated in 16 cases., Results: Median UI/Creat at recruitment was 53.3 ug/g. UI/Creat was significantly higher in supplemented women at T1 and T2. Tg levels were lower at T1 and T2 in women with UI/Creat ≥ 150 ug/g, and in the Iodine group at T2 ( p = 0.02). There was a negative correlation between Tg and UI/Creat throughout the study ( p = 0.03, r = -0.1268). A lower TSH level was found in the Iodine group at T3 ( p = 0.001). TV increased by +Δ7.43% in the Iodine group, and by +Δ11.17% in the Placebo group. No differences were found between the newborns' TSH levels on screening the two groups., Conclusion: Tg proved a good parameter for measuring iodine intake in our placebo-controlled series. Iodine supplementation did not prove harmful to pregnancy in areas of mild-to-moderate iodine deficiency, with no appreciable harmful effect on thyroid function.

Aldosterone is the main mineralocorticoid hormone, responsible of the regulation of fluid and electrolyte balance and blood pressure. It acts also as a pro-inflammatory factor responsible of an increased cardiovascular risk, independent from blood pressure values. After the discovery of mineralocorticoid receptor (MR) in mononuclear leukocytes, further studies supported its role in inflammatory and even autoimmune mechanisms underlying several diseases. In particular, recent studies reported a possible involvement of aldosterone in some gynecological conditions and diseases, characterized by inflammation, hypertension and increased cardio-metabolic risk, such as use of hormonal contraceptives, preeclampsia, polycystic ovary syndrome, uterine fibroids, and endometriosis. The aim of this mini-review is to report the possible involvement of aldosterone in all these gynecological conditions, suggesting different pathogenetic mechanisms and new target treatments of MR blockers for these diseases.

Objective: To investigate endometrial scratch injury (ESI) as an intervention to improve IVF outcome in women undergoing a first ET., Design: Systematic review and meta-analysis., Setting: Not applicable., Patient(s): Infertile women undergoing a first fresh/frozen embryo transfer., Intervention(s): We included published and unpublished data from randomized controlled trials in which the intervention group received ESI and controls received placebo or no intervention. Pooled results were expressed as relative risk (RR) with 95% confidence interval (CI). The review protocol was registered in PROSPERO to start the data extraction (CRD42018087786)., Main Outcome Measure(s): Ongoing pregnancy/live birth rate (OPR/LBR), clinical pregnancy rate (CPR), multiple pregnancy rate (MPR), miscarriage rate (MR), and ectopic pregnancy rate (EPR)., Result(s): Seven studies were included (1,354 participants). We found a nonsignificant difference between groups in terms of OPR/LBR, CPR, MR, MPR, and EPR. Subgroup analysis found that ESI on the day of oocyte retrieval (achieved by a Novak curette) reduced OPR/LBR (RR 0.31, 95% CI 0.14-0.69) and CPR (RR 0.36, 95% CI 0.18-0.71), whereas ESI during the cycle preceding ET (performed through soft devices) had no effect on OPR/LBR and CPR. No difference in the impact of ESI was observed between fresh and frozen embryo transfer., Conclusion(s): Current evidence does not support performing ESI with the purpose of improving the success of a first ET attempt., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of the present systematic review and meta-analysis was to summarize evidence on the effectiveness of testosterone supplementation for poor ovarian responders (POR) on IVF outcomes. The primary outcome was live birth rate (LBR); secondary outcomes were clinical pregnancy rate (CPR), miscarriage rate (MR), total and MII oocytes, and total embryos., Methods: This meta-analysis of randomized controlled trials (RCTs) evaluates the effects of testosterone administration before/during COS compared with a control group in patients defined as POR. The primary outcome was live birth rate (LBR); secondary outcomes were clinical pregnancy rate (CPR), miscarriage rate (MR), total and MII oocytes, and total embryos. Pooled results were expressed as risk ratio (RR) or mean differences (MD) with 95% confidence interval (95% CI). Sources of heterogeneity were investigated through sensitivity and subgroup analysis. All analyses were performed by using the random-effects model., Results: Women receiving testosterone showed higher LBR (RR 2.29, 95% CI 1.31-4.01, p = 0.004), CPR (RR 2.32, 95% CI 1.47-3.64, p = 0.0003), total oocytes (MD = 1.28 [95% CI 0.83, 1.73], p < 0.00001), MII oocytes (MD = 0.96 [95% CI 0.28, 1.65], p = 0.006), and total embryos (MD = 1.17 [95% CI 0.67, 1.67], p < 0.00001) in comparison to controls, with no difference in MR (p = ns). Sensitivity and subgroup analysis did not provide statistical changes to the pooled results., Conclusions: Testosterone therapy seems promising to improve the success at IVF in POR patients. Further RCTs with rigorous methodology and inclusion criteria are still mandatory.

Astaxanthin (Asta), red pigment of the carotenoid family, is known for its anti-oxidant, anti-cancer, anti-diabetic, and anti-inflammatory properties. In this study, we evaluated the effects of Asta on isolated human sperm in the presence of human papillomavirus (HPV) 16 capsid protein, L1. Sperm, purified by gradient separation, were treated with HPV16-L1 in both a dose and time-dependent manner in the absence or presence of 30 min-Asta pre-incubation. Effects of HPV16-L1 alone after Asta pre-incubation were evaluated by rafts (CTB) and Lyn dislocation, Tyr-phosphorylation (Tyr-P) of the head, percentages of acrosome-reacted cells (ARC) and endogenous reactive oxygen species (ROS) generation. Sperm membranes were also analyzed for the HPV16-L1 content. Results show that HPV16-L1 drastically reduced membrane rearrangement with percentage of sperm showing head CTB and Lyn displacement decreasing from 72% to 15.8%, and from 63.1% to 13.9%, respectively. Accordingly, both Tyr-P of the head and ARC decreased from 68.4% to 10.2%, and from 65.7% to 14.6%, respectively. Asta pre-incubation prevented this drop and restored values of the percentage of ARC up to 40.8%. No alteration was found in either the ROS generation curve or sperm motility. In conclusion, Asta is able to preserve sperm by reducing the amount of HPV16-L1 bound onto membranes.

We conducted an observational cohort study to evaluate whether drugs used for hypothalamic inhibition may impact thyroid function of infertile women scheduled for fresh nondonor in vitro fertilization/intracytoplasmic sperm injection treatment. We considered eligible for inclusion in the study only women with normal thyroid function (serum thyroid-stimulating hormone [TSH] range: 0.2-4.0 mIU/L, serum thyroxin values: 9-22 pmol/L) and negative personal history for previous thyroid disorders. According to which protocols were implemented to gain hypothalamic inhibition, patients were assigned to group A (70 women treated by long gonadotropin-releasing hormone [GnRH] agonist protocol) or to group B (86 women treated by flexible GnRH antagonist protocol). Before initiating controlled ovarian stimulation (COS), both groups were further stratified into 4 subgroups: A1 (46 of the 70 women) and B1 (61 of the 86 women) in women with a baseline TSH value <2.5 mIU/L, whereas those with a baseline value ≥2.5 mIU/L were assigned to groups A2 (24 of the 70 women) and B2 (25 of the 86 women). Prior to initiating stimulation (T-0), 17-β-estradiol (E(2)) and TSH serum values were dosed in all women and repeated on T-5 (day 5 of COS) and subsequently every 2 days until T-ov-ind (ovulation induction day) and T-pick-up (oocytes retrieval day). In case of detection of TSH levels above the cutoff, patients were screened for thyroxin and thyroid autoantibody serum values. In group A, E(2) at T-ov-ind was significantly increased compared to group B (P < .01), whereas TSH values showed an opposite trend (not significantly modified in group A, whereas significantly increased in group B; P < .001). A total of 64 women were found to have TSH values above the cutoff during COS: 7 in group A (11%) and 57 in group B (89%). Among them, 5 (71.4%) of the 7 in group A displayed hypothyroidism (and 4 of the 5 autoantibody positivity), whereas in group B, 6 (10.5%) of the 57 displayed hypothyroidism (and 2 of the 6 autoantibody positivity; P < .001). No pregnancies were observed in women with hypothyroidism, whereas in the 53 women with "isolated" increased TSH (normal T4, negative antibodies), we reported a 20.7% clinical pregnancy rate and a 54.5% ongoing pregnancy rate. Our preliminary data, despite requiring further confirmation, seem to suggest that the various drugs used for gaining hypothalamic control during COS could interfere through different mechanisms with physiological function of thyroid axis, potentially affecting its regulation., (© The Author(s) 2015.)

We have recently demonstrated that excessive aldosterone (Aldo) secretion in primary aldosteronism (PA) is associated with red blood cells (RBC) senescence. These alterations were prevented/inhibited by cortisol (Cort) or canrenone (Can) raising the hypothesis that Aldo effects in RBC may be mediated by mineralocorticoid receptor (MR), though to date MR has never been demonstrated in human RBC. The aim of this multicenter comparative study was to investigate whether Aldo effects were mediated by MR in these a-nucleated cells. We included 12 healthy controls (HC) and 22 patients with PA. MR presence and activation were evaluated in RBC cytosol by glycerol gradient sedimentation, Western blotting, immuno-precipitation and radioimmunoassay. We demonstrated that RBC contained cytosolic MR, aggregated with HSP90 and other proteins to form multiprotein complex. Aldo induced MR to release from the complex and to form MR dimers which were quickly proteolyzed. Cort induced MR release but not dimers formation while Can was not able to induce MR release. In addition, RBC cytosol from PA patients contained significantly higher amounts of both MR fragments (p<0.0001) and Aldo (p<0.0001) concentrations. In conclusion, in RBC a genomic-like Aldo pathway is proposed involving MR activation, dimerization and proteolysis, but lacking nuclear transcription. In addition, dimers proteolysis may ensure a sort of Aldo scavenging from circulation by entrapping Aldo in MR fragments.

In humans, stem cell factor (SCF), produced during follicular phase, may reflect a successful stimulation and oocyte maturation and so it may be a predictor of in vitro fertilization (IVF) outcome. An observational cohort study was conducted on 37 poor responders scheduled for fresh nondonor IVF/intracytoplasmic sperm injection treatment with standard controlled ovarian stimulation (COS) using recombinant follicle-stimulating hormone (rFSH; S-COS group). A total of 35 women received a second treatment using both rFSH and recombinant luteinizing hormone (rLH; LH-COS group). From 144 samples collected at pickup day, serum concentration of SCF (s-SCF) and follicular levels of SCF (f-SCF) were measured by enzyme-linked immunosorbent assay (ELISA) kit. No differences were observed between the 2 protocols in terms of both f-SCF and s-SCF levels. The comparison between f-SCF and s-SCF levels showed a strong linear correlation. The comparison between s-SCF levels and clinical outcomes showed a statistically significant correlation between both the number of metaphase II (MII) oocytes retrieved and the embryos obtained after fertilization. Cases with at least 3 MII oocytes showed s-SCF values >800 pg/mL, 2 MII oocytes >600 pg/mL, and 1 MII oocytes >400 pg/mL. In 100% of cases with s-SCF <400 pg/mL, no MII oocytes were recovered. All 5 pregnancies occurred in patients with s-SCF values >1000 pg/mL. The introduction of s-SCF assay in the management of poor-responder patients may contribute to solving the dilemma of whether to cancel or proceed with the stimulation cycle., (© The Author(s) 2015.)

Vulvar cancer (VC) represents about 4% of gynecologic malignancies, its incidence increases with age and peak incidence is found between 70-79 years. In cases of locally advanced disease surgery is often required and radical vulvectomy, with or without mono-bilateral inguino-femoral lymphadenectomy, is standard management. Various devices have been implemented in gynecological surgery in an attempt to minimize or avoid frequent intra/postoperative complications linked to energy use, unfortunately the majority of these devices require monopolar or bipolar energy. Ultracision® represents a unique surgical device capable of performing both cutting and coagulation at different intensities without use of electric energy. The use of Ultracision® in the radical treatment of VC has advantages both in terms of intraoperative and postoperative complications responsible for the reduction of surgical time and blood loss, complete tissue removal according to oncological criteria, diminished desensitization of peripheral areas and reduction of wound complications. These advantages have been widely demonstrated and contribute to making Ultracision® a cost-effective option in the routine treatment of patients affected by vulvar cancer especially when considering its safety in cardiopathic patients with implanted pacemaker. If the impressive results achieved in radical vulvar surgery will be confirmed, scalpel use could be proposed as routine for surgery of the routinely in surgical approach of vulvar and perineal area, in both benign and malignant disease.

This study examined the possible involvement of carbonic anhydrase activation in response to an endometriosis-related increase in oxidative stress. Peripheral blood samples obtained from 27 healthy controls and 30 endometriosis patients, classified as having endometriosis by histological examination of surgical specimens, were analysed by multiple immunoassay and carbonic anhydrase activity assay. Red blood cells (RBC) were analysed for glutathionylated protein (GSSP) content in the membrane, total glutathione (GSH) in the cytosol and carbonic anhydrase concentration and activity. In association with a membrane increase of GSSP and a cytosolic decrease of GSH content in endometriosis patients, carbonic anhydrase significantly increased (P < 0.0001) both monomerization and activity compared with controls. This oxidation-induced activation of carbonic anhydrase was positively and significantly correlated with the GSH content of RBC (r = 0.9735, P < 0.001) and with the amount of the 30-kDa monomer of carbonic anhydrase (r = 0.9750, P < 0.001). Because carbonic anhydrase activation is implied in many physiological and biochemical processes linked to pathologies such as glaucoma, hypertension, obesity and infections, carbonic anhydrase activity should be closely monitored in endometriosis. These data open promising working perspectives for diagnosis and treatment of endometriosis and hopefully of other oxidative stress-related diseases. Endometriosis is a chronic disease associated with infertility and local inflammatory response, which is thought to spread rapidly throughout the body as a systemic subclinical inflammation. One of the causes in the pathogenesis/evolution of endometriosis is oxidative stress, which occurs when reactive oxygen species are produced faster than the endogenous antioxidant defence systems can neutralize them. Once produced, reactive oxygen species can alter the morphological and functional properties of endothelial cells, including permeability and adhesion molecule expression, thus contributing to ongoing inflammation. Due to their main cellular functions--delivery of O2 from lung to tissue and removal of CO2 from tissue to lung--red blood cells (RBC) are exposed to oxidative stress. Carbon dioxide in tissue capillaries diffuses into red cells, where it is rapidly hydrated by the action of cytosolic carbonic anhydrase. Analysis of the oxidation status of endometriotic RBC membranes showed a high content of glutathionylated proteins, indicating pre-existing oxidation-related alterations. The increase in glutathionylated proteins was correlated to increased carbonic anhydrase activity in endometriotic RBC compared with healthy controls. Carbonic anhydrase is a family of metalloenzymes involved in many physiological processes such as acid-base homeostasis, respiration, carbon dioxide and ion transport, and bone resorption, and in the regulation of ureagenesis, gluconeogenesis, lipogenesis and tumourigenesis. Due to the potential implication of carbonic anhydrase activation in many pathologies, such as glaucoma, hypertension, obesity and infections, carbonic anhydrase activity should be closely monitored in endometriosis to prevent possible complications and/or worsening of related conditions., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Nowadays, the ovarian reserve (OR) is considered more important than chronological age to estimate female reproductive capability. We conducted a retrospective, observational, and cohort study in order to detect the best predictor marker of OR, ovarian response, chances to obtain high-quality embryos, and pregnancy after in vitro fertilization (IVF) cycle in elderly women. For all eligible patients (aged between 40 and 50 and admitted to their first IVF cycle for primary infertility), we investigated the biochemical parameters and ultrasound aspects of ovaries and how they affected IVF outcomes. Age, basal follicle-stimulating hormone, basal luteinizing hormone, and basal-17β-estradiol are better related to the dose of gonadotropin used during a controlled ovarian stimulation cycle. Basal anti-Müllerian hormone (AMH), antral follicular count (AFC), and maximum serum level of 17β-estradiol before pickup resulted the best predictors of chances to retrieve at least 6 oocytes (at least 3 in metaphase II) and to have at least 1 to 3 embryos. The basal AMH, AFC and maximum serum level of 17β-estradiol before pickup continue to show higher correlation to pregnancy rate. The maximum endometrial thickness at pickup resulted important to predict the pregnancy rate and the chances to detect ongoing pregnancy. It seems mandatory to well define the ovarian biological age rather than the chronological one in women older than 40 years of age in order to give the best counseling and to choose the most appropriate IVF protocols.

Context: Aldosterone (Aldo) effects include NADPH oxidase activation involved in Aldo-related oxidative stress. Red blood cells (RBCs) are particularly sensitive to oxidative assault, and both the formation of high molecular weight aggregates (HMWAs) and the diamide-induced Tyr phosphorylation (Tyr-P) level of membrane band 3 can be used to monitor their redox status., Objective: The Aldo-related alterations in erythrocytes were evaluated by comparing in vitro evidence., Design: This was a multicenter comparative study., Study Participants: The study included 12 patients affected by primary aldosteronism (PA) and 6 healthy control subjects (HCs), whose RBCs were compared with those of patients with PA. For in vitro experiments, RBCs from HCs were incubated with increasing Aldo concentrations., Main Outcome Measures: The Tyr-P level, band 3 HMWA formation, and autologous IgG binding were evaluated., Results: In patients with PA, both Tyr-P levels and band 3 HMWAs were higher than those in HCs. RBCs from HCs were treated with increasing Aldo concentrations in both platelet-poor plasma (PPP) and charcoal-stripped (CS)-PPP. Results showed that Aldo had dose- and time-dependent effects on band 3 Tyr-P and HMWA formation in CS-PPP more than in PPP. These effects were almost completely prevented by canrenone or cortisol. Aldo-related membrane alterations led to increased autologous IgG binding., Conclusions: Erythrocytes from patients with PA show oxidative-like stress evidenced by increased HMWA content and diamide-induced band 3 Tyr-P level. Aldo effects are mediated by the mineralocorticoid receptor, as suggested by the inhibitory effects of canrenone, an antagonist of Aldo. In CS-PPP, in which Aldo induces remarkable membrane alterations leading to IgG binding, Aldo may be responsible for premature RBC removal from circulation.

Background: childbirth is a crucial experience in women's life as it has a substantial psychological, emotional and physical impact. A childbirth positive experience is important to the woman, infant's health and well-being, and mother-infant relationship. Furthermore, it is useful for the care providers to guarantee the best preparation, health service and support to childbearing women. The Childbirth Perception Questionnaire (CPQ) is a 27-item instrument designed to assess women's perception of their childbirth experience., Objectives: to provide a first attempt to adapt the Childbirth Perception Questionnaire (CPQ) using a sample of Italian women. The psychometric properties of the scale and the quality of women's childbirth experience perception were assessed. Furthermore, the potential relation between the childbirth perception and the pain perception was explored., Design: two separate studies were conducted. In Study 1, the factor structure and the reliability of the Italian translation of CPQ were assessed. Also a quantitative analysis of respondents' mean ratings was conducted. In Study 2 the relation between the CPQ and the Italian Pain Questionnaire (IPQ) was examined., Setting: an inpatient gynaecologic-obstetric unit in a university medical centre in Italy., Participants: 195 women in Study 1 and 92 women in Study 2 completed the questionnaires., Methods: in Study 1 the translated form of CPQ was administered in the 24-48 hours post partum. In Study 2, the participants completed the Italian version of the CPQ and the Italian Pain Questionnaire (IPQ) in the same postpartum time frame. Socio-demographic details and information about women's obstetric history were collected in both Study 1 and Study 2., Findings: an exploratory factor analysis revealed a 24-item scale with a three-factor structure. The Italian version of the questionnaire was labelled Childbirth Experience Perception Scale (CEPS) and composed of three subscales: Labour and Delivery Perception, Control Perception and Change Perception. The questionnaire presented satisfactory internal consistency's indexes both in Study 1 (α coefficients range: .66-.83) and in Study 2 (α coefficients range: .70-.86). The analysis of women's mean scores on CEPS revealed a significant effect of age, social economic status, amniocentesis test, type of childbirth, childbirth preference, and disagreement between actual and preferred childbirth (p<.05). A significant correlation between the CEPS and IPQ scales was found (p<.05)., Conclusion: the current research evidenced that the Italian first adaptation of the CPQ, the Childbirth Experience Perception Scale, may be a valid and reliable measure of childbirth experience perception for use in different women's health clinical outcome and studies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Generation of controlled amounts of reactive oxygen species (ROS) and phosphorylation of protein tyrosine residues (Tyr) are two closely related changes involved in sperm capacitation. This study investigated the effect of altered endogenous ROS production on Tyr-phosphorylation (Tyr-P), acrosome reaction (AR) and cell viability during sperm capacitation. The possible origin of the altered ROS production was also evaluated by apocynin (APO) or oligomycin (Oligo) addition., Methods: A total of 63 samples of purified sperm were analysed for ROS production by enhanced chemiluminescence, Tyr-P pattern by immunocytochemistry, and AR and viability by fluorochrome fluorescein isothiocyanate (FITC)-labelled peanut (Arachis hypogaea) agglutinin and propidium iodide positivity, respectively., Results: Samples were divided into four categories depending on the ability of sperm to produce ROS, expressed as Relative Luminescence Units (RLU), in capacitating conditions: low ROS production (LRP), range about 0.0-0.05 RLU; normal (NRP), 0.05-0.1 RLU; high (HRP), 0.1-0.4 RLU; very high (VHRP) 0.4-2.0 RLU. In NRP sperm heads, capacitation induced Tyr-P in 87.9 ± 4.3%, and the AR occurred in 62.5 ± 5.4% of cells; in LRP, HRP and VHRP Tyr-P labelling rarely spread over the head, acrosome-reacted cells only accounted for a small number of sperm, and the non-viable cells (NVC) were increased. The addition of APO, but not Oligo, drastically decreased ROS production in analysed samples., Conclusions: This study proposes the optimal threshold for endogenous ROS production for correct sperm viability and functioning, and indicates the direct involvement of APO-sensitive NADPH oxidase in ROS production.

Objective: The aims of our study were to determine on the one hand a correlation between the presence of anti-Helicobacter pylori (anti-H. pylori) IgG antibodies in serum and cervical mucus of women with idiopathic infertility, and on the other hand the effect of these antibodies on cervical mucus quality, in particular related to the ability of spermatozoa to penetrate it., Study Design: We analysed anti-H. pylori IgG antibodies in the serum and cervical mucus of 67 patients diagnosed with idiopathic infertility using the Quanta Lite H. pylori IgG test. The penetration of normal sperm, in 15 cervical mucus samples positive for anti-H. pylori antibodies and in 15 negative samples, was assessed using the simplified slide test., Results: A significant positive correlation emerged between anti-H. pylori IgG antibody concentrations in the serum and in the cervical mucus (r=0.9275; p<0.00001). In the 15 anti-H. pylori IgG mucus-positive samples the slide test showed abnormal penetration by the spermatozoa., Conclusions: Our study demonstrated that the presence of anti-H. pylori antibody in the cervical mucus can be involved in female infertility, interfering with sperm progression. Considering the close correlation found between serum and cervical mucus anti-H. pylori antibody titres, measuring serum antibodies could become an additional test, in particular in couples with unexplained infertility., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: To investigate the association of AMH and AMHRII polymorphisms with reproductive abilities in a sample of women with idiopathic infertility., Design: Case-control study., Setting: University Department of Obstetrics and Gynecology, and University Unit of Clinical Genetics., Patient(s): 76 women with idiopathic sterility and 100 fertile women as controls., Intervention(s): Genotyping was performed by high-resolution melt analysis., Main Outcome Measure(s): Genotype distribution and allele frequency of AMH and AMHRII polymorphisms. Reconstruction of haplotype alleles to evaluate the linkage disequilibrium between single nucleotide polymorphisms., Result(s): Allele frequencies of -482 A>G, IVS 5-6 C>T, IVS 10+77 A>G, 146T>G polymorphisms are statistically significantly different in infertile patients compared with controls., Conclusion(s): Genetic variants of AMH and AMHRII genes seem to be associated with infertility, suggesting a role in the pathophysiology of normo-estrogenic and normo-ovulatory infertility. A clearer understanding of their function in ovarian physiology may help clinicians to find a role for antimüllerian hormone measurement in the field of reproductive medicine., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)