The kisspeptin system in and beyond reproduction: exploring intricate pathways and potential links between endometriosis and polycystic ovary syndrome.

Endometriosis and polycystic ovary syndrome (PCOS) are two common female reproductive disorders with a significant impact on the health and quality of life of women affected. A novel hypothesis by evolutionary biologists suggested that these two diseases are inversely related to one another, representing a pair of diametrical diseases in terms of opposite alterations in reproductive physiological processes but also contrasting phenotypic traits. However, to fully explain the phenotypic features observed in women with these conditions, we need to establish a potential nexus system between the reproductive system and general biological functions. The recent discovery of kisspeptin as pivotal mediator of internal and external inputs on the hypothalamic-pituitary-gonadal axis has led to a new understanding of the neuroendocrine upstream regulation of the human reproductive system. In this review, we summarize the current knowledge on the physiological roles of kisspeptin in human reproduction, as well as its involvement in complex biological functions such as metabolism, inflammation and pain sensitivity. Importantly, these functions are known to be dysregulated in both PCOS and endometriosis. Within the evolving scientific field of "kisspeptinology", we critically discuss the clinical relevance of these discoveries and their potential translational applications in endometriosis and PCOS. By exploring the possibilities of manipulating this complex signaling system, we aim to pave the way for novel targeted therapies in these reproductive diseases.

Diagnosis and management of infertility: NICE-adapted guidelines from the Italian Society of Human Reproduction.

In Italy the fertility rate is very low, and an increasing number of patients are infertile and require treatments. The Italian Law concerning the safety of patient care, and the professional liability of health professionals, indicates that health professionals must comply with the recommendations set out in the guidelines developed by public and private bodies and institutions, as well as scientific societies and technical-scientific associations of the health professions, except for specific cases. Unfortunately, no guideline for the diagnosis and the management of infertility is currently available in Italy. In 2019, the Italian Society of Human Reproduction pointed out the need to produce Italian guidelines and subsequently approved the establishment of a multidisciplinary and multiprofessional working group (MMWG) to develop such a guideline. The MMWG was representative of 5 scientific societies, one national federation of professional orders, 3 citizens' and patients' associations, 5 professions (including lawyer, biologist, doctor, midwife, and psychologist), and 3 medical specialties (including medical genetics, obstetrics and gynecology, and urology). The MMWG chose to adapt a high-quality guideline to the Italian context instead of developing one from scratch. Using the Italian version of the Appraisal of Guidelines for Research and Evaluation II scoring system, the National Institute of Clinical Excellence guidelines were selected and adapted to the Italian context. The document was improved upon by incorporating comments and suggestions where needed. This study presents the process of adaptation and discusses the pros and cons of the often-neglected choice of adapting rather than developing new guidelines.

Review of the impact of COVID-19 on male reproduction, and its implications on assisted reproductive technology services.

The announcement in 2019 of a new coronavirus disease that quickly became a major pandemic, is an exceptional challenge to healthcare systems never seen before. Such a public health emergency can largely influence various aspects of people's health as well as reproductive outcome. IVF specialists should be vigilant, monitoring the situation whilst contributing by sharing novel evidence to counsel patients, both pregnant women and would-be mothers. Coronavirus infection might adversely affect pregnant women and their offspring. Consequently, this review paper aims to analyse its potential risks for reproductive health, as well as potential effects of the virus on gamete function and embryo development. In addition, reopening fertility clinics poses several concerns that need immediate addressing, such as the effect of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) on reproductive cells and also the potential risk of cross-contamination and viral transmission. Therefore, this manuscript summarizes what is currently known about the effect of the SARS-CoV-2 infection on medically assisted reproductive treatments and its effect on reproductive health and pregnancy.

Effect of local aromatase inhibition in endometriosis using a new chick embryo chorioallantoic membrane model.

Endometriosis is an oestrogen-dependent, inflammation-driven gynaecologic disorder causing severe disability. Endometriosis implants are characterized by unbalanced local oestrogen metabolism leading to hyperoestrogenism and aromatase up-regulation is one of main mechanism involved. Aromatase inhibitors such as letrozole or anastrozole use in young women are associated with severely side effects limiting their long-term clinical use. An endometriosis-targeted inhibition of local aromatase could be a viable alternative, although the role of the local inhibition of this enzyme is still unclear. Using a new chick embryo allantoic membrane (CAM) model incorporating xenografted human endometriosis cyst, we showed that topical treatment with anastrozole reduced lesion size, although oestrogens produced by CAM female embryo blunted this effect. Xenografted human endometriosis CAM is a new efficient model for the screening of new drugs targeting endometriosis tissue.

Pelvic floor muscle training for prevention and treatment of urinary incontinence during pregnancy and after childbirth and its effect on urinary system and supportive structures assessed by objective measurement techniques.

PURPOSE: During the second and the third trimesters of pregnancy and in the first 3 months following childbirth, about one-third of women experience urinary incontinence (UI). During pregnancy and after delivery, the strength of the pelvic floor muscles may decrease following hormonal and anatomical changes, facilitating musculoskeletal alterations that could lead to UI. Pelvic floor muscle training (PFMT) consists in the repetition of one or more sets of voluntary contractions of the pelvic muscles. By building muscles volume, PFMT elevates the pelvic floor and the pelvic organs, closes the levator hiatus, reduces pubovisceral length and elevates the resting position of the bladder. Objective of this review is to evaluate the efficacy of PFMT for prevention and treatment of UI during pregnancy and after childbirth and its effect on urinary system and supportive structures assessed by objective measurement techniques. METHODS: The largest medical information databases (Medline-Pubmed, EMBASE, Lilacs, Cochrane Library and Physiotherapy Evidence Database) were searched using the medical subject heading terms "pelvic floor muscle training", "prevention", "urinary incontinence", "urinary stress incontinence", "objective measurement techniques", "pregnancy, "exercise", "postpartum" and "childbirth" in different combinations. RESULTS AND CONCLUSIONS: Overall, the quality of the studies was low. At the present time, there is insufficient evidence to state that PFMT is effective in preventing and treating UI during pregnancy and in the postpartum. However, based on the evidence provided by studies with large sample size, well-defined training protocols, high adherence rates and close follow-up, a PFMT program following general strength-training principles can be recommended both during pregnancy and in the postnatal period.

A Pilot Study on Oocyte Retrieval Simulator: A New Tool for Training?

This prospective study was aimed at assessing the usefulness of a box simulator in oocyte pick-up and at establishing whether it could be an appropriate training tool for egg retrieval. Forty-four clinicians, divided in two groups on the grounds of the previous experience (Novices and Experts), participated to two training sessions with a pick-up simulator. Data concerning the mean number of follicles correctly aspired (%OK med), the average time needed to correctly aspirate one follicle (t foll med) and the ratio between the two afore-mentioned parameters (%OK med/t foll med) were collected. At the end of the two sessions all participants completed a questionnaire aimed at assessing the performance of the simulator in terms of realism and acceptability for use. A significant improvement in efficiency (mean number of follicles correctly aspired, 82% versus 75%), speed (mean time needed to aspirate one follicle, 21 versus 28 s) and accuracy (mean percentage of follicles correctly aspirated in one minute, 2.53% versus 1.86%) was noted in the total sample. The performance accuracy was significantly increased in both groups (2.34% versus 1.83% for Novices and 2.50% versus 2.06%, for Experts). Speed was significantly improved in the Novices' group. Simulator-based training has been shown to be effective and useful and it should be considered in training programs.

Lifestyle and fertility: the influence of stress and quality of life on female fertility.

There is growing evidence that lifestyle choices account for the overall quality of health and life (QoL) reflecting many potential lifestyle risks widely associated with alterations of the reproductive function up to the infertility. This review aims to summarize in a critical fashion the current knowledge about the potential effects of stress and QoL on female reproductive function. A specific literature search up to August 2017 was performed in IBSS, SocINDEX, Institute for Scientific Information, PubMed, Web of Science and Google Scholar. Current review highlights a close relationship in women between stress, QoL and reproductive function, that this association is more likely reported in infertile rather than fertile women, and that a vicious circle makes them to have supported each other. However, a precise cause-effect relationship is still difficult to demonstrate due to conflicting results and the lack of objective measures/instruments of evaluation.

Radiations and female fertility.

Hundreds of thousands of young women are diagnosed with cancer each year, and due to recent advances in screening programs, diagnostic methods and treatment options, survival rates have significantly improved. Radiation therapy plays an important role in cancer treatment and in some cases it constitutes the first therapy proposed to the patient. However, ionizing radiations have a gonadotoxic action with long-term effects that include ovarian insufficiency, pubertal arrest and subsequent infertility. Cranial irradiation may lead to disruption of the hypothalamic-pituitary-gonadal axis, with consequent dysregulation of the normal hormonal secretion. The uterus might be damaged by radiotherapy, as well. In fact, exposure to radiation during childhood leads to altered uterine vascularization, decreased uterine volume and elasticity, myometrial fibrosis and necrosis, endometrial atrophy and insufficiency. As radiations have a relevant impact on reproductive potential, fertility preservation procedures should be carried out before and/or during anticancer treatments. Fertility preservation strategies have been employed for some years now and have recently been diversified thanks to advances in reproductive biology. Aim of this paper is to give an overview of the various effects of radiotherapy on female reproductive function and to describe the current fertility preservation options.

Gene expression changes in progression of cervical neoplasia revealed by microarray analysis of cervical neoplastic keratinocytes.

To evaluate the gene expression changes involved in neoplastic progression of cervical intraepithelial neoplasia. Using microarray analysis, large-scale gene expression profile was carried out on HPV16-CIN2, HPV16-CIN3, and normal cervical keratinocytes derived from two HPV16-CIN2, two HPV-CIN3 lesions, and two corresponding normal cervical tissues, respectively. Differentially expressed genes were analyzed in normal cervical keratinocytes compared with HPV16-CIN2 keratinocytes and in HPV16-CIN2 keratinocytes compared with HPV16-CIN3 keratinocytes; 37 candidate genes with continuously increasing or decreasing expression during CIN progression were identified. One of these genes, phosphoglycerate dehydrogenase, was chosen for further characterization. Quantitative reverse transcription-polymerase chain reaction and immunohistochemical analysis confirmed that expression of phosphoglycerate dehydrogenase consistently increases during progression of CIN toward cancer. Gene expression changes occurring during CIN progression were investigated using microarray analysis, for the first time, in CIN2 and CIN3 keratinocytes naturally infected with HPV16. Phosphoglycerate dehydrogenase is likely to be associated with tumorigenesis and may be a potential prognostic marker for CIN progression.

The ultrasonographic detection of follicular rupture at the time of intrauterine insemination: is it really decisive?

Our aim is to assess the impact of the ultrasonographic detection of follicular rupture on the intrauterine insemination success. A total of 313 women undergoing ovarian stimulation for intrauterine insemination were enrolled. Transvaginal ultrasonography was performed to check whether the dominant follicle had ruptured and according to that the patients were divided into two groups. The ultrasound detection of follicular rupture was observed in 156 patients (54%). The independent variables favoring follicular rupture were: Age (t: 7.646, p < 0.0005), FSH value (t: -5.637, p < 0.0005), duration of infertility (t: -4.265, p < 0.0005), menstrual cycle length (t: -4.927, p < 0.0005). Moreover, the logistic regression analysis demonstrated that the predictive variables for follicular rupture were: FSH value (OR 1.7, CI 95% 1.3-2.3, p < 0.0005), duration of infertility (OR 2.6, CI 95% 1.6-4.2, p < 0.0005) and menstrual cycle length (OR 2.4, CI 95% 1.7-3.4, p < 0.0005). Pregnancy occurred in 23 patients of the group A (14.7%) and in 22 patients of the group B (16.5%) without a significant difference (p = 0.6). The logistic regression analysis confirmed that neither the evidence of follicular rupture nor any other variables influenced the pregnancy rate.

Laparoscopic supracervical hysterectomy with transcervical morcellation: our experience.

STUDY OBJECTIVE: To present our experience with laparoscopic supracervical hysterectomy with transcervical morcellation (LSH-TM). DESIGN: A retrospective observational study (Canadian Task Force Classification III). SETTING: Gynecologic Department at Brunico Hospital, Brunico, Italy. PATIENTS: Three hundred sixty-five patients affected by gynecologic benign diseases who underwent LSH-TM. INTERVENTIONS: A minimally invasive surgical technique for supracervical hysterectomy that involves extraction of the morcellated uterus through the cervical canal. MEASUREMENTS AND MAIN RESULTS: We performed LSH-TM successfully in 365 patients; the mean (standard deviation) operating time was 72.24 (23.21) minutes. We registered no intraoperative complications. The main postoperative complications resulted in 2 cases of second-look laparoscopy because of internal bleeding, 5 cases of asymptomatic hematoma around the cervical stump, and 7 cases of pelvic pain. CONCLUSION: Our experience shows that LSH-TM is a safe and easy to perform technique and that it ensures minimal blood loss.

Hysterosalpingo contrast sonography (HyCoSy): let's make the point!

INTRODUCTION: The accurate evaluation of tubal patency as well of the morphologic characteristics of the uterine cavity is a fundamental step in the diagnostic work-up for infertility. Hysteroscopy and laparoscopy and dye have long been regarded as the reference methods to assess uterine morphology and tubal patency, respectively. However, their technical and clinical limitations have supported the introduction of an emerging technique: hysterosalpingo contrast sonography (HyCoSy), which has recently been improved with the use of modern contrast agents and three-dimensional resolution. METHODS: A systematic literature search was performed in electronic databases (PubMed and Scopus). Key search terms included Hysterosalpingo contrast sonography (HyCoSy), Tubal patency, Infertility, Uterine cavity, Ultrasounds. RESULTS: HyCoSy has proved to be as reliable as laparoscopic techniques in the assessment of tubal patency and uterine morphology, and also it overcomes such major drawbacks as hospitalization, radiation exposure, anesthesia and use of iodinated contrast media. All in all, HyCoSy is considered as a safe and well tolerated outpatient procedure, which apparently favors the onset of spontaneous pregnancies. CONCLUSION: This paper provides a comprehensive overview of the literature dealing with HyCoSy to support its use as a first-line technique in standard infertility work-up.

Impact of soluble HLA-G levels and endometrial NK cells in uterine flushing samples from primary and secondary unexplained infertile women.

The aim of this research was to determine the levels of human leukocyte antigen G (HLA-G) and endometrial Natural Killer ((e)NK) cell percentages in uterine flushing samples from primary and secondary infertile women. sHLA-G levels were lower in the uterine flushing samples from primary infertile women in comparison with women with secondary infertility. Lower CD56+KIR2DL4+ (e)NK cell percentages were detected in primary infertile women compared with secondary infertile women. This is the first study demonstrating that primary and secondary unexplained infertilities are characterized by different basal sHLA-G levels and CD56+KIR2DL4+ (e)NK cell percentages.

Bisphenol A and the female reproductive tract: an overview of recent laboratory evidence and epidemiological studies.

Bisphenol A (BPA) is a high production volume monomer used for making a wide variety of polycarbonate plastics and resins. A large body of evidence links BPA to endocrine disruption in laboratory animals, and a growing number of epidemiological studies support a link with health disorders in humans. The aim of this review is to summarize the recent experimental studies describing the effects and mechanisms of BPA on the female genital tract and to compare them to the current knowledge regarding the impact of BPA impact on female reproductive health. In particular, BPA has been correlated with alterations in hypothalamic-pituitary hormonal production, reduced oocyte quality due to perinatal and adulthood exposure, defective uterine receptivity and the pathogenesis of polycystic ovary syndrome. Researchers have reported conflicting results regarding the effect of BPA on premature puberty and endometriosis development. Experimental studies suggest that BPA's mechanism of action is related to life stage and that its effect on the female reproductive system may involve agonism with estrogen nuclear receptors as well as other mechanisms (steroid biosynthesis inhibition). Notwithstanding uncertainties and knowledge gaps, the available evidence should be seen as a sufficient grounds to take precautionary actions against excess exposure to BPA.

Doppler velocimetry of the ovarian artery as a tool to detect LH surge in stimulated cycles.

Our aim was to assess the velocimetric pattern of the ovarian artery as a possible marker of LH surge in stimulated cycles. A total of 130 women undergoing ovarian stimulation for intrauterine insemination were randomized in two groups. Each woman was stimulated with 75 IU of recombinant FSH starting from the third day of the cycle. Velocimetric indices of the dominant ovarian artery were compared between patients with spontaneous LH surge and those needing HCG administration to trigger dominant follicle rupture. The pulsatility index and the ratio between peak systolic flow and lowest diastolic flow were significantly higher in women that had a spontaneous triggering of ovulation. These parameters had a high and very significant positive correlation with the dosage of luteinizing hormone. Threshold values of 2.60 for PI and 7.68 for S/D had a high sensitivity and specificity to predict LH surge. These velocimetric results demonstrated that an increased resistance in the dominant ovarian artery is correlated to LH surge in stimulated cycles. It may represent a sign of relevant clinical utility in timing of intrauterine insemination and/or natural intercourse.

In vitro endothelial cell proliferation assay reveals distinct levels of proangiogenic cytokines characterizing sera of healthy subjects and of patients with heart failure.

Although myocardial angiogenesis is thought to play an important role in heart failure (HF), the involvement of circulating proinflammatory and proangiogenic cytokines in the pathogenesis and/or prognosis of HF has not been deeply investigated. By using a highly standardized proliferation assay with human endothelial cells, we first demonstrated that sera from older (mean age 52 ± 7.6 years; n = 46) healthy donors promoted endothelial cell proliferation to a significantly higher extent compared to sera obtained from younger healthy donors (mean age 29 ± 8.6 years; n = 20). The promotion of endothelial cell proliferation was accompanied by high serum levels of several proangiogenic cytokines. When we assessed endothelial cell proliferation in response to HF patients' sera, we observed that a subset of sera (n = 11) promoted cell proliferation to a significantly lesser extent compared to the majority of sera (n = 18). Also, in this case, the difference between the patient groups in the ability to induce endothelial cell proliferation correlated to significant (P < 0.05) differences in serum proangiogenic cytokine levels. Unexpectedly, HF patients associated to the highest endothelial proliferation index showed the worst prognosis as evaluated in terms of subsequent cardiovascular events in the follow-up, suggesting that high levels of circulating proangiogenic cytokines might be related to a worse prognosis.

Vaginal lactoferrin administration before genetic amniocentesis decreases amniotic interleukin-6 levels.

AIM: To verify the eventual efficacy of lactoferrin (LF), an iron-binding glycoprotein, to decrease the amniotic concentration of interleukin-6 (IL-6). METHODS: We prospectively enrolled 60 Caucasian patients at the 16th week of their singleton physiological gestation. A vaginal compound containing 300 mg of LF was administered randomly 4 or 12 h prior to amniocentesis, as to obtain 3 groups: A, 20 untreated patients; B, 20 treated 4 h before amniocentesis; C, 20 treated 12 h before amniocentesis. RESULTS: A normal karyotype was registered in all cases. The comparison of the distribution of IL-6 among the 3 groups showed a highly significant difference (p = 0.001). The difference between mean values of group B and both groups C and A was shown to be highly significant (p = 0.006 and p = 0.03, respectively). In contrast, there was no significant difference between mean values of groups A and C. CONCLUSION: Vaginal LF administration decreases amniotic IL-6 concentration. We therefore suggest that the glycoprotein may exert a protective role against ominous pregnancy complications linked to an increased level of the cytokine, such as abortion secondary to amniocentesis.

Rare case of massive congenital bilateral chylothorax in a hydropic fetus with true mosaicism 47,XXX/46,XX.

Fetal congenital chylothorax is a rare condition that occurs sporadically or can be associated with abnormal karyotype or structural chromosomal anomalies. We report a unique case of fetal congenital bilateral chylothorax associated with mosaicism 47,XXX/46,XX. A female fetus affected by massive bilateral hydrothorax and ascites was diagnosed at 34(+1) weeks of gestation. Previous ultrasonographic exams were completely normal. Immune causes of hydrops were excluded. Elective cesarean section was performed soon after bilateral thoracocentesis. The analysis of drained pleural fluid revealed its lymphatic nature. The fetal karyotyping, performed on chorionic villi at the 11th week, had shown mosaicism 47,XXX/46,XX, later confirmed in the newborn's blood. We hypothesized that chylothorax may be part of the phenotypic spectrum of 47 XXX karyotype and we suggest an ultrasound follow-up of the fetus at closer intervals than the routine timing for this condition, even if it is not usually characterized by severe phenotypic features.

Long and fluctuating bone fragments in uterine isthmus: a curious feature of true osseous metaplasia.

Osseous metaplasia in the uterine cavity is a rare phenomenon arising from an unusual transformation of non-osseous connective tissue into mature bone. It is unclear how this alteration occurs and it has no single clinical manifestation. We report a case of asymptomatic endometrial osseous metaplasia of the isthmus with a singular picture: numerous long, floating bone-like structures in the cavity. The lesion was treated by operative hysteroscopy. Histological findings described a rare picture of true osseous metaplasia with the extraordinary presence of cells referable to areas of hematopoietic tissue in the cavities of trabecular bone. Physicians should be more informed and alert regarding this rare disorder in all its strange shapes and localizations, so as to be able to follow suitable therapy.

Can Doppler study of the ovarian artery predict the fertility outcome of intrauterine insemination?

BACKGROUND: To test the velocimetric pattern of the ovarian artery as a routine ovarian reserve test. METHODS: We enrolled 317 consecutive patients from January 2011 to June 2012. At the second day of the menstrual cycle, a transvaginal ultrasound was performed to evaluate the antral follicle count and ovarian volume, and Doppler of both ovarian arteries was also performed. Controlled ovarian stimulation was performed and the patients were divided in two groups according to the result of the intrauterine insemination: group A (nonpregnant women) and group B (pregnant women). RESULTS: Ovarian velocimetric pattern was similar between the two groups. Follicle stimulating hormone value had a significant correlation with the ultrasound markers; however, the multiple regression linear analysis showed that the only independent variables were the antral follicle count (t = -2.74, p = 0.008) and the systolic/diastolic ratio (t = 3.95, p = 0.0005). The best parameters in predicting the pregnancy were the mean ovarian volume, total and partial antral follicle count between 7 and 10 mm, and the mean resistance index (area under the curve: 0.744, 0.671, 0.667, 0.573, respectively). CONCLUSIONS: The Doppler study of the ovarian arteries did not add significant information about the ovarian reserve status. Only the mean resistance index had a significant diagnostic accuracy, but its specificity (53%) is too low to consider it a screening test.