Proposal for targeted, neo-evolutionary-oriented secondary prevention of early-onset endometriosis and adenomyosis. Part II: medical interventions.

According to consistent epidemiological data, the slope of the incidence curve of endometriosis rises rapidly and sharply around the age of 25 years. The delay in diagnosis is generally reported to be between 5 and 8 years in adult women, but it appears to be over 10 years in adolescents. If this is true, the actual onset of endometriosis in many young women would be chronologically placed in the early postmenarchal years. Ovulation and menstruation are inflammatory events that, when occurring repeatedly for years, may theoretically favour the early development of endometriosis and adenomyosis. Moreover, repeated acute dysmenorrhoea episodes after menarche may not only be an indicator of ensuing endometriosis or adenomyosis, but may also promote the transition from acute to chronic pelvic pain through central sensitization mechanisms, as well as the onset of chronic overlapping pain conditions. Therefore, secondary prevention aimed at reducing suffering, limiting lesion progression, and preserving future reproductive potential should be focused on the age group that could benefit most from the intervention, i.e. severely symptomatic adolescents. Early-onset endometriosis and adenomyosis should be promptly suspected even when physical and ultrasound findings are negative, and long-term ovulatory suppression may be established until conception seeking. As nowadays this could mean using hormonal therapies for several years, drug safety evaluation is crucial. In adolescents without recognized major contraindications to oestrogens, the use of very low-dose combined oral contraceptives is associated with a marginal increase in the individual absolute risk of thromboembolic events. Oral contraceptives containing oestradiol instead of ethinyl oestradiol may further limit such risk. Oral, subcutaneous, and intramuscular progestogens do not increase the thromboembolic risk, but may interfere with attainment of peak bone mass in young women. Levonorgestrel-releasing intra-uterine devices may be a safe alternative for adolescents, as amenorrhoea is frequently induced without suppression of the ovarian activity. With regard to oncological risk, the net effect of long-term oestrogen-progestogen combinations use is a small reduction in overall cancer risk. Whether surgery should be considered the first-line approach in young women with chronic pelvic pain symptoms seems questionable. Especially when large endometriomas or infiltrating lesions are not detected at pelvic imaging, laparoscopy should be reserved to adolescents who refuse hormonal treatments or in whom first-line medications are not effective, not tolerated, or contraindicated. Diagnostic and therapeutic algorithms, including self-reported outcome measures, for young individuals with a clinical suspicion of early-onset endometriosis or adenomyosis are proposed.

Proposal for targeted, neo-evolutionary-oriented, secondary prevention of early-onset endometriosis and adenomyosis. Part I: pathogenic aspects.

The potential for repeated ovulation and menstruation is thought to have provided a Darwinian advantage during the Palaeolithic. Reproductive conditions remained relatively stable until the pre-industrial era, characterized by late menarche, very young age at first birth, multiple pregnancies, and prolonged periods of lactational amenorrhoea. For hundreds of thousands of years, menstruators experienced few ovulatory cycles, even though they were genetically adapted to ovulate and menstruate every month. In the post-industrial era, the age at menarche gradually declined, the age at first birth progressively increased, and breastfeeding became optional and often of short duration. This created a mismatch between genetic adaptation and socio-environmental evolution, so that what was initially a probable reproductive advantage subsequently contributed to increased susceptibility to diseases associated with lifetime oestrogen exposure, such as ovarian, endometrial and breast cancer and, hypothetically, also those associated with the number of ovulatory menstruations, such as endometriosis and adenomyosis. The incidence of endometriosis shows a steep and progressive increase around the age of 25 years, but given the consistently reported delay in diagnosis, the actual incidence curve should be shifted to the left, supporting the possibility that the disease has its roots in adolescence. This raises the question of whether, from an evolutionary point of view, anovulation and amenorrhoea should not still be considered the physiological state, especially in the postmenarchal period. However, an increase in the frequency of endometriosis in recent decades has not been demonstrated, although this deserves further epidemiological investigation. In addition, as endometriosis occurs in a minority of individuals exposed to retrograde menstruation, other important pathogenic factors should be scrutinised. Research should be resumed to explore in more detail the transtubal reflux of not only blood, but also endometrial cells, and whether they are systematically present in the peritoneal fluid after menstruation. If repetitive ovulatory menstruation during the early reproductive years is shown to increase the risk of endometriosis and adenomyosis development and progression in susceptible individuals, hormonal interventions could be used as secondary prevention in symptomatic adolescents.

Unexplained infertility and age-related infertility: indistinguishable diagnostic entities but different IVF prognosis.

STUDY QUESTION: Is IVF indicated for couples with age-related infertility? SUMMARY ANSWER: IVF may be of doubtful utility for age-related infertility. WHAT IS KNOWN ALREADY: A diagnosis of unexplained infertility is drawn when the diagnostic work-up fails to identify any patent cause. Although typically managed uniformly, unexplained infertility is likely to comprise a wide range of conditions, including age-related infertility (at least in older women). Unfortunately, no validated tests for the identification of age-related infertility exist and these women are typically treated as unexplained cases. However, homologous ART may be less effective for these women because these techniques may be unable to treat the detrimental effects of ageing on oocyte competence. STUDY DESIGN, SIZE, DURATION: Women aged 18-42 years who underwent IVF procedures between January 2014 and December 2021 were selected retrospectively. In the first part of the study, we aimed to assess whether the proportion of women with unexplained infertility (i.e. without patent causes of infertility) increased with age. In the second part of the study, women with unexplained infertility were matched 1:1 by age, study period, and duration of infertility, to those with a patent cause of infertility. If our hypothesis is valid, the first part of the study should highlight an increase in the proportion of unexplained infertility with age. Moreover, in the second part of the study, one should observe a sharper decrease in the rate of IVF success of the procedure with age in women with an unremarkable work-up compared to those with a definite cause of infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were included if: they had been trying to conceive for more than 2 years, they had retrieved more than three oocytes, and had not undergone previous IVF attempts. We exclude couples with severe male factor (criptozoospermia), chronic anovulation, untreated hydrosalpinx, or intracavitary diseases. The first part of the study aimed at investigating the relative proportion of unexplained infertility with age. The outcome of the second part was the distribution of the live births between unexplained versus explained infertility, in women younger or older than 35 years. Only the results of the first IVF cycle were considered (including both fresh and frozen cycles). The live birth rate corresponded to the cumulative chance of a live birth per oocyte retrieval. MAIN RESULTS AND THE ROLE OF CHANCE: One thousand five hundred and thirty-five women were selected for the first part of the study; 742 of them had unexplained infertility (48%). The frequency of this diagnosis was lower among women aged <35 years (40%) compared to those ≥35 years (52%) (P < 0.001). A clear gradient emerged when considering smaller intervals of age (P < 0.001). A total of 1134 women (567 unexplained cases and 567 explained cases) were selected for the second part of the study. Baseline variables were comparable between women with unexplained and explained infertility. Among women younger than 35 years (n = 229 unexplained cases and 229 explained cases), 108 live births were observed in women with unexplained infertility (47%) and 88 in those with explained infertility (38%). In comparison, among women older than 35 years, the live births occurred in 90 (27%) and 114 (34%) couples, respectively (P = 0.03). The adjusted odds ratio (OR) for a live birth in older women with unexplained infertility was 0.63 (95% CI: 0.43-0.94). In other words, the effectiveness of IVF in older women with unexplained infertility is reduced by an additional 37% when compared to women of similar age with a patent cause of infertility. Moreover, when considering smaller intervals of age, a gradient of the adverse effect of age on the distribution of live births between unexplained and explained infertility emerged (P = 0.003). Overall, these results support the hypothesis that IVF may be of modest benefit in women with age-related infertility. The decline in IVF success is sharper in women with unexplained infertility compared to those with explained infertility, indirectly suggesting that IVF cannot effectively treat age-related infertility. LIMITATIONS, REASONS FOR CAUTION: We postulated that the greater decline in IVF success with age in the unexplained group could be related to the concomitant increase in the proportion of women with age-related infertility. However, even if this is theoretically logical, the unavailability of validated tools to diagnose age-related infertility makes our inference speculative. We cannot exclude that the prevalence of other unknown causes of infertility that cannot also be effectively overcome with IVF could increase with age. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that IVF may be of modest utility for treating age-related infertility. Offering this procedure to older women with an unremarkable infertility work-up may be questioned. However, the diagnosis of age-related infertility remains challenging and identifying a biomarker that could reliably diagnose age-related infertility is a priority. STUDY FUNDING/COMPETING INTEREST(S): The study was partially funded by the Italian Ministry of Health-current research IRCCS and by a specific grant supported by Ferring. ES declares receiving honoraria for lectures at meetings from IBSA and Gedeon-Richter and he also handles private grants of research from Ferring, IBSA, Theramex, and Gedeon-Richter. All the other authors do not have any conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Müllerian anomalies and endometriosis as potential explanatory models for the retrograde menstruation/implantation and the embryonic remnants/celomic metaplasia pathogenic theories: a systematic review and meta-analysis.

STUDY QUESTION: Does endometriosis prevalence differ in patients with obstructive Müllerian anomalies (OMA) versus those with nonobstructive Müllerian anomalies (NOMA), and in patients with NOMA versus those without Müllerian anomalies? SUMMARY ANSWER: The quantitative synthesis of published data demonstrates a substantially increased prevalence of endometriosis in patients with OMA compared with those with NOMA, and a similar prevalence in patients with NOMA and those without Müllerian anomalies. WHAT IS KNOWN ALREADY: The pathogenesis of endometriosis has not been definitively clarified yet. A higher prevalence of endometriosis in patients with OMA than in those with NOMA would support the retrograde menstruation (RM)/implantation theory, whereas a higher prevalence of endometriosis in the NOMA group than in the group without Müllerian anomalies would support the embryonic remnants/celomic metaplasia hypothesis. STUDY DESIGN, SIZE, DURATION: This systematic review with meta-analysis was restricted to full-length, English-language articles published in peer-reviewed journals between 1980 and 2023. The PubMed and EMBASE databases were searched using the keyword 'endometriosis' in combination with 'Müllerian anomalies', 'obstructive Müllerian anomalies', 'female genital malformations', 'retrograde menstruation', 'infertility', 'pelvic pain', and 'classification'. References from relevant publications were screened, and PubMed's 'similar articles' and 'cited by' functions were used. PARTICIPANTS/MATERIALS, SETTING, METHODS: Studies were selected if they reported the prevalence of surgically confirmed endometriosis in either individuals with OMA compared to those with NOMA, or patients with NOMA compared to those without Müllerian anomalies. Cohort and case-control studies and case series were deemed eligible for inclusion. Noncomparative studies, studies not reporting both the number of individuals with endometriosis and the total number of those with Müllerian anomalies or with other gynecological conditions, those including exclusively data on patients with absent or uncertain menstrual function (e.g. complete Müllerian agenesis category), or with imperforate hymen were excluded. Two reviewers independently abstracted data. The risk of bias was assessed with the Risk of Bias In Non-randomized Studies of Exposures tool. The overall certainty of the evidence was graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. MAIN RESULTS AND THE ROLE OF CHANCE: Seven retrospective studies were included. The overall mean estimate of endometriosis prevalence was 47% (95% CI, 36-58%) in patients with OMA, and 19% (95% CI, 15-24%) in patients with NOMA, with a common odds ratio (OR) of 4.72 (95% CI, 2.54-8.77). The overall mean estimate of endometriosis prevalence in patients with NOMA was 23% (95% CI, 20-27%), and that in patients without Müllerian anomalies was 21% (95% CI, 20-22%), with a common OR of 0.95 (95% CI, 0.57-1.58). The overall certainty of the evidence according to GRADE guidelines was judged as low for both comparisons. LIMITATIONS, REASON FOR CAUTION: Some NOMA subtypes may create a partial obstacle to menstrual efflux and/or generate dysfunctional myometrial contractions that favor transtubal reflux, thus increasing the risk of endometriosis and limiting the difference between OMA and NOMA. As infertility and pelvic pain are strongly associated with endometriosis, women with these symptoms are inappropriate controls. Confounding by indication could explain the lack of difference in endometriosis prevalence between patients with NOMA and those without Müllerian anomalies. WIDER IMPLICATIONS OF THE FINDINGS: The results of this meta-analysis support the validity of the RM theory but do not definitively rule out alternative hypotheses. Thus, RM may be considered the initiator for the development of endometriotic lesions, while not excluding the contribution of both inheritable and tissue-specific genetic and epigenetic modifications as disease-promoting factors. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this review. P.Ve. is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada, and the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate; and maintains both a public and private gynecological practice. E.S. discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures. All other authors declare they have no conflict of interest. REGISTRATION NUMBER: N/A.

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.

The neglected emotional drawbacks of the prioritization of embryos to transfer.

In recent years, increasing efforts have been made to develop advanced techniques that could predict the potential of implantation of each single embryo and prioritize the transfer of those at higher chance. The most promising include non-invasive preimplantation genetic testing for aneuploidy and artificial intelligence-based algorithms using time lapse images. The psychological effect of these add-ons is neglected. One could speculate that embarking on another transfer after one or more failures with the prospect of receiving an embryo of lower potential may be distressing for the couple. In addition, the symbolic and mental representation of an embryo with 'lower capacity to implant' is currently unknown but could affect couples' choices and wellbeing. These emotional responses may also undermine adherence to the programme and, ultimately, its real effectiveness. Future trials aimed at evaluating the validity of prioritization procedures must also consider the emotional burden on the couples.

Preterm birth in singleton pregnancies conceived by in vitro fertilization or intracytoplasmic sperm injection: an overview of systematic reviews.

BACKGROUND: The rate of preterm birth of singletons conceived through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is increased, being as high as 15% to 16% across Europe and the United States. However, the underlying etiology, phenotype, and mechanisms initiating preterm birth (PTB) are poorly understood. OBJECTIVE: To quantify the PTB risk and examine supposed etiology in IVF/ICSI singleton pregnancies compared to naturally conceived. STUDY DESIGN: Overview of reviews including all available systematic reviews with meta-analysis comparing PTB risk in IVF/ICSI and naturally conceived singletons. A comprehensive search of PubMed/MEDLINE, Embase, Scopus, and Cochrane Library databases was performed up to December 31, 2023. Information available on etiology, phenotype, initiation of PTB, and relevant moderators was retrieved and employed for subgroup analyses. Random-effects meta-analysis models were used for pooling effect measures. Estimates were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The extent of overlap in the original studies was measured using the corrected covered area assessment. The quality of the included reviews was evaluated with the AMSTAR 2 tool. The Grading of Recommendations Assessment, Development and Evaluation approach was applied to rate evidence certainty. The protocol was registered on PROspective Register of Systematic Reviews (CRD42023411418). RESULTS: Twelve meta-analyses (16,522,917 pregnancies; ˃433,330 IVF/ICSI) were included. IVF/ICSI singletons showed a significantly higher PTB risk compared to natural conception (PTB ˂37 weeks: OR: 1.72, 95% CI: 1.57-1.89; PTB<32 weeks: OR: 2.19, 95% CI: 1.82-2.64). Influential analysis reinforced the strength of this association. Subgroup analyses investigating supposed etiology revealed a comparable risk magnitude for spontaneous PTB (OR: 1.79, 95% CI: 1.56-2.04) and a greater risk for iatrogenic PTB (OR: 2.28, 95% CI: 1.72-3.02). PTB risk was consistent in the subgroup of conventional IVF (OR: 1.95, 95% CI: 1.76-2.15) and higher in the subgroup of fresh only (OR: 1.79, 95% CI: 1.55-2.07) vs frozen-thawed embryo transfers (OR: 1.39, 95% CI: 1.34-1.43). There was minimal study overlap (13%). The certainty of the evidence was graded as low to very low. CONCLUSION: Singletons conceived through IVF/ICSI have a 2-fold increased risk of PTB compared to natural conception, despite the low certainty of the evidence. There is paucity of available data on PTB etiology, phenotype, or initiation. The greater risk increase is observed in fresh embryo transfers and involves iatrogenic PTB and PTB ˂32 weeks, likely attributable to placental etiology. Future studies should collect data on PTB etiology, phenotype, and initiation. IVF/ICSI pregnancies should undertake specialistic care with early screening for placental disorders, cervical length, and growth abnormalities, allowing appropriate timely follow-up, preventive measures, and therapeutic interventions strategies.

Probability of second live birth after first natural and medically assisted reproduction-mediated live birth: A historical cohort study.

INTRODUCTION: Evidence on the role of medically assisted reproduction (MAR) in achieving the desired number of children is very limited. The aim of the current investigation was to assess the probability and the mode of conception of a second live birth according to the mode of conception of the first one. MATERIAL AND METHODS: This historical cohort study was based on administrative data from regional healthcare databases. Women hospitalized for childbirth in Lombardy between January 1, 2007 and December 31, 2017 were identified. The probability of a second live birth up to 2021 was estimated using the Kaplan-Meier method. We calculated this probability according to the mode of conception of the first birth, and the analysis was also performed in strata of maternal age at first birth. Cox proportional hazards models were fitted to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the association between mode of conception at first live birth and the probability of having a second live birth. Mothers were right-censored if they moved out of the region, died, or did not have a second live birth by the end of follow-up. RESULTS: We identified 431 333 women who had their first live birth after a natural conception and 16 837 who had their first live birth after MAR. The probability of having a second live birth was 58.6% and 32.1%, respectively in the two groups (HR = 0.68, 95% CI: 0.66-0.70). Considering solely women who naturally conceived their first live birth, the probability to have a second child with MAR was 1.1% and to have a second child naturally 59.3%. The corresponding values were 11.5% and 25.2% in the group of women with a first MAR-mediated live birth. CONCLUSIONS: In our cohort, one woman out of 10 having a first MAR-mediated live birth underwent MAR programs again. Considering women who had a first natural live birth, this proportion was drastically reduced. In the field of MAR, more attention should be given to the capacity of a couple to achieve the number of desired children.

Return rate following a live birth obtained with ART: frequency and determinants.

PURPOSE: To understand how often couples return to ART centres for a second child. METHODS: Retrospective monocentric cohort study including women who had a first live birth with IVF. The primary objective was to assess the rate of those returning for a second child within five years of the previous pregnancy. The secondary aim was to disentangle the determinants of this rate. RESULTS: A total of 374 patients were included, of whom 188 returned (50%, 95% CI 45-55%). Among those who did not return (n = 186), four (2%) referred to another ART Center and 24 were unreachable. Of the 158 contacted subjects that did not refer for ART, 53 (34%, 95% CI 27-41%) conceived naturally, 57 (36%, 95% CI 29-44%) abandoned their intent of parenthood, and 48 (30%, 95% CI 24-38%) unsuccessfully attempted natural conception. These 48 women (13%) who expressed interest in a second child but did not undergo ART were compared to those seeking a second pregnancy through ART. Baseline characteristics were similar except for an older age (Median 36, IQR: 34-38 vs 34, IQR: 32-36, p = 0.001). Additionally, in terms of IVF cycle characteristics, women who did not return were more likely to achieve their first pregnancy with a fresh transfer rather than a frozen transfer (75% vs 59%, p = 0.05). They also had a higher number of retrieved oocytes (Median 10, IQR: 7-13 vs 9, IQR: 5-12) and less frequently cryopreserved embryos (27% vs 52%, p = 0.003). CONCLUSION: The proportion of couples who have conceived with ART and who are interested in having a second child is high. Our results underline the importance of paying more attention to the number of intended children, as this information could influence clinical management.

ART and the forgotten siblings: a call for research.

A broader definition of infertility is the incapacity to have the intended number of children. However, most literature on ART exclusively focuses on live birth as an outcome, rather than on the capacity to fully realize the reproductive wishes of the couples. This issue has probably received scant attention because the total fertility rate is below replacement levels in affluent countries, and one may simplistically assume that only a minority of couples may be interested in more than one child. This assumption, however, is unproven and presumably erroneous. Unfortunately, evidence on the rate of return in couples who conceived their first child with ART is scant and information on the intended number of children in infertile couples is lacking. In general, we plea for more research on this subject. The documentation of an intended number of children above two and a high return rate in infertile couples may lead to changes in clinical practice, such as the storage of oocytes or embryos prior to initiating embryo transfers. This could improve the chance of conceiving the second child when the couple comes back some years later. In addition, the identification of the determinants for non-return as well as those explaining the gap between the intended and the realized number of children may reveal specific barriers and possibly how to tackle them. However, at present, available evidence is insufficient to advocate any intervention. Thorough research is warranted.

Anti-Müllerian hormone predicts positive sperm retrieval in men with idiopathic non-obstructive azoospermia-findings from a multi-centric cross-sectional study.

STUDY QUESTION: Is it possible to identify a reliable marker of successful sperm retrieval (+SR) in men with idiopathic non-obstructive azoospermia (iNOA) undergoing microdissection testicular sperm extraction (mTESE)? SUMMARY ANSWER: A higher likelihood of +SR during mTESE is observed in men with iNOA and lower preoperative serum anti-Müllerian hormone (AMH) levels, with good predictive accuracy achieved using an AMH threshold of <4 ng/ml. WHAT IS KNOWN ALREADY: AMH has been previously linked to +SR in men with iNOA undergoing mTESE prior to ART. STUDY DESIGN, SIZE, DURATION: A multi-centre cross-sectional study was carried out with a cohort of 117 men with iNOA undergoing mTESE at three tertiary-referral centres. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from 117 consecutive white-European men with iNOA presenting for primary couple's infertility associated with a pure male factor at three centres were analysed. Descriptive statistics was applied to compare patients with negative (-SR) versus +SR at mTESE. Multivariate logistic regression models were fitted to predict +SR at mTESE, after adjusting for possible confounders. Diagnostic accuracy of the factors associated with +SR was assessed. Decision curve analyses were used to display the clinical benefit. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 60 (51.3%) men had an -SR and 57 (48.7%) had a +SR at mTESE. Patients with +SR had lower levels of baseline AMH (P = 0.005) and higher levels of estradiol (E2) (P = 0.01). At multivariate logistic regression analysis, lower levels of AMH (odds ratio: 0.79; 95% CI: 0.64-0.93, P = 0.03) were associated with +SR at mTESE, after adjusting for possible confounders (e.g. age, mean testicular volume, FSH, and E2). A threshold of AMH <4 ng/ml achieved the highest accuracy for +SR at mTESE, with an AUC of 70.3% (95% CI: 59.8-80.7). Decision curve analysis displayed the net clinical benefit of using an AMH <4 ng/ml threshold. LIMITATIONS, REASONS FOR CAUTION: There is a need for external validation in even larger cohorts, across different centres and ethnicities. Systematic reviews and meta-analysis to provide high level of evidence are lacking in the context of AMH and SR rates in men with iNOA. WIDER IMPLICATIONS OF THE FINDINGS: Current findings suggest that slightly more than one in two men with iNOA had -SR at mTESE. Overall, men with iNOA with lower levels of AMH had a significantly higher percentage of successful SR at surgery. A threshold of <4 ng/ml for circulating AMH ensured satisfactory sensitivity, specificity, and positive predictive values in the context of +SR at mTESE. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by voluntary donations from the Urological Research Institute (URI). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Endometriosis and IVF treatment outcomes: unpacking the process.

Advanced endometriosis is associated with a reduction of IVF success. Surgical damage to the ovarian reserve following the excision of endometriomas has been claimed as a critical factor in the explanation of this detrimental effect. However, it is generally inferred that other mechanisms might also hamper IVF success in affected women. They include diminished responsiveness to ovarian stimulation, altered steroidogenesis, a decline in oocyte quality, reduced fertilization and embryo development, and impaired implantation. To navigate these limitations, we scrutinized available literature for studies specifically designed to address distinct phases of the IVF process. Utmost consideration was given to intra-patient ovarian response comparisons in women with unilateral endometriomas and to studies applying a meticulous matching to control confounders. The following observations have been drawn: 1) endometriosis has a negligible impact on ovarian response. A slight reduction in stimulation response can only be observed for endometriomas larger than 4 cm. Follicular steroidogenesis is unaffected; 2) oocyte quality is not hampered. Fertilization rates are similar, and intracytoplasmic sperm injection (ICSI) is not justified. Embryonic development is uncompromised, with no increase in aneuploidy rate; 3) endometrial receptivity is either unaffected or only slightly impacted. In conclusion, our study suggests that, aside from the well-known negative effect on ovarian reserve from excisional endometrioma surgeries, endometriosis does not significantly affect IVF outcomes.

The neglected role of preimplantation genetic testing for Lynch syndrome.

Preimplantation genetic testing for monogenic/single-gene disorders (PGT-M) is a procedure employed in the field of assisted reproductive technology to avoid the transmission of genetic diseases to the offspring. Hereditary cancer syndromes represent a diffuse and accepted indication for PGT-M, but take-up differs among the different disorders. Its use is markedly lower for the genes causing Lynch syndrome compared with the breast cancer type 1 or 2 susceptibility genes (BRCA1/2), despite the similar prevalence and severity of the two conditions. Reasons to explain this difference have not been explored. First, Lynch syndrome may be more frequently undiagnosed compared with hereditary breast and ovarian cancer syndrome. In addition, the different take-up may be due to different patient perceptions of the conditions and of the management options. Finally, this distinct attitude may depend on the awareness and sensibility of the professionals caring for affected patients. The authors' considerations are, however, speculative, and specific studies aimed at disentangling the causes of the different receptions of PGT-M are warranted to understand how to tackle this gap. In the meantime, we believe that empowerment regarding PGT-M of all individuals with hereditary cancer syndromes, including Lynch syndrome, is ethically due, and plead for a more active involvement of caregivers.

Is endometrial receptivity affected in women with endometriosis? Results from a matched pair case-control study of assisted reproductive technology treatments.

RESEARCH QUESTION: Is endometriosis detrimental to embryo implantation? DESIGN: A retrospective matched case-control study of women with a surgical or ultrasound diagnosis of endometriosis at Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico di Milano between 2015 and 2021. Women with endometriosis who underwent a 'freeze-all' cycle during an IVF treatment were eligible to be included. They were matched to patients without the disease, who also underwent cryopreserved blastocyst transfer cycles, in a 1:1 ratio by age (±1 year), and number (=) and quality (±1 top versus low) of cryopreserved blastocysts. All women underwent single frozen embryo transfer, and assisted reproductive technology outcomes suggested by the Core Outcome Measure for Infertility Trials initiative were evaluated. The main outcome was the cumulative live birth rate per cycle. RESULTS: One hundred and one women with endometriosis and 101 matched unaffected women were included. Cumulative live birth rate per cycle did not vary between women with and without endometriosis (50% versus 58%, respectively; P = 0.32). On the basis of the Kaplan-Meier analysis, the predicted success rates over four embryos transferred were also similar (74% versus 82%, respectively; P = 0.67). CONCLUSION: In women with moderate or severe endometriosis, these retrospective results seem to indicate no or a limited effect of the disease on endometrial receptivity.

Non-response to first-line hormonal treatment for symptomatic endometriosis: overcoming tunnel vision. A narrative review.

One-fourth to one-third of women with endometriosis receiving first-line hormonal treatment lacks an adequate response in terms of resolution of painful symptoms. This phenomenon has been ascribed to "progesterone resistance", an entity that was theorized to explain the gap between the ubiquity of retrograde menstruation and the 10% prevalence of endometriosis among women of reproductive age.Nevertheless, the hypothesis of progesterone resistance is not free of controversies. As our understanding of endometriosis is increasing, authors are starting to set aside the traditionally accepted tunnel vision of endometriosis as a strictly pelvic disease, opening to a more comprehensive perspective of the condition. The question is: are patients not responding to first-line treatment because they have an altered signaling pathway for such treatment, or have we been overlooking a series of other pain contributors which may not be resolved by hormonal therapy?Finding an answer to this question is evermore impelling, for two reasons mainly. Firstly, because not recognizing the presence of further pain contributors adds a delay in treatment to the already existing delay in diagnosis of endometriosis. This may lead to chronicity of the untreated pain contributors as well as causing adverse consequences on quality of life and psychological health. Secondly, misinterpreting the consequences of untreated pain contributors as a non-response to standard first-line treatment may imply the adoption of second-line medical therapies or of surgery, which may entail non-negligible side effects and may not be free of physical, psychological and socioeconomic repercussions.The current narrative review aims at providing an overview of all the possible pain contributors in endometriosis, ranging from those strictly organic to those with a greater neuro-psychological component. Including these aspects in a broader psychobiological approach may provide useful suggestions for treating those patients who report persistent pain symptoms despite receiving first-line hormonal medical treatment.

Conventional IVF performs similarly in women with and without endometriosis.

PURPOSE: A reduced oocyte competence has been claimed as one of the factors underlying infertility in women with endometriosis. This idea has justified the hypothesis that intracytoplasmic sperm injection (ICSI), rather than conventional IVF (c-IVF), may overcome oocyte impairment and ensure better assisted reproduction technology (ART) outcomes; however, data from the literature are controversial. Thus, the aim of this study was to compare ART success rates following (c-IVF) between women with and without endometriosis in the presence of normozoospermic partners. METHODS: This is a retrospective, matched case-control study of 314 patients who underwent c-IVF cycles between January 2014 and December 2020. Women with endometriosis were matched in a 1:1 ratio with patients undergoing ART for other indications, considering age (± 6 months), number of oocytes retrieved (± 1), and study period. The main outcome measures included total fertilization failure, fertilization rate, embryo quality, cumulative clinical pregnancy, and live birth rates. RESULTS: The fertilization rate and the proportion of women with total fertilization failure did not differ between women with and without endometriosis. Similarly, all other embryological variables did not also differ, except for the number of top-quality cleavage stage embryos which was higher in the endometriosis group. Cumulative clinical pregnancy and live birth rates were similar between women with and without endometriosis. CONCLUSION: A diagnosis of endometriosis does not negatively affect the performance of c-IVF; thus, c-IVF can be efficiently used in women affected, unless a male factor is also involved. This issue holds clinical relevance to help operators on their insemination technique decision-making.

Follicular steroidogenesis in random start protocols for oocyte cryopreservation.

PURPOSE: Random start protocols are commonly used for oocyte cryopreservation in women with cancer. However, albeit generally reassuring, available evidence is still insufficient to rule out a sub-optimal cycle outcome. This study aimed to compare follicular steroidogenesis between women initiating the random start protocol in the luteal phase and those initiating in the follicular phase. METHODS: Consecutive women with cancer scheduled for oocyte cryostorage were prospectively recruited. We excluded those requiring a concomitant letrozole assumption. All women received a standardized protocol with recombinant FSH and GnRH antagonists. At the time of oocyte retrieval, follicular fluids were pooled, and a sample was collected and frozen at -80 °C. All samples were assayed concomitantly after thawing by liquid chromatography-tandem mass spectrometry. The concentration of 15 different steroid hormones was determined. RESULTS: Seventy-one women were recruited. Thirty-three initiated the ovarian stimulation in the luteal phase, while the remaining 38 initiated in the follicular phase. Baseline characteristics were generally similar. Cycle outcome did also not differ; the median (interquartile range) number of frozen mature oocytes was 9 (5-14) and 10 (5-21), respectively (p = 0.42). None of the 15 tested steroid hormones differed. CONCLUSIONS: The endocrine microenvironment surrounding oocytes is not markedly influenced by the phase of the menstrual cycle at the initiation of ovarian stimulation. This result further supports the validity of random start protocols.

Progesterone levels during ovarian stimulation in segmented ART cycles inversely correlate with normalized birthweight of neonates conceived through subsequent frozen-thawed embryo transfer.

PURPOSE: To evaluate the association between serum progesterone (P) at the day of ovulation trigger and neonatal birthweight in singletons born after frozen-thawed embryo transfer in segmented ART cycles. METHODS: A retrospective multicenter cohort study involving data from patients who achieved uncomplicated pregnancy and term delivery of ART-conceived singleton babies following a segmented GnRH antagonist cycle. The main outcome was birthweight's z-score of the neonate. Univariate and multivariate linear logistic regression analyses were made to investigate the relation of z-score with variables inherent to the patient and to the ovarian stimulation. The variable P per oocyte was created by dividing the value of progesterone at ovulation trigger by the number of oocytes retrieved at oocyte retrieval. RESULTS: A total of 368 patients were included in the analysis. At univariate linear regression, the birthweight z-score of the neonate appeared to be inversely related to both P levels at the ovulation trigger (- 0.101, p = 0.015) and P levels per oocyte at trigger (- 1.417, p = 0.001), while it was directly related to the height of the mother (0.026, p = 0.002) and to the number of previous live births (0.291, p = 0.016). In multivariate analysis, both serum P (- 0.1; p = 0.015) and P per oocyte (- 1.347, p = 0.002) maintained the significant inverse association with birthweight z-score after adjusting for height and parity. CONCLUSIONS: Serum progesterone level on the day of ovulation trigger inversely correlates with normalized birthweight of neonates in segmented GnRH antagonist ART cycles.

Extracellular vesicle research in reproductive science: Paving the way for clinical achievements†.

Mammalian conception involves a multitude of reciprocal interactions via a molecular dialogue between mother and conceptus. Extracellular vesicles (EVs) are secreted membrane-encapsulated particles that mediate cell-to-cell communication in various contexts. EVs, which are present in seminal, follicular, oviductal, and endometrial fluids, as well as in embryo secretions, carry molecular constituents that impact gamete maturation, fertilization, early embryo development, and embryo-maternal communication. The distribution, concentration, and molecular cargo of EVs are regulated by steroid hormones and the health status of the tissue of origin, and thus are influenced by menstrual phase, stage of conception, and the presence of infertility-associated diseases. EVs have been recognized as a novel source of biomarkers and potential reproductive medicine therapeutics, particularly for assisted reproductive technology (ART). There are still many technological and scientific hindrances to be overcome before EVs can be used in clinical diagnostic and therapeutic ART applications. Issues to be resolved include the lack of standardized measurement protocols and an absence of absolute EV quantification technologies. Additionally, clinically suitable and robust EV isolation methods have yet to be developed. In this review, we provide an overview of EV-mediated interactions during the early stages of reproduction from gamete maturation to embryo implantation and then outline the technological progress that must be made for EV applications to be translated to clinical settings.