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Sperm motility is a crucial factor in male fertility. Photobiomodulation (PBM) has been reported to increase sperm motility, but a consistent approach suitable for identifying standardizable protocols is lacking. We collected asthenozoospermic (n = 70) and normozoospermic (n = 20) semen. The asthenozoospermic samples were irradiated with an 810 nm diode laser, in continuous wave mode, at 0.25 W, 0.5 W, 1 W and 2 W for 60 s on a circular area of 1 cm 2  through a novel handpiece with an innovative flat-top profile. Sperm motility was assessed immediately, after 30 and 60 min. A sample size calculator, unpaired t-test and one-way ANOVA with post-hoc Tukey HSD tests were used for statistics. One and 2 W were the most effective outputs in increasing progressive motility compared to control (p < 0.001). The maximum effect was immediately after 1 W-PBM (p < 0.001) and decreased after 60 min (p < 0.001). Time physiologically decreased vitality (p < 0.001), but less in the 1 W-PBM samples (p < 0.05). 1 W-PBM did not affect chromatin condensation. Asthenozoospermic samples displayed an impairment of 80% in oxygen consumption and ATP production and a slight inefficiency of oxidative phosphorylation compared to normozoospermic samples (p < 0.001). 1 W-PBM partially restored the functionality of aerobic metabolism (p < 0.001) by recovery of oxidative phosphorylation efficiency. PBM did not affect lactate dehydrogenase (glycolysis pathway). No irradiated samples increased accumulated malondialdehyde, a marker of lipidic peroxidation. In conclusion, PBM improves progressive motility in asthenozoospermia through increased mitochondrial energetic metabolism without harmful oxidative stress., (© 2024. The Author(s).)

Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1-34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11 + cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts., (© 2024. The Author(s).)

Background: Cryopreservation of human spermatozoa is a widely used technique in the assisted reproduction technology laboratory for the storage of gametes for later use, for the fertility preservation and for sperm donation programs. Cryopreservation can cause damage to membrane, cytoskeletal, acrosome and increased oxidative stress, sperm DNA damage and transcriptome changes. To assess the impact of storage time on the transcriptome of frozen human spermatozoa, semen samples were collected from 24 normospermic donors of whom 13 had cryostored semen for a short-time (1 week) and 11 had cryostored semen for a long-time (median 9 years)., Results: RNA was extracted from each frozen-thawed sperm sample, randomized in pools, and analyzed by microarrays. Five transcripts were in higher abundance in the long-time respect to the short-time storage group. Functional annotation enrichment disclosed that that the length of cryostorage has no effect on critical pathways involved in sperm physiology and function., Conclusions: The storage time of cryopreserved human spermatozoa does not affect pathways involved in fertility., (© 2024. The Author(s).)

Purpose: This position statement by the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR) aims to establish an optimal framework for fertility preservation outside the standard before oncological therapies. Key topics include the role of fertility units in comprehensive fertility assessment, factors impacting ovarian potential, available preservation methods, and appropriate criteria for offering such interventions., Methods: The SIFES-MR writing group comprises Italian reproductive physicians, embryologists, and scientists. The consensus emerged after a six-month period of meetings, including extensive literature review, dialogue among authors and input from society members. Final approval was granted by the SIFES-MR governing council., Results: Fertility counselling transitions from urgent to long-term care, emphasizing family planning. Age, along with ovarian reserve markers, is the primary predictor of female fertility. Various factors, including gynecological conditions, autoimmune disorders, and prior gonadotoxic therapies, may impact ovarian reserve. Oocyte cryopreservation should be the preferred method. Women 30-34 years old and 35-39 years old, without known pathologies impacting the ovarian reserve, should cryopreserve at least 12-13 and 15-20 oocytes to achieve the same chance of a spontaneous live birth they would have if they tried to conceive at the age of cryopreservation (63% and 52%, respectively in the two age groups)., Conclusions: Optimal fertility counselling necessitates a long-term approach, that nurtures an understanding of fertility, facilitates timely evaluation of factors that may affect fertility, and explores fertility preservation choices at opportune intervals., (© 2024. The Author(s).)

Approximately 10% to 15% of breast cancer cases in young women are diagnosed in patients harbouring germline (g) pathogenic or likely pathogenic variants (PVs) in the BReast CAncer 1 ( BRCA1 ) or BReast CAncer 2 ( BRCA2 ) genes. Preclinical and clinical studies showed a potential negative effect of germline BRCA 1/2 (g BRCA1/2 ) PVs on ovarian reserve and reproductive potential, even before starting anticancer therapies. The aim of this article is to summarize the current literature on the fertility potential of young g BRCA1/2 PVs carriers with breast cancer and the risk of gonadotoxicity associated with anticancer treatments. Moreover, we describe the available evidence on the efficacy of fertility preservation techniques in young g BRCA1/2 PVs carriers and the safety data on having a pregnancy after breast cancer treatment., (© The Author(s) 2024.)

Sperm cryopreservation is a procedure widely used to store gametes for later use, to preserve fertility in patients prior to gonadotoxic treatments or surgery, and for sperm donation programs. The purpose of the study was to assess the impact of cryopreservation on human sperm transcriptome. Semen samples were collected from 13 normospermic men. Each sample was divided into two aliquots. The total RNA was immediately extracted from one aliquot. The second aliquot was frozen and total RNA was extracted after a week of storage in liquid nitrogen. The RNA samples were randomized in four pools, each of six donors, and analyzed by microarrays. The paired Significance Analysis of Microarray was performed. We found 219 lower abundant transcripts and 28 higher abundant transcripts in cryopreserved sperm than fresh sperm. The gene ontology analysis disclosed that cryopreservation alters transcripts of pathways important for fertility (i.e., spermatogenesis, sperm motility, mitochondria function, fertilization, calcium homeostasis, cell differentiation, and early embryo development), although the increase of some transcripts involved in immune response can compensate for the harmful effects of freezing., Competing Interests: M.L. reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD, and Exact Sciences and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Knight, and Takeda, Travel Grants from Gilead and Daiichi Sankyo, and research support (to the Institution) from Gilead outside the submitted work. P.A. reports speaker honoraria from Gedeon Richter, Merck, and Organon outside the submitted work. The other authors declare no conflicts of interest.

In the registrational trials, follitropin delta was compared with a fixed dose of 150 UI of follitropin alpha/beta, finding higher chances to reach a target response of 8-14 oocytes compared to controls. For this reason, follitropin delta is marketed as particularly useful in expected hyper-responder patients. The main outcome of this study is to report if comparable results are reached in a real-life scenario with follitropin alpha/beta personalized doses, based on patients' characteristics. This is a retrospective study performed in two public fertility centres. All first cycles from January 2020 to June 2022 with either follitropin delta (cases) or alpha/beta (controls) in patients with antiMüllerian hormone >2.5 ng/ml were compared by an inverse probability weighting approach based on propensity score. The follitropin total dose was higher in controls (1179.06 ± 344.93 vs. 1668.67 ± 555.22 IU, p<0.001). The target response of 8-14 oocytes was reached by 40.2% of cases and 40.7% of controls (odds ratio (OR) 0.99, 95% confidence interval (CI) 0.65-1.53, p=0.98). Fewer than 8 oocytes were collected in 24.1% of cases and 22% of controls (OR 1.10, 95% CI 0.71-1.69, p=0.67); more than 14 oocytes in 35.7% of cases and 37.3% of controls (OR 0.83, 95% CI 0.54-1.28, p=0.40). Our experience did not find worse results in term of proportion of patients who reached the target response with an algorithm-chosen dose of follitropin delta compared to a personalised starting dose of follitropin alpha/beta, with follitropin delta having the advantage of objectivity. Larger numbers are needed to confirm these results.

Since essential factors have changed in recent years in assisted reproduction technologies (ARTs), this study reassessed the association between ART and breech presentation. We primarily aimed to estimate the correlation between ART and breech at delivery. Secondary purposes were to evaluate the correlation between other subfertility treatments (OSTs) and breech and to assess possible confounding factors and temporal trends. This study investigated the 31,692,729 live birth certificates from US states and territories in the 2009-2020 period. The inclusion criteria were singleton births reporting the method of conception and the presentation at delivery. The outcome was the breech presentation at delivery, while the primary exposure was ART, the secondary exposure was OST, and the potential confounding factors from the literature were considered. ART (OR 2.32 CI.95 2.23-2.41) and OST (OR 1.79 CI.95 1.71-1.87) were independent and significant risk factors for breech at delivery ( p < 0.001). This study confirmed breech presentation risk factors maternal age, nulliparity, tobacco smoke, a previous cesarean delivery (CD), neonatal female sex, gestational age, and birth weight. Black race and Hispanic origin were verified to be protective factors. We found breech prevalence among ART and OST to be stable during the study period. Meanwhile, newborn birth weight was increased, and the gap between breech and other presentations in ART was reduced. Our results indicate that singleton pregnancies conceived by ART or OST were associated with a higher risk of breech at delivery. Well-known risk factors for the breech presentation were also confirmed. Some of these factors can be modified by implementing interventions to reduce their prevalence (e.g., tobacco smoke and previous CD).

Background: The reproductive hormone oxytocin facilitates labour, birth and postpartum adaptations for women and newborns. Synthetic oxytocin is commonly given to induce or augment labour and to decrease postpartum bleeding., Aim: To systematically review studies measuring plasma oxytocin levels in women and newborns following maternal administration of synthetic oxytocin during labour, birth and/or postpartum and to consider possible impacts on endogenous oxytocin and related systems., Methods: Systematic searches of PubMed, CINAHL, PsycInfo and Scopus databases followed PRISMA guidelines, including all peer-reviewed studies in languages understood by the authors. Thirty-five publications met inclusion criteria, including 1373 women and 148 newborns. Studies varied substantially in design and methodology, so classical meta-analysis was not possible. Therefore, results were categorized, analysed and summarised in text and tables., Results: Infusions of synthetic oxytocin increased maternal plasma oxytocin levels dose-dependently; doubling the infusion rate approximately doubled oxytocin levels. Infusions below 10 milliunits per minute (mU/min) did not raise maternal oxytocin above the range observed in physiological labour. At high intrapartum infusion rates (up to 32 mU/min) maternal plasma oxytocin reached 2-3 times physiological levels. Postpartum synthetic oxytocin regimens used comparatively higher doses with shorter duration compared to labour, giving greater but transient maternal oxytocin elevations. Total postpartum dose was comparable to total intrapartum dose following vaginal birth, but post-caesarean dosages were higher. Newborn oxytocin levels were higher in the umbilical artery vs. umbilical vein, and both were higher than maternal plasma levels, implying substantial fetal oxytocin production in labour. Newborn oxytocin levels were not further elevated following maternal intrapartum synthetic oxytocin, suggesting that synthetic oxytocin at clinical doses does not cross from mother to fetus., Conclusions: Synthetic oxytocin infusion during labour increased maternal plasma oxytocin levels 2-3-fold at the highest doses and was not associated with neonatal plasma oxytocin elevations. Therefore, direct effects from synthetic oxytocin transfer to maternal brain or fetus are unlikely. However, infusions of synthetic oxytocin in labour change uterine contraction patterns. This may influence uterine blood flow and maternal autonomic nervous system activity, potentially harming the fetus and increasing maternal pain and stress., (© 2023. The Author(s).)

Background: The male reproductive system may be a potential target for SARS-CoV-2 since the presence of ACE and TMPRS2 receptors. After a first report of the presence of SARS-CoV-2 in semen of COVID-19 patients, several papers reported that SARS-CoV-2 was not detected in the semen. However, some evidences indicated that COVID-19 disease could impair semen parameters. During the infection, or in a short period after, a reduction in sperm concentration and motility and an increase in DNA fragmentation were observed, even in asymptomatic patients. There is no conclusive data exploring whether this damage changes with time. We investigated whether COVID-19 disease has a negative impact on semen parameters and male reproductive potential after recovery., Methods: In this longitudinal retrospective study, we enrolled 20 men who had COVID-19 disease. We compared sperm parameters in samples collected before COVID-19 and after infection (8.3 ± 4.8 months). We also evaluated the reproductive potential in pre- and post-COVID-19 infertility treatments of 8 self-controlled couples as well as in 40 cycles after COVID-19 infection of the male partner., Results: For most patients, we obtained results of more than one semen analysis before and after COVID-19. After adjusting for age, days of sexual abstinence, frequency of ejaculations and presence of fever, we found no significant difference over time in any semen parameter. The interval between COVID-19 infection and subsequent infertility treatments was 10.7 ± 7.5 months. There were no differences in the embryological and clinical outcomes of infertility treatments performed before and after male infection. One couple obtained a single pregnancy in the post COVID-19 IUI. Normal fertilization (65%), cleavage (99%) and blastocyst development (40%) rates in treatments performed after male infection were within the expected range of competencies. A total of 5 singleton and 1 twin clinical pregnancies were obtained, and 6 healthy children were born. A total of 10 blastocysts have been cryopreserved., Conclusion: Our data are reassuring that COVID-19 disease has no negative effect on semen quality and male reproductive potential when semen samples are collected three months or more after infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Stigliani, Massarotti, Bovis, Maccarini, Anserini and Scaruffi.)

Purpose: To assess whether mRNA and viral vector coronavirus disease 2019 (COVID-19) vaccines detrimentally affected semen parameters., Materials and Methods: In this prospective study, we enrolled 101 men vaccinated for COVID-19 (76% received mRNA vaccines, 20% viral vector vaccines, 2% a mixed formulation, and for 2 men no information about vaccine type was available) in 2021 and with a previous semen analysis. For each man we compared semen parameters before and after vaccination., Results: Post-vaccine samples were obtained at a median of 2.3±1.5 months after the second dose. After vaccination, the median sample volume significantly decreased (from 3.0 to 2.6 mL, p=0.036), whereas the median sperm concentration, the progressive motility, and total motile sperm count increased (from 25.0 to 43.0 million/mL, p<0.0001; from 50% to 56%, p=0.022; from 34.8 to 54.6 million, p<0.0001, respectively). Thirty-four patients were oligospermic before the vaccine, and also in these patients we observed a significant increase of sperm parameters after vaccine. Finally, we confirmed the aforementioned results in men who received a mRNA or a viral vector vaccine., Conclusions: The semen parameters following COVID-19 vaccination did not reflect any causative detrimental effect from vaccination, and for the first time we demonstrated that this applies to both mRNA and viral-vector vaccines. The known individual variation in semen and the reduced abstinence time before the post-vaccine sample collection may explain the increases in sperm parameters., Competing Interests: The authors have nothing to disclose., (Copyright © 2022 Korean Society for Sexual Medicine and Andrology.)

Importance: As life span has increased among patients with cancer, survivorship has become an important component of breast cancer care. Among survivorship concerns, adequate contraceptive counseling is needed for premenopausal patients who are not seeking to become pregnant., Objective: To examine contraceptive use and chosen methods and to assess factors associated with contraceptive use over time in patients with early breast cancer., Design, Setting, and Participants: The Cancer Toxicity (CANTO) study was a multicenter nationwide prospective cohort study that enrolled women diagnosed with stage I to stage III breast cancer in France between March 2012 and December 2017. This analysis included 2900 premenopausal women who were 50 years of age or younger at diagnosis. Data were analyzed from July 2020 to July 2022., Exposures: Contraceptive use and method at diagnosis, shortly after the end of primary treatment (year 1), and during follow-up (year 2)., Main Outcomes and Measures: Contraceptive use and methods were longitudinally evaluated at diagnosis, year 1, and year 2 after breast cancer diagnosis. Multivariable logistic regression models were used to assess the associations of clinical, socioeconomic, treatment, adverse effect, and patient-reported outcome variables with contraceptive use after diagnosis., Results: A total of 2900 patients (mean [SD] age, 43.1 [5.6] years) were included in the analysis; 2050 of 2894 women (70.8%) received chemotherapy, and 2305 of 2880 women (80.0%) received endocrine therapy. After diagnosis, 1182 of 2625 patients (45.0%) at year 1 and 1553 of 2363 patients (65.7%) at year 2 reported consulting with a gynecologist in the previous year. At diagnosis, 1487 of 2744 patients (54.2%) reported contraceptive use, with most patients (921 of 1470 women [62.7%]) using hormonal methods. The use of contraception significantly decreased after diagnosis (911 of 2342 patients [38.9%] at year 1 and 808 of 1961 patients [41.2%] at year 2; P < .001 for trend), when most patients (848 of 900 women [94.2%] at year 1 and 767 of 805 women [95.3%] at year 2) reported use of nonhormonal methods; these methods were primarily reversible mechanical approaches (copper intrauterine devices: 656 of 848 patients [77.4%] at year 1 and 577 of 767 patients [75.2%] at year 2; male condoms: 115 of 848 patients [13.6%] at year 1 and 110 of 767 patients [14.3%] at year 2). In the multivariable model, factors significantly associated with contraceptive use at year 1 included using contraception at diagnosis (adjusted odds ratio [aOR], 4.02; 95% CI, 3.15-5.14), being younger (aOR, 1.09; 95% CI, 1.07-1.13 per decreasing year), having better sexual function (aOR, 1.13; 95% CI, 1.07-1.19 per 10-point increment), having children (aOR, 4.21; 95% CI, 1.80-9.86), reporting the presence of leukorrhea (aOR, 1.32; 95% CI, 1.03-1.70), receiving tamoxifen treatment alone (aOR, 1.39; 95% CI, 1.01-1.92), and consulting with a gynecologist in the previous year (aOR, 1.29; 95% CI, 1.02-1.63). Similar factors were associated with contraceptive use at year 2, with the addition of partnered status (aOR, 1.61; 95% CI, 1.07-2.44)., Conclusions and Relevance: Findings from this study support the importance of raising awareness and improving targeted contraceptive counseling for premenopausal women with early breast cancer.

Several myths and misconceptions exist about hormones in women with familial predisposition to cancer, and there are few real-life data on their prescription and uptake. To better understand how they are prescribed and accepted in healthy carriers of a BRCA1/2 pathogenetic variant, an online survey was uploaded on Google Forms and shared through social media closed groups of patients' associations, aBRCAcadabra and ACTO Campania. A total of 241 questionnaires were collected. Sexual quality of life was considered of the utmost importance by most of the respondents (mean score of 7 ± 2.8/10), but they felt the counseling they received by healthcare professionals on the topic was insufficient (4.9 ± 3.2/10). Only 57 women out of 233 (24.5%) had used hormonal contraception after being diagnosed as carriers of a BRCA pathogenetic variant, and 42 out of 148 (28.4%) underwent menopause hormonal therapy. The majority of women (53.6% for contraception and 61.5% for menopause) reported being dissatisfied with the counseling received, and 58.2% were not aware of the protective effect of hormonal contraception on the risk of ovarian cancer. An educational effort is desirable to guarantee healthy BRCA carriers reliable contraception and evidence-based menopause counseling.

Multiple sclerosis is a chronic disease that may lead to different types of symptoms and disabilities. with the better quality of life and decreased disability due to early diagnosis and the availability of disease-modifying therapies (DMTs), the treating physician is increasingly asked to counsel patients on its effects on fertility and reproduction. In particular, reproductive issues are still scarcely studied and discussed in men. Among the still open questions are the following: (a) Does multiple sclerosis cause infertility per sè? (b) Is multiple sclerosis correlated with conditions that increase the risk of infertility? (c) Do DMTs or other therapies for multiple sclerosis impact gonadal function in men? The aim of this review is to provide an overview on the available literature data about the reproductive issues unique to men with multiple sclerosis, underlining the numerous areas where evidence is lacking and, therefore, the priorities for future research.

A significant number of women receive a cancer diagnosis before their age of natural menopause. Among these patients, the most frequent neoplasms are breast cancer, gynecological, and hematological malignancies. Premature ovarian insufficiency and infertility are among the most feared short- to long-term consequences of anticancer treatments in premenopausal patients. Both patient- and treatment-related characteristics are key factors in influencing the risk of gonadotoxicity with the use of chemotherapy. The cryopreservation of oocytes/embryos is a standard strategy for fertility preservations offered to young women interested in future family planning, but it does not allow gonadal function protection during chemotherapy. Ovarian suppression with gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is now recommended as an option to reduce the risk of gonadotoxicity in order to avoid the negative consequences of premature ovarian insufficiency in premenopausal women receiving cytotoxic therapy, including those not interested in fertility preservation. This review summarizes the risk of treatment-induced gonadotoxicity in premenopausal patients and the evidence available on the protective role of administering GnRHa during chemotherapy to preserve ovarian function.