BACKGROUND:Over time, family structures have grown more complex, diversifying adult relationships. While research has compared marital, cohabiting and living apart together relationships based on quality and health, less is known about their sexual dynamics. Theoretical frameworks suggest that co-resident relationships may integrate sexuality differently from living apart together unions, where physical separation can either strengthen or weaken sexual intimacy. This study addresses this gap by analysing sexual function and satisfaction among men in marital, cohabiting and living apart together relationships. Exploring the relationship between living apart together unions and sexual and hormonal aspects can enhance our understanding of the links between hormones and the social and relational dynamics of contemporary society. METHODS:We analysed cross-sectional data from the European Male Ageing Study, a non-interventional cohort study conducted in eight European countries from 2005 to 2008. The sample included 3259 men aged 40-79 years who reported their relationship status. Sexual function was evaluated using the validated European Male Ageing Study sexual function questionnaire. Hormonal, lifestyle and health indicators were also collected. Statistical analyses, including ANCOVA, were used to adjust for confounders such as age, education, lifestyle and comorbidities. RESULTS:Living apart together relationships were reported by 6.9% of the cohort, similar to the 7.0% in cohabiting relationships, while 86.0% were married. Living apart together men were younger, more educated, and had a higher prevalence of smoking compared to married men. Compared to those in co-residential relationships, men in living apart together relationships showed higher levels of free testosterone, greater sexual desire and satisfaction, and increased frequency of sexual activity, morning erections and masturbation. Cohabiting men were in an intermediate position, with married men reporting the lowest sexual desire and activity. CONCLUSIONS:Our findings align with previous research, suggesting that living apart together relationships are associated with higher levels of sexual function and satisfaction. However, this is observed without the broader benefits of co-residence, such as emotional security, shared responsibilities and partner's health oversight. Further research is needed to clarify the interplay between relationship type, sexual and health well-being.

BACKGROUND:Childhood cancer survivors (CCS) are reported to have decreased bone mineral density (BMD). PURPOSE:Is premature ovarian insufficiency (POI) an important risk factor for low BMD in CCS at long term follow-up? PATIENTS AND METHODS:Altogether 167 female CCS, median age 34 (19-57) years, treated for childhood cancer under age 18 years between 1964 and 2008, with a follow-up time of 25 (12-41) years, and 164 matched controls took part in this cross-sectional study, including blood samples, anthropometric measurements, dual-energy X-ray absorptiometry (DXA), and questionnaires. RESULTS:CCS with primary POI (n = 22) had lower BMD in lumbar spine L1-L4 1.13 (0.79-1.39) g/cm2 compared with controls 1.20 (0.84-1.56) g/cm2 (p = 0.005) and lower BMD in femoral neck 0.89 (0.72-1.16) g/cm2 compared with controls 1.00 (0.69-1.48) g/cm2 (p = 0.020). CCS with primary POI had significantly reduced levels of androgens and low BMI < 20 kg/m2 (p = 0.003). Odds Ratio for a low BMD < - 1 SD in L1-L4 was increased among CCS with primary POI (2.76 (1.01-7.52)), but also after abdominal irradiation (3.42 (1.52-7.70)) and all irradiation (1.98 (1.05-3.76)). CONCLUSIONS:Female childhood cancer survivors are at risk of low BMD and POI is an additional risk factor at long term follow-up. Besides hypogonadism and insufficient Hormone Replacement Therapy (HRT), abdominal radiotherapy, low levels of androgens and low BMI may confer to the risk.

An increasing proportion of young male cancer patients are cured, why the issue of quality of life (QoL) of survivors plays an important role. Several studies have shown that, among young subjects treated for malignant disease, well preserved reproductive function represents one of the most important aspects of the QoL. In this chapter, the current evidence as well as gabs of knowledge regarding the impact of cancer and cancer treatment on testicular function – including fertility, androgen production and health of the offspring – are summarized. Also recommendations for preservation of fertility prior to cancer therapy as well as clinical management of reproductive issues in male cancer survivors, are given.

Data on cancer risk in offspring of men with testicular germ cell cancer (TC) remain limited. We assessed the risk of childhood and adolescent and young adult (AYA) cancer in offspring of men with TC. Men diagnosed with TC in the Danish Cancer Registry (1943-2017) were identified (TC probands). For each TC proband, 10 men matched on birth year, alive, and cancer-free at the proband's date of diagnosis were selected from the National Civil Registration System (non-TC probands). Offspring were identified in the Danish Birth Registry, with cancer diagnoses obtained from national registries. Cumulative incidences, hazard ratios (HRs), with 95% confidence intervals (CIs) were calculated for childhood cancer (0-14 years) and AYA cancer (15-39 years), including TC specifically versus other cancers. Offspring were included regardless of whether they were born before or after their father's diagnosis (for TC probands) or the corresponding index date (for non-TC probands). Childhood cancer rates were similar between sons of TC probands and non-TC probands (HR 1.0, 95% CI 0.6-1.7) and daughters (HR 1.1, 95% CI 0.6-1.9). For AYA cancer, rates in daughters were comparable, while sons of TC probands had an increased rate (HR 1.9, 95% CI 1.6-2.4). This increase was driven by TC (HR 3.6, 95% CI 2.7-4.8), with no significant difference in rates of other cancers. The rate of childhood cancer in offspring of men with TC is comparable to the rate of the general population, while the elevated AYA cancer rate in sons is attributable to a higher rate of TC.

Whereas the link between impaired male fertility and risk of testicular and prostate cancer is well established, studies investigating non-reproductive cancer risk among men with impaired reproductive function are scarce and show conflicting results. The aim of the study was to compare the risk of developing non-reproductive cancers in men achieving paternity through assisted reproduction as compared to those conceiving naturally. All first-time fathers n = 1 137 829 in Sweden during the period January 1994 to December 2014 were included and followed from the time of conception until date of cancer diagnosis, death, or end of follow-up (31st of December 2014). Conception by intracytoplasmic sperm injection (ICSI) or use of donated spermatozoa was used as proxy for impaired male fertility. As controls we used males who conceived spontaneously. National register based cohort study. By linking the Swedish multigeneration register with the Swedish medical birth register (MBR), all men conceiving their 1st child between 1994 and 2014 in Sweden were identified (n = 1 181 490). Information on mode of conception was derived from the MBR or the Q-IVF register. Men with history of cancer prior to conception, missing covariate data, and those with missing information to estimate gestational age were excluded (n = 43 661). From the Swedish cancer registry data was retrieved on cancer diagnoses during follow-up. Fathers´ fertility status was based on mode of conception i.e. naturally, standard in-vitro fertilization (IVF) or ICSI. Diagnosis of any type of non-reproductive cancer according to International Classification of Diseases 7th revision (ICD-7) after the time of conception. Among 1 137 829 men, 20 142 and 14 540 achieved paternity through IVF and ICSI treatment, respectively. ICSI-fathers and those using donated spermatozoa were, as compared to those conceiving spontanouesly, at an increased risk of non-reproductive cancers (adjusted hazardo ratio (aHR) 1.3; 95

BackgroundProstate cancer therapy with surgical or chemical castration with gonadotropin-releasing hormone (GnRH) agonists has been linked to elevated follicle-stimulating hormone (FSH) levels, which may contribute to secondary health disorders, including atherosclerosis and diabetes. Although recent findings suggest a role for FSH beyond the reproductive system, its metabolic impact remains unclear and difficult to disentangle from that of androgens. In this study, we examined the metabolic changes induced by FSH and distinguished them from those caused by testosterone.MethodsPlasma samples from temporarily medically castrated young men (n = 33) treated with FSH and/or testosterone were characterized by proteomics and metabolomics approaches. All subjects received GnRH antagonists. Sixteen men were randomized to recombinant FSH (300 IU 3 times/week) for 5 weeks, while seventeen men served as controls. After 3 weeks, all men received 1000 mg intramuscular testosterone undecanoate. Blood samples were collected at the start, after 3 weeks and after 5 weeks. The proteome and metabolome signatures were characterized in all samples.ResultsFSH significantly upregulates key proteins involved in the modulation of inflammatory response and innate immune system (P ≤ 0.03) and dysregulates lipid metabolism, evidenced by downregulation of multiple apolipoproteins (P ≤ 0.04) and increased levels of cholesterol and glycerophospholipids (P ≤ 0.03). In addition, low FSH levels were correlated with a reduction in the active form of vitamin D (P < 0.02). These results highlight the short-term metabolic impacts of FSH in males.Conclusions and Clinical ImplicationsOur findings underlined the FSH effect on extragonadal systems and its connection to metabolic disorders often seen as secondary effects of prostate cancer treatment.

BACKGROUND:Endocrine science remains underrepresented in European Union research programs despite the fundamental role of hormone health in human wellbeing. Analysis of the CORDIS database reveals a persistent gap between the societal impact of endocrine disorders and their research prioritization. At national funding level, endocrine societies report limited or little attention of national research funding towards endocrinology. The EndoCompass project-a joint initiative between the European Society of Endocrinology and the European Society of Paediatric Endocrinology, aimed to identify and promote strategic research priorities in endocrine science to address critical hormone-related health challenges. METHODS:Research priorities were established through comprehensive analysis of the EU CORDIS database covering the Horizon 2020 framework period (2014-2020). Expert consultation was conducted to identify key research priorities, followed by broader stakeholder engagement including society members and patient advocacy groups. RESULTS:Research priorities encompass variations in sex development, hypothalamic-pituitary-gonadal regulation, and female and male reproductive disorders. Key areas include improving diagnostic capacity through (epi)genetic analysis, optimizing hormonal treatments, developing fertility preservation strategies. Special emphasis is placed on establishing pan-European registries, developing novel reproductive technologies, and exploring environmental impacts on reproductive health. CONCLUSIONS:This component of the EndoCompass project provides an evidence-based roadmap for strategic research investment. This framework identifies crucial investigation areas into reproductive and developmental endocrinology pathophysiology, prevention, and treatment strategies, ultimately aimed at reducing the burden of these disorders on individuals and society. The findings support the broader EndoCompass objective of aligning research funding with areas of the highest potential impact in endocrine health.

Objective: To study the association between sperm deoxyribonucleic acid fragmentation index (DFI) and the odds of preeclampsia and other adverse perinatal outcomes after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment. Design: A prospective cohort study including infertile couples undergoing conventional IVF or ICSI treatment and their children. Data regarding preeclampsia and perinatal outcomes were derived from the Swedish National Birth Register. Patient(s): A total of 1,594 infertile couples undergoing IVF or ICSI treatment and their 1,660 children conceived by assisted reproduction. Exposure: Sperm DFI measured by Sperm Chromatin Structure Assay. Main Outcome Measure(s): The primary outcome was preeclampsia. The secondary outcomes were preterm birth (FTB), low birth weight, low Apgar score, and small for gestational age. Result(s): With a DFI level of < 20% as a reference, the odds ratio (OR) of preeclampsia statistically significantly increased in the group with a DFI level of >= 20% when IVF was used as the fertilization method (OR, 2.2; 95% confidence interval, 1.1-4.4). Already at the DFI levels of >= 10%, in IVF pregnancies, the OR of preeclampsia increased in a dose-response manner, from a prevalence of 3.1% in the reference group to > 10% among those with a DFI level of >= 30%. The DFI was not associated with the OR of preeclampsia in the ICSI group. In the entire cohort, a DFI level of >= 20% was associated with an increased OR of FTB (OR, 1.4; 95% confidence interval, 1.0-2.0). Conclusion(s): High DFI level was associated with increased odds of FTB and, in IVF pregnancies, also increased odds of preeclampsia. (c) 2024 by American Society for Reproductive Medicine.

ObjectiveThis study aimed to compare cumulative [fresh and frozen embryo transfers from one ovarian stimulation (OS) cycle] pregnancy and live birth rates in women for whom the choice between recombinant FSH (rFSH) and urinary FSH (uFSH) for OS was linked to FSH receptor (FSHR) N680S genotype and compared these to non-genotyped controls.MethodsTo define the optimal combination of FSH type and FSHR genotype, 475 women were allocated to either the rFSH group or to the uFSH group for OS. The number of aspirated oocytes, cumulative pregnancy rates, and live birth rates in the first OS cycle were determined. Subsequently, their FSHR N680S (rs6166) variant was analyzed. Clinical data were backed up by in vitro experiments, in which COS-1 cells were transfected with homozygous FSHR variants and stimulated with either uFSH or rFSH. cAMP was measured to evaluate receptor activity. Thereafter, a sub-cohort of 221 who received optimal FSH treatment in relation to their FSHR genotype was selected from the total cohort of 475 women. Cumulative pregnancy and live birth rates were compared between 991 non-genotyped controls and these 221 women. Binary logistic regression was used to explore the odds ratios (ORs) and 95% confidence intervals (CIs) for cumulative pregnancy and live birth rates in the first OS cycle among genotyped and optimally treated women, with the non-genotyped cohort set as the reference. Adjustment was made for age, body mass index, and method of fertilization.ResultsThe combined clinical and in vitro data indicated that uFSH was the optimal choice for FSHR N680S S-allele carriers, whereas rFSH was the hormone of choice for asparagine (NN) subjects. The sub-cohort consisting of uFSH-treated S-carriers together with rFSH-treated NN-carriers had a significantly higher chance of pregnancy (51% vs. 40%; OR: 1.40, 95% CI 1.12-1.75, p=0.003) and live birth (40% vs. 29%; OR: 1.55, 95% CI 1.23-1.96, p<0.001) compared to non-genotyped women, in whom the choice of hormone was based on a standard clinical evaluation.ConclusionA significantly increased chance of pregnancy and live birth can be achieved by a genotype-guided approach. While the administration of uFSH should be the choice for S-carriers, rFSH is beneficial for NN-carrying women.

What characterizes today’s infertile couples in terms of primary infertility cause and subsequent treatment outcomes after the first treatment cycle? Following the first fresh embryo transfer, the couples achieved a live birth rate of 46.4%. Notably, overall 25% of the couples had unexplained infertility. Infertility affects 15 − 25% of all couples, and can be associated with severe psychological, social, and economic consequences. The causes of infertility are many and complex, and the condition is often symptomatically treated with assisted reproductive technologies (ART). So far, we have characterized infertile couples, finding that 30% experience male factor infertility, 30% female factor infertility, and 30% face a combination. Further, approximately 30% of couples referred to fertility treatment do not achieve a live birth. Thus, a continued characterization of infertile couples and the treatment success is imperative for targeting needed areas for further investigation and subsequent improvement of treatments. This prospective cohort study is an ongoing bi-national cohort initiated in June 2020 in Denmark and Sweden. The Danish study sites comprise four public fertility clinics in The Capital Region and one andrology department. To date, the cohort consists of 747 Danish opposite-sex couples. We included couples referred to public fertility clinics, collecting data from blood and semen samples and medical records. Couples were classified into five infertility groups: female, male, mixed, unexplained, and PGT-M/SR. Reproductive outcomes, including LBR, were assessed after the first fresh IVF/ICSI cycle. Data are presented as N (%) or median (5–95 percentile) and stratified by infertility cause. Couples referred for PGT-M/SR were excluded from analyses on infertility cause and reproductive outcomes. The median age for women was 32.1 years (26.4 − 39.5) and 33.6 years (27.5 − 44.5) for men. The median relationship length was 5 years (2-11) and nearly all couples cohabitated. In all 153 (20.5%) were characterized with a female infertility factor only, 254 (34.0%) with male factor only and 100 (13.4%) with mixed factors, while 178 (23.8%) had an unexplained factor. Of the 747 couples, we had follow-up information on 635 couples as 54 couples never started fertility treatment and 23 couples only participated in the baseline visit while the remaining 36 were still undergoing treatment*. IVF/ICSI was the first treatment choice in 498 (78.4%) couples, while 81 couples (12.8%) had insemination in their first treatment cycle. Of the 498 couples starting an IVF/ICSI cycle, an embryo was transferred in 289 (58.0%). Freeze-all strategy was chosen in 109 (21.9%) cycles, with ovarian stimulation syndrome (OHSS) or the risk of OHSS being the main reason (63.3%) for postponing embryo transfer. LBR was 46.4% after first fresh embryo transfer and the pregnancy loss rate was 10%. LBR stratified on infertility cause were higher in couples with male factor infertility (52.6%) and lowest in couples with unexplained infertility (38.4%). *Cycle characteristics will be updated. Our results are preliminary as the study is on-going and only includes data from the Danish sites. Further, the results are solely from the Capital Region of Denmark, which may not be generalizable to the general infertile population in Denmark. This cohort is one of the largest prospective cohorts of infertile couples worldwide and the collected data from the included couples will contribute to important research for future gains of infertile couples. Yes

BACKGROUND:Endocrine science remains underrepresented in European Union research programmes despite the fundamental role of hormone health in human wellbeing. Analysis of the CORDIS database reveals a persistent gap between the societal impact of endocrine disorders and their research prioritisation. At national funding level, endocrine societies report limited or little attention of national research funding towards endocrinology. The EndoCompass project-a joint initiative between the European Society of Endocrinology and the European Society of Paediatric Endocrinology-aimed to identify and promote strategic research priorities in endocrine science to address critical hormone-related health challenges. METHODS:Research priorities were established through comprehensive analysis of the EU CORDIS database covering the Horizon 2020 framework period (2014-2020). Expert consultation was conducted to identify key research priorities, followed by broader stakeholder engagement including society members and patient advocacy groups. RESULTS:Research priorities encompass re-evaluation of progestins in breast cancer treatment; strategies to disrupt AR signalling in prostate cancer; surveillance for endocrine sequelae in childhood cancer survivors; understanding genotoxic effects on fertility; and management of checkpoint inhibitor endocrinopathies and familial cancer syndromes. Emphasis is placed on precision medicine and metabolic factors in cancer. CONCLUSIONS:This component of the EndoCompass project provides an evidence-based roadmap for strategic research investment. This framework identifies crucial investigation areas into cancer-endocrine pathophysiology, prevention, and treatment strategies, ultimately aimed at reducing the burden of these disorders on individuals and society. The findings support the broader EndoCompass objective of aligning research funding with areas of highest potential impact in endocrine health.

Several studies have shown the association between decreased insulin sensitivity and the risk of male hypogonadism. Homeostatic model assessment of insulin resistance (HOMA-IR) is a well-established marker of decreased insulin sensitivity. The triglyceride-glucose index (TyG), calculated as ln fasting triglyceride mg/dLx fasting glucose mg/dL/2, was recently suggested to be a cheaper and a reliable surrogate marker to detect insulin resistance (IR). Our aim was to compare the performance of those two indexes in the prediction of male hypogonadism. The data on 192 men from infertile couples (18-50 years; sperm concentration <20 x 106/mL) and 199 population-based matched controls collected during the years 2009-2012 (baseline) were evaluated retrospectively. Half of these subjects (72 subfertile men and 122 controls) were reinvestigated 5-10 years later (median year (range): 7 (5-10)). The patients receiving any hormonal therapy were excluded. Hypogonadism was defined as fasting, morning serum testosterone below 12 nmol/L. In receiver operating characteristic curve analysis, the optimal diagnostic cutoff values for baseline HOMA-IR and TyG to predict MetS at re-examination were 2.68 (Area Under Curve (AUC) = 0.886, p < 0.001) and 8.60 (AUC = 0.816, p <0.001), respectively. Moreover, in binary logistic regression analysis performed on the whole cohort using these thresholds for high values of HOMA-IR and high TyG, the odds-ratios (ORs) for hypogonadism were 6.48 (95% Confidence Interval (CI): 3.77-11.2; p <0.001) and 3.58 (95% CI: 2.17-5.94; p <0.001), respectively. Even though high HOMA-IR levels provided better risk estimates, high TyG was also highly related to the risk of hypogonadism. These markers can be utilized to identify men being at high risk of hypogonadism.

Objective To study the association between sperm DNA fragmentation index (DFI) and the odds of preeclampsia and other adverse perinatal outcomes after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment. Design A prospective cohort study including infertile couples undergoing conventional IVF or ICSI treatment and their children. Data regarding preeclampsia and perinatal outcomes were derived from the Swedish National Birth Register. Subjects 1594 infertile couples undergoing IVF or ICSI treatment and their 1660 children conceived by assisted reproduction. Exposure Sperm DNA fragmentation index measured by Sperm Chromatin Structure Assay. Main outcome measures The primary outcome was preeclampsia. Secondary outcomes were preterm birth, low birth weight, low Apgar score, and small for gestational age. Results With DFI < 20% as a reference, the OR for preeclampsia was statistically significantly increased in the group with DFI ≥ 20% when IVF was used as fertilization method (OR 2.2; 95% CI 1.1 to 4.4; p = 0.02). Already at DFI levels ≥ 10%, in IVF pregnancies, preeclampsia odds were increased in a dose-response manner, from a prevalence of 3.1% in the reference group to more than 10% among those with DFI of 30% or higher. The DFI was not associated with preeclampsia odds in the ICSI group. In the entire cohort, DFI ≥ 20% was associated with an increased OR of preterm birth (OR 1.4; 95% CI 1.0 to 2.0; p = 0.03). Conclusion High DNA fragmentation index was associated with increased odds of preterm birth and, in IVF pregnancies, also increased odds of preeclampsia.

Male reproductive impairment has been linked with an increased risk of numerous non-communicable diseases. Yet, epidemiological data on renal disease among subfertile men is scarce. Therefore, by using male childlessness as a proxy for male infertility, we aimed to investigate its association with renal function. Data was sourced from a population-based cohort including 22,444 men. After exclusion of men aged < 45 years (n = 10,842), the remaining men were divided into two groups: these being childless (n = 5494) and fathers (n = 6108). Logistic regression was applied to explore the association between male childlessness and renal impairment. Childless men as compared to fathers, were more likely to have an estimated-glomerular filtration rate < 60 ml/min/1.73m(2 )(OR 1.36, 95 CI 1.08-1.70; p = 0.008). After adjustment for age, marital status, smoking habits, diabetes, hypertension and other components of metabolic syndrome, childless men were also more likely to have dipstick proteinuria (OR 1.85, 95 CI 1.16-2.95; p = 0.01). With the growing panorama of disease associated with male reproductive impairment, men with fertility issues may constitute a target population with potential benefit from closer follow-up of their renal function.

Background The risk of inflammatory diseases is sex-dependent, but it remains unknown whether this is due to the impact of sex hormones or sex chromosomes. Transgender individuals represent a unique cohort for studying the relative influence of endocrine and chromosomal factors. Here we compared serum levels of B-cell activating-factor (BAFF) and tumor necrosis factor (TNF) in transgender men (TM), transgender women (TW), cisgender women (CW) and cisgender men (CM). Methods BAFF and TNF were measured in the serum of 26 CW, 30 CM, 27 TM and 16 TW individuals. To determine the responsiveness of immune cells, TNF was measured in bacterial lipopolysaccharide (LPS)-treated peripheral leukocytes. Results BAFF was higher in CF (998 pg/mL) and TW (973 pg/mL) compared to CM (551 pg/mL) ( P < 0.0001) and TM (726 pg/mL) ( P < 0.0001). No difference in BAFF levels was shown between subjects grouped according to the number of X chromosomes. TNF was higher in CM (174 pg/mL) than TW (2.3 pg/mL) ( P = 0.027) and TM (27.4 pg/mL) ( P = 0.028). LPS-induced TNF was higher in CM (2524 pg/mL) and TM (2078 pg/mL) than in CW (1332 pg/mL) (both P < 0.0001) and TW (1602 pg/mL) (both P = 0.009). Discussion Sex hormones and sex chromosomes have different impacts on cytokines involved in the sex-dependent inflammatory response. The concentration of BAFF and LPS-stimulated TNF secretion depended on sex hormone levels, whereas basal TNF was regulated by both sex hormone-dependent and -independent factors.

Objective: To study the effect of methotrexate on male fertility and subsequent effects on their children, for which data are scarce and contradictory. Design: Nationwide multiregister cohort study. Setting: Not applicable. Subject(s): All children born alive in Sweden between 2006 and 2014 and their fathers. Three cohorts were defined: children to fathers with periconceptional methotrexate exposure (exposed cohort), children whose fathers stopped methotrexate intake >= 2 years before conception (previously exposed cohort), and children to fathers with no methotrexate exposure (control cohort). Exposure(s): The father having at least one dispensed methotrexate prescription from pharmacies 0-3 months before conception, along with at least one more dispensed methotrexate prescription 0-12 months before conception (periconceptional exposure). Previously exposed cohort: the father having no dispensed methotrexate prescriptions in the 2 years before conception, but having at least two dispensed prescriptions before that. Main outcome measures: Congenital anomalies (major and any; primary outcomes), preterm birth (PTB) and being small for gestational age (SGA; secondary outcomes), as well as need of intracytoplasmic sperm injection(ICSI) to achieve pregnancy (primary outcome in exposed cohort vs. controls, exploratory outcome in previously exposed cohort vs. controls). Outcomes were analyzed using logistic regression. Results: A total of 223 children to fathers with periconceptional methotrexate exposure were identified, along with 356 children whose fathers stopped methotrexate intake >= 2 years before conception and 809,706 not methotrexate-treated controls. In children with fathers periconceptionally exposed to methotrexate, the adjusted and unadjusted odds ratios (95% confidence intervals) for major congenital anomalies were 1.1 (0.4-2.6) and 1.1 (0.4-2.4), any congenital anomalies 1.3 (0.7-2.4) and 1.4 (0.7-2.3), PTB 1.0 (0.5-1.8) and 1.0 (0.5-1.8), SGA 1.1 (0.4-2.6) and 1.0 (0.4-2.2), and conception by use of ICSI 3.9 (2.2-7.1) and 4.6 (2.5-7.7). Use of ICSI was not increased among fathers who stopped methotrexate intake >= 2 years before conception, having adjusted and unadjusted odds ratios 0.9 (0.4-1.9) and 1.5 (0.6-2.9). Conclusion: This study suggests that paternal periconceptional methotrexate use does not increase risk of congenital anomalies, PTB, or SGA in the offspring but (C) 2023 by American Society for Reproductive Medicine.