Childhood cancer survivors (CCS) are at increased risk of developing several late complications, often in adulthood. It is therefore essential that accurate information is provided to both the CCS and healthcare providers when transitioning to adult healthcare. Since the first publication of the Swedish national guidelines for long-term follow-up in 2016, long-term follow-up clinics for adult CCS have been established at all six university hospitals, offering at least one visit at the age of twenty-five. Dedicated transition clinics at paediatric cancer centres offer two to three visits during adolescence in preparation for the transition, including an individual dialogue between the young person and the paediatric oncologist or nurse. Further developments are ongoing, including the introduction of specialised transition nurses and a more structured element into the visits.

Childhood cancer survivors (CCSs) face a high risk of long-term cardiovascular complications(1), influenced by modifiable cardiovascular risk factors(2). Health related limitations may affect individual ability to establish and maintain a healthy life style. Current guidelines advocate regular cardiovascular surveillance, stratified by previous cancer treatment(2). In this prospective pilot study of young adult CCSs with normal LVEF (≥50%) and follow up time ≥5 years after childhood cancer, we have assessed cardiovascular function, life style and health related quality of life. Cardiovascular function (echocardiography, ankle brachial index (ABI) and blood pressure), endothelial function (EndoPAT), metabolic status (biomarkers), questionnaires on life style factors and health related quality of life (RAND-36(3)) were analysed. The study included 18 patients (7 females, 9 males), March 2023-September 2024. Median age at inclusion was 26 years (range 22-39 years) and median follow up time from primary cancer diagnosis, 14.7 years (range 6.8-33.5 years). Median age at primary cancer diagnosis was 12.6 years (range 1.9-17.7 years). The high-risk-group (defined as cumulative doxorubicin equivalent doses(4) ≥250 mg/m2 or chest radiotherapy ≥15 Gy, or a combination of doxorubicin doses ≥100 mg/m2 and any chest radiotherapy) included 13 patients with median cumulative doxorubicin equivalent dose 300 mg/m2 (range 80-810), including 6 patients with radiotherapy involving the heart, median dose 25 Gy (range 1.8-39.9) and 2 patients with total body irradiation. The non-high-risk group consisted of 5 patients with median cumulative doxorubicin equivalent dose 120 mg/m2 (range 0-240 mg/m2) and included one patient with cranial radiotherapy. Two high risk patients had slightly impaired ABI. Reactive hyperemia index (RHI) registered by EndoPAT, demonstrated normal median values in the high-risk and non-high-risk group (2.14 respectively 1.98, with 1.67 as cut-off for normal) and no difference in range (1.54-2.75 respectively 1.52-2.53). No patient with subnormal RHI had systolic blood pressure ≥140 mmHg. Overweight (BMI 25-29) was found in 33%. Physical activity levels were lower than recommended(5) in a majority: 10/18 reported less than 75 min of high level of physical activity, including 8 with less than 120 min of low intensity physical activity per week. Regular tobacco use was reported in 11/18 individuals (3 smoking, 8 snuff). Health related quality of life scores, RAND-36, indicated lower emotional role functioning (RE) scores (emotional limitations to engage in everyday life) in the CCS-groups when compared with corresponding age groups in established reference population(6) (Figure 1). Our results highlight the importance of addressing lifestyle factors and quality of life in prospective studies, as this may be the heart of matter for optimizing cardiovascular outcomes in young adult CCSs with normal LVEF.

STUDY QUESTION:Which spermatogonial differentiation states are present in prepubertal testes under normal conditions and following chemotherapy-induced depletion of spermatogonia in paediatric patients with cancer? SUMMARY ANSWER:Single-cell transcriptomic analysis reveals that only undifferentiated spermatogonia are present in prepubertal boys, while differentiated states emerge during puberty, with reduced protein expression of advanced spermatogonial markers observed in younger patients, those treated with alkylating agents, or those with a diminished spermatogonial pool. WHAT IS KNOWN ALREADY:Paediatric oncology treatments often involve gonadotoxic therapies that can impair spermatogonial stem cells, increasing the risk of subfertility. While five distinct spermatogonial subpopulations have been identified in adult testes via single-cell RNA sequencing, their presence in prepubertal testes of childhood cancer patients remains to be confirmed through marker protein expression. STUDY DESIGN, SIZE, DURATION:Gene expression profiles of spermatogonial subpopulations were investigated using single-cell RNA sequencing data from six testicular samples of healthy boys aged 0-17 years. Protein expression patterns were examined via immunofluorescence staining in 14 biobank control samples (median age: 4.9 years; range: 0.6-13.1 years) and in 31 prepubertal testicular tissue samples of paediatric patients with cancer (median age: 6.8 years; range: 0.7-13.1 years). PARTICIPANTS/MATERIALS, SETTING, METHODS:Gene expression profiles of UTF1 (states 0-1), ID4 (states 0-1), PIWIL4 (states 0-1), FGFR3 (states 0-2), and KIT (state 4), were analysed in testicular cells of paediatric origin obtained from our previously published open-access data source (GSE134144 and GSE120508). The protein expression of these spermatogonial subpopulation markers was evaluated by counting immunofluorescence-positive cells per analysed area. Marker expression was correlated with prior chemotherapy exposure and spermatogonia numbers. Exposure to alkylating agents was quantified as the cumulative cyclophosphamide equivalent dose (CED), and anthracycline exposure as the cumulative doxorubicin isoequivalent dose equivalents (DIE). A depleted spermatogonia pool was defined as having S/T Z-scores lower than -7 SD. MAIN RESULTS AND THE ROLE OF CHANCE:Transcriptomic analysis confirmed that germ cells in the prepubertal testis consist solely of undifferentiated spermatogonia. The expression of KIT protein, defining differentiated spermatogonia, was positively correlated with age (P < 0.001). A reduction in the number of spermatogonia expressing ID4 protein was associated with higher CED (P = 0.001), and spermatogonia expressing KIT protein with higher CED and DIE exposure (P = 0.005, and P = 0.035, respectively). A depleted spermatogonia pool (S/T Z-score <-7 SD) correlated with fewer spermatogonia expressing ID4 (P = 0.033), FGFR3 (P = 0.050), and KIT (P = 0.051) proteins. These results indicate that distinct protein expression patterns were observed following chemotherapy-induced reduction of the spermatogonial pool, with reduced expression of ID4, FGFR3, and KIT proteins. Numbers of spermatogonia positive for markers indicating more naïve, undifferentiated states, such as UTF1 and PIWIL4, did not correlate with spermatogonial pool reduction. LIMITATIONS, REASONS FOR CAUTION:The study population was heterogeneous in terms of age and treatment exposure. Moreover, the impact of specific cancer treatments could not be individually assessed. Limited tissue availability reduced the statistical power of the study, and repeated double or triple immunofluorescence staining could not be performed. As a result, the correlations between the expression of different spermatogonial markers can only be considered indicative trends. Child testicular control tissue samples were considered normal for inclusion if no testicular pathology was reported. However, detailed information on prior medical treatments or testicular volumes for the patients in this biobank was unavailable. WIDER IMPLICATIONS OF THE FINDINGS:Our observations suggest that alkylating agents have dose-dependent effects on all spermatogonial subpopulations. However, spermatogonial subtypes expressing the protein markers UTF1 and PIWIL4 were more resistant to chemotherapy-induced depletion of the spermatogonial pool, potentially representing true reserve stem cells. The identification of reserve stem cells could provide a valuable method for evaluating the fertility potential of testicular tissue collected for fertility preservation in prepubertal and peripubertal boys. STUDY FUNDING/COMPETING INTEREST(S):This study was supported by grants from the Swedish Childhood Cancer Fund (PR2019-0123; PR2022-0115; TJ2020-0023) (J.-B.S.), Finnish Cancer Society (K.J.), Finnish Foundation for Paediatric Research (K.J.), Swedish Research Council (2018-03094; 2021-02107) (J.-B.S.), and Birgitta and Carl-Axel Rydbeck's Research Grant for Paediatric Research (2020-00348; 2020-00335; 2021-00073; 2022-00317, 2024-00255) (J.-B.S., K.J.). Y.C. and Y.Y. received a scholarship from the Chinese Scholarship Council. J.S. was supported by a grant from Mary Béves Foundation for Childhood Cancer Research. H.B.O. was supported by the Sultan Qaboos University in Oman. The authors declare no competing interests. TRIAL REGISTRATION NUMBER:N/A.

STUDY QUESTION Can human pre- and peri-pubertal testicular cells obtained from childhood cancer patients, previously treated with chemotherapy, form testicular organoids (TOs)?SUMMARY ANSWER Organoid formation from testicular tissue collected from childhood cancer patients positively correlates with SRY-Box transcription factor 9 (SOX9) expression in Sertoli cells, which in turn negatively correlates with previous exposure to alkylating chemotherapy.WHAT IS KNOWN ALREADY Pre- and peri-pubertal boys exposed to highly gonadotoxic therapies can only safeguard their fertility potential through testicular tissue cryopreservation. Today, there is no established clinical tool to restore fertility using these testicular samples. Organoids hold promise in providing fundamental early insights in creating such platforms. However, the generation of TOs that closely resemble the innate testis, to enable a thorough monitoring of the necessary steps for germ cell differentiation and somatic functionalities, remains a challenge.STUDY DESIGN, SIZE, DURATION We used a Matrigel-based three-layer gradient culture system to generate human TOs and to reveal whether chemotherapy exposure affects TO formation capacity and the functionality of pre- and peri-pubertal testicular somatic cells. Testicular cells of 11 boys (aged 7.7 +/- 4.1 (mean +/- SD) years) were assessed for TO formation in relation to previous chemotherapy exposure and SOX9 expression in histological sections of paraffin-embedded testicular tissue samples collected on the day of biopsy and compared with testicular tissue samples obtained from 28 consecutive patients (aged 6.9 +/- 3.8 (mean +/- SD) years). All 39 patients were part of the fertility preservation project NORDFERTIL; an additional 10 samples (from boys aged 5.5 +/- 3.5 (mean +/- SD) years, without an underlying pathology) in an internal biobank collection were used as controls.PARTICIPANTS/MATERIALS, SETTING, METHODS We obtained 49 testicular tissue samples from boys aged 0.8-13.4 years. Fresh samples (n = 11) were dissociated into single-cell suspensions and applied to a three-layer gradient culture system for organoid formation. Histological sections of another 28 samples obtained as part of the fertility preservation project NORDFERTIL, and 10 samples from a sample collection of a pathology biobank were used to evaluate the effects of prior exposure to alkylating agents on testicular samples. Testicular organoid formation was defined based on morphological features, such as compartmentalized structures showing cord formation, and protein expression of testicular cell-specific markers for germ and somatic cells was evaluated via immunohistochemical staining. Hormone secretion was analysed by specific enzyme-linked immunosorbent assays for testosterone and anti-M & uuml;llerian hormone (AMH) production.MAIN RESULTS AND THE ROLE OF CHANCE Our results revealed that 4 out of 11 prepubertal testicular samples formed TOs that showed compartmentalized cord-like structures surrounded by interstitial-like areas and increasing levels of both testosterone as well as AMH over a 7-day culture period. We observed that SOX9 expression was correlated positively with TO formation. Moreover, exposure to alkylating agents before biopsy was inversely correlated with SOX9 expression (P = 0.006).LARGE SCALE DATA N/A.LIMITATIONS, REASONS FOR CAUTION Due to the limited amount of material available, only 11 out of the 39 pre- and peri-pubertal testicular tissue samples could be used for the organoid formation experiments. The testicular tissue samples obtained from a sample collection of the internal biobank of Department of Pathology, Karolinska University Hospital were considered normal and included in the study if no testicular pathology was reported. However, detailed information regarding previous medical treatments and/or testicular volumes of the patients included in this biobank was not available.WIDER IMPLICATIONS OF THE FINDINGS Our observations suggest that SOX9 expression may serve as a putative indicator of TO formation, indicating a critical role of Sertoli cells in promoting organoid formation, seminiferous tubule integrity, and testicular function in pre- and peri-pubertal testicular tissue.STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grants from the Swedish Childhood Cancer Foundation (PR2019-0123; PR2022-0115; TJ2020-0023) (J.-B.S.), Finnish Cancer Society (K.J.), Finnish Foundation for Paediatric Research (K.J.), Swedish Research Council (2018-03094; 2021-02107) (J.-B.S.), and Birgitta and Carl-Axel Rydbeck's Research Grant for Paediatric Research (2020-00348; 2020-00335; 2021-00073; 2022-00317) (J.-B.S. and K.J.). Y.C. and Y.Y. received a scholarship from the Chinese Scholarship Council. J.P.A-L. was supported by a Starting Grant in Medicine and Health (2022-01467) from the Swedish Research Council. R.T.M. was supported by a UKRI Future Leaders Fellowship (MR/S017151/1). The MRC Centre for Reproductive Health was supported by an MRC Centre Grant (MR/N022556/1). The authors declare no competing interests.

In Sweden, approximately 350 children and teenagers up to 18 years of age are diagnosed with cancer each year. The survival rate is high, above 80%, but the majority of those who survive will experience at least one late complication. The risk of late complications after treatment are mainly related to cumulative dose exposure of specific chemotherapeutic agents as well as radiation doses to certain organs at risk. A Swedish national working group has developed a national care program with recommendations for follow-up during childhood and adult life after childhood cancer treatment. Besides specific follow-up recommendations, the long-term follow-up care program describes both the organization needed to ensure adequate information to patients during their teenage years as well as the basic resources needed to provide a proper follow-up service for adults who survived childhood cancer.

RESEARCH QUESTION:Are age-normalized reference values for human ovarian cortical follicular density adequate for tissue quality control in fertility preservation? DESIGN:Published quantitative data on the number of follicles in samples without known ovarian pathology were converted into cortical densities to create reference values. Next, a sample cohort of 126 girls (age 1-24 years, mean ± SD 11 ± 6) with cancer, severe haematological disease or Turner syndrome were used to calculate Z-scores for cortical follicular density based on the reference values. RESULTS:No difference was observed between Z-scores in samples from untreated patients (0.3 ± 3.5, n = 30) and patients treated with (0.5 ± 2.9, n = 48) and without (0.1 ± 1.3, n = 6) alkylating chemotherapy. Z-scores were not correlated with increasing cumulative exposure to cytostatics. Nevertheless, Z-scores in young treated patients (0-2 years -2.1 ± 3.1, n = 10, P = 0.04) were significantly lower than Z-scores in older treated patients (11-19 years, 2 ± 1.9, n = 15). Samples from patients with Turner syndrome differed significantly from samples from untreated patients (-5.2 ± 5.1, n = 24, P = 0.003), and a Z-score of -1.7 was identified as a cut-off showing good diagnostic value for identification of patients with Turner syndrome with reduced ovarian reserve. When this cut-off was applied to other patients, analysis showed that those with indications for reduced ovarian reserve (n = 15) were significantly younger (5.9 ± 4.2 versus 10.7 ± 5.9 years, P = 0.004) and, when untreated, more often had non-malignant haematologic diseases compared with those with normal ovarian reserve (n = 24, 100% versus 19%, P = 0.009). CONCLUSION:Z-scores allow the estimation of genetic- and treatment-related effects on follicular density in cortical tissue from young patients stored for fertility preservation. Understanding the quality of cryopreserved tissue facilitates its use during patient counselling. More research is needed regarding the cytostatic effects found in this study.

Fertility preservation for male childhood cancer survivors not yet capable of producing mature spermatozoa, relies on experimental approaches such as testicular explant culture. Although the first steps in somatic maturation can be observed in human testicular explant cultures, germ cell depletion is a common obstacle. Hence, understanding the spermatogonial stem cell (SSC) niche environment and in particular, specific components such as the seminiferous basement membrane (BM) will allow progression of testicular explant cultures. Here, we revealed that the seminiferous BM is established from 6 weeks post conception with the expression of laminin alpha 1 (LAMA 1) and type IV collagen, which persist as key components throughout development. With prepubertal testicular explant culture we found that seminiferous LAMA 1 expression is disrupted and depleted with culture time correlating with germ cell loss. These findings highlight the importance of LAMA 1 for the human SSC niche and its sensitivity to culture conditions.

The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population‐based cohort of childhood cancer survivors. A cohort of 26 334 1‐year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127 531 age‐ and sex‐matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first‐time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared to the expected numbers derived from the comparison cohort. In total, 1987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% confidence interval, 1.29‐1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0‐44.5), osteoporosis, RR 4.53 (3.28‐6.27), fractures, RR 1.27 (1.20‐1.34), osteochondropathies, RR 1.57 (1.28‐1.92) and osteoarthrosis, RR 1.48 (1.28‐1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high‐risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors.

Sir, Despite several evidence-based guidelines available to promote fertility preservation (FP) for young patients and children, young patients still report FP as one of the top five unmet needs during their cancer care.1 Surveys have identified barriers that limit patients' access to FP, including organization-related barriers, such as lack of inter-professional cooperation, unclear referral paths for FP and the cost of the procedures.2-4 Organizational issues are particularly a problem for young female patients, who may retain fertility potential after cancer treatment during childhood but have a high risk of developing premature ovarian failure once they reach adulthood. When transitioning from childhood care to adult healthcare, routines for surveillance of infertility risks are lacking. An organization for surveillance of ovarian function is needed to give these patients the opportunity to preserve their fertility before an early menopause. Additionally, although a high proportion of practicing pediatric oncologists recognizes that it is their responsibility to discuss possible fertility impairment following treatment, they also acknowledge low confidence in their knowledge about FP methods.5 In Sweden, all university hospitals covering large regions/counties have developed programs for FP. Currently established FP strategies, including the cryopreservation of sperms, oocytes or embryos,6 are offered free of charge to patients, when indicated for medical reasons, within the tax-funded healthcare system. Previous research has evidenced inequalities in cancer patients' access to counseling and FP despite this healthcare platform.7 Methods that are still considered experimental or under development for FP of children, such as the cryopreservation of ovarian tissue and the cryopreservation of pre-pubertal testicular tissue,6, 8 are restricted to centers that have Ethics Review Board-approved research protocols. To ensure that healthcare providers become familiar with the methods for FP options and that these could be offered to patients in Sweden regardless of their residence, the Swedish Association of Local Authorities and Regions requested national guidelines. A multidisciplinary working group including specialists in reproductive medicine, pediatric oncology, pediatric endocrinology, andrology and assisted reproductive technologies from the Swedish University Hospitals was set up in 2012. The work was summarized in a comprehensive document that describes the group of patients that should be offered FP due to a substantial risk of infertility following cytotoxic treatment of cancer during childhood and adolescence, and the available methods. The guidelines are in line with international recommendations, adapted to the Swedish healthcare system, and intended to be supportive to healthcare personnel in facilitating discussions about FP with pediatric cancer patients and their guardians/relatives. The final recommendations highlight the importance of providing complete and accurate information on the current methods for FP but also their limitations, as well as the provision of information on alternative routes to becoming a parent in the future, such as gamete donation and adoption. Fertility-related information should be provided by healthcare personnel with training in that field. Supportive care by a psychologist or counselor is recommended to assist patients and their families in decision-making. The guidelines also specifically recommend that fertility counseling is offered to evaluate opportunities for undergoing FP after completion of cancer treatment, whenever FP was not possible or performed before the initiation of cancer treatment. This often occurs due to the frequent need to start treatment immediately and/or at a very young age. One suggested time-point for check up is when the children complete their follow up at the pediatric clinic when reaching adult age and are referred to adult healthcare services. Since 2016, the follow up of patients treated for childhood cancer has been standardized through a healthcare program in Sweden.9 After completion, the guidelines were submitted on a cycle of referrals to: academic associations for pediatrics, oncology, endocrinology and reproductive medicine in Sweden; the head and responsible clinician for each of Sweden's pediatric oncology centers; local and county authorities for healthcare provision; pediatric oncology nurses; the Swedish Ethical Council; patient associations; and stakeholders. After approval, the document was made public on the Swedish Human Tissue Authority's website in 2015 (www.vavnad.se).10 The working group recognized the need to periodically update the guidelines in the future, according to relevant advances in reproductive medicine and research. Booklets to provide age-adapted patient information to young children or older adolescents were also created, and these have been available online since November 2017 in Swedish, English, Finnish, Spanish and Arabic. Videos for teenagers explaining reproductive biological facts, the negative impact of cancer treatment on fertility and the available methods for FP are also available on the website (see Supporting Information Appendix S1). The UNGA network meetings for production of the Swedish guidelines were supported by the Swedish Association of Local Authorities and Regions, SALAR (Sveriges Kommuner och Landsting, SKL). This work was supported by research grants from Stockholm County Council and Karolinska Institutet, the Swedish Childhood Cancer Foundation and the Swedish Cancer Society to K.R.-W. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Treatment with chemotherapy, radiotherapy, or surgery that involves reproductive organs can cause impaired spermatogenesis, testosterone deficiency, and physical sexual dysfunction in male pubertal, adolescent, and young adult cancer survivors. Guidelines for surveillance and management of potential adverse effects could improve cancer survivors' health and quality of life. Surveillance recommendations vary considerably, causing uncertainty about optimum screening practices. This clinical practice guideline recommended by the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium, developed using evidence-based methodology, critically synthesises surveillance recommendations for gonadotoxicity in male childhood, adolescent, and young adult (CAYA) cancer survivors. The recommendations were developed by an international multidisciplinary panel including 25 experts in relevant medical specialties, using a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. The aim of the recommendations is to enhance evidence-based care for male CAYA cancer survivors. The guidelines reveal the paucity of high-quality evidence, highlighting the need for further targeted research.

I dag lever 80 procent av patienterna med cancer i barn- och ungdomsaren fem ar efter diagnos. Ungefar 6 000–7 000 individer i Sverige ar fore detta barncancerpatienter. Sena komplikationer till sj ...

I dag lever 80 procent av patienterna med cancer i barn- och ungdomsaren fem ar efter diagnos. Ungefar 6 000–7 000 individer i Sverige ar fore detta barncancerpatienter. Sena komplikationer till sj ...

The coxsackievirus and adenovirus receptor (CAR) is a cell adhesion molecule expressed in epithelial tight junctions and other cell-cell contacts. Using indirect immunofluorescence, quantitative RT-PCR, and Western blots, the expression and distribution of CAR in developing and adult testis are examined. CAR is highly expressed in both Sertoli and germ cells during perinatal and postnatal development, followed by a rapid down-regulation of both mRNA and protein levels. Interestingly, we find that CAR is a previously unknown downstream target for FSH because CAR mRNA levels were induced in primary cultures of FSH-stimulated Sertoli cells. In contrast to other epithelia, CAR is not a general component of tight junctions in the seminiferous epithelium, and Sertoli cells in the adult testis do not express CAR. Instead, CAR expression is stage dependent and specifically found in migratory germ cells. RT-PCR also demonstrated the presence of junctional adhesion molecule-like (JAML) in the testis. JAML was previously reported by others to form a functional complex with CAR regulating transepithelial migration of leukocytes. The expression of JAML in the testis suggests that a similar functional complex might be present during germ cell migration across the blood-testis barrier. Finally, an intermediate compartment occupied by CAR-positive, migrating germ cells and flanked by two occludin-containing junctions is identified. Together, these results implicate a function for CAR in testis morphogenesis and in migration of germ cells across the blood-testis barrier during spermatogenesis.

The somatic Sertoli cell plays an essential role in embryonic determination of male somatic sex and in spermatogenesis during adult life. One individual Sertoli cell supplies a clone of developing germ cells with nutrients and growth factors and it is well established that the number of Sertoli cells present is closely correlated to both testicular size and sperm output. Sertoli cells continue to proliferate and differentiate until the beginning of puberty, when they cease dividing and start nursing the germ cells. At this point in time, the future capacity of the testis for sperm production has thus been determined. Prior to puberty the Sertoli cells are immature and differ considerably with respect to morphology and biochemical activity from the mature cell. The several investigations that have focused on hormonal and paracrine regulation of the functions of the mature cell are reviewed here, but the mechanisms underlying the maturation and general maintenance of well-functioning Sertoli cells remain obscure. An alarming decline in male reproductive health has been observed in several Western countries during recent decades. Disturbance of Sertoli cell differentiation is thought to be involved in the pathogenesis of both a poor sperm count and testicular cancer. It is speculated that environmental agents that disrupt the estrogenic/androgenic balance in the testis may play a role in this connection.

We have reported earlier that interleukin-1 (IL-1) is a potent growth factor for immature Sertoli cells (somatic cells in the testis required for testicular development and later spermatogenesis) and that this effect is synergistic with the mitogenic effect of follicle-stimulating hormone (FSH). The aim of the present study was to determine whether MAPK pathways are involved in mediating the mitogenic effect of IL-1 on Sertoli cells. Western blotting revealed that IL-1α activated p38 MAPK and JNK/SAPK, but not ERK, in Sertoli cells from 8- or 9-day-old rat. The inhibitor of p38 MAPK SB203580 attenuated the IL-1α-induced proliferation of Sertoli cells, as assessed by 3H-thymidine incorporation and supravital staining as well as by direct cell counting. We conclude that the p38 MAPK pathway mediates the proliferative effect of IL-1α on immature Sertoli cells in vitro. Since the mitogenic effect of FSH is mediated via ERK, the synergistic action of IL-1α and FSH may be explained by their different intracellular signalling pathways. Induction of IL-1 by inflammation, infection or other tissue injuries may result in testicular damage by interfering with normal Sertoli cell development and thus future spermatogenesis.