Rodolfo Alberto Rey

Congenital hypogonadotropic hypogonadism (CHH) in boys and adolescents requires age- and developmentally appropriate treatment to address androgen deficiency, testicular maturation, pubertal development, and ultimately fertility. The dynamic physiology of the hypothalamic-pituitary-testicular axis necessitates therapeutic strategies that differ substantially between infancy and adolescence. This review examines current pharmacological approaches to CHH across childhood and adolescence, focusing on testosterone, dihydrotestosterone, gonadotropins, pulsatile gonadotropin-releasing hormone (GnRH), and emerging kisspeptin-based therapies. Literature search was made in Pubmed for the period 1990-2026. Testosterone remains the standard approach for for inducing secondary sexual characteristics and effectively promotes virilization, growth, bone accrual, and psychosocial well-being, but does not induce testicular maturation or spermatogenesis. Gonadotropin therapy, particularly sequential follicle-stimulating hormone followed by luteinizing hormone or human chorionic gonadotropin, more directly promotes Sertoli-cell maturation, testicular growth, and spermatogenesis. Early gonadotropin treatment in infancy can reproduce several features of physiological mini-puberty, although its long-term reproductive benefits remain uncertain. Pulsatile GnRH is physiologically attractive but limited by availability and treatment complexity, whereas kisspeptin remains investigational. Treatment should be individualized according to developmental stage, testicular phenotype, therapeutic goals, anticipated fertility, treatment burden, and patient preferences. Major unmet needs include pediatric-specific formulations, optimized regimens, comparative trials, biomarkers of treatment response, and long-term reproductive outcomes.

Context: Survival after pediatric hematologic malignancies has improved substantially, increasing concern regarding endocrine sequelae. While gonadotoxic effects on germ cells are characterized in adult survivors, the early impact of cancer and chemotherapy on hypothalamic–pituitary–testicular axis during childhood and adolescence remains insufficiently studied. Design: We conducted a prospective longitudinal cohort study including 63 boys and adolescents with acute lymphoblastic leukemia, acute myeloid leukemia, or non-Hodgkin lymphoma treated at a tertiary pediatric center in Argentina between 2013 and 2019. Hormonal markers of Sertoli cell (AMH, inhibin B, FSH) and Leydig cell function (testosterone, LH) were serially assessed from diagnosis, throughout chemotherapy, and up to 3 years after treatment completion. Results: In prepubertal boys, Sertoli cell function was mildly impaired at diagnosis, with reduced AMH and FSH levels. AMH increased during induction chemotherapy, fluctuated during treatment, and normalized thereafter, remaining stable up to 3 years post-treatment. Transient FSH suppression coincided with exposure to high-dose corticosteroids. Boys entering puberty during follow-up showed persistently elevated AMH relative to pubertal stage, suggesting delayed Sertoli cell maturation. In pubertal patients, a transient seminiferous tubular dysfunction, reflected by increased FSH and decreased inhibin B occurred, with recovery by 3 years after treatment. Mild compensated Leydig cell dysfunction persisted, characterized by elevated LH despite normal testosterone concentrations. Conclusions: Testicular dysfunction associated with pediatric hematologic malignancies is mostly reversible. However, delayed Sertoli cell maturation and persistent compensated Leydig cell insufficiency indicate residual testicular vulnerability, underscoring the importance of long-term endocrine surveillance during and after the end of chemotherapy.

To advance the understanding of Congenital Hypogonadotropic Hypogonadism (CHH), we aimed to refine the catalog of causal genes and variants. We systematically collected variants reported in the literature and created CHH_vd, a curated database. In parallel, we developed CHH_vip, a custom-built computational pipeline for variant annotation and classification, which integrates data from CHH_vd and external sources. Gene network and term enrichment analyses were applied to generate disease-specific gene panels. Our systematic review retrieved 352 scientific studies, documenting 1937 patients carrying a total of 2603 variants, of which 1518 were unique, distributed across 143 genes. All variants were incorporated into CHH_vd (publicly available) and reclassified using CHH_vip according to ACMG/AMP guidelines and ClinGen SVI working group recommendations. Changes in classifications of clinical relevance [from/to Pathogenic, Likely Pathogenic, or High_VUS (Variant of Uncertain Significance with High Probability of Pathogenicity)] were identified for 238 variants when comparing with InterVar, a bioinformatics tool for clinical interpretation of genetic variants. The genes GNRHR, ANOS1, PLXNA1, and SEMA7A were particularly implicated in pathogenicity reassignment, having a comparatively high number of variants downgraded (to more benign). Through CHH_vd, we provide an updated view of the genes impacted by genetic variation in CHH, highlighting marked genetic heterogeneity. The implementation of curated gene panels, combined with CHH_vip, a reproducible platform for compiling and interpreting variation data, may optimize the filtering and classification processes, thereby reducing diagnostic turnaround time.

Complex genetic syndromes represent a diagnostic challenge due to their diverse phenotypic presentations, which often evolve over time and may not be fully evident at birth. Disorders of sex development (DSD) comprise congenital conditions with discordance between chromosomal, gonadal, and/or genital sex. In 46,XY gonadal dysgenesis, undervirilisation or female-appearing genitalia may occur despite a normal karyotype, and diagnosis increasingly relies on genomic approaches. Prenatal and postnatal growth failure has been described in patients with syndromic 46,XY DSD. We report a male patient with SGA, lack of postnatal catch-up growth, and syndromic dysgenetic 46,XY DSD followed longitudinally from infancy to 11 years, in whom whole-exome sequencing (WES) reanalysis revealed a pathogenic 2.7 Mb microdeletion at 3q27.1q27.2. Systematic review of previously reported 3q27.1 deletions identified overlapping phenotypes but limited documentation of gonadal dysfunction. Curation of 71 genes within the deleted region highlighted DVL3 and CLCN2 as potential contributors to the gonadal phenotype, although functional evidence remains lacking. This case expands the phenotypic spectrum of 3q27.1 microdeletion syndrome, suggesting that 46,XY gonadal dysgenesis may represent an under-recognised feature. It also underscores the importance of copy number variant (CNV) analysis and periodic re-evaluation of sequencing data to increase diagnostic yield.

Introduction: Delayed puberty in males requires differentiation between self-limited delay and congenital hypogonadotropic hypogonadism (CHH), including Kallmann syndrome (KS). Case Presentation: We report an adolescent male presenting with delayed puberty and anosmia, consistent with KS. Hormonal evaluation confirmed CHH, and MRI demonstrated olfactory bulb agenesis. Targeted next-generation sequencing identified two heterozygous variants in functionally related genes: a pathogenic nonsense variant in PROK2 and a missense variant in PROKR2 classified as a variant of uncertain significance. Given their ligand-receptor relationship, oligogenic analysis was performed. The variant combination was prioritized as highly likely disease-causing by ORVAL/VarCoPP and further supported by OLIDA-based interpretation, providing objective evidence for digenic inheritance. Parental segregation confirmed trans inheritance. Conclusion: To our knowledge, this is the first report with objective support for the high likelihood of the existence of a digenic etiology in a patient with CHH, based on the use of OLIDA, which provides a standardized framework for the interpretation of oligogenic combinations. These findings highlight the contribution of multilocus variation to CHH and underscore the need for standardized approaches to interpret oligogenic mechanisms in clinical practice.

Introduction: Considering that testicular volume (TV) is probably not an adequate marker of pubertal onset in boys born small for gestational age (SGA), we aimed to describe the progression of pubertal clinical and biochemical characteristics, comparing the trajectory of TV with other parameters as markers of pubertal onset in boys born SGA. Methods: We performed a retrospective, descriptive study of a cohort of boys born SGA with longitudinal follow-up. We determined the TV at the time when serum AMH decreased ≥30% or LH attained 0.35 IU/L. Results: Thirty boys born SGA were included: 16 of 30 (53.3%) had LH ≥0.35 IU/L and 7 of 24 boys (29.2%) had a decline ≥30% in serum AMH with a TV <4 mL. LH ≥0.35 IU/L and AMH decrease ≥30% were observed at least 1 year before TV 4–5 mL in 11 of 22 (50%) and 3 of 19 (15.8%) boys, respectively. During follow-up, higher serum LH, FSH, and testosterone and lower AMH levels than those expected for TV were observed, indicating that some boys born SGA have a more advanced stage of puberty than their TV suggests. Conclusion: We identified a subgroup of boys born SGA in whom hormonal changes typical of initial puberty (serum LH ≥0.35 IU/L and AMH decline ≥30%) occurred before a clinical diagnosis of pubertal onset (TV ≥4 mL) was evident. These results indicate that TV 4 mL is not a reliable clinical sign of pubertal onset in all boys born SGA and that other biomarkers, such as serum LH and AMH, may need to be assessed.

There is growing interest in replacing steroid immunoassays with liquid chromatography–tandem mass spectrometry-based methods in many clinical and research applications. The aim of the present work is to develop and validate an ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS)-based method using atmospheric pressure chemical ionisation (APCI) to quantify cortisol, androstenedione, testosterone, pregnenolone, progesterone, 17-hydroxyprogesterone, 17-hydroxypregnenolone, and dehydroepiandrosterone in paediatric serum samples. Sample preparation was performed by protein precipitation using 100 µL of sample. The analytical method was validated in accordance with FDA and EMA international guidelines. Commercial quality control materials and a reference material (NIST®SRM®1950) were analysed for external assessment. Clinical applicability was tested in 61 infants under three months of age (50 healthy infants, eight preterm neonates, and three patients with confirmed adrenal disorders). The LLOQs were lower than 8 nmol/L; within- and between-run CVs were <12 %. Accuracy, in terms of recovery, was 89–111 %. Serum cortisol levels varied widely in healthy infants, and only testosterone levels exhibited sexual dimorphism (p < 0.0001). Androstenedione and 17-hydroxyprogesterone levels were significantly higher in the preterm group compared with babies born at term. Patients with confirmed adrenal pathologies exhibited abnormal steroid profiles. A novel, accurate, and sensitive UHPLC-APCI-MS/MS-based method for the simultaneous analysis of eight steroids in serum was developed, validated and successfully applied to infants younger than three months of age. The method enabled detection of abnormal values of precursors and steroid hormones in patients with adrenal disorders, with the potential for a large impact on paediatric patient care.

Disorders of pubertal onset and progression are a common cause for referral to paediatric endocrinologists, with delayed puberty in males being particularly frequent. Pubertal development depends on the hypothalamic-pituitary-testicular (HPT) axis, which is established during fetal life and undergoes distinct phases: fetal androgen production, postnatal "minipuberty", and reactivation during adolescence. Key regulators include GnRH neurons, Sertoli and Leydig cells, and biomarkers such as AMH, inhibin B, testosterone and INSL3. Puberty is marked clinically by testicular enlargement beyond 4 mL, usually at a median age of 11.5 years. Delayed puberty is defined as absence of testicular enlargement by age 14. The most common cause is self-limited delayed puberty (SLDP), often familial and benign. Functional hypogonadotropic hypogonadism due to chronic illness, and permanent central hypogonadism (congenital or acquired), account for additional cases. Congenital hypogonadotropic hypogonadism (CHH), including Kallmann syndrome, is frequently genetic, with variants in genes such as FGFR1, ANOS1 and GNRHR. Clinical assessment includes family history, growth patterns, and red flags such as micropenis, cryptorchidism or anosmia.

Background: Endocrine science remains underrepresented in European Union research programs despite the fundamental role of hormone health in human well-being. 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.