Disorders of sex development: challenges for the future

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Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 Oxidoreductase deficiency

Context: P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency. \ud \ud Objective: The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty. \ud \ud Design: Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted. \ud \ud Results: Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations. \ud \ud Conclusion: Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR

Obesity is positively associated with dehydroepiandrosterone sulfate concentrations at 7 y in Chilean children of normal birth weight.

BACKGROUND: In low-birth-weight girls, obesity increases the risk of premature adrenarche and metabolic complications. However, the consistency of this association in normal-birth-weight children and its potential mediators remain unknown. OBJECTIVES: The objectives were to assess the associations between obesity indicators and dehydroepiandrosterone sulfate (DHEAS) at 7 y of age and to evaluate the role of hormonal markers on these associations. DESIGN: We assessed in 969 participants (6.9 y; 48% girls; all Tanner I) in the Growth and Obesity Chilean Cohort Study the associations between DHEAS and weight, BMI, waist circumference (WC), waist-to-height ratio, skinfold thickness, and percentage total fat (bioimpedance) and determined whether these associations were related to insulin, insulin-like growth factor I (IGF-I), and leptin. We also compared BMI and height growth from 0 to 7 y of age in nonobese and obese children with normal and high DHEAS (≥75th percentile) at 7 y. RESULTS: DHEAS concentrations were similar between girls (30.3 ±1.86 μg/dL) and boys (29.4 ±1.73 μg/dL) (P > 0.05); 17.3% of children were obese (BMI-for-age z score ≥2 SD). Adiposity indicators were positively and similarly associated with DHEAS [ie, BMI, β standardized regression coefficient: 0.23 (95% CI: 0.17, 0.29); WC, β standardized regression coefficient: 0.23 (95% CI: 0.16, 0.30)]; these associations were only partially related to IGF-I and leptin. Obese children had twice the risk of high DHEAS (OR: 2.16; 95% CI: 1.51, 3.09); at 7 y, obese children with high DHEAS were fatter and more centrally obese than their counterparts (P 0.05). None of the results differed by sex (P > 0.05). CONCLUSION: In children of normal birth weight, obesity is positively associated with DHEAS at 7 y of age

Molecular regulation of adrenal androgen biosynthesis

The biosynthesis of adrenal androgens is catalysed by steroid-modifying enzymes. Over the past decade, co-factors were explored to regulate these enzymes: P450 oxidoreductase (POR) delivers electrons to the key androgen-producing cytochrome P450 enzyme CYP17A1. In addition, sulfation of the principal androgen precursor dehydroepiandrosterone (DHEA) catalysed by the enzyme SULT2A1, supported by its co-factor 3’-phosphoadenosine-5’-phosphosulfate (PAPS) synthase 2 (PAPSS2), has been found more recently as a gatekeeper of androgen activation. Here, we have further characterised children with defects of enzymes of the androgen pathway, namely CYP17A1 and POR. We report the first human missense mutation of cytochrome b5, which supports electron transfer from POR to CYP17A1. In addition, we have explored the molecular regulation of DHEA sulfation by $in$ $vitro$ and $in$ $vivo$ studies. The results from our studies provide important information on the clinical course, the diagnostic steroid fingerprint and underlying molecular mechanisms of conditions affecting androgen generation. The $in$ $vitro$ studies on DHEA sulfation confirm that the PAPSS2 isoform crucially regulates SULT2A1. Our $in$ $vivo$ study in children with deficiencies of the steroid sulfatase (STS) enzyme, the counterpart of SULT2A1, suggests that STS does not play a major role in DHEA metabolism but is more active before puberty

Wpływ sposobu uprawy roli i nawożenia azotem na zmiany właściwości fizycznych gleby w uprawie pszenżyta ozimego

In 2001–2003 a study at Agricultural Station of University of Wrocław examined the effect of different tillage systems: conventional, simplified (spray of Roundup instead of post harvest tillage and shallowing of sow ploughing, swirl harrowing or cultivatoring instead of sow ploughing) and direct sowing on selected physical properties of the soil (soil moisture, bulk density, porosity, soil compaction). The experiment was conducted as a field experiment, split-plot method, in four replications on medium textured soil, very good rye complex. The studies were carried out for winter triticale. It was found that chemical spray instead of post-harvest tillage increased the soil compaction, bulk density and soil moisture and also decreased the total porosity of the soil. The highest values of the examined properties of the soil were noticed under no-tillage system. Nitrogen fertilization had a significant influence on the changes of physical properties of the soil

Premature adrenarche and metabolic risk:a systematic review and meta-analysis

Objective: Premature adrenarche (PA), characterised by pre-pubertal adrenal androgen excess and hyperandrogenic symptoms, is considered a forerunner of polycystic ovary syndrome, which comes with increased metabolic risk. Here, we aimed to systematically evaluate the evidence on surrogate parameters of metabolic risk in children with PA. Methods: We searched major databases (1990-March 2025) for studies on PA in children analysing body composition and markers of glucose and lipid metabolism. Two reviewers independently selected studies, collected data, and appraised study quality. Results were standardised, tabulated, and pooled for meta-analysis. Results: Twenty-five case-control studies reported on 694 children with PA and 567 healthy controls (boys and girls). Height standard deviation score (SDS), weight SDS, and body mass index SDS were significantly higher in PA than in controls. Children with PA also presented with higher fasting insulin (FI) levels than controls (MD: 15.04, 95% CI: 5.27-24.81 pmol/L; I2 = 91%). These findings persisted after sensitivity analysis for gender and risk of bias assessment. Other markers of metabolic risk, such as fasting glucose, HOMA-IR, mean serum glucose and insulin during the oral glucose tolerance test, and fasting lipids, did not differ between children with PA and controls. Conclusions: Children with PA are taller, heavier, and have higher FI levels than their healthy peers at presentation. We observed significant heterogeneity of reported outcomes with generally small participant numbers in the included studies. Large-scale studies with comprehensive, unified assessment and long-term follow-up are needed to explore the extent of metabolic dysfunction that may develop over time

Management aspects of congenital adrenal hyperplasia during adolescence and transition to adult care

The adolescent period is characterised by fundamental hormonal changes, which affect sex steroid production, cortisol metabolism and insulin sensitivity. These physiological changes have a significant impact on patients with congenital adrenal hyperplasia (CAH). An essential treatment aim across the lifespan in patients with CAH is to replace glucocorticoids sufficiently to avoid excess adrenal androgen production but equally to avoid cardiometabolic risks associated with excess glucocorticoid intake. The changes to the hormonal milieu at puberty, combined with poor adherence to medical therapy, often result in unsatisfactory control exacerbating androgen excess and increasing the risk of metabolic complications due to steroid over‐replacement. With the physical and cognitive maturation of the adolescent with CAH, fertility issues and sexual function become a new focus of patient care in the paediatric clinic. This requires close surveillance for gonadal dysfunction, such as irregular periods/hirsutism or genital surgery‐associated symptoms in girls and central hypogonadism or testicular adrenal rest tumours in boys. To ensure good health outcomes across the lifespan, the transition process from paediatric to adult care of patients with CAH must be planned carefully and early from the beginning of adolescence, spanning over many years into young adulthood. Its key aims are to empower the young person through education with full disclosure of their medical history, to ensure appropriate follow‐up with experienced physicians and facilitate access to multispecialist teams addressing the complex needs of patients with CAH

Human DHEA sulfation requires direct interaction between PAPS synthase 2 and DHEA sulfotransferase SULT2A1

The high-energy sulfate donor 3-phosphoadenosine-5-phosphosulfate (PAPS), generated by human PAPS synthase isoforms PAPSS1 and PAPSS2, is required for all human sulfation pathways. Sulfotransferase SULT2A1 uses PAPS for sulfation of the androgen precursor dehydroepiandrosterone (DHEA), thereby reducing downstream activation of DHEA to active androgens. Human PAPSS2 mutations manifest with undetectable DHEA sulfate, androgen excess, and metabolic disease, suggesting that ubiquitous PAPSS1 cannot compensate for deficient PAPSS2 in supporting DHEA sulfation. In knockdown studies in human adrenocortical NCI-H295R1 cells, we found that PAPSS2, but not PAPSS1, is required for efficient DHEA sulfation. Specific APS kinase activity, the rate-limiting step in PAPS biosynthesis, did not differ between PAPSS1 and PAPSS2. Co-expression of cytoplasmic SULT2A1 with a cytoplasmic PAPSS2 variant supported DHEA sulfation more efficiently than co-expression with nuclear PAPSS2 or nuclear/ cytosolic PAPSS1. Proximity ligation assays revealed protein–protein interactions between SULT2A1 and PAPSS2 and, to a lesser extent, PAPSS1. Molecular docking studies showed a putative binding site for SULT2A1 within the PAPSS2 APS kinase domain. Energy-dependent scoring of docking solutions identified the interaction as specific for the PAPSS2 and SULT2A1 isoforms. These findings elucidate the mechanistic basis for the selective requirement for PAPSS2 in human DHEA sulfation.</p

The diagnostic value of stimulated androgen ratios in 5-alpha reductase type 2 (SRD5A2) deficiency:a case series and review of the literature

Objectives: Precise and timely diagnosis is essential in the management of children born with atypical genitalia/differences or disorders of sex development (DSD) to provide optimal personalised care. Establishing the diagnosis can be challenging and time-consuming. The human chorionic gonadotrophin (hCG) stimulation test is useful in assessing male gonadal function, and stimulated testosterone: 5α-dihydrotestosterone (T:DHT)&gt;10 suggests 5-alpha reductase type 2 (SRD5A2) deficiency. Methods: We report the clinical, hormonal and genetic data of patients with 46, XY DSD with genetically confirmed SRD5A2 deficiency to assess the value of the hCG-stimulated T:DHT ratio in the diagnostic work-up. Additionally, we reviewed the literature on the usefulness of hCG-stimulated androgen ratios in determining DSD aetiology. Results: Of 14 patients with genetically confirmed SRD5A2 deficiency, including one novel variant, nine underwent hCG stimulation test: seven in infancy, one at 4 years and one at puberty. A T:DHT ratio above 10 was observed in seven patients (median: 15; range: 10.7–66.5). Two patients, aged one month and 4 years, had ratios of 8.3 and 4.4, respectively. Urinary steroid profiling (GC/MS) suggested SRD5A2 deficiency in all patients who had the testing (n=13). No association was found between T:DHT ratios and age at presentation or external masculinisation score (EMS). Conclusions: The hCG stimulation test appears less sensitive than urinary steroid profiling in establishing the diagnosis of SRD5A2 deficiency