The Stature of Boys Is Inversely Correlated to the Levels of Their Sertoli Cell Hormones: Do the Testes Restrain the Maturation of Boys?

The testes of preadolescent boys appear to be dormant, as they produce only trace levels of testosterone [1]. However, they release supra-adult levels of Müllerian Inhibiting Substance (MIS, anti-Müllerian hormone) and lesser levels of inhibin B (InhB), for unknown reasons [2], [3]. Boys have a variable rate of maturation, which on average is slower than girls. The height of children relative to their parents is an index of their maturity [4], [5]. We report here that a boy's level of MIS and InhB is stable over time and negatively correlates with his height and his height relative to his parent's height. This suggests that boy's with high levels of MIS and InhB are short because they are immature, rather than because they are destined to be short men. The levels of MIS and InhB in the boys did not correlate with known hormonal modulators of growth, and were additive with age and the growth hormone/IGF1 axis as predictors of a boy's height. If MIS and InhB were causal regulators of maturity, then the inter-boy differences in the levels of these hormone produces variation in maturation equivalent to 18-months of development. MIS and InhB may thus account for most of the variation in the rate of male development. If boys lacked these hormones, then an average 5-year-old boy would be over 5 cm taller than age-matched girls, making boys almost as dimorphic as men, for height. This indicates that boys have a high growth potential that is initially suppressed by their testes. The concept of the childhood testes suppressing an adult male feature appears paradoxical. However, the growth of children requires intergenerational transfer of nutrients. Consequently, the MIS/InhB slowing of male growth may have been historically advantageous, as it would minimizes any sex bias in the maternal cost of early child rearing

Genetics In Endocrinology: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 "DSDnet"

The differential diagnosis of differences or disorders of sex development (DSD) belongs to the most complex fields in medicine. It requires a multidisciplinary team conducting a synoptic and complementary approach consisting of thorough clinical, hormonal and genetic workups. This position paper of EU COST (European Cooperation in Science and Technology) Action BM1303 "DSDnet" was written by leading experts in the field and focuses on current best practice in genetic diagnosis in DSD patients. Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step. Subsequently, further analyses comprise molecular studies of monogenic DSD causes or analysis of copy number variations (CNV), or both. Panels of candidate genes provide rapid and reliable results. Whole exome and genome sequencing (WES and WGS) represent valuable methodological developments that are currently in the transition from basic science to clinical routine service in the field of DSD. However, in addition to covering known DSD candidate genes, WES and WGS help to identify novel genetic causes for DSD. Diagnostic interpretation must be performed with utmost caution and needs careful scientific validation in each DSD case

Measuring procedures for surface evaluation of additively manufactured powder bed-based polymer and metal parts

AbstractPowder bed-based additive manufacturing has become increasingly important for industrial applications. In the light of this, qualitative considerations such as the geometrical accuracy, the resulting mechanical properties, and the surface quality of additively manufactured parts must be taken into account. Optical measuring techniques such as confocal laser scanning microscopy, fringe projection and focus variation as well as profilometers are evaluated here, to determine the surface quality of powder bed-based manufactured parts. Even though these surface evaluation methods are established commercially, no standardized measuring procedure has yet been established. Within an experimental study the validity and accuracy of surface measurement methods are evaluated below, taking the limitations of each measurement system and the comparability of areal surface textures into account. The examinations are carried out with the powder materials EN-AW2024, Ti-6V-4Al and PA12, which are processed by electron beam melting, and laser beam melting of metals and polymers. Guidance for a consistent and comparable surface evaluation is thereby provided

Addressing gaps in care of people with conditions affecting sex development and maturation

Differences of sex development are conditions with discrepancies between chromosomal, gonadal and phenotypic sex. In congenital hypogonadotropic hypogonadism, a lack of gonadotropin activity results primarily in the absence of pubertal development with prenatal sex development being (almost) unaffected in most patients. To expedite progress in the care of people affected by differences of sex development and congenital hypogonadotropic hypogonadism, the European Union has funded a number of scientific networks. Two Actions of the Cooperation of Science and Technology (COST) programmes - DSDnet (BM1303) and GnRH Network (BM1105) - provided the framework for ground-breaking research and allowed the development of position papers on diagnostic procedures and special laboratory analyses as well as clinical management. Both Actions developed educational programmes to increase expertise and promote interest in this area of science and medicine. In this Perspective article, we discuss the success of the COST Actions DSDnet and GnRH Network and the European Reference Network for Rare Endocrine Conditions (Endo-ERN), and provide recommendations for future research

Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling.

Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH, encoded by H6PD) cause apparent cortisone reductase deficiency (ACRD). H6PDH generates cofactor NADPH for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol. Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD). Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism. To describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases. Clinical, biochemical and genetic assessment of two female patients presenting during childhood. In addition, results of urinary steroid profiling in a total of ten ACRD/CRD patients were compared to identify distinguishing characteristics. Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD. Mutant expression studies confirmed loss of H6PDH activity in both cases. Urinary steroid metabolite profiling by gas chromatography/mass spectrometry suggested ACRD in both cases. In addition, we were able to establish a steroid metabolite signature differentiating ACRD and CRD, providing a basis for genetic diagnosis and future individualised management. Steroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD. This will provide a useful tool in stratifying unresolved adrenal hyperandrogenism in children with premature adrenarche and adult females with polycystic ovary syndrome (PCOS)

Disorders of sex development: effect of molecular diagnostics

Disorders of sex development (DSDs) are a diverse group of conditions that can be challenging to diagnose accurately using standard phenotypic and biochemical approaches. Obtaining a specific diagnosis can be important for identifying potentially life-threatening associated disorders, as well as providing information to guide parents in deciding on the most appropriate management for their child. Within the past 5 years, advances in molecular methodologies have helped to identify several novel causes of DSDs; molecular tests to aid diagnosis and genetic counselling have now been adopted into clinical practice. Occasionally, genetic profiling of embryos prior to implantation as an adjunct to assisted reproduction, prenatal diagnosis of at-risk pregnancies and confirmatory testing of positive results found during newborn biochemical screening are performed. Of the available genetic tests, the candidate gene approach is the most popular. New high-throughput DNA analysis could enable a genetic diagnosis to be made when the aetiology is unknown or many differential diagnoses are possible. Nonetheless, concerns exist about the use of genetic tests. For instance, a diagnosis is not always possible even using new molecular approaches (which can be worrying for the parents) and incidental information obtained during the test might cause anxiety. Careful selection of the genetic test indicated for each condition remains important for good clinical practice. The purpose of this Review is to describe advances in molecular biological techniques for diagnosing DSDs

Curing and Infiltration Behavior of UV-Curing Thermosets for the Use in a Combined Laser Sintering Process of Polymers

The investigation in this study addresses a new additive manufacturing process, which enables the production of multi-material parts consisting of thermosets and thermoplastics. A liquid thermoset resin will be applied with a micro value syringe in the laser sintering (LS) system. The liquid thermoset reacts parallel to the laser exposure of the thermoplastic powder. Therefore, in this study the UV curing and the infiltration behavior of the thermoset will be investigated under process relevant conditions. The investigations show a strong temperature dependent absorption of the liquid in the powder bed, whereas, the surface tension of the liquid plays a minor role. Furthermore, the UV curing of the thermosets takes place at low interaction times and at lamp powers between 100 and 300 mW/cm².Mechanical Engineerin

Curing Behavior of Thermosets for the Use in a Combined Selective Laser Sintering Process of Polymers

Selective laser sintering (SLS) of polymers is an additive manufacturing process, which enables the production of functional technical components. Unfortunately, the SLS process is restricted regarding the materials that can be processed and thus resulting component properties are limited. The investigations in this study illustrates a totally new additive manufacturing process which combines reactive liquids like thermoset resins and thermoplastics to generates multi material SLS parts. To introduce thermoset resins into the regular SLS process, the time-temperature-dependent curing behavior of the thermoset and the infiltration behavior has to be understood in order to assess the process behavior. The curing behavior was analyzed by rotational viscosimeter. Furthermore, the fundamental infiltration behavior was analyzed with micro dosing infiltration experiments. Finally, a thermoset resin in combination with a dosing system was chosen for integration in a laser sintering system.Mechanical Engineerin

Aging Behavior of Polyamide 12: Interrelation Between Bulk Characteristics and Part Properties

The high process temperatures in combination with long building times during the laser sintering process lead to chemical and physical aging mechanisms on the polymeric feed material. The unmolten partcake material, which acts as a supporting structure, can be removed after each building process and reused for further processes. However, material as well as bulk properties are changed due to thermal and mechanical load during the laser sintering process. Within this paper the interrelation between the aging state, bulk values and resulting part properties like porosity, surface roughness and mechanical behavior are derived. Therefore, polyamide 12 powder is used for at least five processing cycles without refreshing. Before and after each building process, bulk characteristics and changes of the particle surface were determined. Specimens were manufactured during the laser sintering process in order to study the part density, roughness and mechanical behavior.Mechanical Engineerin