Adrenal cortex development and related disorders leading to adrenal insufficiency.

The adult human adrenal cortex produces steroid hormones that are crucial for life, supporting immune response, glucose homeostasis, salt balance and sexual maturation. It consists of three histologically distinct and functionally specialized zones. The fetal adrenal forms from mesodermal material and produces predominantly adrenal C19 steroids from its fetal zone, which involutes after birth. Transition to the adult cortex occurs immediately after birth for the formation of the zona glomerulosa and fasciculata for aldosterone and cortisol production and continues through infancy until the zona reticularis for adrenal androgen production is formed with adrenarche. The development of this indispensable organ is complex and not fully understood. This article gives an overview of recent knowledge gained of adrenal biology from two perspectives: one, from basic science studying adrenal development, zonation and homeostasis; and two, from adrenal disorders identified in persons manifesting with various isolated or syndromic forms of primary adrenal insufficiency

Development and function of the fetal adrenal.

The adrenal cortex undergoes multiple structural and functional rearrangements to satisfy the systemic needs for steroids during fetal life, postnatal development, and adulthood. A fully functional adrenal cortex relies on the proper subdivision in regions or 'zones' with distinct but interconnected functions, which evolve from the early embryonic stages to adulthood, and rely on a fine-tuned gene network. In particular, the steroidogenic activity of the fetal adrenal is instrumental in maintaining normal fetal development and growth. Here, we review and discuss the most recent advances in our understanding of embryonic and fetal adrenal development, including the known causes for adrenal dys-/agenesis, and the steroidogenic pathways that link the fetal adrenal with the hormone system of the mother through the fetal-placental unit. Finally, we discuss what we think are the major open questions in the field, including, among others, the impact of osteocalcin, thyroid hormone, and other hormone systems on adrenal development and function, and the reliability of rodents as models of adrenal pathophysiology

Stable Metabolic Control but Increased Demand for Professional Support in Children with Type 1 Diabetes in the Past Ten Years in Bern/Switzerland: A Quality Control Study.

Introduction Lower HbA1c targets and increasingly complex diabetes management with substantially increasing costs dominate today's type 1 diabetes therapy in children and adolescents. Objective To evaluate metabolic control in children and adolescents with type 1 diabetes and assess associated factors, evaluate determinants for frequency of healthcare contacts, and compare actual with historical data. Method This cross-sectional observational study collected data on 178 children and adolescents with type 1 diabetes treated at the University Children's Hospital in Bern. Results Mean HbA1c was 7.9% (63 mmol/mol), 33.1% (59/178) of children reached the target of HbA1c < 7.5% (<59 mmol/mol), and 18.0% (32/178) had an HbA1c value < 7.0% (<53 mmol/mol). Compared to historical data, stable HbA1c levels appeared with a doubled proportion of individuals using insulin pumps. Metabolic control was worse with a longer duration of diabetes and younger age at diagnosis but better when parents came from a Western European country. Age at the consultation, use of diabetes technology and native language influenced the number of healthcare contacts. Younger patients, patients using CSII, and patients without an official Swiss language as mother tongue had more consultations with a healthcare professional than older and native language individuals. Conclusion The metabolic targets in childhood and adolescent type 1 diabetes are still unmet despite a shift towards more technology. Our study documents a higher demand for support and supervision in specific patient groups. An investment to increase healthcare contacts could help combat the increase in total diabetes cost and significantly improve metabolic control

The serum steroid signature of PCOS hints at the involvement of novel pathways for excess androgen biosynthesis.

CONTEXT Polycystic ovary syndrome (PCOS) is defined by androgen excess and ovarian dysfunction in the absence of a specific physiological diagnosis. The best clinical marker of androgen excess is hirsutism, while the best biochemical parameter is still a matter of debate. Current consensus guidelines recommend, among other hormones, serum free testosterone as an important serum parameter to measure androgen excess. Recently, however, novel active androgens and androgen metabolic pathways have been discovered. OBJECTIVE To assess the contribution of novel androgens and related steroid biosynthetic pathways to the serum steroid pool in PCOS women in comparison to healthy controls. DESIGN This is a case control study, wherein PCOS was diagnosed according to the AE-PCOS 2009 criteria. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry. SETTING Yeditepe University and associated clinics in Istanbul, Turkey, together with Bern University Hospital Inselspital, Bern, Switzerland. PARTICIPANTS 42 PCOS women and 42 matched, healthy control women. MAIN OUTCOME MEASURES Assessment of 34 steroids compartmentalized in four androgen related pathways: the classic androgen pathway, the backdoor pathway, the C11-oxy backdoor pathway, and the C11-oxy (11β-hydroxyandrostenedione) pathway. RESULTS Metabolites of all four pathways were identified in healthy and PCOS women. Highest concentrations were found for progesterone in controls and androstenedione in PCOS. Lowest levels were found for 11-ketotestosterone in controls compared to PCOS, and for 20α-hydroxyprogesterone in PCOS compared to controls. PCOS also had higher serum testosterone levels compared to the controls. PCOS women had overall higher levels of steroid metabolites of all four androgen pathways compared to healthy controls. CONCLUSIONS Novel alternative pathways contribute to the androgen production in healthy and PCOS women. Hyperandrogenism in PCOS is characterized by an overall increase of serum androgens in the classic, backdoor and C11-oxy pathways. While monogenetic disorders of steroid biosynthesis can be recognized by a specific pattern in the steroid profile, no diagnostic pattern or classifier was found in the serum for PCOS

Anti-Müllerian hormone levels in girls and adolescents with Turner syndrome are related to karyotype, pubertal development and growth hormone treatment

STUDY QUESTION In girls and adolescents with Turner syndrome (TS), is there a correlation between serum AMH levels and karyotype, spontaneous puberty and other biochemical markers of ovarian function, or growth hormone (GH) therapy? SUMMARY ANSWER Serum anti-Müllerian hormone (AMH) correlates with karyotype, pubertal development, LH, FSH and are measurable in a higher percentage of TS patients under GH therapy. WHAT IS KNOWN ALREADY Most girls with TS suffer from incomplete sexual development, premature ovarian failure and infertility due to abnormal ovarian folliculogenesis. Serum AMH levels reflect the ovarian reserve in females, even in childhood. STUDY DESIGN, SIZE, DURATION Cross-sectional study investigating 270 karyotype proven TS patients aged 0-20 years between 2009 and 2010. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Studies were conducted at three University Children's hospitals in Europe. Main outcome measures were clinical data concerning pubertal development as well as laboratory data including karyotype, serum AMH, LH, FSH, estradiol (E2), inhibin B and IGF. RESULTS AND THE ROLE OF CHANCE Serum AMH was detectable in 21.9% of all TS girls and correlated strongly with karyotypes. A measurable serum AMH was found in 77% of TS girls with karyotype 45,X/46,XX, in 25% with ‘other' karyotypes and in only 10% of 45,X TS girls. A strong relationship was also observed for measurable serum AMH and signs of spontaneous puberty such as breast development [adjusted odds ratio (OR) 19.3; 95% CI 2.1-175.6; P = 0.009] and menarche (crude OR 47.6; 95% CI 4.8-472.9; P = 0.001). Serum AMH correlated negatively with FSH and LH, but did not correlate with E2 and inhibin B. GH therapy increased the odds of having measurable AMH in TS (adjusted OR 4.1; 95% CI 1.9-8.8; P < 0.001). LIMITATIONS, REASONS FOR CAUTION The cross-sectional design of the study does not allow longitudinal interpretation of the data; for that further studies are needed. High percentage of non-measurable AMH levels in the cohort of TS require categorized analysis. WIDER IMPLICATIONS OF THE FINDINGS Serum AMH levels are a useful marker of the follicle pool and thus ovarian function in pediatric patients with TS. These findings are in line with the published literature. The finding that GH therapy may affect AMH levels is novel, but must be confirmed by future longitudinal studie

Short-Term Effects of Elexacaftor/Tezacaftor/Ivacaftor Combination on Glucose Tolerance in Young People With Cystic Fibrosis—An Observational Pilot Study

BACKGROUND: The effect of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on glucose tolerance and/or cystic-fibrosis-related diabetes (CFRD) is not well understood. We performed an observational study on the short-term effects of ELX/TEZ/IVA on glucose tolerance. METHODS: Sixteen adolescents with CF performed oral glucose tolerance tests (OGTT) before and 4–6 weeks after initiating ELX/TEZ/IVA therapy. A continuous glucose monitoring (CGM) system was used 3 days before until 7 days after starting ELX/TEZ/IVA treatment. RESULTS: OGTT categories improved after initiating ELX/TEZ/IVA therapy (p = 0.02). Glucose levels of OGTT improved at 60, 90, and 120 min (p < 0.05), whereas fasting glucose and CGM measures did not change. CONCLUSION: Shortly after initiating ELX/TEZ/IVA therapy, glucose tolerance measured by OGTT improved in people with CF. This pilot study indicates that ELX/TEZ/IVA treatment has beneficial effects on the endocrine pancreatic function and might prevent or at least postpone future CFRD

Effects of 2-year physical activity and dietary intervention on adrenarchal and pubertal development: the PANIC study.

CONTEXT Childhood overweight has been linked to earlier development of adrenarche and puberty, but it remains unknown if lifestyle interventions influence sexual maturation in general populations. OBJECTIVE To investigate if a 2-year lifestyle intervention influences circulating androgen concentrations and sexual maturation in a general population of children. DESIGN AND PARTICIPANTS A 2-year intervention study in which 421 prepubertal and mostly normal-weight 6-9-year-old children were allocated either to a lifestyle intervention group (119 girls, 132 boys) or a control group (84 girls, 86 boys). INTERVENTION A 2-year physical activity and dietary intervention. MAIN OUTCOME MEASURES Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone concentrations, and clinical adrenarchal and pubertal signs. RESULTS The intervention and control groups had no differences in body size and composition, clinical signs of androgen action, and serum androgens at baseline. The intervention attenuated the increase of dehydroepiandrosterone (p = 0.032), dehydroepiandrosterone sulfate (p = 0.001), androstenedione (p = 0.003), and testosterone (p = 0.007) and delayed pubarche (p = 0.038) in boys but it only attenuated the increase of dehydroepiandrosterone (p = 0.013) and dehydroepiandrosterone sulfate (p = 0.003) in girls. These effects of lifestyle intervention on androgens and the development of pubarche were independent of changes in body size and composition but the effects of intervention on androgens were partly explained by changes in fasting serum insulin. CONCLUSIONS A combined physical activity and dietary intervention attenuates the increase of serum androgen concentrations and sexual maturation in a general population of prepubertal and mostly normal-weight children, independently of changes in body size and composition

Approach to the virilizing girl at puberty

Virilization is the medical term for describing a female who develops characteristics associated with male hormones (androgens) at any age, or when a newborn girl shows signs of prenatal male hormone exposure at birth. In girls, androgen levels are low during pregnancy and childhood. A first physiologic rise of adrenal androgens is observed at the age of 6 to 8 years and reflects functional activation of the zona reticularis of the adrenal cortex at adrenarche, manifesting clinically with first pubic and axillary hairs. Early adrenarche is known as “premature adrenarche.” It is mostly idiopathic and of uncertain pathologic relevance but requires the exclusion of other causes of androgen excess (eg, nonclassic congenital adrenal hyperplasia) that might exacerbate clinically into virilization. The second modest physiologic increase of circulating androgens occurs then during pubertal development, which reflects the activation of ovarian steroidogenesis contributing to the peripheral androgen pool. However, at puberty initiation (and beyond), ovarian steroidogenesis is normally devoted to estrogen production for the development of secondary female bodily characteristics (eg, breast development). Serum total testosterone in a young adult woman is therefore about 10- to 20-fold lower than in a young man, whereas midcycle estradiol is about 10- to 20-fold higher. But if androgen production starts too early, progresses rapidly, and in marked excess (usually more than 3 to 5 times above normal), females will manifest with signs of virilization such as masculine habitus, deepening of the voice, severe acne, excessive facial and (male typical) body hair, clitoromegaly, and increased muscle development. Several medical conditions may cause virilization in girls and women, including androgen-producing tumors of the ovaries or adrenal cortex, (non)classical congenital adrenal hyperplasia and, more rarely, other disorders (also referred to as differences) of sex development (DSD). The purpose of this article is to describe the clinical approach to the girl with virilization at puberty, focusing on diagnostic challenges. The review is written from the perspective of the case of an 11.5-year-old girl who was referred to our clinic for progressive, rapid onset clitoromegaly, and was then diagnosed with a complex genetic form of DSD that led to abnormal testosterone production from a dysgenetic gonad at onset of puberty. Her genetic workup revealed a unique translocation of an abnormal duplicated Y-chromosome to a deleted chromosome 9, including the Doublesex and Mab-3 Related Transcription factor 1 (DMRT1) gene