The "backdoor pathway" of androgen synthesis in human male sexual development.

Mammalian sex determination (male versus female) is largely controlled by genes, whereas sex differentiation (development of reproductive structures) is largely controlled by hormones. Work in the 20th century indicated that female external anatomy was a "default" pathway of development not requiring steroids, whereas male genital development required testicular testosterone plus dihydrotestosterone (DHT) made in genital skin according to a "classic" pathway. Recent work added the description of an alternative "backdoor" pathway of androgen synthesis discovered in marsupials. Unique "backdoor steroids" are found in human hyperandrogenic disorders, and genetic disruption of the pathway causes disordered male sexual development, suggesting it plays an essential role. O'Shaughnessy and colleagues now show that the principal human backdoor androgen is androsterone and provide strong evidence that it derives from placental progesterone that is metabolized to androsterone in nontesticular tissues. These studies are essential to understanding human sexual development and its disorders.

A Novel Mitochondrial Complex of Aldosterone Synthase, Steroidogenic Acute Regulatory Protein, and Tom22 Synthesizes Aldosterone in the Rat Heart.

Aldosterone, which regulates renal salt retention, is synthesized in adrenocortical mitochondria in response to angiotensin II. Excess aldosterone causes myocardial injury and heart failure, but potential intracardiac aldosterone synthesis has been controversial. We hypothesized that the stressed heart might produce aldosterone. We used blue native gel electrophoresis, immunoblotting, protein crosslinking, coimmunoprecipitations, and mass spectrometry to assess rat cardiac aldosterone synthesis. Chronic infusion of angiotensin II increased circulating corticosterone levels 350-fold and induced cardiac fibrosis. Angiotensin II doubled and telmisartan inhibited aldosterone synthesis by heart mitochondria and cardiac production of aldosterone synthase (P450c11AS). Heart aldosterone synthesis required P450c11AS, Tom22 (a mitochondrial translocase receptor), and the intramitochondrial form of the steroidogenic acute regulatory protein (StAR); protein crosslinking and coimmunoprecipitation studies showed that these three proteins form a 110-kDa complex. In steroidogenic cells, extramitochondrial (37-kDa) StAR promotes cholesterol movement from the outer to inner mitochondrial membrane where cholesterol side-chain cleavage enzyme (P450scc) converts cholesterol to pregnenolone, thus initiating steroidogenesis, but no function has previously been ascribed to intramitochondrial (30-kDa) StAR; our data indicate that intramitochondrial 30-kDa StAR is required for aldosterone synthesis in the heart, forming a trimolecular complex with Tom22 and P450c11AS. This is the first activity ascribed to intramitochondrial StAR, but how this promotes P450c11AS activity is unclear. The stressed heart did not express P450scc, suggesting that circulating corticosterone (rather than intracellular cholesterol) is the substrate for cardiac aldosterone synthesis. Thus, the stressed heart produced aldosterone using a previously undescribed intramitochondrial mechanism that involves P450c11AS, Tom22, and 30-kDa StAR. SIGNIFICANCE STATEMENT: Prior studies of potential cardiac aldosterone synthesis have been inconsistent. This study shows that the stressed rat heart produces aldosterone by a novel mechanism involving aldosterone synthase, Tom22, and intramitochondrial steroidogenic acute regulatory protein (StAR) apparently using circulating corticosterone as substrate. This study establishes that the stressed rat heart produces aldosterone and for the first time identifies a biological role for intramitochondrial 30-kDa StAR.

Temperature Elevation During Neonatal and Pediatric Fixed Wing Transport in a Subtropic Climate: A Descriptive Study.

OBJECTIVE: We sought to describe the degree of temperature elevation (∆T) among children transported in a subtropical climate (Florida) via fixed wing aircraft and identify potential relationships between patient weight and ∆T. METHODS: We performed a retrospective cohort study in children < 18 years of age undergoing interfacility transport via fixed wing aircraft from January 2016 through July 2020. The study outcomes were ∆T, maximum patient temperature, ambient temperature, and heat index. Bivariate cohorts defined by patient weight (5 kg) were compared using Fisher exact, Student t-, and Wilcoxon rank sum analyses. Exploratory testing included receiver operator characteristic curve analyses and unadjusted logistic regression. RESULTS: Of the 58 children studied, 25 (43%) were ≤ 5 kg, and 33 (57%) were > 5 kg. Compared with children > 5 kg, those ≤ 5 kg had greater ∆T (0.8° ± 0.6°C vs. 0.2° ± 0.3°C), maximum patient temperature (37.3° ± 0.6°C vs. 36.8° ± 0.4°C), and proportion with ≥ 1°C ∆T (36% vs. 3%). No child > 5 kg had a temperature > 38°C, and no differences were observed for heat index or ambient temperature. Receiver operating characteristic analysis of patient weight on ∆T ≥ 1°C yielded an area under the curve of 0.86 (cutoff of 3.5 kg; sensitivity = 81.3%, specificity = 80%). Patient weight was inversely associated with ∆T ≥ 1°C (odds ratio = 0.69; 95% confidence interval, 0.49-0.96). CONCLUSIONS: Young children appear at greatest risk for developing environmental hyperthermia during interfacility fixed wing transport.

NIST Standards for Measurement, Instrument Calibration, and Quantification of Gaseous Atmospheric Compounds.

There are many gas phase compounds present in the atmosphere that affect and influence the earth's climate. These compounds absorb and emit radiation, a process which is the fundamental cause of the greenhouse effect. The major greenhouse gases in the earth's atmosphere are carbon dioxide, methane, nitrous oxide, and ozone. Some halocarbons are also strong greenhouse gases and are linked to stratospheric ozone depletion. Hydrocarbons and monoterpenes are precursors and contributors to atmospheric photochemical processes, which lead to the formation of particulates and secondary photo-oxidants such as ozone, leading to photochemical smog. Reactive gases such as nitric oxide and sulfur dioxide are also compounds found in the atmosphere and generally lead to the formation of other oxides. These compounds can be oxidized in the air to acidic and corrosive gases and contribute to photochemical smog. Measurements of these compounds in the atmosphere have been ongoing for decades to track growth rates and assist in curbing emissions of these compounds into the atmosphere. To accurately establish mole fraction trends and assess the role of these gas phase compounds in atmospheric chemistry, it is essential to have good calibration standards. The National Institute of Standards and Technology has been developing standards of many of these compounds for over 40 years. This paper discusses the development of these standards.

Development of a Northern Continental Air Standard Reference Material.

The National Institute of Standards and Technology (NIST) recently began to develop standard mixtures of greenhouse gases as part of a broad program mandated by the 2009 United States Congress to support research in climate change. To this end, NIST developed suites of gravimetrically assigned primary standard mixtures (PSMs) comprising carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) in a dry-natural air balance at ambient mole fraction levels. In parallel, the National Oceanic and Atmospheric Administration (NOAA) in Boulder, Colorado, charged 30 aluminum gas cylinders with northern hemisphere air at Niwot Ridge, Colorado. These mixtures, which constitute NIST Standard Reference Material (SRM) 1720 Northern Continental Air, were certified by NIST for ambient mole fractions of CO2, CH4, and N2O relative to NIST PSMs. NOAA-assigned values are also provided as information in support of the World Meteorological Organization (WMO) Global Atmosphere Watch (GAW) Program for CO2, CH4, and N2O, since NOAA serves as the WMO Central Calibration Laboratory (CCL) for CO2, CH4, and N2O. Relative expanded uncertainties at the 95% confidence interval are <±0.06% of the certified values for CO2 and N2O and <0.2% for CH4, which represents the smallest relative uncertainties specified to date for a gaseous SRM produced by NIST. Agreement between the NOAA (WMO/GAW) and NIST values based on their respective calibration standards suites is within 0.05%, 0.13%, and 0.06% for CO2, CH4, and N2O, respectively. This collaborative development effort also represents the first of its kind for a gaseous SRM developed by NIST.

Development of a southern oceanic air standard reference material.

In 2009, the United States Congress charged the National Institute of Standards and Technology (NIST) with supporting climate change research. As part of this effort, the Gas Sensing Metrology Group at NIST began developing new gas standard mixtures for greenhouse gas mixtures relevant to atmospheric measurements. Suites of gravimetrically prepared primary standard mixtures (PSMs) were prepared at ambient concentration levels for carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) in a dry-air balance. In parallel, 30 gas cylinders were filled, by the National Institute of Water and Atmospheric Research (NIWA) in Wellington, New Zealand, to high pressure from pristine southern oceanic air at Baring Head, New Zealand, and shipped to NIST. Using spectroscopic instrumentation, NIST analyzed the 30 cylinder samples for mole fractions of CO2, CH4, and N2O. Certified values were assigned to these mixtures by calibrating the instrumentation with the PSM suites that were recently developed at NIST. These mixtures became NIST Standard Reference Material (SRM) 1721 Southern Oceanic Air and are certified for ambient mole fraction, the first of their kind for NIST. The relative expanded uncertainties corresponding to coverage intervals with 95% probability are no larger than 0.06% of the certified values, representing the smallest uncertainties to date ever assigned to an NIST gas SRM.

Electron transfer by human wild-type and A287P mutant P450 oxidoreductase assessed by transient kinetics: functional basis of P450 oxidoreductase deficiency.

Cytochrome P450 oxidoreductase (POR) is a 2-flavin protein that transfers electrons from NADPH via its FAD and FMN moieties to all microsomal cytochrome P450 enzymes, including steroidogenic and drug-metabolizing P450s. Defects in the POR gene can cause POR deficiency (PORD), manifested clinically by disordered steroidogenesis, genital anomalies and skeletal malformations. We examined the POR mutant A287P, which is the most frequent cause of PORD in patients of European ancestry and partially disrupts most P450 activities in vitro. Flavin content analysis showed that A287P is deficient in FAD and FMN binding, although the mutation site is distant from the binding sites of both flavins. Externally added flavin partially restored the cytochrome c reductase activity of A287P, suggesting that flavin therapy may be useful for this frequent form of PORD. Transient kinetic dissection of the reaction of POR with NADPH and the reduction in cytochrome c by POR using stopped-flow techniques revealed defects in individual electron transfer steps mediated by A287P. A287P had impaired ability to accept electrons from NADPH, but was capable of a fast FMN → cytochrome c electron donation reaction. Thus the reduced rates of P450 activities with A287P may be due to deficient flavin and impaired electron transfer from NADPH.

Investigating adsorption/desorption of carbon dioxide in aluminum compressed gas cylinders.

Between June 2010 and June 2011, the National Institute of Standards and Technology (NIST) gravimetrically prepared a suite of 20 carbon dioxide (CO2) in air primary standard mixtures (PSMs). Ambient mole fraction levels were obtained through six levels of dilution beginning with pure (99.999%) CO2. The sixth level covered the ambient range from 355 to 404 µmol/mol. This level will be used to certify cylinder mixtures of compressed dry whole air from both the northern and southern hemispheres as NIST standard reference materials (SRMs). The first five levels of PSMs were verified against existing PSMs in a balance of air or nitrogen with excellent agreement observed (the average percent difference between the calculated and analyzed values was 0.002%). After the preparation of a new suite of PSMs at ambient level, they were compared to an existing suite of PSMs. It was observed that the analyzed concentration of the new PSMs was less than the calculated gravimetric concentration by as much as 0.3% relative. The existing PSMs had been used in a Consultative Committee for Amount of Substance-Metrology in Chemistry Key Comparison (K-52) in which there was excellent agreement (the NIST-analyzed value was -0.09% different from the calculated value, while the average of the difference for all 18 participants was -0.10%) with those of other National Metrology Institutes and World Meteorological Organization designated laboratories. In order to determine the magnitude of these losses at the ambient level, a series of "daughter/mother" tests were initiated and conducted in which the gas mixture containing CO2 from a "mother" cylinder was transferred into an evacuated "daughter" cylinder. These cylinder pairs were then compared using cavity ring-down spectroscopy under high reproducibility conditions (the average percent relative standard deviation of sample response was 0.02). A ratio of the daughter instrument response to the mother response was calculated, with the resultant deviation from unity being a measure of the CO2 loss or gain. Cylinders from three specialty gas vendors were tested to find the appropriate cylinder in which to prepare the new PSMs. All cylinders tested showed a loss of CO2, presumably to the walls of the cylinder. The vendor cylinders exhibiting the least loss of CO2 were then purchased to be used to gravimetrically prepare the PSMs, adjusting the calculated mole fraction for the loss bias and an uncertainty calculated from this work.

Potential role of increased oxygenation in altering perinatal adrenal steroidogenesis.

BACKGROUND: At birth, the large fetal adrenal involutes rapidly, and the patterns of steroidogenesis change dramatically; the event(s) triggering these changes remain largely unexplored. Fetal abdominal viscera receive hypoxic blood having a partial pressure of oxygen of only ~2 kPa (20-23 mm Hg); perinatal circulatory changes change this to adult values (~20 kPa). We hypothesized that transition from fetal hypoxia to postnatal normoxia participates in altering perinatal steroidogenesis. METHODS: We grew midgestation human fetal adrenal cells and human NCI-H295A adrenocortical carcinoma cells in 2% O2, then transitioned them to 20% O2 and quantitated steroidogenic mRNAs by quantitative PCR and microarrays. RESULTS: Transitioning fetal adrenal cells from hypoxia to normoxia increased mRNAs for 17α-hydroxylase/17,20 lyase (P450c17), 3ß-hydroxysteroid dehydrogenase (3ßHSD2), and steroidogenic acute regulatory protein (StAR). We repeated the protocol with NCI-H295A cells acclimated to hypoxia for 15 d, quantitating 31,255 transcripts by microarray. Using an arbitrary 1.5-fold difference, 1 d of normoxia increased 4 transcripts and decreased 56, whereas 2 d of normoxia increased 62 transcripts and decreased 105. P450c17, 3ßHSD2, and StAR were ranked among the top eight increased transcripts. CONCLUSION: These data suggest that the hypoxic/normoxic transition at birth contributes to perinatal changes in adrenal steroidogenesis.

Phosphorylation of human cytochrome P450c17 by p38α selectively increases 17,20 lyase activity and androgen biosynthesis.

Cytochrome P450c17, a steroidogenic enzyme encoded by the CYP17A1 gene, catalyzes the steroid 17α-hydroxylation needed for glucocorticoid synthesis, which may or may not be followed by 17,20 lyase activity needed for sex steroid synthesis. Whether or not P450c17 catalyzes 17,20 lyase activity is determined by three post-translational mechanisms influencing availability of reducing equivalents donated by P450 oxidoreductase (POR). These are increased amounts of POR, the allosteric action of cytochrome b5 to promote POR-P450c17 interaction, and Ser/Thr phosphorylation of P450c17, which also appears to promote POR-P450c17 interaction. The kinase(s) that phosphorylates P450c17 is unknown. In a series of kinase inhibition experiments, the pyridinyl imidazole drugs SB202190 and SB203580 inhibited 17,20 lyase but not 17α-hydroxylase activity in human adrenocortical HCI-H295A cells, suggesting an action on p38α or p38ß. Co-transfection of non-steroidogenic COS-1 cells with P450c17 and p38 expression vectors showed that p38α, but not p38ß, conferred 17,20 lyase activity on P450c17. Antiserum to P450c17 co-immunoprecipitated P450c17 and both p38 isoforms; however, knockdown of p38α, but not knockdown of p38ß, inhibited 17,20 lyase activity in NCI-H295A cells. Bacterially expressed human P450c17 was phosphorylated by p38α in vitro at a non-canonical site, conferring increased 17,20 lyase activity. This phosphorylation increased the maximum velocity, but not the Michaelis constant, of the 17,20 lyase reaction. p38α phosphorylates P450c17 in a fashion that confers increased 17,20 lyase activity, implying that the production of adrenal androgens (adrenarche) is a regulated event.

Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation.

Human sexual determination is initiated by a cascade of genes that lead to the development of the fetal gonad. Whereas development of the female external genitalia does not require fetal ovarian hormones, male genital development requires the action of testicular testosterone and its more potent derivative dihydrotestosterone (DHT). The "classic" biosynthetic pathway from cholesterol to testosterone in the testis and the subsequent conversion of testosterone to DHT in genital skin is well established. Recently, an alternative pathway leading to DHT has been described in marsupials, but its potential importance to human development is unclear. AKR1C2 is an enzyme that participates in the alternative but not the classic pathway. Using a candidate gene approach, we identified AKR1C2 mutations with sex-limited recessive inheritance in four 46,XY individuals with disordered sexual development (DSD). Analysis of the inheritance of microsatellite markers excluded other candidate loci. Affected individuals had moderate to severe undervirilization at birth; when recreated by site-directed mutagenesis and expressed in bacteria, the mutant AKR1C2 had diminished but not absent catalytic activities. The 46,XY DSD individuals also carry a mutation causing aberrant splicing in AKR1C4, which encodes an enzyme with similar activity. This suggests a mode of inheritance where the severity of the developmental defect depends on the number of mutations in the two genes. An unrelated 46,XY DSD patient carried AKR1C2 mutations on both alleles, confirming the essential role of AKR1C2 and corroborating the hypothesis that both the classic and alternative pathways of testicular androgen biosynthesis are needed for normal human male sexual differentiation.

Distinguishing deficiencies in the steroidogenic acute regulatory protein and the cholesterol side chain cleavage enzyme causing neonatal adrenal failure.

OBJECTIVES: To determine the genetic basis of disordered steroidogenesis in Kuwaiti siblings. STUDY DESIGN: Two siblings (46,XX and 46,XY) had normal female external genitalia and severe glucocorticoid and mineralocorticoid deficiency presenting in the first month of life. Abdominal ultrasonography showed normal size adrenal glands, suggesting cholesterol side chain cleavage enzyme (P450scc) deficiency. The CYP11A1 gene encoding P450scc and the STAR gene encoding the steroidogenic acute regulatory protein (StAR) were directly sequenced from leukocyte DNA. RESULTS: All exons and intron/exon boundaries of the CYP11A1 gene were normal; the STAR gene was homozygous for a novel 14-base deletion/frameshift in exon 4 (g.4643_4656del), so that no functional protein could be produced. Both parents and an unaffected sibling were heterozygous; zygosity was confirmed with a BsmF1 restriction fragment length polymorphism. CONCLUSIONS: Unlike most patients with StAR deficiency, our patients did not have the massive adrenal hyperplasia typical of congenital lipoid adrenal hyperplasia. The distinction between StAR and P450scc deficiency may require gene sequencing.

Prenatal treatment of congenital adrenal hyperplasia: risks outweigh benefits.

Prenatal treatment of congenital adrenal hyperplasia by administering dexamethasone to a woman presumed to be carrying an at-risk fetus has been described as safe and effective in several reports. A review of data from animal experimentation and human trials indicates that first-trimester dexamethasone decreases birthweight; affects renal, pancreatic beta cell, and brain development; increases anxiety; and predisposes to adult hypertension and hyperglycemia. In human studies, first-trimester dexamethasone is associated with orofacial clefts, decreased birthweight, poorer verbal working memory, and poorer self-perception of scholastic and social competence. Numerous medical societies have cautioned that prenatal treatment of congenital adrenal hyperplasia with dexamethasone should only be done in prospective clinical research settings with institutional review board approval, and therefore is not appropriate for routine community practice.

Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.

Deficient activities of multiple steroidogenic enzymes have been reported without and with Antley-Bixler syndrome (ABS), but mutations of corresponding cytochrome P450 enzymes have not been found. We identified mutations in POR, encoding P450 oxidoreductase, the obligate electron donor for these enzymes, in a woman with amenorrhea and three children with ABS, even though knock-out of POR is embryonically lethal in mice. Mutations of POR also affect drug-metabolizing P450 enzymes, explaining the association of ABS with maternal fluconazole ingestion.

History of Adrenal Research: From Ancient Anatomy to Contemporary Molecular Biology.

The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3ß-hydroxysteroid dehydrogenase, 11ß-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders.

Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3.

OBJECTIVES: CYP2C9 is a microsomal cytochrome P450 that receives electrons from P450 oxidoreductase (POR) to metabolize about 15% of clinically used drugs. Similar to many P450 enzymes, CYP2C9 is polymorphic, with the hypomorphic *2 and *3 variants accounting for about 20% of White alleles. POR is also polymorphic, with the amino acid sequence variant A503V accounting for 19-37% of alleles in different populations. We aimed to understand how polymorphisms in these two interacting proteins might affect drug metabolism. METHODS: We assayed the activities of CYP2C9.1, CYP2C9.2, and CYP2C9.3 to metabolize diclofenac, flurbiprofen, and tolbutamide using a wild type or one of four POR variants (Q153R, A287P, R457H, and A503V). Human CYP2C9 and POR variants were expressed in bacteria, purified, and reconstituted in vitro and the Michaelis constant and maximum velocity were measured with each CYP2C9/POR combination and each substrate. RESULTS: With wild-type POR, the CYP2C9 activities were CYP2C9.1>CYP2C9.2>>CYP2C9.3 with all three substrates. Both the common A503V polymorphism and the rare Q153R variant showed modest increases in activity with all three CYP2C9 isoforms and all three substrates. This is in contrast to previous studies in which A503V showed a modest loss of function with CYP1A2, CYP2C19, CYP2D6, CYP3A4, and CYP17A1. The disease-causing POR variants A287P and R457H had a very low or unmeasurable activity with all CYP2C9 isoforms and all substrates, which is consistent with their low activities with other CYPs. CONCLUSION: POR variants affect CYP2C9 activities. The impact of a POR variant on catalysis varies with the isoform of CYP2C9 and the assay substrate.

Prenatal treatment of congenital adrenal hyperplasia-not standard of care.

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is a common autosomal recessive disorder due to mutations in the CYP21A2 gene. Since genetic counselors play a crucial role in educating families about inherited disorders, they need to have thorough knowledge regarding the pathophysiology of CAH especially the effects on the fetus, the complex genetics of this disorder, and the controversies surrounding experimental prenatal dexamethasone treatment. Affected female fetuses may have varying degree of virilization of the external genitalia. Starting in the 1980's, supraphysiologic glucocorticoid treatment was used to decrease the virilization of the external genitalia of affected female fetuses. However, recent clinical observations, animal studies and greater awareness of the details of human fetal adrenal physiology raise concerns regarding the safety of this prenatal treatment. We review the pathophysiology of CAH, the safety and ethical considerations of prenatal dexamethasone treatment and the views of multiple medical societies that conclude that this experimental therapy should only be done in prospective trials approved by ethical review boards.

A Brief History of the Pediatric Endocrine Society (PES).

The Pediatric Endocrine Society (PES) was initially established in 1972 as the Lawson Wilkins Pediatric Endocrine Society (LWPES), by some of Wilkins' former fellows. As the society grew from its 37 founding members and Dr. Wilkins' influence faded, the name of the society was changed in 2010 and now counts about 1,500 members, mostly from the US and Canada. Pediatric endocrine training programs headed by (LW)PES members have welcomed fellows from throughout the world, many of whom have gone on to leadership positions in their home countries. Starting in 1981, the (LW)PES has collaborated with pediatric endocrine societies around the world in quadrennial meetings, fostering collaborations, transfer of ideas, devising joint practice guidelines, and enjoying one another's fellowship and counsel. The PES presently has committees and special interest groups concerned with all aspects of pediatric endocrinology, assuring that our clinical and academic resources reflect both breadth and depth. To celebrate our 50th anniversary, selected members have written the historical manuscripts featured in this special issue of Hormone Research in Pediatrics. These historical reviews delve into the origins of our specialty, sometimes deep into antiquity, provide useful background information, and illustrate the kinds of intellectual struggles that have led to the development of contemporary pediatric endocrinology, worldwide.

A Brief History of Congenital Adrenal Hyperplasia.

The adrenal has played a major role in the history of pediatric endocrinology. Cases of congenital adrenal hyperplasia (CAH) were reported in the 19th century, leading to the understanding that the adrenal influenced sexual phenotypes as well as being mysteriously required for survival. Numerous adrenal steroids were isolated in the early 20th century, and bioassays eventually distinguished glucocorticoids, mineralocorticoids, and androgens. Treatment of CAH with cortisone in 1950 by Wilkins and by Bartter and Albright revolutionized clinical endocrinology and launched a productive era of pediatric adrenal research. Through careful clinical studies, Wilkins established the contemporary approach to treating CAH. Alfred Bongiovanni identified defective 21-hydroxylation in CAH in 1957, followed by deficiencies of 3ß-hydroxysteroid dehydrogenase and 11ß-hydroxylase. P450 enzymes were described in 1962-1964, and 21-hydroxylation was the first activity ascribed to a P450. Accurate assays for 17OH-progesterone in newborns and in response to ACTH permitted the diagnosis of CAH in children and families. Application of the techniques of molecular genetics elucidated genetic and biochemical bases of these disorders from 1984 to 2004. Pediatric endocrinologists played central roles in identifying the genes responsible for both common and rare forms of congenital adrenal hyperplasia and determining their most appropriate treatments.