Measuring steroids in hair opens up possibilities to identify congenital adrenal hyperplasia in developing countries.

OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) in developing countries have limited access to appropriate laboratory facilities for diagnosis and follow-up. The aim of this study is to evaluate steroid measurement in hair as a diagnostic tool to identify and monitor CAH in these patients. DESIGN: A method was developed to measure steroids in hair, the stability of steroids in hair was assessed, and the concentration range in healthy volunteers was determined. Hair samples of patients, before and after starting therapy, were transported at ambient temperature to The Netherlands for analysis. PATIENTS: Twenty-two Indonesian CAH patients and 84 healthy volunteers participated. MEASUREMENTS: Cortisol, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone in hair were measured by liquid chromatography with tandem mass spectrometry. RESULTS: Steroids in hair could be measured and remained stable (<4.9% deviation) for at least 3 weeks at 4°C and 30°C. In each of the untreated patients, hair concentrations of 17OHP (9.43-1135 pmol/g), androstenedione (36.1-432 pmol/g), and testosterone (2.85-69.2 pmol/g) were all above the upper limit of the corresponding range in healthy volunteers; 5.5 pmol/g, 13 pmol/g, and 1.8 pmol/g, respectively. After starting glucocorticoid treatment, the steroid concentrations in the hair of CAH patients decreased significantly for androstenedione (73%) and testosterone (59%) after 6 months. CONCLUSIONS: CAH could be confirmed in Indonesian patients based on the concentration of 17OHP, androstenedione, and testosterone in hair, and a treatment effect was observed. These findings open up opportunities to diagnose and/or monitor CAH in developing countries with a simple noninvasive technique.

Familiarity and genetic literacy among medical students in Indonesia.

BACKGROUND: There is a lack of genetic knowledge among health care professionals especially in some developing countries such as Indonesia. Based on our experience, genetic disorders receive less attention in medical education and professionals. This study aims to determine the familiarity and literacy of genetics among medical students in Indonesia. METHODS: A total of 1003 Indonesian medical (pre-clinical and clinical) students completed the Rapid Estimate of Adult Literacy in Genetics (REAL-G) questionnaire with a total score of seven for familiarity and eight for genetic literacy. The Mann-Whitney U test was used to compare the familiarity and genetic literacy scores between pre-clinical and clinical students. RESULTS: The average scores of familiarity and genetic literacy were 5.63 ± 0.96 and 6.37 ± 0.83, respectively. Genetic familiarity was higher (p = 0.043) among clinical students than pre-clinical students, while there was no significant difference in genetic literacy (p = 0.362) between pre-clinical and clinical students. Genetic familiarity does not impact the level of genetic literacy. However, medical students' genetic literacy is influenced by demographic characteristics, such as age, sex, university type, genetic learning experience, university accreditation, and university location. CONCLUSIONS: In general, Indonesian medical students have relatively good familiarity and literacy in genetics although further study is necessary to accurately measure the genetic familiarity and literacy in medical students and general public.

Turner syndrome in diverse populations.

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p < .001) was found for TS versus general population controls and 0.925 (p < .001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome.

Sociocultural aspects of disorders of sex development.

Disorders of sex development (DSD) is a congenital condition in which the development of chromosomes, gonads, hormones, and reproductive structures are atypical. DSD brings with it a psychological impact on the affected individual and their families. The consensus statement on management of DSD strongly advised an integrated and multidisciplinary approach in providing care to the affected individuals. Studies have been conducted focusing on medical intervention, and more recently, there is increasing attention paid to psychological aspects of DSD. However, studies reporting cultural aspects of DSD are lacking. This review provides an overview on how culture impacts the affected individuals in coping with DSD and making decisions with regard to gender assignment or reassignment, help-seeking behavior for medical treatments, attitudes toward medical treatment, religious beliefs, and values concerning marriage and fertility. The involvement of social scientists is needed to study sociocultural aspects of DSD from more diverse cultures, to help affected individuals and their families in gaining better social acceptance. Birth Defects Research (Part C) 108:380-383, 2016. © 2016 Wiley Periodicals, Inc.

Knowledge of genetics and attitudes toward genetic testing among university students in Indonesia.

The development in human genetics must be tracked with the knowledge to provide support and positive attitudes towards genetic research and its healthcare applications, including genetic testing. Unfortunately, there has been a delay in enacting public policies related to the genetics professionals as well as the diagnosis, treatment, and prevention of genetic diseases in Indonesia. This research was conducted to build an overview of genetic knowledge and public attitudes toward genetic testing among Indonesian undergraduates. This cross-sectional study involved undergraduate students selected using the convenience sampling method. The questionnaire consisted of two parts: a true/false questionnaire (16 statements) regarding knowledge of genetics and a 5-points Likert scale questionnaire (27 statements) pertaining to attitudes towards genetic testing. A total of 1596 undergraduate students completed online questionnaire. The highest knowledge score and the most positive overall attitudes were observed in the healthcare-related majors compared to those who studied science and technology and social and humanity. A weak positive correlation was observed between knowledge and attitude toward genetic testing (Pearson's r = 0.206, p < 0.001). Undergraduate students from healthcare-related majors displayed better in both knowledge of genetics and had more positive attitudes toward genetic testing.

Critical issue in the identification of Down syndrome and its problems in Central Java, Indonesia: The fact of needing health care and better management.

We conducted a cross-sectional study to describe the health care problems of children with Down syndrome in Central Java, Indonesia. A total of 162 children (81 boys, 81 girls) with Down syndrome were included. Congenital heart defects and hypothyroidism were found in about 50%, followed by vision and hearing problems in 27.7% and 17.3%, respectively. Almost half of cases were diagnosed after the first month of age. Advanced maternal age was identified in more than 50%, and less than 10% was based on karyotype analysis. This study describes the essential issues such as critical co-morbidities, delayed diagnosis, advanced maternal age, and lack of (accessibility to) genetic testing facilities; thus, better health care and management is needed.

Experiences and Challenges with Congenital Hypothyroidism Newborn Screening in Indonesia: A National Cross-Sectional Survey.

The expansion of newborn screening (NBS) for congenital hypothyroidism (CH) is essential to reducing the number of preventable intellectual disabilities in children. Because of logistical issues, including geographic extremes, distinct cultures, and 4.8 million births annually, Indonesia has struggled to achieve universal NBS coverage. A national cross-sectional electronic survey was conducted to explore challenges in CH NBS. Responses from 423 healthcare professionals and program administrators across 30 provinces in Indonesia were collected. The major challenges reported were refusal from families (39.2%), newborns being discharged <24 h (38.3%), and limited availability of filter paper (35.9%). The respondents considered refusal from families to be due to fear, while others did not understand the necessity of CH NBS. The vast majority of respondents believed that parents do not have sufficient understanding regarding CH NBS (96.5%). Our study found that only 38.5% of respondents had received formal CH NBS training, with pediatric endocrinologists being the only profession in which all respondents had been trained. Concerted efforts are needed to improve the access to and availability of resources, increase the capacity for sample collection and analysis, empower healthcare professionals, and develop educational resources to promote understanding and acceptance of NBS amongst families.

Childhood Obesity as a Global Problem: a Cross-sectional Survey on Global Awareness and National Program Implementation

Objective: The rising global epidemic of childhood obesity is a major public health challenge. Despite the urgency, there is a lack of data on the awareness and implementation of preventative measures. The aim of this study was to identify areas for improvement in the prevention and management of childhood obesity worldwide. Methods: A cross-sectional electronic survey was distributed to 132 members of national pediatric societies of the International Pediatric Association. Results: Twenty-eight (21.2%) participants, each from a different country across six World Health Organization (WHO) regions completed the survey. Most participants reported that national prevalence data of childhood obesity is available (78.6%), and the number increased during the Coronavirus disease-2019 pandemic (60.7%). In most countries (78.6%), the amount of sugar and salt in children's products is provided but only 42.9% enacted regulations on children-targeted advertising. Childhood obesity prevention programs from the government (64.3%) and schools (53.6%) are available with existing support from private or non-profit organizations (71.4%). Participants were aware of WHO's guidance concerning childhood obesity (78.6%), while fewer were aware of The United Nations International Children's Emergency Fund's (UNICEF) guidance (50%). Participants reported that WHO/UNICEF guidance acted as a reference to develop policies, regulations and national programs. However, progress was hindered by poor compliance. Lastly, participants provided suggestions on tackling obesity, with responses ranging from developing and reinforcing policies, involvement of schools, and prevention across all life stages. Conclusion: There are different practices in implementing prevention measures to counter childhood obesity globally, particularly in statutory regulation on food advertising and national programs. While support and awareness was relatively high, implementation was hindered. This reflects the need for prompt, country-specific evaluation and interventions.

The role of uncoupling protein 2 and 3 genes polymorphism and energy expenditure in obese Indonesian children.

AIM: Uncoupling protein (UCP) genes, which may contribute to energy metabolism in mitochondria, may be involved in the pathogenesis of obesity. We analyzed the differences in energy expenditure between single nucleotide polymorphisms (SNPs) UCP3-55C/T, UCP3 Y210Y, and UCP2 A55V among Indonesian children. METHODS: The study included 76 schoolchildren (36 obese and 40 healthy; mean age, 12.8 years) in Semarang, Indonesia. Body composition was measured by bioelectrical impedance analysis; resting energy expenditure (REE) by indirect calorimetry; physical activity by uniaxial accelerometer; and total energy expenditure (TEE) by the equations extrapolated from REE and physical activity. UCP3-55C/T, UCP3 Y210Y, and UCP2 A55V were examined by restriction length fragment polymorphism analysis. RESULTS: The TEE of the subjects with the T/T genotype at UCP3-55C/T after adjusting for fat-free mass (63.2±7.2 kcal/kg/day) and T/T at UCP2 A55V (62.8±5.6 kcal/kg/day) was lower than that of the subjects with the C/C and C/T genotypes (p<0.05). The REE of the subjects with these T/T genotypes tended to be lower than that of the subjects with C/C and C/T (p≥0.05). No significant differences in REE or TEE were found between the UCP3 Y210Y genotypes. CONCLUSIONS: The subjects with the T/T genotypes of UCP3-55C/T or UCP2 A55V had lower TEE than those with other genotypes.

Factors influencing illness uncertainty in parents of children with congenital adrenal hyperplasia in a developing country: A cross-sectional study.

Background: Illness uncertainty in parents of children with congenital adrenal hyperplasia (CAH) refers to parents' inability to create meaning in events related to their children having CAH. This may influence their role in caring for children with CAH. Objective: The study aimed to determine factors associated with illness uncertainty experienced by parents of children with CAH in a developing country. Methods: A cross-sectional study was conducted on 80 parents (43 mothers and 37 fathers) of children with CAH, selected using consecutive sampling methods. The Parent's Perception of Uncertainty Scale (PPUS) was used to measure the illness uncertainty levels. Data were collected from March 2020 to October 2020. Independent t-test and chi-square test were used to determine factors (parent's gender, age, educational level, monthly household income, number of children with CAH, history of child death due to CAH, child's age when first diagnosed with CAH, duration of therapy, gender change, type of CAH (salt wasting/SW or simple virilizing/SV), current gender, and genitoplasty) influencing illness uncertainty in parents. Results: The mean scores of PPUS were 42.3 ± 12.91, and the majority of parents had a low PPUS score (49; 61%). Parents of children with SW-CAH showed higher uncertainty (44.2 ± 12.77) than those with SV-CAH (32.6 ± 8.86; p = 0.003). Parents who lost their children due to CAH were more likely to report a moderate illness uncertainty than parents who never experienced child mortality due to CAH (χ2(1, 80) = 4.893; p = 0.027). Conclusion: The factors significantly affecting uncertainty in parents of children with CAH determined in this study might help healthcare professionals, including nurses, to play a pivotal role in giving pertinent information regarding their children's health, disease, and therapy to help manage parental uncertainty.

Ten-Year Experience of a Global and Freely Accessible e-Learning Website for Pediatric Endocrinology and Diabetes.

The European Society for Paediatric Endocrinology (ESPE) interactive website, https://www.espe-elearning.org, was first published online in 2012. We describe the various applications of the content of the e-learning website that has been greatly expanded over the last 10 years. A large module on pediatric diabetes was added with the support of the International Society for Paediatric and Adolescent Diabetes (ISPAD). A separate multilingual module was created that focuses on frontline health care providers in limited resource settings. This module has been well received, particularly in targeted parts of the world. e-Learning may also be an opportunity to expand or tailor educational activities for learners according to their differing learning needs. The e-learning website provides guidelines for those interested in general pediatrics, neonatology, clinical genetics, and pediatric gynecology. We also describe various new applications such as master classes in the format of interactive video lectures and joint and complementary e-learning/e-consultation webinars. Finally, international certification was recently realized as e-learning courses were recognized by the European Accreditation Council for Continuing Medical Education (EACCME). As a result of the social distancing measures introduced to control the COVID-19 pandemic, digital education, whether individual or in a virtual classroom setting, has become even more important since e-learning can connect and engage individuals across geographic boundaries as well as those who live in remote areas. The future of education delivery may include hybrid learning strategies, which include in-person and e-learning platforms. Combined e-learning and e-consultation webinars illustrate how international academic institutions, learned medical specialty societies and networks are uniquely placed to deliver balanced, disease-oriented, and patient-centered e-learning education and at the same time provide expert consultation. Moreover, they are well equipped to maintain professional standards and to offer appropriate accreditation.

Corrigendum: Challenges in the treatment of late-identified untreated congenital adrenal hyperplasia due to CYP11B1 deficiency: Lessons from a developing country.

[This corrects the article DOI: 10.3389/fendo.2022.1015973.].

Lessons Learned from 17 Years of Multidisciplinary Care for DSD Patients at A Single Indonesian Center.

BACKGROUND: Our Multidisciplinary Team (MDT) is a large specialized team based in Semarang, Indonesia that cares for a wide variety of pediatric and adult individuals with Differences of Sex Development (DSD) from across Indonesia. Here we describe our work over the last 17 years. METHODS: We analyzed phenotypic, hormonal and genetic findings from clinical records for all patients referred to our MDT during the period 2004 to 2020. RESULTS: Among 1184 DSD patients, 10% had sex chromosome DSD, 67% had 46,XY DSD and 23% had 46,XX DSD. The most common sex chromosome anomaly was Turner syndrome (45,X) (55 cases). For patients with 46,XY DSD under-masculinization was the most common diagnosis (311 cases) and for 46,XX DSD a defect of Müllerian development was most common (131 cases) followed by Congenital Adrenal Hyperplasia (CAH) (116 cases). Sanger sequencing, MLPA and targeted gene sequencing of 257 patients with 46,XY DSD found likely causative variants in 21% (55 cases), with 13 diagnostic genes implicated. The most affected gene coded for the Androgen Receptor. Molecular analysis identified a diagnosis for 69 of 116 patients with CAH, with 62 carrying variants in CYP21A2 including four novel variants, and seven patients carrying variants in CYP11B1. In many cases these genetic diagnoses influenced the clinical management of patients and families. CONCLUSIONS: Our work has highlighted the occurrence of different DSDs in Indonesia. By applying sequencing technologies as part of our clinical care, we have delivered a number of genetic diagnoses and identified novel pathogenic variants in some genes, which may be clinically specific to Indonesia. Genetics can inform many aspects of DSD clinical management, and whilst many of our patients remain undiagnosed, we hope that future testing may provide answers for even more.

Challenges in the treatment of late-identified untreated congenital adrenal hyperplasia due to CYP11B1 deficiency: Lessons from a developing country.

Background: Congenital Adrenal Hyperplasia (CAH) due to CYP11B1 is a rare autosomal recessive adrenal disorder that causes a decrease in cortisol production and accumulation of adrenal androgens and steroid precursors with mineralocorticoid activity. Clinical manifestations include cortisol deficiency, ambiguous genitalia in females (differences of sex development (DSD)), and hypertension. Medical treatment recommendations are well defined, consisting of glucocorticoid treatment to substitute glucocorticoid deficiency and consequently normalize adrenal androgen and precursors levels. Current guidelines also emphasize the need for specialized multidisciplinary DSD teams and psychosocial support. In many developing countries, care for DSD patients, especially when caused by an adrenal disease, is challenging due to the lack of infrastructure, knowledge, and medication. Objective: The study aims to report the conflicting decision-making process of medical treatment and sex assignment in late-identified CAH patients in developing countries. Methods: We describe the clinical and biochemical findings and the psychological assessment of five affected but untreated family members with CAH due to CYP11B1 deficiency. Results: All patients had a 46,XX karyotype, ambiguous genitalia, low cortisol levels, and hypertension. Two identified as males, two as females, and one had undecided gender. The patients were counselled that refusing treatment will lead to infertility and the potential risk of developing Addisonian crisis and severe hypertension. However, all 46,XX CAH males refused treatment with glucocorticoids due to the expected lowering of adrenal androgens as their main source of testosterone. None of the patients developed Addisonian crisis, probably due to some residual cortisol activity and glucocorticoid activity of elevated adrenal steroid precursors. Conclusion: Medical treatment and sex assignment in late-identified 46,XX CAH patients in Indonesia may often depend on local and cultural factors. The management of DSD conditions may have to be individualized and integrated into the psychological and social context of the affected family.

Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments.

Cytochrome b-245 Alpha Chain Gene Variants and Arterial Function in Indonesian Short Stature Children.

BACKGROUND: The association between short stature, undernutrition and the risk to cardiovascular disease has been clinically established. Genetic factor, particularly the variants in cytochrome b-245 alpha chain (CYBA) gene, which alter the formation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase level, might affect arterial function. This study aimed to observe the association between single nucleotide variants (SNVs) of the CYBA gene and the arterial function of short stature children to understand the reason why some people with short stature develop cardiovascular disease. METHODS: A total of 142 genomic deoxyribonucleic acid (DNA) samples have been collected from short stature children in Brebes, Central Java, Indonesia. Four common single-nucleotide polymorphisms (SNPs): C242T (rs4673), A640G (rs1049255), -930A>G (rs9932581) and *49A>G (rs7195830) in the CYBA gene were examined using TaqMan allelic discrimination assay. The arterial function was measured using transthoracic echocardiography and described as aortic stiffness and distensibility index. Statistical analysis was done to find a significant difference in arterial function between genotypes of each SNV. RESULTS: A P-value of < 0.05 was considered significant. In rs9932581 (-930A>G) of CYBA gene, the subjects with GG genotype were found to have significantly lower arterial stiffness and higher distensibility compared to AA and AG genotypes. No significant difference was found in the other SNVs. CONCLUSION: The GG genotype in rs9932581 of the CYBA gene might have a protective effect on cardiovascular disease in short stature children.

Attitudes of Indonesian health science undergraduates toward sexuality in individuals with intellectual disabilities.

BACKGROUND: Sexuality is a fundamental part of the lives of human beings. However, a significant inequality exists regarding the right of an individual with intellectual disabilities. AIMS: This study aimed to explore the attitudes of undergraduate health science students toward sexuality in individuals with intellectual disability (ID) in Indonesia. METHODS: A cross-sectional study was performed using the Indonesian version of Attitudes toward Sexuality Questionnaires in Intellectual Disability (ASQ-ID). This study involved 617 students in medical, psychology, and public health undergraduate programs. RESULTS: Among all participants (n = 617, male = 137, female = 480), the attitude towards self-control was found a significant difference among all three health science undergraduates (p = .01). The psychology students had the most favorable attitudes toward self-control compared to other students. The difference was found between medical and public health students and between public health and psychology students with p = .009 and p = .011, respectively. Religion was significantly affected for the non-reproductive sexual behavior subscale (p = .038). The religion was found to have significant effect on the attitude towards nonreproductive sexual behavior subscale (p = .038). CONCLUSIONS: Results show that Indonesian undergraduate students majoring in the health sciences have varying attitudes toward sexuality in individuals with ID. Medical and psychology students have more favorable attitudes toward self-control, whereas public health students have less favorable attitudes. Their religion influencing the attitudes toward nonreproductive sexual behavior.

Surveillance and prevalence of fragile X syndrome in Indonesia.

Fragile X syndrome (FXS) is the most prevalent inherited cause of intellectual disability (ID) and autism spectrum disorder (ASD). Many studies have been conducted over the years, however, in Indonesia there is relatively less knowledge on the prevalence of FXS. We reviewed all studies involving FXS screening and cascade testing of the high-risk population in Indonesia for two decades, to elucidate the prevalence, as well as explore the presence of genetic clusters of FXS in Indonesia. The prevalence of FXS in the ID population of Indonesia ranged between 0.9-1.9%, while in the ASD population, the percentage was higher (6.15%). A screening and cascade testing conducted in a small village on Java Island showed a high prevalence of 45% in the ID population, suggesting a genetic cluster. The common ancestry of all affected individuals was suggestive of a founder effect in the region. Routine screening and subsequent cascade testing are essential, especially in cases of ID and ASD of unknown etiology in Indonesia.

We All Have a Role to Play: Redressing Inequities for Children Living with CAH and Other Chronic Health Conditions of Childhood in Resource-Poor Settings.

CLAN (Caring and Living as Neighbours) is an Australian-based non-governmental organisation (NGO) committed to equity for children living with chronic health conditions in resource-poor settings. Since 2004, CLAN has collaborated with a broad range of partners across the Asia Pacific region to improve quality of life for children living with congenital adrenal hyperplasia (CAH). This exploratory case study uses the Knowledge to Action (KTA) framework to analyse CLAN's activities for children living with CAH in the Asia Pacific. The seven stages of the KTA action cycle inform a systematic examination of comprehensive, collaborative, sustained actions to address a complex health challenge. The KTA framework demonstrates the "how" of CLAN's approach to knowledge creation and exchange, and the centrality of community development to multisectoral collaborative action across a range of conditions, cultures and countries to redressing child health inequities. This includes a commitment to: affordable access to essential medicines and equipment; education, research and advocacy; optimisation of medical management; encouragement of family support groups; efforts to reduce financial burdens; and ethical, transparent program management as critical components of success. Improvements in quality of life and health outcomes are achievable for children living with CAH and other chronic health conditions in resource-poor settings. CLAN's strategic framework for action offers a model for those committed to #LeaveNoChildBehind.

Glucocorticoid Activity of Adrenal Steroid Precursors in Untreated Patients With Congenital Adrenal Hyperplasia.

CONTEXT AND OBJECTIVE: We describe the clinical features and biochemical characteristics of a unique population of severely affected untreated patients with congenital adrenal hyperplasia (CAH) from an Indonesian population with proven cortisol deficiency but without clinical signs of cortisol deficiency. We evaluated the in vitro glucocorticoid activity of all relevant adrenal steroid precursors occurring in patients with CAH. DESIGN: Cross-sectional cohort study and translational research. INTERVENTION/MAIN OUTCOME MEASURES: Adrenal steroid precursor concentrations before and 60 minutes after ACTH administration to 24 untreated patients with CAH (3 to 46 years) with proven cortisol deficiency (<500 nmol/L post-ACTH) measured by liquid chromatography-tandem mass spectrometry were compared with six control patients (Mann-Whitney U test). Glucocorticoid receptor (GR) activation was determined by dual-luciferase assays in human embryonic kidney cells transfected with the GR and exposed to increasing amounts of adrenal steroid precursors for 24 hours. RESULTS: Blood concentrations of the steroid precursors 11-deoxycortisol (457 nmol/L, P = 0.003), 11-deoxycorticosterone (55 nmol/L, P = 0.003), 17-hydroxyprogesterone (610 nmol/L, P < 0.001), progesterone (29 nmol/L, P < 0.001), and 21-deoxycortisol (73 nmol/L) were strongly elevated compared with control subjects. The GR was activated with comparable potency to cortisol by corticosterone and 21-deoxycortisol or with 4 to 100 times lower potency by 11-hydroxyprogesterone, 11-deoxycortisol, aldosterone, 11-deoxycorticosterone, progesterone, and 17-hydroxyprogesterone. CONCLUSIONS: We identified strongly elevated adrenal steroid precursor concentrations in blood from untreated patients with CAH and demonstrated glucocorticoid activity of these adrenal precursors in vitro, suggesting a possible role of these precursors in the clinical phenotype of these patients. Further studies are necessary to evaluate the role of these precursors in more detail.