Congenital Adrenal Hyperplasia Patients Research Articles

Reduced short term memory in congenital adrenal hyperplasia (CAH) and its relationship to spatial and quantitative performance

Girls and women with classical congenital adrenal hyperplasia (CAH) experience elevated androgens prenatally and show increased male-typical development for certain behaviors. Further, individuals with CAH receive glucocorticoid (GC) treatment postnatally, and this GC treatment could have negative cognitive consequences. We investigated two alternative hypotheses, that: (a) early androgen exposure in females with CAH masculinizes (improves) spatial perception and quantitative abilities at which males typically outperform females, or (b) CAH is associated with performance decrements in these domains, perhaps due to reduced short-term-memory (STM). Adolescent and adult individuals with CAH (40 female and 29 male) were compared with relative controls (29 female and 30 male) on spatial perception and quantitative abilities as well as on Digit Span (DS) to assess STM and on Vocabulary to assess general intelligence. Females with CAH did not perform better (more male-typical) on spatial perception or quantitative abilities than control females, failing to support the hypothesis of cognitive masculinization. Rather, in the sample as a whole individuals with CAH scored lower on spatial perception (p≤.009), a quantitative composite (p≤.036), and DS (p≤.001), despite no differences in general intelligence. Separate analyses of adolescent and adult participants suggested the spatial and quantitative effects might be present only in adult patients with CAH; however, reduced DS performance was found in patients with CAH regardless of age group. Separate regression analyses showed that DS predicted both spatial perception and quantitative performance (both p≤.001), when age, sex, and diagnosis status were controlled. Thus, reduced STM in CAH patients versus controls may have more general cognitive consequences, potentially reducing spatial perception and quantitative skills. Although hyponatremia or other aspects of salt-wasting crises or additional hormone abnormalities cannot be ruled out as potential contributors, elevated GCs appear to be the most likely contributor to reductions in STM. Additional efforts to monitor GC administration protocols may help achieve optimal cognitive outcomes. Educational intervention for individuals with CAH might also be useful.

Should we question early feminizing genitoplasty for patients with congenital adrenal hyperplasia and XX karyotype?

BackgroundThere is a wide difference of opinion between the medical–surgical community and advocacy group regarding Disorders of Sexual Development (DSD) secondary to congenital adrenal hyperplasia (CAH) being ranked in the intersex category. This rupture is even more evident when the issue of genitoplasty is brought up. For physicians it is obvious and unequivocal that a person with CAH and an XX karyotype has a female gender identity, whereas associations tend to rank persons with CAH in the intersex category and advocate holding-off on surgical management. Material/MethodsA retrospective case study vs. control group, spanning over 40years, included 21 patients who were treated in 3 different centers. Each patient and their parents were contacted independently and interviewed regarding interpersonal relationships, psychological impact of genitoplasty, gender identity and opinion on optimal care management for this disorder. Three couples controls (parent–child) per CAH patients were used and matched according to age, sex assigned at birth and ethnic origin. ResultsSex assigned at birth seemed to concord with the gender identity perceived by the patients in 85.7% of cases. In fact, 89.7% of patients and 100% of parents felt that feminizing genitoplasty should be performed within the first year of life. There is however a significant difference compared to controls who felt that surgical management should occur later on in life. No difference was highlighted during childhood regarding parents–child relationships or social integration. However, during adolescence, the parents–child relationship tended to be significantly more painful for the CAH group. Integrating their parenting role was significantly harder for patients in the CAH-DSD group. In the population of CAH-DSD patients who had genitoplasty the level of sexual fulfillment was not lower to the one reported by the control group. ConclusionFemale sex assignment seems legitimate according to this study and the development of gender identity in these patients matches the sex assigned at birth. Resolving early on the adequacy of the genital anatomy with the sex assigned is promoted by patients as well as their parents. Proper psychomotor development and sexual satisfaction underline the absence of complications related to the surgical technique and the relevance of early surgical management.

Hormonal circadian rhythms in patients with congenital adrenal hyperplasia: identifying optimal monitoring times and novel disease biomarkers.

The treatment goal in congenital adrenal hyperplasia (CAH) is to replace glucocorticoids while avoiding androgen excess and iatrogenic Cushing's syndrome. However, there is no consensus on how to monitor disease control. Our main objectives were to evaluate hormonal circadian rhythms and use these profiles to identify optimal monitoring times and novel disease biomarkers in CAH adults on intermediate- and long-acting glucocorticoids. This was an observational, cross-sectional study at the National Institutes of Health Clinical Center in 16 patients with classic CAH. Twenty-four-hour serum sampling for ACTH, 17-hydroxyprogesterone (17OHP), androstenedione (A4), androsterone, DHEA, testosterone, progesterone and 24-h urinary pdiol and 5β-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (TminAC) and maximal (TmaxAC) adrenocortical hormone levels after dose administration was calculated. A significant rhythm was confirmed for ACTH (r(2), 0.95; P<0.001), 17OHP (r(2), 0.70; P=0.003), androstenedione (r(2), 0.47; P=0.043), androsterone (r(2), 0.80; P<0.001), testosterone (r(2), 0.47; P=0.042) and progesterone (r(2), 0.64; P=0.006). The mean (s.d.) TminAC and TmaxAC for 17OHP and A4 were: morning prednisone (4.3 (2.3) and 9.7 (3.5) h), evening prednisone (4.5 (2.0) and 10.3 (2.4) h), and daily dexamethasone (9.2 (3.5) and 16.4 (7.2) h). AUC0-24 h progesterone, androsterone and 24-h urine pdiol were significantly related to 17OHP. In CAH patients, adrenal androgens exhibit circadian rhythms influenced by glucocorticoid replacement. Measurement of adrenocortical hormones and interpretation of results should take into account the type of glucocorticoid and time of dose administration. Progesterone and backdoor metabolites may provide alternative disease biomarkers.

Male gender identity in children with 46,XX DSD with congenital adrenal hyperplasia after delayed presentation in mid-childhood

Background/aimGirls with congenital adrenal hyperplasia (CAH) diagnosed at birth have some masculine behaviors but rarely convert to male gender. In developing countries, however, diagnosis and treatment (with secondary androgen suppression) are delayed. We aimed to assess effect of delayed treatment of CAH on gender identity. MethodsAs part of a cross-sectional, case–control study of children with disorders of sex development (DSD), there were 11 patients with CAH. Patients and caregivers answered a questionnaire about gender identity, and behavior was assessed by observing toy play. Patients were examined for Prader score and gender identity. ResultsOf 11 CAH patients initially raised as girls, 3 (27%) had converted to male gender at presentation (5, 9, 9years) (Prader 3, 4, 4). Of the remaining 8 patients, one 4-year-old (Prader 2) had a male gender identity score. The remaining girls (2–13years, mean 8.1) (Prader 1–3) had gender identity scores in the female range. ConclusionsOne third (4/11) of CAH patients presenting in mid-childhood had male gender identity scores, and ¾ had assumed male gender role. Although social and cultural factors are important in developing countries, this result suggests that delayed treatment may trigger male gender identity, and delayed female genital surgery may be unwise.

Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease characterized by impaired adrenal steroidogenesis and most often caused by CYP21A2 gene mutations. For the first time, we reported complete spectrum and frequency of CYP21A2 gene mutations in 61 unrelated patients with classical and non-classical CAH from Serbia. Direct DNA sequencing of whole CYP21A2 gene and polymerase chain reaction with sequence-specific primers for detection of CYP21A1P/CYP21A2 chimeras were combined. We identified 18 different pathogenic alleles-two of them novel. Mutation detection rate was highest in patients with salt-wasting form of CAH (94.7%). The most prevalent mutation was intron 2 splice site mutation, c.290-13A/C>G (18.5%). Other mutation frequencies were: CYP21A1P/CYP21A2 chimeras (13%), p.P30L (13%), p.R356W (11.1%), p.G110fs (7.4%), p.Q318X (4.6%), p.V281L (4.6%), p.I172N (2.8%), p.L307fs (2.8%), p.P453S (1.9%), etc. Mainly, frequencies were similar to those in Slavic populations and bordering countries. However, we found 6.5% of alleles with multiple mutations, frequently including p.P453S. Effects of novel mutations, c.386T>C (p.Leu129Pro) and c.493T>C (p.Ser165Pro), were characterized in silico as deleterious. The effect of well-known mutations on Serbian patients' phenotype was as expected. The first comprehensive molecular genetic study of Serbian CAH patients revealed two novel CYP21A2 mutations. This study will enable genetic counseling in our population and contribute to better understanding of molecular landscape of CAH in Europe.

Adrenal Steroid Metabolites Accumulating in Congenital Adrenal Hyperplasia Lead to Transactivation of the Glucocorticoid Receptor.

Patients with congenital adrenal hyperplasia (CAH) are often clinically less severely affected by cortisol deficiency than anticipated from their enzymatic defect. We hypothesize that adrenal steroid hormone precursors that accumulate in untreated or poorly controlled CAH have glucocorticoid activity and partially compensate for cortisol deficiency. We studied the in vitro effects of 17-hydroxyprogesterone (17OHP), progesterone (P), 21-deoxycortisol (21DF), and androstenedione (Δ4) on the human glucocorticoid receptor (hGR). Competitive binding assays were performed in HeLa cells. Nuclear translocation of the hGR was studied by transfection of COS-7 cells with a GFP-tagged hGR and fluorescence microscopy. Transactivation assays were performed in COS-7 cells and in HEK 293 cells after cotransfection with hGR and luciferase reporter vectors using a dual luciferase assay. 17OHP, P, and 21DF are able to bind to the hGR with binding affinities of 24-43% compared with cortisol. Δ4 has a low binding affinity. Incubation with 21DF led to complete nuclear translocation of the hGR, whereas treatment with 17OHP or P resulted in partial nuclear translocation. 21DF transactivated the hGR with an EC50 approximately 6 times the EC50 of cortisol. 17OHP and P transactivated the hGR with EC50s of more than 100 times the EC50 of cortisol. No hGR transactivation was detected after incubation with Δ4. 21DF, 17OHP, and P are able to bind, translocate, and transactivate the hGR in vitro and thus may have glucocorticoid activity. 21DF might have a clinically relevant agonistic effect on the hGR and could potentially partially compensate the cortisol deficiency in CAH patients.

CYP21A2 mutation analysis in Korean patients with congenital adrenal hyperplasia using complementary methods: sequencing after long-range PCR and restriction fragment length polymorphism analysis with multiple ligation-dependent probe amplification assay.

CYP21A2 mutation analysis of congenital adrenal hyperplasia (CAH) is challenging because of the genomic presence of a homologous CYP21A2 pseudogene and the significant incidence of pseudogene conversion and large deletions. The objective of this study was to accurately analyze the CYP21A2 genotype in Korean CAH patients using a combination of complementary methods. Long-range PCR and restriction fragment length polymorphism analyses were performed to confirm valid amplification of CYP21A2 and to detect large gene conversions and deletions before direct sequencing. Multiple ligation-dependent probe amplification (MLPA) analysis was conducted concurrently in 14 CAH-suspected patients and six family members of three patients. We identified 27 CYP21A2 mutant alleles in 14 CAH-suspected patients. The c.293-13A>G (or c.293-13C>G) was the most common mutation, and p.Ile173Asn was the second, identified in 25% and 17.9% of alleles, respectively. A novel frame-shift mutation of c.492delA (p.Glu 164Aspfs*24) was detected. Large deletions were detected by MLPA in 10.7% of the alleles. Mutation studies of the six familial members for three of the patients aided in the identification of haplotypes. In summary, we successfully identified CYP21A2 mutations using both long-range PCR and sequencing and dosage analyses. Our data correspond relatively well with the previously reported mutation spectrum analysis.

Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia.

The contiguous gene deletion syndrome (CAH-X) was described in a subset (7%) of congenital adrenal hyperplasia (CAH) patients with a TNXA/TNXB chimera, resulting in deletions of CYP21A2, encoding 21-hydroxylase necessary for cortisol biosynthesis, and TNXB, encoding the extracellular matrix glycoprotein tenascin-X (TNX). This TNXA/TNXB chimera is characterized by a 120-bp deletion in exon 35 and results in TNXB haploinsufficiency, disrupted TGF-β signaling, and an Ehlers Danlos syndrome phenotype. The objective of the study was to determine the genetic status of TNXB and resulting protein defects in CAH patients with a CAH-X phenotype but not the previously described TNXA/TNXB chimera. Design, Settings, Participants, and Intervention: A total of 246 unrelated CAH patients were screened for TNXB defects. Genetic defects were investigated by Southern blotting, multiplex ligation-dependent probe amplification, Sanger, and next-generation sequencing. Dermal fibroblasts and tissue were used for immunoblotting, immunohistochemical, and coimmunoprecipitation experiments. The genetic and protein status of tenascin-X in phenotypic CAH-X patients was measured. Seven families harbor a novel TNXB missense variant c.12174C>G (p.C4058W) and a clinical phenotype consistent with hypermobility-type Ehlers Danlos syndrome. Fourteen CAH probands carry previously described TNXA/TNXB chimeras, and seven unrelated patients carry the novel TNXB variant, resulting in a CAH-X prevalence of 8.5%. This highly conserved pseudogene-derived variant in the TNX fibrinogen-like domain is predicted to be deleterious and disulfide bonded, results in reduced dermal elastin and fibrillin-1 staining and altered TGF-β1 binding, and represents a novel TNXA/TNXB chimera. Tenascin-X protein expression was normal in dermal fibroblasts, suggesting a dominant-negative effect. CAH-X syndrome is commonly found in CAH due to 21-hydroxylase deficiency and may result from various etiological mechanisms.

AB079. Phenotype variation in untreated 46,XX congenital adrenal hyperplasia

Simple virilizing congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder characterized by 21 hydroxylase deficiency leading to excessive androgen production. In infants with 46,XX karyotype, prenatal exposure of androgen overproduction leads to a gradual virilization of the external genital. Consequently, babies are born with an ambiguous genital which complicates sex assignment. Genital virilization will be progressive if these babies remain untreated. In country where newborn screening is available, patients with CAH are identified soon after birth and receive medication afterward, unlike in Indonesia. Many parents and patients with CAH did not seek healthcare professionals due to lack of information about inheritance and clinical manifestation of CAH. In Indonesia, newborn screening has not been applied yet; management and therapy for CAH are only available in some big cities but glucocorticoid medications need to be imported. Diagnosis was established using karyotype, hormonal and gene mutation analysis. In this study, we reported 30 patients with different physical appearance i.e., big phallus, one or two ending perineum, very severe chordae, labioscrotal fusion, complete labial fusion with scrotalization, masculization, no breast development, severe hyperpigmentation, appears Adam’s apple and short stature. Sex assignment is still a dilemma; some of the children were raised as males, females, or left undefined. The complex management of children and adults with CAH highlights the importance of raising awareness among medical personnels to promote early detection and treatment for CAH patients. Genetic counseling is essential for these families.

Determining clinical and biological indicators for health outcomes in adult patients with childhood onset of congenital adrenal hyperplasia

Adverse outcomes in adult congenital adrenal hyperplasia (CAH) patients are frequent. The determinants of them have not yet been established. To establish the prevalence of adverse outcomes and to find determining factors for each of them. Cross-sectional monocentric study of 104 patients with childhood onset of CAH (71 women, 33 men). Analysis established first the determinants of clinical, hormonal, genetic variables and second a composite criterion for some of the outcomes and determinants. BMI was above 25 kg/m(2) in 44% of the cohort, adrenal hyperplasia and/or nodules were present in 45% of the patients, and irregular menstrual cycles and hyperandrogenism were found in 50 and 35% of the women respectively. In univariate analysis, the determinants of these outcomes were all linked to disease control, especially 17-hydroxyprogesterone (17OHP) and androstenedione concentrations. Low weight was a determinant of abnormal bone mineral density (BMD) (60% of the cohort). Multivariate analysis confirmed these data. A classic form (CF) of CAH was a determinant of testicular adrenal rest tumors (TARTs) (36% of the men). Total cumulative glucocorticoid dose was a determinant of BMI and TART, whereas fludrocortisone dose was a determinant of TART (P=0.03). In men, the composite criterion was associated with androstenedione concentration and CF. In women, the composite criterion was associated with total testosterone concentration. The present study confirms the high prevalence of adverse outcomes in CAH patients. These are, most often, related to disease control. The impaired health status of adults with CAH could therefore be improved through the modification of treatment.

Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to accumulation of steroid precursors and adrenal androgens. These steroids may have a biological effect on the steroid receptor with clinical consequences on diagnostics and treatment in CAH patients. Therefore, we analysed the effect of accumulated steroids [17-hydroxyprogesterone (17OHP), progesterone, androstenedione and testosterone] on aldosterone-mediated transactivation of the human mineralocorticoid receptor (hMR). Methods: A transactivation assay using transiently transfected COS7 cells was employed. Cells were co-transfected with hMR-cDNA, MMTV-luciferase and renilla-luciferase expression vectors. Transfected cells were incubated with six different steroid concentrations in addition to aldosterone (10^-10<smlcap>M</smlcap>). Luciferase and renilla activities were measured to quantify hMR transactivation. Results: Linear regression analysis showed statistically significant linear inhibition of transactivation of the hMR by 10^-10<smlcap>M</smlcap> aldosterone in the presence of increasing 17OHP [F(1,5) = 11.34, p = 0.019] and progesterone [F(1,5) = 11.08, p = 0.021] concentrations. In contrast, neither androstenedione nor testosterone affected hMR transactivation by aldosterone at a concentration of 10^-10<smlcap>M</smlcap>. Conclusion: Our study shows for the first time that neither androstenedione nor testosterone has a biological effect on aldosterone-mediated transactivation of the hMR. 17OHP and progesterone have an anti-mineralocorticoid effect in vitro that may clinically lead to an increased requirement of mineralocorticoids in poorly controlled CAH patients.

Congenital adrenal hyperplasia patient perception of 'disorders of sex development' nomenclature.

BackgroundAs the benefits of patient-centered care have become more widely recognized, it is important to understand patients’ sentiments regarding aspects affecting their care. In an effort to display more sensitivity to patient concerns, the term “disorders of sex development” (DSD) was proposed in 2006 as new nomenclature to replace older terms that were considered to have negative connotations.MethodsThe objective of the study was to examine the views of congenital adrenal hyperplasia (CAH) patients and their caregivers regarding the new nomenclature. The study was observational to evaluate the views of the CAH community, and the primary endpoint was perception of the term DSD. The study was conducted as a survey about views regarding DSD nomenclature. The survey was sent via email to eligible subjects. Along with a short introduction explaining the term DSD, the survey was sent to eligible CAH patients and their caregivers. 589 CAH patients or family members participated in the survey.ResultsA total of 589 responses were received (255 classical females, 104 non-classical females, 174 males, 56 not specified) (547 U.S., 42 international) (128 CAH patients, 408 parents or other family members). 70.6% had never heard the term DSD. 71.0% disliked or strongly disliked the term DSD. 83.6% stated they did not identify with the term DSD. 76.0% felt that the term DSD has a negative effect on the CAH community. There was no significant difference in opinion of DSD between classical females and other CAH patients, between US and international, between surgical and non-surgical patients, or between patients and parents. There was no correlation with patient age.ConclusionsOur results indicate that the majority of parents and patients with CAH are dissatisfied with the term DSD. Our results highlight the challenges within the field of DSD to reach a consensus regarding a sensitive topic and to bridge the gap between current medical practice and patient satisfaction. It is the authors’ belief that reconsideration of the current nomenclature and ongoing dialogue between the medical community and patients will eventually lead to removal of stigmatization, better management protocols, and improved outcomes.

Reduction in daily hydrocortisone dose in adrenal insufficiency improves significantly bone mineral density – Results from a 2-years prospective trial

Introduction: Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive life-long glucocorticoid (GC) replacement therapy. Today daily GC doses are still higher than the reported adrenal cortisol production rate, and are not able to reproduce the physiological secretion pattern. This might result in long-term morbidities such as osteoporosis. Until now no prospective trial was performed investigating the long-term effect of GC dose changes in PAI and CAH patients.

Inadequate Cortisol Response to the Tetracosactide (Synacthen®) Test in Non-Classic Congenital Adrenal Hyperplasia: An Exception to the Rule?

Aims: To describe cortisol response to tetracosactide and to review the literature on adrenal function in non-classic congenital adrenal hyperplasia (NCCAH) patients. Methods: We compared cortisol responses to tetracosactide (250 μg) between NCCAH patients and a comparison group (CG) of patients with premature pubarche and normal tetracosactide test. An adequate cortisol response was defined as a peak ≥18 μg/dl. Results: We included 35 NCCAH patients (26 girls, 9 boys), whose mean age at testing was 7.0 years (0.8-15.6), and 47 patients in the CG (39 girls, 8 boys), whose mean age was 7.2 years (0.5-9.9). Baseline cortisol was significantly higher in the NCCAH group than in the CG [12.9 (4.3-22.2) vs. 9.7 (4.2-16.2) μg/dl, respectively; p = 0.0006]. NCCAH patients had lower cortisol peak response compared to the CG [18.2 (6.3-40) vs. 24.9 (12-30.3) μg/dl, respectively; p < 0.0001]. Peak cortisol was <18 μg/dl in 21/35 (60%) NCCAH patients versus 1/47 (2.1%) in the CG. No NCCAH patients had acute adrenal insufficiency, but 2 reported severe fatigue that improved with hydrocortisone. Conclusions: The cortisol response to tetracosactide was inadequate (<18 μg/dl) in 60% of patients with NCCAH. Hydrocortisone therapy may deserve consideration when major stress (surgery, trauma, childbirth) or objectively documented fatigue occurs in NCCAH patients with inadequate cortisol response.

Gender Dysphoria in 46,XX Persons with Adrenogenital Syndrome Raised as Females: An Addendum.

Gender Dysphoria in 46,XX Persons with Adrenogenital Syndrome Raised as Females: An Addendum.

Evaluation of Blood Pressure and Left Ventricular Parameters in Children with Classical Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: An Egyptian Experience

Background/Aims: Congenital Adrenal Hyperplasia (CAH) patients are at higher risk of systemic hypertension secondary to high steroid dose therapy. Our aim was to look for early cardiovascular changes in young CAH patients, by the analysis of BP levels and echocardiographic parameters. We aimed also to investigate the possible risk factors that may contribute to such effects. Methods: We evaluated blood pressure measurements (using international percentiles) and echocardiography in 53 CAH pediatric patients. Thirty healthy age and sex matched children were included as controls. Results: It was found that 10(18.9%) patients had elevated BP and 23(43.4%) patients had hypertension. Out of those hypertensive patients, 7 (13.2%) patients had systolic hypertension, 3 (5.6%) patients had diastolic hypertension, and 13 (24.5%) patients had combined systolic and diastolic hypertension. BP levels of CAH cases were positively correlated with Hydrocortisone doses (r=0.14, P value=0.038) and negatively correlated with 17-OH-progesterone levels (r=-0.15, P value=0.023). Our patients had myocardial hypertrophy with increased left ventricular wall thickness, greater mean LVM and LVMI. Age and hypertension were predictors of LV hypertrophy. Conclusions: The present study showed that a considerable portion of CAH patients had hypertension. Their BP levels were influenced by Glucocorticoids (GCs) doses.

Interrelationships Among Cortisol, 17-Hydroxyprogesterone, and Androstenendione Exposures in the Management of Children With Congenital Adrenal Hyperplasia

Hydrocortisone is the standard replacement therapy for children with congenital adrenal hyperplasia (CAH). Relationships between cortisol exposures and pharmacodynamic responses of 17-hydroxyprogesterone and androstenedione exposures have not been systematically evaluated.Objectives(1)...

Clinical manifestations of testicular adrenal rest tumor in males with congenital adrenal hyperplasia.

PurposeIn male patients with congenital adrenal hyperplasia (CAH), the presence of testicular adrenal rest tumors (TARTs) have been reported, however their prevalence and clinical manifestations are not well known. Untreated TARTs may lead to testicular structural damage and infertility. This study was conducted to investigate the prevalence of TARTs in male patients with CAH, and characterize the manifestations to identify contributing factors to TART.MethodsAmong 102 CAH patients aged 0-30 years, 24 male patients have been regularly followed up in our outpatient clinic at Severance Children's Hospital from January 2000 to December 2014. In order to reveiw the characteristics of TART patients, we calculated the mean levels of hormones during the 5 years before the time of investigation. Five patients underwent follow-up scrotal ultrasonography (US) after adjusting the dosage of glucocorticoids.ResultsTARTs were detected in 8 of the 13 patients (61.5%). The median age of TARTs diagnosis was 20.2 years with the youngest case being 15.5 years old. The mean serum level of adrenocorticotropic hormone (ACTH) was higher in the TARTs patient group compared to the non-TARTs group (P<0.05). The tumor size decreased in 3 cases, slightly increased in 1 case, and had no change in another case.ConclusionThe serum ACTH level might be associated with the growth promoting factor for TARTs, but the exact mechanism has not been clearly identified. Screening for TARTs using US is important in male patients with CAH for early-detection and prevention of ongoing complications, such as infertility.

Variation in absorption and half-life of hydrocortisone influence plasma cortisol concentrations.

Hydrocortisone therapy should be individualized in congenital adrenal hyperplasia (CAH) patients to avoid over and under replacement. We have assessed how differences in absorption and half-life of cortisol influence glucocorticoid exposure. Forty-eight patients (21 M) aged between 6·1 and 20·3years with CAH due to CYP21A2 deficiency were studied. Each patient underwent a 24-h plasma cortisol profile with the morning dose used to calculate absorption parameters along with an intravenous (IV) hydrocortisone (15mg/m(2) body surface area) bolus assessment of half-life. Parameters derived were maximum plasma concentration (Cmax ), time of maximum plasma concentration (tmax ), time to attaining plasma cortisol concentration <100nmol/l and half-life of cortisol. Mean half-life was 76·5±5·2 (range 40-225·3) min, Cmax 780·7±61·6nmol/l and tmax 66·7 (range 20-118) min. Time taken to a plasma cortisol concentration less than 100nmol/l was 289 (range 140-540) min. Those with a fast half-life and slow tmax took longest to reach a plasma cortisol concentration less than 100nmol/l (380±34·6min), compared to those with a slow half-life and fast tmax (298±34·8min) and those with a fast half-life and fast tmax (249·5±14·4min) (One-way anovaF=4·52; P=0·009). Both rate of absorption and half-life of cortisol in the circulation play important roles in determining overall exposure to oral glucocorticoid. Dose regimens need to incorporate estimates of these parameters into determining the optimum dosing schedule for individuals.

The frequency and the effects of 21-hydroxylase gene defects in congenital adrenal hyperplasia patients.

Congenital adrenal hyperplasia (CAH) is a group of genetic endocrine disorders, caused by enzyme deficiencies in the conversion of cholesterol to cortisol. More than 90% of the cases have 21-hydroxylase deficiency (21-OHD). The clinical phenotype of the disease is classified as classic, the severe form, and nonclassic, the mild form. In this study, it was planned to characterize the mutations that cause 21-OHD in Turkish CAH patients by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis and to investigate the type of CAH (classic or nonclassic type) that these mutations cause. A total of 124 CAH patients with 21-OHD and 100 healthy volunteers were recruited to the study. Most of the mutations were detected by direct sequencing. Large gene deletions/duplications/conversions were investigated with MLPA analysis. Results were evaluated statistically. At the end of our study, 66 different variations were detected including SNPs and deletions/duplications/conversions. Of these variations, 18 are novel, of which three cause amino acid substitutions. In addition, 15 SNPs which cause amino acid changes were identified among these variations. If similar results are obtained in different populations, these mutations, in particular the novel mutation 711 G>A, may be used as markers for prenatal diagnosis.