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Felix Schreiner, Magdalini Tozakidou, Rita Maslak, Ute Holtkamp, Michael Peter, Bettina Gohlke, and Joachim Woelfle

Objective

17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns.

Design

GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography–tandem mass spectrometry method (LC–MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody.

Results

There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC–MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S- and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited.

Conclusions

Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated.

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Julia Rohayem, Lena Maria Bäumer, Michael Zitzmann, Susanne Fricke-Otto, Klaus Mohnike, Bettina Gohlke, Felix Reschke, Claus Jourdan, Hermann L Müller, Désirée Dunstheimer, Johannes Weigel, Norbert Jorch, Elke Müller-Roßberg, Erwin Lankes, Imke Gätjen, Annette Richter-Unruh, Berthold P Hauffa, Sabine Kliesch, Aniko Krumbholz, and Jurgen Bramswig

Objective: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumors (TARTs) in young males with congenital adrenal hyperplasia (CAH).

Design: Combined cross-sectional and retrospective clinical study.

Methods: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as “poor”, “moderate” or “medium”. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes.

Results: Semen quality was similar in males with CAH and controls (p = 0.066), however patients with “poor” past control and large TARTs, or with “poor” current CAH control, had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was “poor” (1.8 ± 0.9 U/L; “good”: 3.9 ± 2.2 U/L); p = 0.015); luteinizing hormone was decreased if it was “poor” (1.8 ± 0.9 U/L; p = 0.041) or “moderate” (1.9 ± 0.6 U/L; “good”: 3.0 ± 1.3 U/L; p = 0.025). None of the males with “good” past CAH control, 50% of those with “moderate” past control and 80% with “poor” past control had bilateral TARTs. The prevalence of TARTs in males with severe (class null or A) CYP21A2 mutations was 53%, and 25% and 0% in those with milder class B and C mutations, respectively.

Conclusions: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TARTs. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.