Behavioral Effects of Prenatal Versus Postnatal Androgen Excess in Children with 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia

Context: Prenatal dexamethasone therapy is used in female foetuses with congenital adrenal hyperplasia to suppress androgen excess and prevent virilisation of the external genitalia. The traditional dexamethasone dose of 20 µg/kg/d has been used since decades without examination in clinical trials and is thus still considered experimental. Objective: Because the traditional dexamethasone dose potentially causes adverse effects in treated mothers and foetuses, we aimed to provide a rationale of a reduced dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on a pharmacokinetics-based modelling and simulation framework. Methods: Based on a published dexamethasone dataset a nonlinear mixed-effects model was developed describing maternal dexamethasone pharmacokinetics. In stochastic simulations (n=1000) a typical pregnant population (n=124) was split into two dosing arms receiving either the traditional 20 µg/kg/d dexamethasone dose or reduced doses between 5 and 10 µg/kg/d. Target maternal dexamethasone concentrations, identified from literature, served as threshold to be exceeded by 90% of mothers at steady state to ensure foetal hypothalamic‐pituitary‐adrenal axis suppression. Results: A two-compartment dexamethasone pharmacokinetic model was developed and subsequently evaluated to be fit for purpose. The simulations, including a sensitivity analysis regarding the assumed foetal:maternal dexamethasone concentration ratio, resulted in 7.5 µg/kg/d to be the minimum effective dose and thus our suggested dose. Conclusions: We conclude that the current experimentally used dexamethasone dose is 3-fold higher than needed, possibly causing harm in treated foetuses and mothers. The clinical relevance and appropriateness of our recommended dose should be tested in a prospective clinical trial.

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MANAGEMENT OF ENDOCRINE DISEASE: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update on the management of adult patients and prenatal treatment

Acta Endocrinologica ◽

10.1530/eje-16-0888 ◽

2017 ◽

Vol 176 (4) ◽

pp. R167-R181 ◽

Cited By ~ 24

Author(s):

Anne Bachelot ◽

Virginie Grouthier ◽

Carine Courtillot ◽

Jérôme Dulon ◽

Philippe Touraine

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Management Strategies ◽

The United States ◽

Fertility Treatment ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Androgen Excess ◽

Classic Cah ◽

21 Hydroxylase Deficiency ◽

And Control

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and in some cases aldosterone deficiency associated with androgen excess. Goals of treatment are to replace deficient hormones and control androgen excess, while avoiding the adverse effects of exogenous glucocorticoid. Over the last 5 years, cohorts of adults with CAH due to 21-hydroxylase deficiency from Europe and the United States have been described, allowing us to have a better knowledge of long-term complications of the disease and its treatment. Patients with CAH have increased mortality, morbidity and risk for infertility and metabolic disorders. These comorbidities are due in part to the drawbacks of the currently available glucocorticoid therapy. Consequently, novel therapies are being developed and studied in an attempt to improve patient outcomes. New management strategies in the care of pregnancies at risk for congenital adrenal hyperplasia using fetal sex determination and dexamethasone have also been described, but remain a subject of debate. We focused the present overview on the data published in the last 5 years, concentrating on studies dealing with cardiovascular risk, fertility, treatment and prenatal management in adults with classic CAH to provide the reader with an updated review on this rapidly evolving field of knowledge.

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Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab051 ◽

2021 ◽

Author(s):

Deborah P Merke ◽

Ashwini Mallappa ◽

Wiebke Arlt ◽

Aude Brac de la Perriere ◽

Angelica Lindén Hirschberg ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Disease Control ◽

Standard Therapy ◽

Extension Study ◽

Modified Release ◽

Adrenal Hyperplasia ◽

Androgen Excess ◽

Phase 3 ◽

Patient Reported ◽

17 Hydroxyprogesterone

Abstract Context Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. Objective We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. Methods A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. Results The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months’ extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy). Conclusion MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.

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The Response of Pituitary Gonadotropes to Synthetic LRF in Children with Glucocorticoid-Treated Congenital Adrenal Hyperplasia: Lack of Effect of Intrauterine and Neonatal Androgen Excess

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem-40-2-318 ◽

1975 ◽

Vol 40 (2) ◽

pp. 318-325 ◽

Cited By ~ 33

Author(s):

E. O. REITER ◽

M. M. GRUMBACH ◽

S. L. KAPLAN ◽

F. A. CONTE

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adrenal Hyperplasia ◽

Androgen Excess

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Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2017.12.016 ◽

2018 ◽

Vol 178 ◽

pp. 221-228 ◽

Cited By ~ 19

Author(s):

Clemens Kamrath ◽

Lisa Wettstaedt ◽

Claudia Boettcher ◽

Michaela F. Hartmann ◽

Stefan A. Wudy

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adrenal Hyperplasia ◽

Androgen Excess

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Novel Therapies for Treating Short Stature with Congenital Adrenal Hyperplasia

International Journal of Infertility & Fetal Medicine ◽

10.5005/jp-journals-10016-1017 ◽

2011 ◽

Vol 2 (2) ◽

pp. 45-50

Author(s):

Joe Leigh Simpson ◽

Michael Christopher Hann ◽

Anisha Kshetrapal ◽

Maria I New

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adult Height ◽

Treatment Strategies ◽

Gonadotropin Releasing Hormone ◽

Novel Therapies ◽

Adrenal Hyperplasia ◽

Androgen Excess ◽

Releasing Hormone ◽

Salt Wasting ◽

Hormone Analogs

ABSTRACT Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders in which various errors in adrenal biosynthesis pathways lead to impaired cortisol secretion, possible impairment of mineralocorticoid production and androgen excess. Glucocorticoid replacement therapy is the primary treatment for CAH; however, the combination of androgen excess and high doses of glucocorticoids contributes to shortened adult height. Novel approaches to address this problem are being developed, particularly the use of growth hormone (GH) and gonadotropin releasing hormone analogs (GnRHa). In this review, we document and compare the effectiveness of these novel therapies in ameliorating the decreased adult height observed in patients with CAH. Available data indicate effectiveness of these novel treatment strategies, suggesting widespread implementation of these treatment strategies should be tested with the expectation of being recommended as the standard of care. Abbreviations Congenital adrenal hyperplasia (CAH); Salt wasting (SW-CAH); Non-salt wasting (NSW-CAH); Growth hormone (GH); Gonadotropin releasing hormone analogs (GnRHa); Luteinizing hormone releasing hormone analog (LHRHa); 21-hydroxylase gene (CYP21); 21-hydroxylase pseudogene (CYP21p); Hypothalamic-pituitary-adrenal (HPA); Corticotropin-releasing hormone (CRH); Adrenocorticotropic hormone (ACTH); Bone mineral density (BMD); Standard score (SDS).

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Simple Virilization Type of Classic Congenital Adrenal Hyperplasia: Case Report

Biomedical & Pharmacology Journal ◽

10.13005/bpj/1497 ◽

2018 ◽

Vol 11 (3) ◽

pp. 1345-1350

Author(s):

I Made Pande Dwipayana ◽

Karismayusa Sudjana ◽

Siswadi Semadi ◽

Ketut Suastika ◽

Made Ratna Saraswati ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Chromosome Analysis ◽

Ambiguous Genitalia ◽

Adrenal Hyperplasia ◽

Laboratory Examination ◽

Androgen Excess ◽

Classic Congenital Adrenal Hyperplasia ◽

Irregular Border ◽

17 Hydroxyprogesterone ◽

High Level

We have reported a case of 21 year old patient with congenital adrenal hyperplasia that manifestated with ambiguous genitalia and other signs of androgen excess. Chromosome analysis revealed 46 XX. Laboratory examination and imaging showed high level of 17-hydroxyprogesterone, undeveloped uterus, two ovaries with follicles, no testicles, no prostate, and mass at upper side of both kidney with irregular border confirmed the diagnosis. It was planned to give glucocorticoid therapy to the patient to suppress androgen level, genital reconstruction surgery and psychosexual therapy to reared as a woman, but she refused all suggestions because she wanted to be considered a man.

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