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Fetal adrenal and gonadal sex hormone synthesis in health and disease

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Role of the adrenal cortex in genital development

European researchers discovered a novel role for the adrenal cortex in the development of external genitalia.

Fundamental Research icon Fundamental Research
Health icon Health

The differentiation of the male and female genital phenotype takes place approximately 7-12 weeks after conception. Although maintaining the appropriate intrauterine hormone environment seems to be essential, there is little information on the intrauterine hormonal milieu and the consequences of hormonal alterations. Recent evidence from congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OH CAH) indicates a role for the foetal adrenal cortex in the sexual differentiation of the external genitalia. Patients carry mutations in the CYP21A2 gene, which encodes the key enzyme 21-hydroxylase of the glucocorticoid pathway. During the EU-funded FSHS (Fetal adrenal and gonadal sex hormone synthesis in health and disease) project, researchers identified a novel androgen pathway in the foetal adrenal cortex. This seems to be implicated in the pathophysiology of oxidoreductase deficiency (ORD), a recently described form of CAH. Researchers investigated this alternative pathway to foetal androgen biosynthesis via steroid metabolome analysis. They tested the urine of pregnant mothers carrying babies affected with 21-OH deficiency as well as affected new-borns. In addition, they employed a mouse model of 21-OH deficiency to investigate the impact of the foetal adrenal-gonadal hormonal cross-talk on the development of testicular and ovarian adrenal rest tumours – the most common cause of infertility in 21-OH CAH. Apart from fundamental insight into genital differentiation, the study also allowed the consortium to participate in a Phase III clinical trial of a novel orphan drug against CAH. This modified release formulation of hydrocortisone is expected to closely mimic the physiological circadian profile of cortisol and provide optimal control of all forms of adrenal insufficiency. By combining basic research with studies on the pathophysiological basis of CAH, FSHS has successfully addressed various disease aspects with obvious benefits for patients.


Adrenal cortex, external genitalia, congenital adrenal hyperplasia, 21-hydroxylase deficiency, FSHS

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