Patients with cortisol excess, Cushing's syndrome, develop a classical phenotype characterized by central obesity, hypertension, and increased cardiovascular mortality. Whilst this observation points to the importance of glucocorticoids, circulating cortisol excess is rare and does not explain the pathogenesis of many common conditions. At a tissue specific level, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) locally regenerates active cortisol from inactive cortisone amplifying glucocorticoid receptor activation in the context of normal circulating cortisol levels. Increased 11beta-HSD1 activity and expression have been implicated in the pathogenesis of many common conditions including, obesity, insulin resistance, the metabolic syndrome, polycystic ovarian syndrome, osteoporosis and glaucoma. Furthermore, selective 11beta-HSD1 inhibition has been proposed as a novel therapeutic strategy in many of these conditions. Here we review the role of 11beta-HSD1 in human disease and discuss the impact of selective 11beta-HSD1 inhibition.
Cortisol , a glucocorticoid, binds the glucocorticoid receptor. However, because of its molecular similarity to aldosterone it is also capable of binding the mineralcorticoid receptor. Both aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor; however, there is vastly more cortisol in circulation than aldosterone. To prevent over-stimulation of the mineralocorticoid receptor by cortisol, 11β-HSD converts the biologically active cortisol to the inactive cortisone, which can no longer bind to the mineralocorticoid receptor. 11β-HSD co-localizes with intracellular adrenal steroid receptors. Licorice , which contains glycyrrhetinic acid , or enoxolone , can inhibit 11β-HSD and lead to a mineralocorticoid excess syndrome .
Congenital adrenal hyperplasia (CAH) is one of the most frequent autosomal recessive disorders. It is characterized by a deficiency of an enzyme involved in cortisol synthesis and in 95% of patients the cause is 21-hydroxylase deficiency. A diagnostic marker is elevated levels of 17- hydroxyprogesterone, a precursor of cortisol. CAH has several clinical forms, and classical or severe forms manifest in the neonatal period with symptoms due to excess adrenal androgen production such as virilization and ambiguity of the external genitalia in affected girls. In more than 70% of patients, there is associated salt wasting (aldosterone deficiency), which can be fatal in males without an early diagnosis. We summarize the various forms of presentation of 21-hydroxylase deficiency and describe diagnosis and treatment with gluco- and mineralocorticoids, with special emphasis on the importance of using stress doses of hydrocortisone when necessary. Current surgical advances provide functional correction in affected patients. Screening programs avoid incorrect sex assignment in the newborn and can save the lives of males with severe forms and salt wasting. We discuss the genetic-molecular diagnosis of CYP21A2 (chromosome 6p ) and its characteristics in the Spanish population. We review future recommendations for the study and management of this disease, including several treatments such as flutamide, growth hormone, and gonadotrophin antagonists, as well as the association with polycystic ovary syndrome. Prenatal diagnosis and treatment in affected female fetuses are feasible and the results are encouraging. We also discuss the management of the transition to adulthood and the importance of follow-up of women with CAH during pregnancy.