Cyp11b1 null mouse, a model of congenital adrenal hyperplasia.
ABSTRACT Patients with congenital adrenal hyperplasia arising from mutations of 11beta-hydroxylase, the final enzyme in the glucocorticoid biosynthetic pathway, exhibit glucocorticoid deficiency, adrenal hyperplasia driven by unsuppressed hypothalamo-pituitary-adrenal activity, and excess mineralocorticoid activity caused by the accumulation of deoxycorticosterone. A mouse model, in which exons 3-7 of Cyp11b1 (the gene encoding 11beta-hydroxylase) were replaced with cDNA encoding enhanced cyan fluorescent protein, was generated to investigate the underlying disease mechanisms. Enhanced cyan fluorescent protein was expressed appropriately in the zona fasciculata of the adrenal gland, and targeted knock-out was confirmed by urinary steroid profiles and, immunocytochemically, by the absence of 11beta-hydroxylase. The null mice exhibited glucocorticoid deficiency, mineralocorticoid excess, adrenal hyperplasia, mild hypertension, and hypokalemia. They also displayed glucose intolerance. Because rodents do not synthesize adrenal androgens, changes in reproductive function such as genital virilization of females were not anticipated. However, adult homozygote females were infertile, their ovaries showing an absence of corpora lutea and a central proliferation of disorganized steroidogenic tissue. Null females responded normally to superovulation, suggesting that raised systemic progesterone levels also contribute to infertility problems. The model reveals previously unrecognized phenotypic subtleties of congenital adrenal hyperplasia.
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ABSTRACT: Despite increasing acknowledgement of hormonal contributions to mood and anxiety disorders, the underlying mechanisms by which gonadal hormones influence psychopathology-related behaviours remain unknown. This review focuses on recent research that examines the influence of gonadal steroid hormones, including androgens, oestrogens, and progesterone, on mood and anxiety-related behaviours in human health and disease. To this aim, the literature was surveyed for studies that assess conditions with suspected underlying hormonal imbalances in otherwise healthy participants (e.g., premenstrual dysphoric disorder, postmenopausal depression) as well as conditions linked to congenital endocrine abnormalities (e.g., Turner Syndrome, Klinefelter Syndrome, polycystic ovary syndrome, congenital adrenal hyperplasia, familial male precocious puberty, androgen insensitivity syndrome). Furthermore, to better inform clinical work and to create a translational bridge, a second goal was to set human psychopathologies and animal models of these conditions side-by-side. In the second part of the review, based on consistencies revealed in the existing literature across conditions, a new model for the impact of gonadal hormones on anxious and depressed behavioural states is proposed. Finally, we conclude by proposing directions for future research, including the development of specific tasks suitable for cross-species comparisons to increase our knowledge of the role of gonadal hormones in mood and anxiety.Psychoneuroendocrinology 08/2014; 46C:114-128. · 5.59 Impact Factor
Dataset: Physiol Genomics
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ABSTRACT: The clinical manifestations of glucocorticoid excess include central obesity, hyperglycaemia, dyslipidaemia, electrolyte abnormalities and hypertension. A century on from Cushing's original case study, these cardinal features are prevalent in industrialised nations. Hypertension is the major modifiable risk factor for cardiovascular and renal disease and reflects underlying abnormalities of sodium homeostasis. Aldosterone is a master regulator of renal sodium transport but here we argue that glucocorticoids are also influential, particularly during moderate excess. The hypothalamic-pituitary-adrenal axis can affect renal sodium homeostasis on multiple levels, systemically by increasing mineralocorticoid synthesis and locally by actions on both the mineralocorticoid and glucocorticoid receptors, both of which are expressed in the kidney. The kidney also expresses both of the 11β-hydroxysteroid dehydrogenase enzymes. The intrarenal generation of active glucocorticoid by 11βHSD1 stimulates sodium reabsorption; failure to down-regulate the enzyme during adaption to high dietary salt causes salt-sensitive hypertension. The deactivation of glucocorticoid by 11βHSD2 underpins the regulatory dominance for sodium transport of mineralocorticoids and defines the "aldosterone-sensitive distal nephron". In summary, glucocorticoids can stimulate renal transport processes conventionally attributed to the renin-angiotensin-aldosterone system. Importantly, sodium and volume homeostasis do not exert a negative feedback on the hypothalamic-pituitary-adrenal axis. These actions are therefore clinically relevant and may contribute to the pathogenesis of hypertension in conditions associated with elevated glucocorticoid levels, such as the metabolic syndrome or chronic stress.The Journal of Physiology 02/2014; · 4.38 Impact Factor