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: To report for the first time a case of postmenopausal endometrial hyperplasia caused by nonclassic 21-hydroxylase deficiency (NC21OHD). The specific combination of mutations associated with this case has never before been reported. Case report. Private academic practice. A 67-year-old woman with uterine bleeding due to endometrial hyperplasia was found to have premenopausal gonadotropins with elevated estrogens. Endocrine workup revealed increased 17-hydroxyprogesterone (17-OHP), which led to molecular testing to establish a diagnosis of NC21OHD. Trial of suppression with low-dose oral dexamethasone. Resolution of postmenopausal bleeding. Total estrogens normalized with treatment, and the endometrial stripe became normal. This is an unusual case of NC21OHD in which the sole presentation was persistent endometrial hyperplasia, with bleeding past the normal age for menopause. In women with unusual endometrial hyperplasias of this type, we suggest endocrine testing before proceeding to hysterectomy.Fertility and sterility 01/2012; 97(4):950-2. · 3.97 Impact Factor
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ABSTRACT: Prostate cancers (PCs), initially responsive to anti-androgen therapies, often advance to a hormone-refractory 'castrate-resistant' PC (CRPC) stage. However, the androgen receptor (AR) pathway remains active and key for cell growth and gene expression within tumours, even in the apparent absence of hormone. Proposed mechanisms to explain progression, including AR amplification/mutation, are insufficient to completely explain CRPC and possible roles of AR cofactors such as prohibitin (PHB) are poorly understood. We investigated whether PHB loss could sensitise PC cells and tumours to adrenal gland-derived androgens, which persist even after androgen ablation, hence contribute to development of CRPC. Using a pair of PC cell lines, inducibly expressing ectopic cDNA or RNAi for PHB, responses to different androgens and hormone concentrations were studied both in vitro and in vivo. PHB was found at the promoters of several genes, both AR and non-AR-regulated, and knockdown increased histone acetylation at these promoters. Further, PHB knockdown increased the rate of AR ligand-induced chromatin binding, and binding rate and occupancy of AR upon the PSA promoter. This resulted in increased cell growth and AR activity in response to all androgens, including promoting a response to the weaker adrenal androgens previously absent at physiological concentrations. In vivo this had functional consequences such that PHB knockdown resulted in androstenedione being sufficient to promote tumour growth, under conditions mimicking those in patients undergoing androgen ablation therapy. We conclude that reduction in PHB levels is sufficient to lower the threshold of AR activity in vitro and in vivo; this may be via a general increase in histone acetylation that could potentially affect signalling by other transcription factors. PHB loss may provide a mechanism for progression to CRPC by sensitising PC cells to 'castrate' conditions-that is, low levels of testicular androgens in the continued presence of weak adrenal and dietary androgens.Oncogene 12/2011; 31(43):4588-98. · 8.56 Impact Factor
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ABSTRACT: To understand the molecular mechanism of hyperglucocorticoidism in obese Zucker rats, this study investigated glucocorticoid synthesis-related factors and their transcription factors in the adrenals. glucocorticoid synthesis-related factors and their transcription factors in the adrenals. The serum corticosterone level after foot shock stress was higher in obese Zucker rats than in lean Zucker rats. after foot shock stress was higher in obese Zucker rats than in lean Zucker rats. In the adrenals from obese Zucker rats, the mRNA and protein levels of steroidogenic acute regulatory protein were higher than those from lean Zucker rats. rats. However, the mRNA level of steroidogenic factor-1(SF-1), an important transcription factor for these glucocorticoid synthesis-related factors, did not differ between lean and obese Zucker rats. glucocorticoid synthesis-related factors, did not differ between lean and obese Zucker rats. Focusing on leptin signal transduction, Akt phosphorylation, which was known to inhibit glucocorticoid secretion, decreased in the adrenals from obese Zucker rats. from obese Zucker rats. We found that the stress-induced glucocorticoid secretion and the glucocorticoid synthesis related factors in the adrenals were increased in obese Zucker rats. factors in the adrenals were increased in obese Zucker rats. The decrease of Akt phosphorylation in the adrenals might induce these increases in obese Zucker rats.adrenals might induce these increases in obese Zucker rats.Acta Physiologica Hungarica 06/2012; 99(2):159-65. · 0.88 Impact Factor