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    ABSTRACT: Maintaining redox balance is essential for normal cellular functions. Any perturbation in this balance due to increased reactive oxygen species (ROS) leads to oxidative stress and may lead to cell dysfunction/damage/death. Mitochondria are responsible for the majority of cellular ROS production secondary to electron leak as a consequence of respiration. Further electron leak by the cytochrome P450 enzymes may render steroidogenic tissues acutely vulnerable to redox imbalance. The adrenal cortex, in particular, is well supplied with both enzymatic (glutathione peroxidases and peroxiredoxins) and non-enzymatic (Vitamins A, C and E) antioxidants to cope with this increased production of ROS due to steroidogenesis. Nonetheless oxidative stress is implicated in several potentially lethal adrenal disorders including X-linked adrenoleukodystrophy, triple A syndrome and most recently familial glucocorticoid deficiency. The finding of mutations in antioxidant defence genes in the latter two conditions highlights how disturbances in redox homeostasis may have an impact on adrenal steroidogenesis.
    Full-text · Article · Mar 2014 · Journal of Endocrinology
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    ABSTRACT: Context:Shortly after birth, pituitary gonadotropin secretion transiently activates in both sexes, and this surge is more robust in preterm (PT) than in full-term (FT) infants. In boys, the gonadotropin surge is associated with testicular activity and is considered an important part of normal reproductive development. In contrast, gonadal activation and its consequences in infant girls are poorly understood.Objective:Our objective was to evaluate the association of postnatal ovarian activity with simultaneous changes in estrogen target tissues in FT and PT girls.Patients and Methods:We measured urinary estradiol (E2) levels in 29 FT and 34 PT girls using a mass spectrometric method from 1 week (D7) to 6 months of age (M1-M6). To assess the contribution of ovarian E2 on urinary E2 levels, the levels in girls were compared with the levels of boys of similar cohorts (29 FT and 33 PT boys). E2 levels were compared with simultaneous changes in estrogenic target tissues including mammary glands in both sexes and uterus and vulvar epithelium in girls.Results:Median urinary E2 levels increased after D7 in girls, but not in boys. Mammary gland diameter was larger in girls than in boys from M4 in FT (P < .001) and M2 in PT infants (P < .0001). In PT girls, E2 levels increased at term and were then higher than those in FT girls (P < .0001). Urinary E2 levels in PT girls were positively associated with mammary gland and uterine growth.Conclusions:These findings indicate that gonadal steroidogenesis activates during the postnatal gonadotropin surge in girls. In addition, the resulting elevated E2 levels affect target tissues, suggesting that postnatal pituitary-ovarian activation plays a role in normal female reproductive development.
    Full-text · Article · Nov 2013 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Melanocortin 2 receptor (MC2R) is the only canonical ACTH receptor. Its functional expression requires the presence of an accessory protein, known as melanocortin receptor 2 accessory protein 1 (MRAP1). The vertebrate genome exhibits a paralogue gene called MRAP2, which is duplicated in zebrafish (MRAP2a and MRAP2b), although its function remains unknown. In this paper, we demonstrate that MRAP2a enables MC4R, a canonical MSH receptor, to be activated by ACTH with a similar sensitivity to that exhibited by MC2R. Both proteins physically interact and are coexpressed in the neurons of the preoptic area, a key region in the control of the energy balance and hypophyseal secretion in fish. ACTH injections inhibit food intake in wild-type zebrafish but not in fish lacking functional MC4R. Both MRAP1 and MRAP2a are hormonally regulated, suggesting that these proteins are substrates for feed-back regulatory pathways of melanocortin signaling. Fasting has no effect on the central expression of MRAP2a but stimulates MRAP2b expression. This protein interacts and is colocalized with MC4R in the tuberal hypothalamic neurons but has no effect on the pharmacologic profile of MC4R. However, MRPA2b is able to decrease basal reporter activity in cell lines expressing MC4R. It is plausible that MRAP2b decreases the constitutive activity of the MC4R during fasting periods, driving the animal toward a positive energy balance. Our data indicate that MRAP2s control the activity of MC4R, opening up new pathways for the regulation of melanocortin signaling and, by extension, for the regulation of the energy balance and obesity.
    Full-text · Article · Oct 2013 · Molecular Endocrinology
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Frontiers of hormone research 03/2013; 41:111-40. DOI:10.1159/000345673
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Neuro-Oncology 06/2014; 16(suppl 1):i14-i16. DOI:10.1093/neuonc/nou067
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