PubMed · 14911523
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F J NATTRASS. 1952. ACTH therapy.. https://pubmed.ncbi.nlm.nih.gov/14911523/
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siRNA oligonucleotides for protein phosphatase 5 (PP5) were designed and transfected into mouse corticotroph AtT20 cells to induce lower PP5 expression levels. PP5-siRNA transfections (at 3 days) produced a approximately 50% down-regulation in targeted protein levels. PP5-underexpressing cells released significantly more ir-ACTH (10-12-fold) relative to baseline levels and promoted POMC release into the media. Neither CRF-mediated ACTH release nor dexamethasone-induced ACTH repression were affected in PP5-siRNA transfected cells. In summary, our observations suggest that endogenous PP5 can exert a negative modulatory effect on basal ACTH release in neurosecretion-competent AtT20 cells through a mechanism as yet unknown but which does not directly involve regulated CRF or glucocorticoid receptor-dependent pathways. However, PP5 may cause mis-sorting of POMC and POMC-derived peptides at the constitutive-like secretory pathway level in an unregulated manner. Such a missorting could lead to impaired processing of POMC.
Antenatal betamethasone administration to enhance fetal lung maturation is associated with transient reductions in fetal heart rate (FHR) variation, breathing, and body movements 2 d after the first dose (d 2). This study examines whether steroid administration affects the natural diurnal rhythms of fetal variables. Sixteen women at 27-32 wk of gestation received two doses of betamethasone 24 h apart. One-hour recordings of FHR, breathing, and body movements were made in the morning, afternoon, and evening of d 2, and again in the morning of d 3. Repeat recordings were obtained at 4-6 d later from 9/16 women. Maternal blood samples were obtained with each recording to determine ACTH and cortisol. No diurnal rhythm was present for FHR, FHR variation, breathing, and body movements on d 2. This resulted from suppression of the expected natural rise in body and breathing movements, and heart rate variation in the course of the day. Suppression of the diurnal rhythm of body movements depended on gestation (R = -0.89; p < 0.01). All variables showed diurnal rhythms 4-6 d later. Maternal ACTH and cortisol diurnal rhythms were completely suppressed on d 2. Four to six days later, the normal diurnal pattern was resumed, although absolute levels of ACTH and cortisol were still suppressed. We conclude that maternal betamethasone administration transiently abolishes the fetal diurnal rhythms of heart rate and its variation, breathing, and body movements.
The fat derived protein leptin has its anorexic action through a number of neuropeptides including an upregulation of corticotropin releasing hormone (CRH) expression in the hypothalamus. However, the influence of leptin on these neuropeptides may be different during stress. The present study used ovariectomized female rhesus monkeys (n=8) to further define the effect of leptin on HPA responsivity. To accomplish this, we assessed the effects of constant leptin infusion on cortisol and ACTH secretion in both a predictable and unpredictable situation as well as in response to dexamethasone suppression-CRH stimulation test. We hypothesized that leptin would attenuate the increase in cortisol and ACTH to a novel, unpredictable situation and would enhance glucocorticoid negative feedback and diminish the response to CRH. Animals were assessed under control placebo conditions and during a 28 day infusion with recombinant human leptin (6 microg/kg/day, SC). Within each treatment condition, HPA responsivity was assessed during no estradiol replacement and acute estradiol replacement that produced serum concentrations of approximately 40 pg/ml. However, the results indicated that neither estradiol alone or in combination with leptin had any consistent effect on the outcome measures. Compared to the control condition, leptin had no effect on the cortisol diurnal rhythm; however, evening but not morning plasma ACTH concentrations were significantly lower during leptin infusion. In contrast, the response in plasma cortisol and ACTH to an unpredictable situation was significantly attenuated by chronic leptin infusion. Furthermore, leptin enhanced glucocorticoid negative feedback and blunted CRH-induced increase in both cortisol and ACTH. Taken together, these data suggest that in the female monkey, leptin has little effect on basal cortisol. However, when the HPA axis is activated, leptin attenuates the neuroendocrine response by enhancing glucocorticoid negative feedback. These data underscore the potential importance of leptin in maintaining homeostasis through its diverse interaction with the HPA axis.