Aging,glucocorticoids and developmental programming

Glucocorticoids are pleiotropic regulators of multiple cell types with critical roles in physiological systems that change across the life-course. Although glucocorticoids have been associated with aging, available data on the aging trajectory in basal circulating glucocorticoids are conflicting. A literature search reveals sparse life-course data. We evaluated (1) the profile of basal circulating corticosterone across the life-course from weaning (postnatal day—PND 21), young adult PND 110, adult PND 450, mature adult PND 650 to aged phase PND 850 in a well-characterized homogeneous rat colony to determine existence of significant changes in trajectory in the second half of life; (2) sex differences; and (3) whether developmental programming of offspring by exposure to maternal obesity during development alters the later-life circulating corticosterone trajectory. We identified (1) a fall in corticosterone between PND 450 and 650 in both males and females (p < 0.05) and (2) higher female than male concentrations (p < 0.05). (3) Using our five life-course time-point data set, corticosterone fell at a similar age but from higher levels in male and female offspring of obese mothers. In all four groups studied, there was a second half of life fall in corticosterone. Higher corticosterone levels in offspring of obese mothers may play a role in their shorter life-span, but the age-associated fall occurs at a similar time to control offspring. Although even more life-course time-points would be useful, a five life-course time-point analysis provides important new information on normative and programmed aging of circulating corticosterone.     

Perinatal programming of central obesity and the metabolic syndrome: role of glucocorticoids

Intrauterine growth retardation (IUGR) is associated with increased prevalence, at the adult age, of central obesity, the metabolic syndrome, and its complications (type 2 diabetes and coronary heart disease). Programming of the corticotropic function is one of the mechanisms underlying the above-mentioned phenomenon. An increased passage of active glucocorticoids from the mother to the fetus can act, at the central nervous system level, to program an enhanced response to stress and, at the peripheral level, in adipose tissue to induce an increased local glucocorticoid exposure and sensitivity. In addition to an improvement of the health of pregnant women, early diagnosis of metabolic and hormonal disturbances is important in children with IUGR, in order to prevent a compensatory catch-up growth and its subsequent obesity, and to set up a therapeutic intervention against the deleterious consequences of hypercorticism.     

Genetic evidence of the programming of beta cell mass and function by glucocorticoids in mice

Aims/hypothesis  

Prenatal exposure to excess glucocorticoids associates with low birthweight in rodents, primates and humans and its involvement in programming glucose homeostasis is suspected. Our aim was to further dissect the role of glucocorticoids on beta cell development and function in mice.     

Prenatal alcohol exposure causes long-term serotonin neuron deficit in mice

BACKGROUND: Previous work from this laboratory showed that prenatal alcohol exposure at approximately 100 mg/dl from embryonic day (E)7 to early midgestation reduced the number and retarded the migration of serotonin (5-HT) neurons in the raphe nuclei in C57BL/6 mice. In this study, we report that the deficit of 5-HT neurons found in midgestation persisted on E18 and into young adulthood. METHODS: Pregnant dams were treated from E7 to E18 in three groups--(1) the alcohol group, fed with liquid diet with 25% ethanol-derived calories; (2) the isocaloric pair-fed group; and (3) the chow group for analysis of concentrations of active caspase-3--to study apoptosis at E18 in the brainstem and the number of 5-HT neurons at E18 and postnatal day 45. The concentrations of active caspase-3 were determined by using a colorimetric assay, and the 5-HT neurons were determined by immunocytochemistry. RESULTS: Prenatal alcohol exposure increased the concentration of active caspase-3 in the brainstem and caused reductions in brain weight by 20% and in the total number of 5-HT-immunostaining neurons in the dorsal and median raphe nuclei by 20% at E18 as compared with those of the pair-fed and chow controls. Continuous observation from prenatal to postnatal stages showed that the reduction of 5-HT-immunostaining neurons in the dorsal and median raphe nuclei persisted in the young adult stage. CONCLUSIONS: Upon prenatal alcohol exposure, an increased concentration of active caspase-3 and a decreased number of 5-HT-immunostaining neurons in the brainstem were observed at E18. The decreased number of 5-HT neurons persisted to the young adult stage of postnatal day 45. This suggests that ethanol has a long-lasting effect on 5-HT deficit. A fetal alcohol exposure-rendered lasting deficit of 5-HT and other transmitter systems may underlie the neuropsychiatric deficits in fetal alcohol spectrum disorder.     

Bone and glucocorticoids

Corticosteroid-induced osteoporosis is the most common form of secondary osteoporosis and the most frequent cause of osteoporosis in young people. Bone loss and fracture risk increase rapidly after the initiation of corticosteroid therapy and are proportional to dose and treatment duration. The increase in fracture risk is not fully assessed by bone mineral density measurement, as it is also related to impaired bone quality and increased risk of falls. Prevention should be considered in all patients beginning corticosteroid therapy, especially as the underlying inflammation in itself impairs bone quality. Bisphosphonates and teriparatide have shown efficacy in the treatment of corticosteroid-induced osteoporosis. Several national and international guidelines are available to improve management of corticosteroid-induced osteoporosis, which remains inadequate. Duration of anti-osteoporotic treatment should be discussed at the individual level, depending on the subject's characteristics and on the progression of the underlying inflammation.     

Prenatal glucocorticoids improve lung morphology and partially restores surfactant mRNA expression in lambs with diaphragmatic hernia undergoing fetal tracheal occlusion

In fetal sheep with surgically created diaphragmatic hernia (DH), tracheal occlusion (TO) can restore lung growth but does not ameliorate the increase in inter-alveolar wall thickness (T(W)). We determined whether prenatal exposure to glucocorticoids (GC) could reduce T(w) in fetuses with DH undergoing TO. At 65 days of gestation, DH was created in 12 fetal sheep, and TO subsequently performed at 110 days (DH/TO). Six of these fetuses were exposed to betamethasone (DH/TO + GC; 0.5 mg/kg; maternal, IM) 48 hr before delivery; Sham operated fetuses (n = 7) served as controls. At 139 days, we measured alveolar surface density (S(V)), parenchymal tissue fraction, T(W), alveolar type 2 (AE2) cell density and lung surfactant protein (SP) mRNA expression. Prenatal GC decreased T(W) and S(V) by 33% and 27% respectively, and increased fixed lung volume (by 55%), AE2 cell density and partially restored SPmRNA expression. Our data indicate that prenatal exposure to GC can reverse some of the negative effects of prolonged fetal TO. We hypothesize that a GC-induced reduction in lung liquid volume during TO contributes, in part, to the observed increase in AE2 cell density and SPmRNA expression.     

Prenatal exposure to high levels of glucocorticoids increases the susceptibility of cerebellar granule cells to oxidative stress-induced cell death

There is growing concern that prenatal exposure to excessive glucocorticoids may have deleterious effects on the development of various organs, including the nervous system. This study aimed at evaluating whether prenatal exposure to high levels of glucocorticoids might produce long-term effects on neuronal cell survival. Pregnant rats were injected i.p. with 0.1 mg/kg dexamethasone (DEX) from day 14 postconception, and cerebellar granule cells (CGC) were prepared from 1-week-old rats from DEX-treated and control dams. After 7 days in culture, cells were exposed to H(2)O(2), methylmercury, or colchicine at concentrations known to induce apoptotic cell death. After exposure to H(2)O(2) or methylmercury, both inducing oxidative stress, the number of apoptotic cells was significantly higher in DEX- than in control-CGC. Because mitochondria play a key role in apoptosis, mitochondrial function was investigated, and a decrease in the threshold level of Ca(2+) necessary for induction of mitochondrial permeability transition, in Ca(2+) accumulation rate, and in oxygen consumption was detected in DEX-CGC. Moreover, the activity of the antioxidant enzyme catalase was significantly decreased in DEX-CGC. A similar decrease in catalase activity was observed in cerebellar homogenate from newborn and 40-day-old DEX-rats. In conclusion, these results indicate that prenatal exposure to high levels of glucocorticoids induces long-lasting changes in CGC rendering them more sensitive to oxidative stress. With the increasing use of multiple doses of glucocorticoids in preterm infants, the possibility that prenatal exposure to excess glucocorticoids may lead to long-term neurological consequences becomes a relevant issue.     

Interaction between adrenal glucocorticoids and parasympathetic activation in mediating hyperinsulinaemia during long-term central neuropeptide Y infusion in rats

Aims/hypothesis. Hypothalamic neuropeptide Y is implicated in the aetiology of obesity and insulin resistance because of its hyperinsulinaemic, hyperphagic effects. We investigated the interaction of adrenal glucocorticoids and the parasympathetic nervous system in the hyperinsulinaemia caused by neuropeptide Y infusion in rats.¶Methods. Neuropeptide Y was intracerebroventricularly given to normal or adrenalectomised rats for 3–6 days with pair-feeding, with or without subcutaneous dexamethasone infusion. We measured basal and intravenous glucose-induced insulinaemia and the effect of prior atropine injection.¶Results. Neuropeptide Y increased basal plasma insulin and C-peptide concentrations (380 ± 90 and 1000 ± 60 pmol/l, vs 190 ± 20 and 590 ± 50 pmol/l in controls, p < 0.05). Neuropeptide Y also increased the plasma concentrations of these hormones as early as 60 s after glucose injection (1630 ± 170 and 3200 ± 170 pmol/l for insulin and C peptide, respectively, vs 1080 ± 80 and 1860 ± 130 pmol/l in controls, p < 0.05). Atropine reversed the effect of neuropeptide Y on basal plasma insulin and C-peptide concentrations but had no effect on post-glucose plasma concentrations. The hyperinsulinaemic effects of neuropeptide Y were prevented by adrenalectomy, but were restored by dexamethasone infusion. Dexamethasone in itself did not statistically significantly increase insulinaemia in adrenalectomised rats. As in intact rats, atropine attenuated the basal hyperinsulinaemia of adrenalectomised rats that had been infused with neuropeptide Y and dexamethasone but had no effect on post-glucose hyperinsulinaemia.¶Conclusion/interpretation. These data suggest firstly that neuropeptide Y infused centrally induces basal hyperinsulinaemia in rats through glucocorticoid-dependant parasympathetic activation to the pancreas. Secondly, neuropeptide Y potentiates glucose-induced insulinaemia through a pathway dependant on adrenal glucocorticoids that cannot be reversed by short-term blockade of the increased parasympathetic tonus. [Diabetologia (2000) 43: 859–865]     

Energy-conserving programming of VVI pacemakers: a telemetry-supported, long-term, follow-up study

Thirty patients with VVI pacemakers (Quantum 253-09, 253-19, Intermedics Inc., Freeport, TX) were observed for a mean of 65 months. Within 12 months after implantation, optimized output programming was performed in 29 patients. This included a decrease in pulse amplitude (22 patients), pulse width (4 patients), and/or pacing rate (11 patients). After 65 months postimplantation, telemetered battery voltage and battery impedance were compared with the predicted values expected when the pulse generator constantly stimulates at nominal program conditions (heart rate 72.3 beats/min, pulse amplitude 5.4 V, pulse width 0.61 ms). Instead of an expected cell voltage of 2.6 V and a cell impedance of 10 k omega mean telemetered values amounted to 2.78 V and 1.4 k omega, respectively. These data correspond to a battery age of 12-15 months at nominal program conditions. This long-term follow-up study suggests that adequate programming will extend battery longevity and thus pulse generator survival in many patients.     

Treatment of ursodeoxycholic acid with glucocorticoids and immunosuppressants may improve the long-term survival rate in primary biliary cholangitis patients

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease. The clinical effectiveness of ursodeoxycholic acid (UDCA) plus glucocorticoids and/or immunosuppressants remains controversial in PBC patients. The study aimed to compare the efficacy of monotherapy and combination therapy in patients with PBC and to assess the factors affecting the efficacy. In this retrospective study, 266 patients diagnosed with PBC were divided into monotherapy group (UDCA), double therapy group (UDCA plus glucocorticoids or immunosuppressants), and triple therapy group (UDCA plus glucocorticoids and immunosuppressants) according to different treatments. Demographic characteristics, immune parameters, biochemistry profiles, and other indicators were evaluated at baseline, 6 months, and 1 year following treatment. The prognosis was evaluated using the Paris II standard. The liver transplant-free survival at 3, 5, 10, and 15 years was predicted by GLOBE score. All statistical analyses were conducted using SPSS (version 24) software (SPSS Inc, Chicago, IL). The long-term survival rate of the triple therapy group was significantly improved compared with the monotherapy group (P = .005). In addition, multivariate analysis showed that abnormal platelet count, alkaline phosphatase, and albumin levels were risk factors for poor response. When IgG levels were elevated but below twice the upper limit of normal, the clinical benefit was not significant compared with monotherapy (P > .05). Compared with monotherapy and double therapy, triple therapy may improve the long-term survival rate of PBC patients. Abnormal platelet count, alkaline phosphatase, and albumin levels were associated with a poor prognosis.     

Dissociation of ACTH and glucocorticoids

It is increasingly clear that significant differential regulation of pituitary and adrenal gland activation exists, leading to a dissociation of plasma adrenocorticotropic hormone and corticosteroid secretion during fetal, postnatal and adult life. An increasing number of preclinical and clinical studies report dissociation of adrenocorticotropic hormone and cortisol levels in critical illness, inflammation and mental disorders. Mechanisms involve an altered adrenal sensitivity, aberrant receptor expression or modulation of adrenal function by cytokines, vasoactive factors or neuropeptides. The degree of dissociation has been associated with the level of complications of sepsis, surgery, malignant disease and depression. The separation of adrenocorticotropic hormone and corticosteroid secretion is of clinical relevance and should be incorporated into our view on endocrine stress regulation.     

促肾上腺皮质激素和糖皮质激素的分离

最近研究发现,垂体和肾上腺活性的调节方式不同于以往的观点,导致在胎儿期、婴幼儿期、成人期血浆促肾上腺皮质激素和皮质类同醇激素分泌水平的分离.越来越多的基础和临床研究表明,在危重症、感染和精神失常时会出现促肾上腺皮质激素和皮质醇水平的分离.其机制包括.肾.上腺敏感性的变化、异常的受体表达及细胞因子、血管活性因子、神经肽等对肾上腺功能的调节.分离的程度与感染、创伤、恶性疾病、抑郁的严重程度有关.促肾上腺皮质激素和皮质类固醇激素分泌分离的现象和临床密切相关,凶此应引起重视.     

Stress and glucocorticoids in aging

This article has considered two themes that have permeated the gerontologic literature--namely, that aging is a time of decreased efficiency in responding to stress and that chronic stress can accelerate aspects of aging. Given the restricted framework of considering adrenocortical function (as a component of the stress response) and glucocorticoid over-exposure (as a component of chronic stress), there is considerable evidence for both of these ideas. The capacity of glucocorticoids to damage the rat hippocampus slowly over the life span and the glucocorticoid hypersecretion that seems to ensue during aging as a result of such hippocampal damage support these long-standing ideas. It should be noted that these two components interact with each other--excessive glucocorticoid secretion damages the hippocampus, and hippocampal damage produces excessive glucocorticoid secretion. This dysregulatory cascade appears to be a normal part of aging in the rat. The role of glucocorticoids in triggering programmed aging and death, while quite dramatic, is probably a phylogenetically rare event; it remains to be seen if the dysregulatory cascade of glucocorticoid excess in the rat is of relevance to aging in other species. Numerous published studies suggest that this cascade is not an obligatory aspect of normal human aging; rather, it appears to be a significant factor in the explanation of some features of pathologies associated with human aging.     

Prenatal programming of reproductive neuroendocrine function: fetal androgen exposure produces progressive disruption of reproductive cycles in sheep

In the agonadal, androgenized ewe testosterone before birth produces a precocious pubertal rise in circulating LH and abolishes the LH surge mechanism. The present study tested two predictions from this model in the ovary-intact female: 1) prenatal androgen exposure produces early ovarian stimulation; and 2) despite early ovarian stimulation, progestogenic cycles would not occur because of the abolition or disruption of the LH surge. Pregnant ewes were injected with testosterone propionate twice per week from either d 30-90 (T60 group; 100 mg/injection) or d 60-90 (T30 group; 80 mg/injection) of gestation (term, 147 d). Control ewes received no injections. At birth, the androgenized and control lambs were divided into two groups: ovary-intact to determine the effects of prenatal androgen on the timing of puberty and subsequent ovarian function, and ovariectomized to assess the timing of the pubertal decrease in sensitivity to estrogen negative feedback and the subsequent increase in LH. Neonatally orchidectomized, estrogen-treated males were included for comparison of the timing of this pubertal rise in LH secretion. Neuroendocrine puberty (determined on the basis of LH increase) was advanced in the androgenized females to a similar age as in males. Repeated progesterone cycles of the same duration and number occurred in the ovary-intact ewes, and they began at the same time as for control females, thus negating both predictions. Differences appeared during the second breeding season, when reproductive cycles were either absent (T60) or disrupted (T30 group). Our findings reveal that exposure to androgens in utero causes a progressive loss of cyclic function in adulthood.