Birth in most animal species is triggered by the fetus through activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis. Preterm birth, may be associated with precocious activation of fetal HPA function, reflecting the fetal response to an adverse intrauterine environment. There is a progressive and concurrent increase of ACTH1-39 and cortisol (F) in the circulation of fetal sheep during the last 15-20 days of pregnancy (term, day 145-150) associated with increased expression of hypothalamic CRH pituitary POMC and adrenal ACTH receptor and steroidogenic enzymes, particularly P450 C17. Similar changes occur with fetal hypoxemia. Negative feedback is ameliorated by decreased pituitary and hypothalamic glucocorticoid receptor, increased CBG, and altered fetal pituitary 11B-hydroxysteroid dehydrogenase type 1. Repeated fetal hypoxemia, diminishes the fetal-pituitary ACTH response, but increases fetal adrenal responsiveness. Fetuses exposed to maternal glucocorticoid in late gestation are growth restricted with altered postnatal HPA responsiveness and glycemic responses that reproduce the insulin resistance of type 2 diabetes. We conclude that the level of fetal HPA activity is crucial not only for determining gestation length, but also predicts pathophysiologic adjustment in later life.

Two experiments were carried out using adult castrated sheep prepared with jugular vein catheters. In Experiment 1, sheep (N=8) were injected iv with saline vehicle, vehicle + 15 or 30 \g=m\g oCRH, or subjected to 120 min mild physical stress (restraint), following a 48 h period during which water was freely available or withheld. Blood samples were taken for 30 min before and 120 min after oCRH injection, and before and during restraint, and the plasma analysed for AVP and cortisol content. Levels of AVP increased by over 500% after dehydration, but were unaffected by oCRH or restraint. In contrast, plasma cortisol was unchanged after dehydration, but increased after oCRH and restraint. Moreover, these cortisol responses were significantly greater when the sheep were dehydrated. In Experiment 2, euhydrated sheep (N =6) were infused iv with saline vehicle or vehicle + AVP for a 5-h pretreatment period, followed by a 2-h experimental period in which the animals were injected with 15 \g=m\g oCRH or subjected to 120 min restraint, as in Experiment 1. Blood samples were taken throughout the experiment from a contralateral catheter and the plasma analysed for AVP and cortisol content. The AVP infusion produced plasma levels of the hormone approximately twice those seen after 48 h dehydration in Experiment 1, but did not affect cortisol secretion. Furthermore, the cortisol response to oCRH, or restraint, was not enhanced by the AVP infusion. These results suggest that pituitary responsiveness to exogenous or endogenous CRH (restraint stress) may be enhanced in sheep by dehydration through a mechanism that does not involve an adrenal or pituitary action of circulating AVP.In vitro studies have shown that both CRH and AVP are able to stimulate the secretion of ACTH in preparations of pituitary cells (1,2). Similarly, ex¬ periments using anesthetized rats (3) and conscious sheep (4,5) have demonstrated that concentrations of CRH and AVP in pituitary portal blood increase in response to stress stimuli. The source of these neuropeptide hormones in the rat is the hypophysiotropic CRH neurons originating in the parvocellular part of the hypothalamic paraventricular nucleus (6) and similar neurosecretory pathways are probably also involved in the sheep (7)(8)(9).In addition to these endogenous systems control¬ ling ACTH release, it is well established that exo¬ genous CRH and AVP will stimulate the pituitary/ adrenocortical axis directly in man and synergistic effects of these hormones on ACTH release have also been demonstrated in sheep (10-13). Also, however, studies have been carried out in man where CRH has been given to individuals in whom the release of AVP has been experimentally stimu¬ lated. These investigations have shown that in¬ creasing neurohypophysial AVP secretion by hypertonic saline infusion (14-16), or dehydration (17), enhances the pituitary-adrenocortical re¬ sponse to CRH. Thus, the pituitary effects of exo¬ genous CRH seem to be facilitated under condi¬ tions where the neurosecretory activity of magnocel...

The mechanisms underlying the crossover of higher prevalence of respiratory diseases from boys to girls during adolescence RATIONALE: are not well understood. Adolescence starts with puberty, characterized by biological processes that result in somatic changes, which in turn may explain this crossover. Puberty is not a clearly understood series of events and there is no standard for its characterization. Epidemiological studies investigating how changes occurring during adolescence influence respiratory health need reliable and feasible puberty markers. A unique cohort for studying pubertal markers is the Isle of Wight (IOW) birth cohort. We use height and lung capacity at age 18 years as external criteria to describe developmental status and to evaluate the role of different pubertal event timings on respiratory health. Children (n=1456) followed up at age 18 years (n=1313; 90.2%) provided information on puberty, allergy status, lung function METHODS: tests, and height. Male puberty variables included age of onset of growth spurt, facial hair growth, body hair growth, voice deepening, and skin changes; girls provided age of onset of growth spurt, body hair growth, breast development, skin changes, and menarche. Linear regression analyses were used to test the association between age of onset of puberty and forced vital capacity (FVC).Of 1313 participating offspring, 653 were male and 660 were female. Pubertal ages were correlated among males and females.

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