It has been obvious for at least 2 decades that there is a paradox that limits understanding of adrenocortical physiology. First, the hypothalamo-pituitary-adrenal (HPA) axis seems to be very sensitive to feedback inhibition by glucocorticoid hormones secreted from the adrenals. Second, stress, which causes ample adrenal steroid secretion, does not appear to inhibit subsequent activity in the HPA axis.Dallman and Jones worked on this problem in the 1970's (1). We showed that prolonged restraint stress of 90 min duration in rats did not inhibit the corticosterone (B) response to the subsequent mild stress of intraperitoneal injection. However, injection of adrenocorticotropin (ACTH) or B which mimicked the B response to restraint, did inhibit the B response to subsequent injection stress. We concluded that stress must induce a facilitatory effect on subsequent responses of the HPA axis to stress (1). Neither of us was satisfied with this entirely deductive approach, and in 1971, in collaboration with Vernikos, we filled a notebook with our unsuccessful attempts to show direct evidence for stressinduced facilitation, studying rats 1 to 2 days after bilateral adrenalectomy and bioassay of ACTH. The results were uninterpretable; we know now that this is because of the extreme disequilibrium in central components of the HPA axis that occurs during the first days after adrenalectomy with removal of the feedback signal.Recently, our laboratory has made considerable progress in making sense of the apparent paradox by reexamining all three aspects of this problem: the effect of chronic stress on function of the HPA axis (2-4); the sensitivity of the adrenocortical system of the intact rat to passive elevation in circulating B (5); and finding direct evidence for a facilitatory effect of stress on some aspects of subsequent activity in the HPA axis (6). The results of these studies have led us to a new understanding of the control of the HPA axis. It seems appropriate for the third Mortyn Jones Memorial Lecture to describe the highlights of these studies. The results of our work, and that of others, in rats, also appear to apply to man, and may be of utility to the understanding of adrenocortical function under normal circumstances as well as in disease . Some characteristics of the HPA axis and corticosteroid feedbackFour major characteristics of activity in the adrenocortical system are shown schematically in Fig. 1. Understanding of these, and the fact that they interact, is critical to the understanding of the whole HPA axis, the design of experiments, and the prediction of outcomes.There is a marked circadian rhythm in basal activity of the HPA axis which informs all other functional aspects of the system (Fig. 1~) . Mean 24 h basal plasma B levels in rats average -5 pg/dl (7). Basal activity during the trough of the rhythm results from constitutive secretory activity of the pituitary and adrenal components of the system without hypothalamic input; basal activity during the peak of the rhythm requires input from the h...

It has been shown that restricting food in lactating rats for the first 2 weeks postpartum at a level of 60% of the ad-libitum daily ration increases the length of lactational dioestrus by about 7 days but little is known about correlated changes in hormone levels. In the first experiment we report changes in LH, prolactin (PRL) and ACTH secretion in food-restricted and ad-libitum fed lactating rats at various stages of lactation. Our results demonstrate that food restriction during the first 2 weeks of lactation did not affect PRL or ACTH secretion, but decreased plasma LH levels despite comparable GnRH receptor density between food-restricted and ad-libitum fed females. In the second experiments we investigated a possible causal relationship between the increased secretion of progesterone seen in food-restricted females and the suppression of plasma LH levels, by determining the effects of bromocryptine treatment and ovariectomy on LH secretion in both ad-libitum fed and food-restricted lactating females. LH suppression in food-restricted lactating females was not affected by ovariectomy or bromocryptine treatment, although the latter treatment significantly increased GnRH receptor number. These data suggest that factors other than ovarian steroids, PRL or increased adrenocortical activity modulate LH secretion and the length of lactational dioestrus in food-restricted lactating females.

The significant increase in childhood obesity has become a particular concern, and it is recognized that the programming of obesity can arise from events occurring in the peri-conception period, prenatally and/or during the early postnatal period. In particular, high intake of dietary fat by the mother has long-term effects that are worse than once thought. This symposium was designed to outline some of the important consequences of maternal high-fat feeding during gestation and lactation, as well as exposure to a high-fat diet (HFD) after weaning, on the programming of homeostatic and hedonic regulation of food intake in both rodents and nonhuman primates (NHPs). Although a consensus emerges that high-fat feeding in early development increases the risk of developing obesity and the metabolic syndrome in adulthood, there is less agreement on the mechanisms through which this risk is conferred. Epigenetic modifications in specific gene promoters within the dopaminergic reward pathways and on the histone code will be discussed. We will also examine the effects of metabolic hormones such as leptin and ghrelin to shape the early development of hypothalamic projections that are critical to control food intake; finally, the importance of placental function in increasing obesity risk in NHP fetus from HFD mothers will be debated.

Activation of gonadotrophin-releasing hormone (GnRHJ pathways is a pivotal event in the process of sexual maturation, however the regulatory influences that precipitate this change and lead to the onset of puberty remain poorly understood. Recent studies indicate that neuropeptide Y (NPY) may participate in the regulation of luteinizing hormone secretion by modulating the pattern of GnRH secretion and by directly altering the pituitary responsiveness to GnRH stimulation. To determine whether NPY plays a role in puberty-associated changes in hypothalamic function, levels of NPY-like immunoreactivity (NPY-IR) were measured in a fragment of the hypothalamus encompassing the median eminence and medial portion of the arcuate nucleus (ME-AN), and also in the remainder of the hypothalamus from male rats of different ages. To identify changes in hypothaiamic NPY linked to the process of sexual development, the effect of delaying sexual maturation by daily afternoon administration of 100 μg melatonin (MT) from 20 to 40 days was investigated. In the hypothalamus and ME-AN, total NPY content increased progressively with age. Expressed as a concentration (fmol/μg extracted protein), peak values for the ME-AN (55.4 ± 7.0) were observed at 30 days of age followed by a decline to lower levels (30.2 ± 1.9) at 40 days. Daily afternoon administration of MT from 20 days of age resulted in significant increases (P<0.01) in the levels of NPY-IR in the ME-AN compared to control values at 30 and 40 days of age. MT was without effect on NPY-IR levels in the remainder of the hypothalamus. When MT was administered in the early morning, a procedure which does not delay sexual maturation, NPY-IR values for the ME-AN region were not different from control rats indicating that the MT-induced changes in NPY were related to the effects on sexual maturation. Using pituitary luteinizing hormone content and seminal vesicle weight as indices of sexual development, significant inverse correlation coefficients (P<0.001) between these parameters and the NPY concentration in the ME-AN were observed (r =-0.79 and -0.70, respectively). From published data it is not possible to conclude whether the main effects of NPY are exerted at the hypothalamic or pituitary level. However, the changes in the NPY content of the ME-AN observed during the onset of puberty, and the influence of MT on these changes, support assertions that NPY is involved in the regulation of sexual maturation.