We have shown that ADX and HYPOX rats exhibit a markedly increased sensitivity to the lethal effects of IL-1-beta and LPS compared to sham controls with an intact HPAA. These results indicated that the reports of lethal effects of cytokines and LPS which generates cytokines in mice with a compromised HPAA were not idiosyncratic or specific to mice but represented a general response that would have been expected in any organism with a compromised HPAA. We further demonstrated that protection against lethal effects due to IL-1-beta or LPS could be produced by treating ADX rats with glucocorticoid in a quantity estimated to be equivalent to corticosterone secretion provoked during stress. In contrast, we found that acutely stalk-sectioned rats with pituitaries disconnected from hypothalamic regulation did not show a markedly increased susceptibility to lethal effects of LPS as did ADX or HYPOX rats. Although a minority of stalk-sectioned rats were killed by LPS, the majority of rats were protected from lethal actions of LPS. This response suggested that an intact pituitary-adrenal axis without the normal hypothalamic control could still provide significant protection presumably due to generation of cytokines which stimulated the pituitary over several hours. The results from our lethality studies clearly underscore the importance of activating the stress axis and increasing glucocorticoid secretion to protect against potentially lethal effects of cytokines that can be induced by immune, infectious, or inflammatory stimuli. Cytokine-stimulated effects can initially result in beneficial actions to the host by promoting immune/inflammatory responses that are protective in nature and help defend against a variety of invading stimuli (infectious, immune, inflammatory, traumatic, neoplastic). Normally the HPAA responds to cytokine stimulation by ultimately increasing glucocorticoid secretion in order to counterregulate cytokine actions, modulate the host response, and protect the host from excessively catabolic effects of unregulated cytokine generation and actions. For many years, clinicians have recognized that patients with deficient glucocorticoid secretion (e.g., Addison's disease or pituitary ACTH deficiency) require increased glucocorticoid replacement during episodes of fever, infection, or inflammatory stress. However, the reasons why stress-equivalent glucocorticoid replacement were required were not entirely clear. Now, we understand that glucocorticoids are critically important for protecting the host against its own defense mechanisms so that the stimulation of cytokines can facilitate a protective response against an invading insult without also killing the host.

Abstract. Parkinson's disease is an age-related degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech, as well as other functions. Symptoms can include tremor, stiffness, slowness of movement, and impaired balance. An estimated four million people worldwide suffer from the disease, which usually affects people over the age of 60. Presently, there is no precedent for approving any drug as having a modifying effect (i.e., slowing or delaying) for disease progression of Parkinson's disease. Clinical trial designs such as delayed start and withdrawal are being proposed to discern symptomatic and protective effects. The current work focused on understanding the features of delayed start design using prior knowledge from published and data submitted to US Food and Drug Administration (US FDA) as part of drug approval or protocol evaluation. Clinical trial simulations were conducted to evaluate the false-positive rate, power under a new statistical analysis methodology, and various scenarios leading to patient discontinuations from clinical trials. The outcome of this work is part of the ongoing discussion between the US FDA and the pharmaceutical industry on the standards required for demonstrating disease-modifying effect using delayed start design.

The corticotropin-releasing hormone (CRH) gene contains a perfect palindromic motif in its promoter region that allows binding of the cyclic adenosine monophosphate response element binding protein, CREB. Since previous studies suggest that the CRH gene can be activated by cyclic adenosine mono-phosphate, we determined whether stress and feedback inhibition by glucocorticoids in CRH-producing neurons in the hypothalamic paraventricular nucleus could be mediated by changes in the phosphorylation of CREB. Antisera to CREB and phospho-CREB Ser¹³³ (PCREB), the active phosphorylated form of CREB, were used for immunohistochemical studies on rat brain. In nonstressed animals CREB immunostaining was confined to the nucleus of cells ubiquitously throughout the hypothalamus, while PCREB immunostaining was discretely localized in magnocellular neurons and only a few cells in the medial parvocellular subdivision of the paraventricular nucleus. Ether and handling stress markedly increased the number of PCREB-labeled neurons in the parvocellular subdivision. Double immunolabeling with CRH antiserum revealed that the majority of hypophysiotropic CRH neurons in stressed animals expressed PCREB. Following systemic administration of dexamethasone (100 µg/day) for 2.5 days, PCREB immunostaining was completely abolished in parvocellular CRH-producing neurons after ether or handling stress. Dexamethasone had no apparent effect on CREB immunostaining. These results demonstrate that glucocorticoids suppress CREB phosphorylation in hypophysiotropic CRH neurons and suggest that prevention of CREB phosphorylation is a possible mechanism for feedback inhibition of CRH biosynthesis by glucocorticoids.

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Following presentation and diagnosis, microprolactinomas usually follow a benign course and rarely progress to macroprolactinomas. However, clinically significant enlargement of prolactinomas during pregnancy, presumably related to estrogen stimulation, has been reported. This report describes a patient with amenorrhea and hyperprolactinemia and a microadenoma by computed tomography scan who developed a macroprolactinoma within 10 months after being placed on estrogen therapy. We propose that exogenous estrogen administration in this patient most likely promoted growth from a microprolactinoma to a macroprolactinoma. This case emphasizes the primary role of dopaminergic agonist therapy in the management of pathological hyperprolactinemia and suggests that estrogen therapy should not be casually given to patients with known prolactinomas to avoid the possibility of promoting tumor growth. A correlate of this approach is that caution regarding estrogen therapy should also be exercised in patients with idiopathic hyperprolactinemia who might have an occult microprolactinoma which could grow following estrogen stimulation. If estrogen treatment is deemed necessary, dopaminergic agonist therapy should also be used prophylactically to prevent potential tumor growth due to estrogen. The patient should then be carefully monitored with periodic serum PRLs and for the development of clinical manifestations suggesting pituitary growth. An imaging study should be performed when there is a significant increase in serum PRL or the development of new clinical manifestations.