Short CommunicationAdrenocorticotropic hormone in serial cerebrospinal fluid in man – Subject to acute regulation by the hypothalamic-pituitary-adrenocortical system?
Introduction
The utility of cerebrospinal fluid (CSF) peptide determinations in psychiatry has been investigated and discussed since several decades assuming that CSF concentrations reflect aspects of specific central nervous system functioning of the respective peptides and thus might provide information relevant to the pathophysiology of psychiatric illnesses (Berrettini et al., 1988). Adrenocorticotropic hormone (ACTH) from the anterior pituitary controls the release of cortisol from the adrenal cortex. Furthermore, ACTH is found in the mediobasal hypothalamus in rats, even after hypophysectomy (Krieger et al., 1977). ACTH-like immunoreactivity in fibers was also detected in thalamus, amygdala, the reticular formation and periaqueductal gray area (Watson et al., 1978), raising the possibility of neuroregulator functioning. Preclinical studies revealed a role of ACTH in motivation, attention, learning, memory, avoidance and sexual behavior (De Wied and Jolles, 1982).
Kleerekoper et al. (1972) first described the presence of ACTH in CSF in healthy humans in concentrations about the same as in plasma. Allen et al. (1974) confirmed these findings; however, they demonstrated no correlation between individual CSF and plasma concentrations and showed that the blood-CSF barrier is relatively impermeable to ACTH in man. Interestingly, both Nakao et al., 1980, Kling et al., 1991 reported significantly lower CSF ACTH levels in patients with Cushing's disease, while patients with major depression showed no significant CSF ACTH alterations versus healthy subjects (Kling et al., 1991). Also in patients with schizophrenia CSF levels of ACTH were not significantly different from those in the healthy control group. In contrast, underweight anorexic patients showed low CSF ACTH levels that returned to normal following weight recovery (Gwirtsman et al., 1989). In patients with dementia of the Alzheimer type significant reduction of CSF ACTH were repeatedly reported (Facchinetti et al., 1984, May et al., 1987, Suemaru et al., 1991). However, the biological underpinnings of these findings and their clinical relevance have not sufficiently been clarified.
So far no data on acute regulation of CSF ACTH in healthy humans or in subjects with psychiatric disorders are available. In a single case of a patient with Nelson syndrome (pituitary tumor following bilateral adrenalectomy for Cushing syndrome) response of CSF ACTH to intravenous administration of 100 mg hydrocortisone was measured (Hoffman et al., 1974): No suppression of elevated CSF ACTH was shown within 120 min and levels even increased. In an exploratory pilot investigation for an intended trial in patients suffering from major depression (other endocrine out-come parameters already published in Kellner et al. (2013) and in Wortmann et al. (2014)), we studied whether ACTH in CSF is acutely influenced by the hypothalamic-pituitary-adrenocortical system, using intravenous hydrocortisone or insulin hypoglycemia as challenges and assumed an inhibitory, resp. suppressive short-term effect.
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Subjects
Fifteen young men (mean age 23.3 years, range 21–27, mean body mass index 25.5 kg/m2, range 22.3–27.5) were studied. They were all non-smokers, did not take any prescription or non-prescription medication and were healthy according to medical history, physical examination, standard blood tests, electrocardiogram and urinary drug screen. None had a history of shift work or transcontinental flights during the past three months. Current and life-time psychiatric disorders were excluded as per the
Hydrocortisone and placebo conditions
Individual time concentration curves during hydrocortisone and placebo conditions are given in Fig. 1A/B, group time concentration curves are shown in Fig. 1C. Mean locations of CSF ACTH were 65.63±2.83 pg/ml in the hydrocortisone vs. 65.45±1.47 pg/ml in the placebo group. Respective AUC values of CSF ACTH were 2.18±12.06 vs. −15.64±7.16. As published previously (Kellner et al., 2013) underlying these experimental conditions CSF cortisol had shown a steady increase after the intravenous injection
Discussion
Our findings do not suggest acute inhibitory or stimulatory effects of HPA system changes on ACTH in serial CSF in healthy man. They are compatible with previous preclinical studies using different acute interventions: in non-human primates acute manipulations such as confinement stress, CRH and dexamethasone administration did not affect CSF ACTH, while peripheral HPA axis hormones showed significant alterations (Kalin et al., 1985a, Kalin et al., 1985b, Kalin, 1986). Further evidence of an
Acknowledgment
We thank Mrs. Iris Remmlinger-Marten and Mrs. Kirsten Huwald for their expert technical help and Dr. Cornelius Fuchs for friendly advice.
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