Coordinate activation of the corticotropic axis by insulin-induced hypoglycemia: simultaneous estimates of β-endorphin, adrenocorticotropin and cortisol secretion and disappearance in normal men

Abstract

In the present study, we investigated the coordinate kinetic response of the corticotropic axis to the acute metabolic stress of hypoglycemia by applying deconvolution analysis to adrenocorticotropin (ACTH), β-endorphin and cortisol concentration-time series generated in seven normal men after intravenous administration of insulin. Hypoglycemic stress resulted in a 22-fold increase in the mean plasma concentration of ACTH to a maximum of 77±15 pmol/l, in conjunction with a 7.5-fold increase in the mean plasma β-endorphin concentration, the maximal value of which was 96±11 pmol/l. Plasma cortisol concentrations increased by 2.6-fold with a mean value of 734±14 nmol/l. Maximal plasma ACTH and β-endorphin concentrations were preceded by discrete secretory bursts with peak amplitudes of 10.5±2.7 and 10.6±2.0 pmol·I−1·min−1 (20-fold and ninefold increases compared to control), respectively. The mass of ACTH released was 114±20 pmol/l (3.4-fold increase), which corresponds to a total amount of 1.25 μg (50% of daily production and 0.5% of reported pituitary stores), assuming a distribution volume of 40 ml/kg. A total amount of 4.4±0.7 mg of cortisol was released after insulin-induced hypoglycemia, based on a mean cortisol secretory mass of 1088±137 nmol/l and a presumed 11.3-1 volume of distribution. Deconvolution-based estimates of the endogenous half-lives of ACTH, β-endorphin and cortisol were 17±0.6, 22±1.7 and 65±5.3 min, respectively. In summary, deconvolution analysis revealed a rapid coordinate activation of ACTH, β-endorphin and cortisol secretion after hypoglycemic stress, which correlated closely but temporally preceded increases in the respective plasma concentrations. Our inference that only a small fraction of pituitary ACTH content is released during hypoglycemic stress emphasizes the large reserve capability of the pituitary corticotropes. The percentage response of adrenal gland to the metabolic stress of hypoglycemia was of lesser magnitude, possibly owing to the rate-limiting properties of cortisol biosynthesis. We conclude that kinetic responses of the hypothalamic—pituitary—adrenal axis to hypoglycemic stress exhibit exquisite temporal synchrony and manifest a marked reserve capacity.

Intraoperative Adrenocorticotropin Levels During Transsphenoidal Surgery for Cushing’s Disease Do Not Predict Cure

“…Measuring a baseline sample before tumor resection might have eliminated this confounder. However, we would still expect a 50% decline in ACTH after 15 min of sampling, based on the half-life of ACTH (7). Because this degree of ACTH reduction was not achieved in all patients over the course of the sampling period, it is likely that normal corticotrophs provided an additional source of ACTH.…”

Rapid Glucocorticoid Receptor-Mediated Inhibition of Hypothalamic–Pituitary–Adrenal Ultradian Activity in Healthy Males

“…Deconvolution parameters comprise basal secretion (␤ 0 ), two half-lives (␣ 1 , ␣ 2 ), secretory-burst mass ( 0 , 1 ), random effects on burst mass ( A ), measurement error ( ), and a three-parameter flexible gamma secretory-burst waveform (␤ 1 , ␤ 2 , ␤ 3 ). For ACTH, the fast half-life was represented as 3.5 min, constituting 37% of the decay amplitude (Iranmanesh et al, 1993). The slow half-life was represented as an unknown variable between 14 and 35 min.…”

Sex differences in ACTH pulsatility following metyrapone blockade in patients with major depression

“…This has been shown for GnRH, the hormone system best characterized with regards to pulse frequency (Midgely and Jaffe, 1971;Knobil, 1990;Veldhuis et al, 1986). In the case of the hypothalamus-pituitary-adrenal axis, under intact glucocorticoid feedback cortisol bursts appear with a 60-90 minute frequency (Iranmanesh et al, 1993;Veldhuis et al, 2001). The negative feedback effects of cortisol may affect both the ultradian rhythm of these bursts as well as the circadian rhythms of ACTH secretion (Veldhuis et al, 2001).…”

“…The negative feedback effects of cortisol may affect both the ultradian rhythm of these bursts as well as the circadian rhythms of ACTH secretion (Veldhuis et al, 2001). Under basal conditions, approximately 18-25 pulses of ACTH or cortisol are seen over 24 hours (Iranmanesh et al, 1993;Young et al, 2001). …”