Corticotropin (ACTH) Research & Studies

Adrenocorticotropic hormone (ACTH) is secreted by the anterior pituitary and stimulates cortisol secretion from the adrenal cortex via the hypothalamic-pituitary-adrenal (HPA) axis. ACTH is clinically important because it regulates cortisol production, a hormone with broad physiologic effects, including suppression of inflammation, stimulation of metabolic activity, and elevation of blood glucose, which are critical components of the stress response. Dysregulation of ACTH activity is associated with disorders such as Cushing syndrome and primary adrenal insufficiency. A thorough understanding of ACTH physiology is essential for accurate diagnosis and management of disorders affecting cortisol regulation. Insight into ACTH dynamics enables clinicians to identify underlying pathologies, tailor therapeutic strategies, and anticipate complications arising from dysregulated cortisol levels.

It is a challenge to determine the origin of Cushing syndrome (CS), especially in patients with low-normal adrenocorticotropic hormone (ACTH) concentrations.

It is widely accepted that the classical dose of 250.0 microg ACTH (1-24) (tetracosactin) is clearly supra-maximal while 1.0 and 0.03 microg have been shown as the maximal and the lowest stimulatory ACTH doses for cortisol (F) secretion in normal young subjects. Testing with low ACTH dose would better evaluate adrenal sensitivity to corticotropin. The aims of the present study were: a) to clarify the adrenal sensitivity to ACTH in patients with different duration of corticotroph insufficiency by testing with low and very low tetracosactin doses; and b) to evaluate diagnostic implication regarding the ability of ACTH tests to distinguish patients with corticotroph insufficiency from normal subjects. In 24 hypopituitaric patients (HYPOPIT, 15 male and 9 female, age 22-50 yr, BMI: 22-26 kg/m2) with corticotrophin deficiency we studied the F, DHEA and aldosterone (A) responses to challenges with low ACTH doses (0.06 or 0.5 microg iv at 0 min) followed by 250 microg iv (at +60 min). The results in HYPOPIT were compared with those recorded in 12 normal controls (NS, 6 male and 6 female, age 22-34 yr, BMI: 20-25 kg/m2). Basal F and DHEA levels in HYPOPIT were lower than in NS, while A levels were similar in both groups. The F responses to ACTH in HYPOPIT were dose-independent and markedly lower (p < 0.0001) than in NS. After the 0.06 and 0.5 microg ACTH dose, 16% of HYPOPIT patients showed AF peak within the range of normal response. No HYPOPIT showed AF peak within the normal range after 250 microg ACTH. The DHEA responses to ACTH in HYPOPIT were dose-independent and markedly lower than in NS (p < 0.0001). Overlap between individual DHEA responses in HYPOPIT and NS was present after 0.06 microg and 0.5 microg but not after 250 microg tetracosactin. The A responses in HYPOPIT were dose-dependent and overlapped with those in NS. The adrenal responses to ACTH in HYPOPIT were not associated with the duration of the disease. In conclusion, the present study shows that the mean F and DHEA but not the A responses to ACTH (1-24) are markedly impaired in hypopituitaric patients with corticotroph insufficiency independently of the duration of the disease. The impaired F and DHEA response to ACTH is also independent of the dose, suggesting the existence of relatively enhanced sensitivity of the fasciculata and reticularis adrenal zone to ACTH but meantime remarkable impairment of the adrenal function due to corticotrophin deficiency. In the present study, testing with submaximal ACTH doses did not distinguish patients with secondary adrenal insufficiency from normal subjects.

Stimulation with corticotropin-releasing hormone (CRH) is one of principal tools for the differential diagnosis of ACTH-dependent Cushing's syndrome. However, different dosages and species of CRH may be employed; further, ACTH levels can be measured by radioimmunoassay (RIA) or immunoradiometric assay (IRMA). The aims of the present study were to perform a reappraisal of the diagnostic accuracy of the CRH test taking these different testing modalities into consideration and to study the correlation between basal ACTH and cortisol levels and their responses to CRH in patients with Cushing's disease.

It is known that glucagon administration elicits ACTH and cortisol responses in humans, although this effect takes place after intramuscular or subcutaneous but not after the intravenous route of administration. The mechanisms underlying this stimulatory effect on corticotroph secretion are unknown but they are unrelated to glucose variations and stress-mediated actions.

This study was undertaken to determine the short-loop negative feedback at the hypothalamic site after adrenalectomy (ADX), when the hypothalamic-pituitary axis was a different set-points. Rats were submitted to the experimental procedure 3 h and 1, 3 and 14 days after bilateral ADX or sham surgery under ether anesthesia by the dorsal approach. ADX rats were supplied with 1.5% NaCl. After decapitation, plasma samples were collected and corticosterone (B) and adrenocorticotrophic hormone (ACTH) concentrations were determined by radioimmunoassay (RIA). Using in vitro incubation of the median basal hypothalamus (MBH) fragment we studied the hypothalamic corticotrophin-releasing hormone (CRH) release under basal conditions and under the inhibitory effect of ACTH. Hypothalamic CRH secretion, determined by direct RIA, without extraction and reported as pg CRH/MBH per 1 h incubation, was inhibited by ACTH administration in a dose-dependent manner, as demonstrated by a significant negative correlation obtained by linear regression analysis of CRH secretion as a function of ACTH dose. However, the percentage of inhibition of CRH secretion was higher at 1 and 3 days than at 14 days after ADX. In conclusion, these in vitro studies demonstrated that ACTH suppressed basal CRH secretion in a dose-dependent manner, an effect compatible with a short-loop feedback mechanism. Furthermore, we demonstrated variable suppressibility of CRH secretion by ACTH at different times after ADX.

ACTH has been used extensively for treatment of massive infantile spasms (MIS) and other intractable seizures. The mechanisms by which ACTH exerts anticonvulsant effects are unknown. ACTH is a neuropeptide with both endocrine and neuromodulatory properties; its efficacy against MIS could derive from intrinsic anticonvulsant properties or from hormonal effects, either directly or through glucocorticoids. We tested ACTH activity against exogenous corticotropin-releasing hormone (CRH)-induced seizures in the infant rat model. CRH was administered into the cerebral ventricles of 85 infant rats aged 5-13 days. ACTH was used either 20-60 min before CRH administration or "chronically" (pretreatment with four doses of ACTH every 6 h, before CRH administration). In a separate group of rat pups, we measured plasma corticosterone to ascertain ACTH availability. Administration of CRH, an age-specific endogenous convulsant, resulted in a prolonged series of seizures after 2- to 55-min latency. There was no difference in latency between controls (9.5 +/- 1.2 min) and ACTH-treated rats (12.4 +/- 2.8 min for combined acute and chronic groups). CRH-induced seizure duration (88.2 +/- 9 vs. 74.7 +/- 9.4 min) and severity of seizures was also unchanged by ACTH treatment. ACTH reached the circulation and caused significant increase in plasma glucocorticoids. ACTH does not block the convulsant action of exogenous CRH in infant rats. An alternative mechanism for the anticonvulsant effect of ACTH may be suppression of synthesis and secretion of an endogenous convulsant, i.e., CRH.

ACTH is secreted by the pituitary following processing of larger molecular weight precursors, proopiomelanocortin and pro-ACTH. Ectopic ACTH syndrome refers to the secretion of ACTH by non-pituitary tumours, but the predominant circulating form of proopiomelanocortin-related peptides remains unclear.

The most common ectopic production of a pituitary hormone is the one of ACTH leading to Cushing's syndrome. Ectopic ACTH-hypersecretion is the cause of Cushing's syndrome in 10-15% of all cases. The ACTH-secreting tumours are often oat-cell carcinomas of the lung, less frequently pancreatic cancers, hypernephromas, or C-cell carcinomas of the thyroid. Some of these tumours may be benign or semi-benign as the rare carcinoid tumours and cause great problems in the differential diagnosis of ACTH-dependent hypercortisolism. Out of 173 of our patients with Cushing's syndrome observed in the last 12 years 21 were caused by ectopic ACTH-production. Of these 21 patients 13 have a small cell carcinoma of the lung. The ectopic ACTH-syndrome often has typical clinical features caused by the levels of ACTH and cortisol leading to hypocalcemic alkalosis with muscle weakness and wasting, carbohydrate intolerance, and hypertension with oedema. The survival time in many of these patients is not long enough to allow them to develop typical signs of Cushing's syndrome though they are often highly pigmented. These patients are easily diagnosed. However, patients with small tumours which do not cause very elevated ACTH-levels and who have the more typical clinical signs of full-blown Cushing's syndrome are difficult to recognize. For the differential diagnosis of ACTH-dependent Cushing's syndrome the corticotropin-releasing hormone (CRH) stimulation test and dexamethasone suppression test with high doses are helpful. In special cases the venous sampling procedure for ACTH-measurements is necessary, also CT or NMR is helpful. Ectopic CRH-production is a rare cause of ACTH-dependent Cushing's syndrome. Patients with ectopic CRH-production and consecutive ACTH-hypersecretion from the pituitary have not been studied extensively. There are especially no well documented results of the use of the CRH-stimulation test in vivo in this group of patients with Cushing's syndrome. On the other hand, in the documented cases, not only CRH-, but also ACTH-production was found in the tumours. So far, this rare cause of ACTH-dependent Cushing's syndrome has to be excluded or confirmed by the measurement of endogenous CRH-levels. But until now we have not been able to detect one single case of ectopic CRH-production using a sensitive homologous CRH-radioimmunoassay over a period of more than 8 years in which we have seen nearly 120 newly diagnosed patients with ACTH-dependent Cushing's syndrome. Only in the plasma and tumour tissue of two patients of other groups have we found high CRH-levels.

The effects of sc injections (at 1500 h) of increasing amounts of synthetic human ACTH-(1-39) (1.25-30 micrograms) on plasma ACTH, cortisol, aldosterone, and 18-hydroxycorticosterone were compared with those of iv injections of 30 and 100 micrograms synthetic human CRH in nine normal men. Five micrograms of ACTH, sc, was the lowest dose that significantly increased plasma levels of the three steroids. CRH (30 micrograms, iv) increased plasma cortisol and 18-hydroxycorticosterone, but not aldosterone, while 100 micrograms CRH also raised aldosterone secretion. The dose-response curve (peak plasma ACTH level vs. maximum increment of plasma cortisol within the first hour) was initially very steep. Plasma ACTH levels between 50 and 60 ng/L (11-13 pmol/L) stimulated cortisol to almost 80% of the maximal increment obtained with plasma ACTH levels above 300 ng/L (greater than 66 pmol/L). This dose-response relationship is similar to that found in clinical tests of the pituitary-adrenal axis (insulin test, metyrapone test). The effects of plasma ACTH released by CRH on cortisol secretion were not significantly different from those of injected ACTH. Our results argue against the hypothesis that the effect of CRH on steroid secretion is mediated or modulated by POMC-derived peptides other than ACTH.

Human peripheral leukocytes infected by virus or treated with endotoxin will, like unstimulated mouse spleen macrophages, synthesize immunoreactive corticotrophin (ir-ACTH) and endorphins. The ir-ACTH produced appears to be identical with authentic ACTH, while enough of the material has been produced in hypophysectomized mice infected with virus to demonstrate a steroidogenic response. Because the production of ACTH by in vivo pituitary cells and by leukocytes is suppressed by dexamethasone both in vitro and in vitro, suggesting that the production of ACTH and endorphins by leukocytes is indeed controlled, we have investigated the effects of corticotropin releasing-factor (CRF), which is known to regulate the pituitary production of both ACTH and beta-endorphin. We now report that the production of ACTH and endorphins by leukocytes is indeed induced by synthetic CRF and, in turn, suppressed by dexamethasone, suggesting that, as in pituitary cells, the proopiomelanocortin (POMC) gene may be expressed and similarly controlled in leukocytes.