High Plasma ACTH Research Articles

Ontogeny of Plasma, CSF and Brainstem ACTH in Piglets: Effects of Hypoxia and Anesthesia

This study was designed to assess the postnatal maturation of adrenocorticotropin (ACTH) levels in piglets under basal conditions and in response to single, acute stressors. ACTH levels were measured by radioimmunoassay in plasma, cerebrospinal fluid (CSF) and in a dorsal medullary slice containing the nucleus tractus solitarii (dmscNTS) of young and older piglets (1.5-6 and 35-43 days old, respectively) under the following experimental conditions: (1) normoxia (both groups); (2) hypoxia, 10% O2/N2 for greater than or equal to 30 min (both groups); (3) sham anesthesia, i.p. saline in normoxia (young group); (4) anesthesia, 25 mg/kg i.p. pentobarbital in normoxia (young group), and (5) anesthesia combined with hypoxia (young group). During normoxia, ACTH levels in young, as compared to older piglets, were higher in CSF (p less than 0.01) and plasma (0.05 less than p less than 0.10) and not different in dmscNTS. Hypoxia produced no ACTH changes in CSF, increased ACTH in plasma of young (p = 0.03) and older piglets (p = 0.09), and decreased ACTH in dmscNTS of older (p = 0.01) and young piglets (p = 0.07). As compared to sham anesthesia, anesthesia did not alter any ACTH levels. Combined hypoxia and anesthesia increased ACTH levels in plasma when compared to normoxia (p less than 0.05), sham anesthesia (p less than 0.05) or anesthesia alone (p less than 0.05), but not when compared to hypoxia alone. We conclude that neonatal swine have high basal ACTH levels and mount significant plasma ACTH responses to a single, acute hypoxic stressor. The presence of ACTH in the region of the NTS supports its possible role as a neuromodulator in the brain.

Long-term salt loading impairs pituitary responsiveness to ACTH secretagogues and stress in rats

Male Wistar rats were allowed to drink tap water ad lib (W), 2% saline (S) or 2% saline containing dexamethasone (S+D, 1 mg/l) for 7 days. On the 8th day rats were subjected to a 3-min ether stress. Plasma ACTH, corticosterone and prolactin concentrations were determined before and after ether exposure. Prestress concentrations of plasma ACTH were low and did not vary among the three groups. In response to ether stress W rats exhibited twice as high plasma ACTH concentrations as did S rats. Rats of the S+D group exhibited a small but statistically significant ACTH response. Plasma corticosterone concentration in S rats was increased while in S+D rats was significantly decreased under resting conditions compared to that in W rats. Ether stress caused large increases in plasma corticosterone concentrations in W and S rats while a small but statistically significant increase was observed in S+D rats. Prolactin responses to ether were smaller in groups S and S+D than in group W. To test whether the decreased ACTH response to ether exposure was a result of a decreased sensitivity of corticotrope cells to corticotropin releasing factor (CRF)-41 or arginine vasopressin (AVP), adenohypophysial fragments from W, S and S+D rats were incubated in the presence of different doses of CRF-41 or AVP. Pituitary fragments obtained from W rats secreted larger amounts of ACTH than did pituitaries from S rats in response to either CRF-41 or AVP. CRF-41 caused only a slight increase and AVP caused no significant increase in ACTH release from pituitary fragments obtained from S+D rats. These results indicate that prolonged osmotic stimulation impairs ACTH and prolactin but not corticosterone responses to ether stress. We suggest that the decreased sensitivity of corticotropes to CRF-41 and AVP is a possible mechanism that could account for the deficient ACTH response to ether stress in S rats.

Transsphenoidal Pituitary Surgery in the Treatment of Patients with Cushing’s Disease

Transsphenoidal adenomectomy is the treatment of choice for patients with Cushing's disease. The combination of high serum and urinary cortisol and high plasma ACTH point to a nonadrenal source for Cushing's syndrome. It is important to rule out an ectopic source of ACTH production. Imaging of the sella with MRI and CT and sampling petrosal sinus blood for ACTH measurement should allow differentiation between the two conditions. For younger patients, every effort should be made to preserve the normal gland. If in the younger patient the adenoma cannot be clearly demonstrated, it is appropriate to remove the central portion of the gland, as advocated by Hardy. Should hypercortisolism persist, radiation therapy to the sella should be considered before attempting total hypophysectomy. In the woman past childbearing age, a total hypophysectomy can readily be considered if a sharply demarcated adenoma is not found. In fact, we counsel our older patients before operation that a total hypophysectomy is a possibility. For the patient with an aggressive tumor that is not cured by pituitary operation, radiation therapy must be considered. If it is not possible to wait for the therapeutic effect of radiation, adrenal suppression with aminoglutethimide, metyrapone, or ketoconazole is indicated. Adrenalectomy may be considered.

Partially compensated hypoadrenalism presenting with persistent skin pigmentation

A 33-year-old female presented in 1966 with striking pigmentation, typical of Addison's disease, and amenorrhea. Endocrine assessment then showed normal basal serum cortisol and urinary hydroxysteroid levels, but serum cortisol did not respond to stimulation with either exogenous ACTH or lysine vasopressin. Steroid replacement treatment was started. Treatment was discontinued by the patient on her own initiative and after some yr she was lost to follow-up. Reassessment in 1986 showed a pigmented patient who had continued in good health. She had a normal basal serum cortisol level with circadian variation. Plasma ACTH levels were high but showed diurnal rhythmicity and suppressed incompletely with 2 mg or 8 mg of dexamethasone/24 h. Plasma aldosterone levels were normal and showed appropriate postural changes, but plasma renin levels were high. This patient has an immunological profile of autoimmune disease with positive adrenal, thyroid microsomal and gastric parietal cell antibodies with a history of a premature menopause which may also be of autoimmune origin. She has been seen over a 20-yr period and despite her appearance still has no biochemical evidence of glucocorticoid or mineralocorticoid deficiency. It is suggested that the patient had compensated hypoadrenalism, with serum cortisol levels maintained in the normal range by high plasma ACTH levels and serum aldosterone levels maintained by high renin levels. The long term result of the high ACTH levels was increased skin pigmentation.

Cushing's Disease Treated by Total Adrenalectomy: Long-term Observations of 43 Patients

Forty-three patients were treated by total adrenalectomy for pituitary-dependent Cushing's disease. The median period of observation was 10 years (range one to 20 years). Thirty-eight patients (88 per cent) had rapid and lasting remissions. Of the 38 in remission, 21 became pigmented but without pituitary enlargement, 11 became pigmented with evidence of further pituitary expansion (Nelson's syndrome) and six neither became pigmented nor showed pituitary expansion. Pituitary expansion was associated with high plasma ACTH values, and treatment of pituitary tumours by surgery or radiotherapy gave poor results. However, when compared with alternative methods of treatment, total adrenalectomy for Cushing's disease is still satisfactory for many patients, despite advances in pituitary surgery, and has advantages over 'medical adrenalectomy' with drugs.

Combined 17a- and 18-Hydroxylase Deficiency Associated with Complete Male Pseudohermaphroditism and Hypoaldosteronism*

A 15-year-old phenotypic female with XY genotype presented with male pseudohermaphroditism, gynecomastia, hypokalemic alkalosis, and hypertension. Being raised as a girl, the patient failed to menstruate and developed no sexual hair. At laparatomy no Müllerian structures were found but testes were removed which showed histologically atrophy of seminiferous tubules and abundant Leydig cells. Deoxycorticosterone (2.0 mg/24 h) and corticosterone (117 mg/24 h) secretion rates were extremely elevated, whereas those of aldosterone (17 micrograms/24 h), deoxycortisol (22 micrograms/24 h), and cortisol (23 micrograms/24 h) were almost unmeasurable. The excretion rates of 18-OH-deoxycorticosterone (less than 0.25 microgram/24 h) and 18-OH-corticosterone (3.0 microgram/24 h) were subnormal in spite of high plasma ACTH levels (200 pg/ml), and deoxycorticosterone (32.2 micrograms/24 h) and corticosterone (269 micrograms/24 h) excess. Gonadotropins were elevated. Deficient 17 alpha-hydroxylation was suspected because of: 1) low levels of 17 alpha-OH-progesterone; 2) diminished excretion rates of both 17 alpha-OH-progesterone and pregnanetriol; and 3) reduced concentrations of dehydroepiandrosterone, androstenedione, and testosterone in testicular tissue. We conclude that this male pseudohermaphrodite with complete female phenotype had 17 alpha-hydroxylase deficiency. The enzymatic defect was linked with an associated 18-hydroxylase deficiency.

ACTH release during passive avoidance behavior

ACTH was measured by radioimmunoassay during learning and retention of a passive avoidance response. Electric footshock, used during the learning trial, appeared to be a weaker stimulus for ACTH release than was the retention test. Moreover high latency scores during retention were associated with high plasma ACTH levels, whereas shorter latencies were associated with lower levels. The results indicate that psychological mechanisms organizing behavioral coping are important in the response of the pituitary-adrenocortical system to stimuli which are related to a previous adversive experience.

Evidence that the Pars Intermedia and Pars Nervosa of the Pituitary do not Secrete Functionally Significant Quantities of ACTH

We have compared the capacity to secrete ACTH in response to stress or adrenalectomy in control rats and in those with total hypophysectomy (H), adenohypophysectomy (AH) with preservation of the intermediate and the neural lobes, neurohypophysectomy (NH) with removal of the pars nervosa and all or part of the pars intermedia with preservation of the adenohypophysis, or incomplete adenohypophysectomy (IAH) in which a portion of the adenohypophysis and all of the pars intermedia and pars nervosa were left intact. Plasma ACTH measured with an N-terminal antibody that reacts on an equimolar basis with ACTH and alpha-MSH but not with other known pituitary hormones was elevated after ether or tourniquet stress in all except the H group. Three weeks after adrenalectomy there was an elevated basal plasma ACTH and an augmented ACTH response to stress in intact and IAH but not in AH rats. When a more specific alpha11-24 ACTH antibody was used there was a high plasma ACTH after ether stress in the IAH, NH, and intact groups but not in the AH or H groups. Adrenal weight and plasma corticosterone after tourniquet or ether stress were indistinguishable in the AH and H groups and were much higher and nearly identical in the intact, NH and IAH groups. We conclude that only the adenohypophysis secretes functionally significant amounts of ACTH. Plasma ACTH detected by the N-terminal antibody in the AH group is probably related to alpha-MSH or similar peptides and is incapable of maintaining adrenal weight or stimulating corticosterone secretion.

IMMUNOREACTIVE ACTH AND CORTISOL PLASMA LEVELS DURING PREGNANCY. DETECTION AND PARTIAL PURIFICATION OF CORTICOTROPHIN‐LIKE PLACENTAL HORMONE: THE HUMAN CHORIONIC CORTICOTROPIN (HCC)

The high plasma cortisol and ACTH levels present in pregnant women as well as the non-parrallelism of their plasma extract dilution curves in comparison with the standard curve in the ACTH radioimmunoassay, are evidence for the presence of an ACTH-like substance during pregnancy which would interfere with the assay. Placental extracts were obtained by acid-acetone extraction, followed by partial purification with oxycellulose and by extraction with porous glass powder. A substance was detected which partially cross-reacted with synthetic human ACTH in the radioimmunoassay and which showed biological activity using the assay procedure described by Liscomb & Nelson. The data sustain the existence of an ACTH-like placental hormone: human chorionic corticotrophin (HCC).

PLASMA ADRENOCORTICOTROPIC HORMONE IN NORMAL SUBJECTS AND PATIENTS WITH ENDOCRINE DISORDERS; WITH OBSERVATIONS ON THE EFFECT OF ADRENAL STEROIDS AND ADRENAL 11β-HYDROXYLASE INHIBITORS

Plasma ACTH was determined according to a modification of Lipscomb and Nelson's method in 10 normal subjects and 17 patients with various endocrine disorders.The effect of the administration of glucocorticoids, aldosterone and adrenal 11β-hydroxylase inhibitors on plasma ACTH was also studied.1. Plasma ACTH was not detected in 5 ml of fresh plasma in 10 normal subjects, and no measurable level of plasma ACTH was found in patients with congenital adrenal hyperplasia, Cushing's syndrome and acromegaly.Plasma from 5 Addisonian patients exhibited high ACTH activity.2. The high plasma ACTH level in Addisonian patients was suppressed to undetectable levels by replacement therapy with glucocorticoids.The rapid suppressing activity of glucocorticoid was more directly demonstrated by the intravenous infusion of cortisol.The administration of d-aldosterone acetate also suppressed plasma ACTH to some extent.3.The oral administration of adrenal llβ-hydroxylase inhibitors, SU-4885 and SU-8874, caused an increase in plasma ACTH levels in 2 normal subjects, I patient with Conn's syndrome and 1 patient with Cushing's syndrome, but failed to cause any demonstrable increase in l normal subject, l patient with panhypopituitarism and l patient with Cushing's syndrome.