Domenico Bochicchio

Failure of somatostatin and octreotide to acutely affect the hypothalamic-pituitary-adrenal function in patients with corticotropin hypersecretion

Although somatostatin inhibits a variety of pituitary and non-pituitary hormones, not univocal data on its effects on ACTH release have been reported so far. In this study we investigated the effects of somatostatin or octreotide on ACTH levels of patients with corticotropin hypersecretion: 7 patients with Addison’s disease, 2 patients previously adrenalectomized for Cushing’s disease, 4 patients with Cushing’s disease and 3 patients with ectopic ACTH syndrome. Plasma ACTH and Cortisol levels were determined after somatostatin (500μg over 60 min) infusion or octreotide (100μg sc) injection. In 5 other patients with Cushing’s disease ACTH and Cortisol responses to CRH (1 μ/kg iv) were evaluated in basal conditions and after octreotide acute administration. In no patients with Addison’s disease any inhibitory influence of somatostatin (Δ % = −21, −25) or octreotide (Δ % = −38 ± 12 vs −39 ± 12 after saline) on plasma ACTH was found. Somatostatin did not significantly inhibit plasma ACTH in the two patients previously adrenalectomized for Cushing’s disease and in 3 patients with Cushing’s syndrome; in other 4 patients with Cushing’s syndrome octreotide did not affect plasma ACTH levels. In 5 patients with Cushing’s disease the plasma ACTH and Cortisol responses to CRH were similar both before (ACTH from 9.9 ± 1.7 pmol/L to 19.4 ± 6.1 pmol/L; Cortisol from 496 ± 43.9 nmol/L to 923 ± 355 nmol/L) and after octreotide injection (ACTH from 8.8 ± 2.4 pmol/L to 19.1 ± 8.2 pmol/L; Cortisol from 510 ± 54.6 nmol/L to 735 ± 220 nmol/L). In conclusion, the acute administration of somatostatin or octreotide is not able to modify ACTH levels in patients with corticotropin hypersecretion either due to hypo-cortisolemic state or consequent to ACTH-secret-ing pituitary or ectopic tumors; moreover, octreotide does not affect the pituitary-adrenal responsiveness to CRH in patients with Cushing’s disease.

The silent corticotropinoma: is clinical diagnosis possible?

Up to now, the diagnosis of silent corticotropin cell pituitary adenomas has been made only on histopathological basis. In this paper we describe 6 women affected with pituitary adenomas, without evident clinical features of hypercortisolism, in whom retrospective data suggested the possibility of clinically diagnosing silent corticotropinomas in vivo. In all patients basal ACTH and Cortisol levels were normal, and the low-dose dexamethasone test constantly suppressed serum Cortisol and urinary 17-hydroxycorti-costeroid levels. The CRH and/or lysine-vasopressin tests, performed in five patients, always induced exaggerated ACTH/cortisol rises. In three cases the response to the opiate agonist loperamide was assessed and no inhibition of ACTH/cortisol levels was found. All patients underwent pituitary surgery. In five cases evidence of corticotropinoma was obtained by immunohistochemistry or immunofluorescence studies; moreover, in one adenoma ACTH was secreted into the culture medium, and in another one CRH and arginine-vasopressin induced a marked intracellular [Ca++] rise. Electron microscopy study of the adenoma, removed from three patients, showed the presence of adenomatous corticotropin cells. Finally, in another woman no hormonal abnormalities were initially observed and she was operated for a “nonfunctioning” pituitary adenoma, but four years later an overt Cushing’s disease appeared, suggesting that a silent corticotropinoma subsequently became functional, although the formation of a different adenoma cannot be excluded. In conclusion, the occurrence of ACTH/cortisol hyperresponsiveness to CRH and/or lysine-vasopressin and the lack of suppression of ACTH/cortisol secretion to opioid agonists in patients with apparently “nonfunctioning” pituitary tumors might allow the in vivo recognition of silent corticotropinomas.

Effects of the opiate agonist loperamide on pituitary-adrenal function in patients with suspected hypercortisolism

In the present work the possible use of loperamide, an opiate agonist, in the dynamic evaluation of patients with suspected hypercortisolism was investigated. The effects of loperamide on plasma ACTH and Cortisol levels were evaluated in normal subjects and in 58 patients with suspected Cushing’s syndrome. The results were compared to those obtained after the overnight dexamethasone suppression test. In normal subjects plasma ACTH and Cortisol levels were significantly (p < 0.005) suppressed by both loperamide (16 mg po) and dexamethasone (1 mg po). In 17 patients, in whom the diagnosis of Cushing’s syndrome was confirmed by subsequent investigations, neither loperamide or dexamethasone inhibited Cortisol (from a baseline of 606 ± 55 nmol/L) to a nadir of 502 ± 43 nmol/L and 539 ± 50 nmol/L, respectively) and ACTH concentration (from a basal level of 70.1 +11.8 pg/ml to a nadir of 46.0 ± 8.6 pg/ml and 54.3 ± 7.5 pg/ml, respectively). In 34 patients, in whom the suspect of hypercortisolism was ruled out, either loperamide or dexamethasone suppressed the pituitary-adrenal axis: Cortisol and ACTH levels significantly fell from 417 ± 24 nmol/L and 28.3 ± 3.5 pg/ml to 60 ± 6 nmol/L and 14.4 ± 1.4 pg/ml after loperamide and to 26 ± 4 nmol and 16.4 ± 1.7 pg/ml after dexamethasone. In 7 patients discordant responses were observed. In 3 patients treated with antiepileptic drugs ACTH and Cortisol levels were inhibited by loperamide, but not by dexamethasone. In 4 other patients a normal suppression was induced by dexamethasone, but not by loperamide: in 2 cases the suspected hypercortisolism was definitely ruled out while in the other two no definitive diagnosis could be established. In these series of patients, the loperamide test equals the 1 mg dexamethasone suppression test in terms of sensitivity, specificity, diagnostic accuracy and predictive value. In conclusion: i) Loperamide administration is practical and reliable in testing the pituitary-adrenal function; ii) The procedure needs only three and half h to be completed and thus it is suitable and compliant to outpatients; iii) Loperamide might be useful in patients in some conditions (drug interference), in which the low-dose dexamethasone test has some limitations.

Effect of Thyrotropin-Releasing Hormone on Growth Hormone Release in Normal Subjects Pretreated with Human Pancreatic Growth Hormone-Releasing Factor 1–44 Pulsatile Administration

Growth hormone (GH) increase after thyrotropin-releasing hormone (TRH) has been documented in many pathological conditions. In order to evaluate whether exposure to growth hormone-releasing factor (GRF) might contribute to this effect in normal subjects, we studied GH responses to placebo, TRH, GRF and GRF plus TRH either in basal condition or after GRF administration. Ten subjects received placebo, TRH, GRF and GRF plus TRH on four separate occasions. GRF induced a clear rise in plasma GH, statistically different from those obtained after placebo or TRH (p less than 0.01). TRH was completely ineffective in both stimulating GH release and amplifying the secretory GH response to GRF. Twenty subjects, subdivided in four groups, received 3 consecutive intravenous GRF boli at two-hour intervals. Two hours later they were given a fourth stimulus: 5 had another 25 micrograms GRF i.v., 5 had 200 micrograms TRH i.v., 5 were tested with simultaneous 25 micrograms GRF and 200 micrograms TRH i.v. injection, and 5 with 1 ml saline. GH secretory responses were quantitated by determining the net incremental area under the curve (nAUC) over 60 min after the administration of each stimulus. The pattern of GH secretion after 1-3 GRF boli was not statistically different among the four groups. Plasma GH nAUC was higher after the first GRF injection than after the following ones (p less than 0.01). The administration of a fourth GRF bolus also caused a GH increase which was significantly smaller than that after the first one (p less than 0.01), but greater than that after placebo (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of sodium-valproate administration on plasma ACTH levels in patients with ACTH hypersecretion

The effects of the acute administration of sodium-valproate (400 mg po) on plasma ACTH levels were studied in 4 patients with Cushing’s disease, 1 with Nelson’s syndrome and in 3 with Addison’s disease. No significant reduction of corticotropin concentration was observed, as compared to saline infusion. These data do not favor the hypothesis of an inhibitory role of sodium-valproate on ACTH secretion in such patients.

Effects of angiotensin II blockade on the responses of the pituitary-adrenal axis to corticotropin-releasing factor in humans.

We investigated the possibility that angiotensin II (ANGII) augments the sensitivity of the pituitary to corticotropin releasing factor (CRF) by com. paring, in patients with essential hypertension, the responses of plasma adrenocorticotropic hormone (ACTH), cortisol, aldosterone, and renin activity to a bolus injection of either 0.5 or 1.0 μg/kg of synthetic ovine CRF in control conditions and after chronic treat. ment with the converting enzyme inhibitor captopril tc block the formation of ANGII: the effects of CRF were examined up to 4 h after its administration. In contro studies, we found that the two doses of CRF induced simliar increments in ACTH and cortisol, the levels of which remained elevated throughout the studies: these changes were associated with increments in plasma aldosterone that were dose dependent, less pronounced, and of shorter duration and with a slight decrease in plasma renin activity. Captopril treatment increased basal plasma renin activity and lowered plasma aldosterone while leaving basal ACTH and cortisol unchanged. During converting enzyme inhibition, the responses of ACTH and cortisol to CRF were similar to those observed in control studies, whereas the changes in plasma aldosterone and plasma renin activity were, respectively, smaller and greater. From these results, it appears that during ANGII blockade the sensitivity of ACTH to CRF stimulation is unaffected, whereas that of the adrenals to ACTH is selectively reduced at the level of the zona glomerulosa.

Value of buserelin testing in the evaluation of hirsute women.

It has been recently reported that many hirsute women are affected with functional ovarian hyperandrogenism (FOH) - a term that encompasses the heterogeneous polycystic ovary syndrome - and show an abnormal ovarian steroidogenic response to gonadotropin-releasing hormone (Gn-RH) agonists. The aims of the present study were to determine the prevalence of FOH by the assessment of 17-hydroxyprogesterone (17-OHP) response to the Gn-RH agonist buserelin, to correlate these abnormal responses to other parameters suggestive of PCOS, and to assess the possible adrenal origin of hyperandrogenism. Therefore, in 33 consecutive women with hirsutism serum LH, FSH, 17-OHP, dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A), Cortisol levels were evaluated in basal conditions and after the administration of buserelin (0.5 mg sc) and ACTH (tetracosactide 0.25 mg iv). Two patients were affected with a non classic congenital adrenal hyperplasia (CAH) -21OH deficiency. In 5 other women ACTH test caused a rate increase 17-OHP (30-0)/30 min >19 nmol/L/min (0.25±0.03; mean ± SE), suggesting the possible existence of heterozygote non classic CAH-21OH. One patient showed a DHEA-S response to ACTH (from 10.3 to 17.2 μmol/L), which was compatible with late-onset 3ß-Hydroxy-Δ5steroid dehydrogenase deficiency. Out of the 25 patients with normal responsiveness to ACTH, 11 women (group A) showed higher 17-OHP and A levels, in comparison to normal women, both in basal conditions (17-OHP= 4.18±0.72 vs 1.74±0.34 nmol/L, p<0.005; A=11.8±1.2 vs 6.0±0.7 nmol/L, p<0.05) and after buserelin (17-OHP= 15.61±1.31 vs 6.96±0.9 nmol/L; A=19.0±1.9 vs 7.5±0.8 nmol/L; p<0.001). In 6 of these 11 patients basal and buserelin-stimulated LH levels were higher than in normals. The remaining 14 patients (group B) showed normal baseline and buserelin-stimulated 17-OHP and A concentrations. In this group only 2 patients had high basal and stimulated LH levels. An augmented LH/FSH ratio was present in 5 and 1 cases of groups A and B, and polycystic ovaries at ultrasonography were observed in 7 and 8 cases of groups A and B, respectively. It is to note that an abnormal 17-OHP response to buserelin was present also in 3 of the 5 patients with abnormal 17-OHP rise after ACTH test, suggesting an adrenal and ovarian cause of hyperandrogenism. In conclusion, an abnormal response to one or both stimulation test was present in 57% of cases: an adrenal origin of hirsutism was detected in 15%, a combined adrenal and ovarian origin was found in 9% and an ovarian cause was present in 33%. Buserelin testing is an useful means to reveal the presence of FOH.

Effect of atrial natriuretic factor infusion on basal and CRH-stimulated ACTH, cortisol and aldosterone levels in patients with Cushing's or Addison's disease

OBJECTIVES While it has been shown that atrial natriuretic factor (ANF) is able to inhibit CRH‐stimulated ACTH secretion in vitro, in normal men conflicting results on its effect on ACTH/cortisol responses to insulin and CRH have been reported. Since no data are available concerning the possible influence of ANF on the hypothalamic‐pituitary‐adrenal axis in states of ACTH hypersecretion, the effect of ANF on pituitary‐adrenal function in basal conditions and after CRH stimulation has been investigated in patients with Cushings (n= 4) and Addisons disease (n= 4).

GH Responsiveness to GHRH in Obese Children before and after Weight Loss

It is well known that obese children show impaired growth hormone (GH) responses to provocative stimuli, such as insulin-induced hypoglycemia (l) , arginine (2) and sleep (2). In addition, Pertzelan et al. (3) have recently demonstrated that obese children show an impaired GH response to GH releasing hormone (GHRH). In this work, we compare GH response to GHRH in obese children before and after weight loss.

Loperamide, an Opiate Analog, Differently Modifies the Adrenocorticotropin Responses to Corticotropin-Releasing Hormone and Lysine Vasopressin in Patients with Addison’s Disease

Loperamide is a peripheral opiate agonist able to inhibit ACTH secretion. In this work, the interactions between loperamide and two ACTH secretagogues, lysine vasopressin (LVP) and corticotropin-releasing hormone (CRH), were investigated in patients with Addisons disease. After loperamide (16 mg orally) or placebo administration, 5 patients received LVP (0.06 IU/kg i.v. over 1 h) and 6 patients received oCRH (1 micrograms/kg i.v. as bolus). In all patients loperamide induced a significant fall in plasma ACTH levels. LVP increased ACTH levels after both loperamide (from 48 +/- 17.3 to a peak of 95 +/- 21 pmol/l) and placebo (from 231 +/- 59.5 to 365 +/- 86.6 pmol/l): the interaction between treatments and time was not significant. CRH caused a rise in plasma ACTH after both loperamide (from 30 +/- 16.6 to a peak of 108 +/- 31 pmol/l) and placebo (from 98.5 +/- 47 to 211 +/- 61.7 pmol/l): the interaction between treatments and time was significant, and the first phase of CRH-induced ACTH secretion was significantly lower after loperamide. These data demonstrate that loperamide differently modifies the stimulatory action of LVP and CRH on ACTH secretion: namely, LVP and loperamide act in an additive manner, while CRH and loperamide interact in a non additive way. Although these findings might be explained by the involvement of different intracellular ACTH-secreting mechanisms, an influence of loperamide on some suprapituitary factors modulating the ACTH response is suggested.