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Influence of corticotrophin on plasma testosterone in normal women

A. Vérine, E. Trouvé-Blanqui, C. Oliver, and J. Boyer

Abstract.

The concentrations of ACTH and testosterone (T) in the plasma from 12 normal women (aged 18–35 years) were simultaneously determined at various times after im injection of 1 mg corticotrophin. The increase in the plasma level of total immunoreactive ACTH was maximal 0.5 h after the injection (mean value 1123 as compared to 36 pg/ml in the basal state); at 48 h, the ACTH level was still 2.4-fold that measured in the basal state. The administration of corticotrophin induced a broad increase in the mean level of plasma T which was highly significant (P < 0.001) at 4, 6, 8, 16 and 24 h after the injection. The maximum T response was detected at 16 h (mean value 477 as compared to 338 pg/ml in the basal state). The results indicate that plasma T is susceptible to stimulation by a pharmacological dose of ACTH in normal women. This effect should be taken into account in evaluating the indication of ACTH as a therapeutic agent.

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On the meaning of low-dose ACTH(1-24) tests to assess functionality of the hypothalamic-pituitary-adrenal axis

P Darmon, F Dadoun, C Frachebois, JG Velut, S Boullu, A Dutour, C Oliver, and M Grino

To analyse further the ACTH(1-24) low-dose test, which is of clinical interest, we have examined the dose-response relationship between plasma ACTH(1-24) and cortisol concentrations after i.v. administration of increasing doses (1, 5 or 250 microg) of ACTH(1-24) as a bolus. In addition, we have measured plasma ACTH(1-39) and cortisol levels after an insulin tolerance test (ITT). Although there was a dose response relationship between plasma ACTH(1-24) immunoreactivity and the dose injected, cortisol peaks were comparable, but lower than those reached after an ITT. Under these experimental conditions, an increase in plasma ACTH as low as 13 pmol/l (i.e. the increase obtained with the 1 microg dose) induced a near maximal cortisol response. Following injection of 1 microg ACTH(1-24), peak ACTH values were short lasting, similar to physiological daily bursts. After injection of 5 microg ACTH(1-24), plasma ACTH concentrations were higher than those reached during an ITT, but clearly shorter lasting. Injection of 250 microg ACTH(1-24) induced strikingly supraphysiological levels of plasma ACTH. We conclude that neither regular nor low-dose ACTH tests can fully reproduce the ITT. Our observations strongly suggest that the low-dose ACTH(1-24) test (1 microg) can be useful to estimate the adrenal sensitivity under basal, physiological conditions.

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Effect of endotoxin on the hypothalamic-pituitary-adrenal axis in sheep

F Dadoun, V Guillaume, N Sauze, J Farisse, JG Velut, JC Orsoni, R Gaillard, and C Oliver

Endotoxin has been shown to stimulate ACTH and cortisol secretion through an action at the hypothalamic level. However, the nature of hypothalamic neurohormones, corticotropin-releasing hormone (CRH) and especially arginine vasopressin (AVP), involved in that regulation is still controversial. The purpose of this study was to determine the effects of an acute i.v. endotoxin administration on CRH and AVP secretion into hypophysial portal blood (HPB). The experiment has been performed in sheep since it is possible to collect HPB and quantify CRH and AVP secretion in this animal under physiological conditions. The release of both peptides into HPB was stimulated by endotoxin injection, the increase in portal AVP being more pronounced than that of CRH. An initial, transient, increase in jugular AVP concentrations was observed, probably due to the activation of magnocellular AVP neurons. In conclusion, our data indicate that the activation of the pituitary-adrenal axis after endotoxin injection is associated with an increased release of both CRH and AVP into HPB. Magnocellular AVP neurons are initially stimulated while parvocellular CRH and AVP neurons are stimulated throughout the experiment.

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Pro-opiomelanocortin in human pregnancy: evolution of maternal plasma levels, concentrations in cord blood, amniotic fluid and at the feto-maternal interface

ML Raffin-Sanson, F Ferre, J Coste, C Oliver, D Cabrol, and X Bertagna

OBJECTIVE: The human placenta normally expresses the pro-opiomelanocortin (POMC) gene. The pattern and secretory kinetics of POMC and/or POMC-derived peptides by the placenta during gestation is still debated. We recently demonstrated that full length POMC was a normal product of the human placenta. The aim of our study was to establish its normal secretory kinetics and to explore its physiological relevance. DESIGN: In a prospective, longitudinal study, thirty normal pregnant women had monthly measurements of plasma POMC. In a cross-sectional study of 128 healthy pregnant women, plasma POMC and human chorionic gonadotrophin (hCG) were concomitantly measured to assess their correlation. Finally, POMC levels were assessed in venous and arterial cord blood samples, in amniotic fluid and in retroplacental blood. METHODS: Plasma POMC was measured by a specific IRMA in unextracted blood or biological fluid. RESULTS: Plasma POMC became detectable by the 8th week of pregnancy and reached its maximum at around the 20th week, remaining stable thereafter. The relationship between POMC and gestation time (weeks) best fitted with a third degree polynomia curve. A significant negative correlation (P=0.01) was observed between plasma levels of POMC and hCG after adjustment for gestation time to take into account the dependence of both hormones on this parameter. POMC was not secreted into the fetal circulation at term, but was present in very high levels in amniotic fluid. The highest levels of POMC were present in the retroplacental blood where the values were 35 times higher than in maternal blood; by comparison, corticotrophin releasing hormone and ACTH values in this compartment were twice or equal to those in the maternal blood. CONCLUSION: Placental POMC secretion increases during the first half of pregnancy and reaches a plateau from the 20th week to delivery. The inverse correlation between POMC and hCG plasma levels, and very high POMC levels at the feto-maternal interface suggest a physiological role for this precursor during pregnancy.

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No loss of sst receptors gene expression in advanced stages of colorectal cancer

V Vuaroqueaux, A Dutour, N Briard, G Monges, M Grino, C Oliver, and L Ouafik

As demonstrated by several studies, the pan-inhibitory peptide somatostatin (SS) is implicated in a large variety of physiological processes in the gastrointestinal tractus. SS inhibits hormonal and gastric acid secretions, and decreases gastric and intestinal motility, mesenteric blood flow and intestinal absorption. In vitro and in vivo studies showed also that the antiproliferative potency of SS analogs may be a target to improve the prognosis of colorectal cancer. Here we report the expression profile of the five SS receptor subtypes (hsst1-5) mRNAs in a large set of tumoral and normal colon. Using reverse transcription-PCR, we showed that hsst5, hsst1 and hsst2 mRNA subtypes were the most frequently expressed hsst mRNA subtypes in normal and pathological colon. Interestingly, we found that the frequency of hsst5 mRNA expression in the left colon was significantly higher in tumors than in normal samples: 81. 2% (13/16) and 36.4% (4/11) respectively (0.025>P>0.01, chi2 test with Yates' correction). We did not find any influence of Dukes' stage on hsst mRNAs expression. Of interest, no loss of hsst2 and hsst5 mRNA expression in advanced stages was noted. Some differences in the frequency of expression of hsst mRNAs according to the origin of the tissue (left or right colon) were evident. The expression of hsst5 and hsst2 mRNA in advanced colorectal carcinoma associated with the development of new SS analogs boost the relevance of colorectal cancer treatment by somatostatin analogs.

Free access

Longitudinal plasma metanephrines preceding pheochromocytoma diagnosis: a retrospective case–control serum repository study

S W Olson, S Yoon, T Baker, L K Prince, D Oliver, and K C Abbott

Objective

Plasma metanephrines (PMN) are highly sensitive for diagnosis of pheochromocytoma, but the natural history of PMN before pheochromocytoma diagnosis has not been previously described. The aim of the study was to compare the progression of PMN before pheochromocytoma diagnosis to matched healthy and essential hypertension disease controls.

Design

A retrospective case–control Department of Defense Serum Repository (DoDSR) study.

Methods

We performed a DoDSR study that compared three longitudinal pre-diagnostic PMN for 30 biopsy-proven pheochromocytoma cases to three longitudinal PMN for age, sex, race, and age of serum sample matched healthy and essential hypertension disease controls. Predominant metanephrine (MN) or normetanephrine (NMN) production was identified for each case and converted to a percentage of the upper limit of normal to allow analysis of all cases together. PMN were measured by Quest Diagnostics.

Results

The predominant plasma metanephrine (PPM) was >100 and 300% of the upper limit of normal a median of 6.6 and 4.1 years before diagnosis respectively. A greater percentage of pheochromocytoma patients had a PPM >100 and >300% of the upper limit of normal compared with combined healthy and essential hypertension disease controls <2, 2–8, and >8 years prior to diagnosis. For patients with a baseline PPM 90–300% of the upper limit of normal, a 25% rate of rise per year was 100% specific for pheochromocytoma.

Conclusions

PPMs elevate years before diagnosis which suggests that delayed diagnoses are common. For mild PMN elevations, follow-up longitudinal PMN trends may provide a highly specific and economical diagnostic tool.

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Species differences between male rat and ram pituitary somatostatin receptors involved in the inhibition of growth hormone secretion

N Briard, A Dutour, J Epelbaum, N Sauze, A Slama, and C Oliver

The sheep is a valuable model in which to study GH neuroregulation as its pattern of GH secretion is very close to that in humans. Furthermore, important differences in somatostatin (SRIH) action between rats and sheep have been found previously. Our goal was to compare in male rat and ram pituitaries the binding characteristics of somatostatin receptors and the effect of SRIH and 17 analogues on GH release. Using radioautography, SRIH binding was seen to be evenly distributed over the anterior pituitary of both species. In the binding assay, binding sites were three times more concentrated in rats than in sheep. Important interspecies differences in the action of SRIH and its analogues were found: they inhibited GH at lower concentrations in rats than in sheep. Seven peptides displayed greater inhibitory ability in sheep than in rats while three were more potent in rats. Agonistic potencies to inhibit GH release in rats were correlated with somatostatin receptors subtype 2 (sst2) affinities. Our data confirm and extend the quantitative differences between rat and sheep in SRIH inhibitory action on GH secretion and confirm that ligand-binding properties of a given receptor subtype cannot be extrapolated across species.

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SOMATOTROPHIC AND CORTICOTROPHIC FUNCTIONS IN PRIMARY HYPOTHYROIDISM BEFORE AND AFTER THYROXINE TREATMENT

M. Minozzi, M. Faggiano, G. Lombardi, C. Carella, T. Criscuolo, Ch. Oliver, and Ph. Vague

ABSTRACT

In 12 patients with primary hypothyroidism the somatotrophic and corticotrophic functions were evaluated before and after thyroxine treatment.

The results confirm a significant decrease, reversible by treatment, of plasma HGH responses to insulin-induced hypoglycaemia and to arginine infusion. Moreover, the results indicate that the impairment of the hypothalamic-pituitary function may also involve the response of plasma ACTH after provocative tests (insulin-induced hypoglycaemia and metyrapone). It must be stressed that the impairment of the corticotrophic function can be revealed only when the responses to provocative tests are evaluated by a direct assay of plasma ACTH and not by plasma corticosteroid modifications. These different responses may account for the conflicting results obtained by other investigators and may be justified by the multiple interference of the thyroid deficiency with the hypothalamic-pituitary-adrenal axis at different levels.

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Effects of acute insulin deficiency on catecholamine and indoleamine content and catecholamine turnover in microdissected hypothalamic nuclei in streptozotocin-diabetic rats

E. H. Oliver, J. L. Sartin, G. Dieberg, C. H. Rahe, D. N. Marple, and R.J. Kemppainen

Abstract. The effects of streptozotocin-induced diabetes on catecholamine and indoleamine concentrations and catecholamine turnover rates in individual microdissected hypothalamic nuclei known, or believed, to be involved in the control of neuroendocrine function, were examined in control, insulin-treated diabetic and acutely insulin-withdrawn diabetic female rats. Streptozotocin-induced diabetes and acute insulin deficiency were demonstrated to result in increased concentrations of epinephrine in the suprachiasmatic nucleus, decreased turnover of epinephrine in the arcuate nucleus and decreased turnover of dopamine in the ventromedial nucleus was found to be increased in the insulin-treated diabetic animals. These data indicate that experimental diabetes and acute insulin deficiency result in the rapid onset of detectable alterations in epinephrine and dopamine activity in specific hypothalamic nuclei. These diabetes-induced changes may cause, or contribute to, the development of secondary neuroendocrine abnormalities known to occur in the diabetic condition.

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Effects of metyrapone infusion on corticotropin-releasing factor and arginine vasopressin secretion into the hypophysial portal blood of conscious, unrestrained rams

B Conte-Devolx, V Guillaume, F Boudouresque, N Graziani, E Magnan, M Grino, N Emperaire, K Nahoul, M Cataldi, and C Oliver

The effects of rapid changes of circulating cortisol levels on ACTH secretion and on corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) concentrations into hypophysial portal blood were studied in six adult rams. Pharmacological adrenalectomy was obtained by 3 h metyrapone infusion (100 mg·kg−1·h−1). Blockade of cortisol synthesis induced a tenfold increase of plasma ACTH levels accompanied by a moderate increase of CRF secretion (150% vs preinjection levels) and a large increment of AVP secretion (535% vs preinjection levels). ACTH levels remained high during the 3 h following the end of metyrapone infusion. During the same period, CRF secretion was still elevated (231% vs preinjection levels), while AVP secretion was further stimulated (2,151% vs preinjection levels). Subsequent hydrocortisone infusion (66 μg·kg−1·h−1) for 2 h induced a rapid decrease of both ACTH and AVP secretion, while CRF levels in hypophysial portal blood still remained elevated. These data suggest that changes in ACTH secretion induced by acute modifications of the negative glucocorticoid feedback are, in addition to the well documented direct effect of cortisol on the corticotropes, mainly mediated by variations of hypothalamic AVP secretion.