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PubMed1990

Hypothalamic-pituitary-adrenal function in patients with the premenstrual syndrome.

Patients with primary affective disorders, such as melancholic depression and anorexia nervosa, frequently have a hyperactive hypothalamic-pituitary-adrenal (HPA) axis, characterized by hypersecretion of CRH and a blunted ACTH response to exogenous CRH. Premenstrual syndrome (PMS) is a luteal phase dysphoric disorder characterized by primarily affective and behavioral disturbances. HPA axis function was compared in PMS patients and control women, respectively, diagnosed by DSM3-R criteria or found to have no current psychiatric disorders, determined by the Schedule for Affective Disorders and Schizophrenia-Lifetime Interview. Urinary free cortisol excretion was the same in PMS and normal women, and no differences in urinary free cortisol excretion between the follicular and luteal phases occurred in either group. Two HPA axis abnormalities, however, were noted when PMS patients were compared to normal women. First, basal evening cortisol concentrations in plasma were significantly decreased, while the time-integrated response of plasma cortisol to ovine (o) CRH was significantly increased. Second, the negative correlation between time-integrated plasma ACTH and cortisol responses to oCRH and basal luteal progesterone concentrations present in normal control women was not seen in the PMS patients. These changes in basal and oCRH-stimulated plasma cortisol levels in association with normal urinary free cortisol excretion suggest that women with PMS might have transient or episodic disturbances of their HPA axis, which appear adequately corrected by this system's servomechanisms. This probably explains the maintenance of regular menstrual cycles in PMS patients, which contrasts with the irregular menses observed in patients with depression, anorexia nervosa, or women who participate in chronic strenuous exercise.

Adrenocorticotropic Hormone↗
PubMed1995

[Metastatic pulmonary carcinoma, revealed by Cushing syndrome, initially considered to have a pituitary origin. Course over 25 years].

It is often difficult to differentiate between Cushing's syndrome and ectopic ACTH hypersecretion which, in rare cases, may result from a carcinoid tumour. Several years may be required before development of patent Cushing's syndrome. We report the 25-year clinical course in a patient with a pulmonary carcinoid tumour. Initially, the hormone results led to the diagnosis of Cushing's syndrome and the patient was treated accordingly. Bilateral adrenectomy was performed in 1969 followed by radiotherapy of the pituitary gland in 1975 for suspected Nelson's syndrome. Actually, the carcinoid tumour, located retrocardially, had gone unnoticed until 1989. Diagnosis was suspected during a hospitalization in our unit and the patient underwent tumour exeresis and left inferior lobectomy. Despite tumour removal and demonstration of tumoural ACTH secretion, the levels of ACTH and beta-lipotrope hormone remained high suggesting lymph node and/or pulmonary metastasis. This observation emphasizes the long clinical course of carcinoid tumours despite their malignancy and the unusual response to the dexamethasone test.

Adrenocorticotropic Hormone↗
PubMed1985

Response of the rat brain beta-endorphin system to novelty: importance of the fornix connection.

In control rats, a step-down inhibitory avoidance training trial using a 0.8 mA footshock, or simple exposure to the training apparatus without footshock, was followed by a decrease of beta-endorphin-like immunoreactivity measured in the hypothalamus and ventral thalamus. The effect of inhibitory avoidance training was also measured in rats submitted to a brain sham operation, to bilateral transection of the dorsal fornix, to anterior or to posterior hypothalamic deafferentation, to adrenal medullectomy, to an adrenal sham operation, to 16 daily ip injections of 0.2 mg/kg dexamethasone, or to 16 daily ip injections of 1 ml/kg saline. The diencephalic beta-endorphin-like immunoreactivity response to training was abolished by fornix transection and was unaffected by all other treatments. This suggests that the response is not mediated by anterior or posterior neural afferents to the hypothalamus, or by a hypersecretion of epinephrine by the adrenal medullae, or of ACTH by the pituitary gland. The response, instead, appears to require the integrity of the pathway that sends projections from the septo-hippocampal system to the hypothalamus. Previous evidence had suggested that the diencephalic beta-endorphin-like immunoreactivity response to training is a result of novelty, and the septo-hippocampal system has been postulated to play a role in the registration of novelty.

Adrenal Medulla↗
PubMed1997

A case of a pony with Cushing's disease.

The pars intermedia of the pituitary gland, and plasma ACTH and cortisol levels in the pony, which was first diagnosed in Japan as indicating equine Cushing's disease, were examined by immunohistochemistry and radioimmunoassay, respectively. The pars intermedia was greatly enlarged and most of its cells were immunoreactive for antisera to both adenocorticotropic hormone (ACTH) and beta-endorphin (beta-End). The plasma ACTH level was elevated when clinical symptoms appeared. The present results reveal that equine Cushing's disease in this pony was induced by the hypersecretion of ACTH and beta-End from the enlarged pars intermedia of the pituitary gland.

Adrenal Glands↗
PubMed1986

Long-term effects of hypothalamic paraventricular lesion on CRF content and stimulated ACTH secretion.

The effect of short-term (1 wk) and long-term (6 wk) lesion of the paraventricular nucleus (PVN) on the hypothalamopituitary-adrenal axis was studied. Six weeks after PVN lesion there was no change in resting morning plasma ACTH and corticosterone levels. The increase of plasma ACTH levels that occurs 8 days after adrenalectomy was inhibited 6 wk after placing a lesion in the PVN. In contrast, 6 wk after PVN lesion the plasma ACTH response measured 3 min after laparatomy and intestinal traction under ether anesthesia was not significantly different from that in the controls. The responsiveness to corticotropin-releasing factor (CRF)-41 of anterior pituitary segments incubated in vitro increased slightly at 6 wk after PVN lesion. The amount of CRF-41-like immunoreactive material in the stalk-median eminence decreased to approximately 14% of the control, while that in neural lobe failed to change. We suggest that the ACTH hypersecretion after adrenalectomy is driven predominantly by CRF-and/or AVP-producing neurons in and around the PVN, whereas other sources of CRF-41, increased pituitary sensitivity or other hypothalamic factors, may restore stress-induced ACTH release in the absence of the region of the PVN.

Adrenalectomy↗
PubMed2002

Cerebrospinal fluid corticotropin-releasing factor (CRF) and vasopressin concentrations predict pituitary response in the CRF stimulation test: a multiple regression analysis.

There is considerable evidence that stress-related psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), are associated with hypersecretion of corticotropin-releasing factor (CRF) within the central nervous system (CNS). One line of evidence that is consistent with central CRF hypersecretion in these disorders is the blunted adrenocorticotropin hormone (ACTH) response to intravenous CRF administration, likely a consequence, at least in part, of downregulation of anterior pituitary CRF receptors. The present study tests the hypothesis that elevated cerebrospinal fluid (CSF) concentrations of CRF and a secondary ACTH secretagogue, arginine vasopressin (AVP), are associated with diminished adenohypophyseal responses in a standard CRF stimulation test. CSF concentrations of CRF and AVP, and plasma ACTH responses to the administration of 1 microg/kg ovine CRF (oCRF) were measured in healthy adult women with and without current major depression and/or a history of significant childhood abuse. The primary outcome measure was ACTH area under the curve (AUC) in the CRF stimulation test. Multiple linear regression was performed to identify the impact of CSF CRF and AVP concentrations upon the pituitary response to CRF stimulation. The regression model explained 56.5% of the variation in the ACTH response to CRF stimulation. The relationship of CSF concentrations of CRF to ACTH responses to CRF were best described by a third-order function that was inversely correlated over most of the range of studied values. The association of ACTH response with CSF concentration of AVP and the dose of oCRF followed second-order kinetics. These findings support the hypothesis that central CRF hypersecretion is associated with a blunted ACTH response to exogenously administered CRF, explaining almost 60% of the variation in the ACTH response to CRF.

Adrenocorticotropic Hormone↗
PubMed1984

Effect of CRF on the release of anterior pituitary hormones in normal subjects and patients with Cushing's disease.

Patterning of plasma ACTH, beta-EP/beta-LPH and cortisol in response to ovine CRF (1 microgram/kg b.w.t. injected i.v.), was studied in three normal subjects and in five patients with Cushing's disease, two of whom had undergone total bilateral adrenalectomy. CRF caused in all subjects a prompt and concurrent rise of plasma hormone levels. The hormonal response was of the same magnitude in normal controls and in the three untreated Cushing's patients, but was much greater in the two adrenalectomized subjects. No changes were noted, after CRF, in plasma levels of GH, PRL, TSH, LH and FSH. These findings indicate that CRF specifically promotes the pituitary release of ACTH and ACTH-related peptides both in normal subjects and patients with Cushing's disease. In view of the likely CRF hypersecretion of the adrenalectomized patients, their ACTH and beta-EP/beta-LPH hyperresponsiveness to exogenous CRF would denote that the peptide does not down regulate its own pituitary receptors.

Adolescent↗
PubMed1990

Studies of the regulation of the hypothalamic-pituitary-adrenal axis in sheep with hypothalamic-pituitary disconnection. II. Evidence for in vivo ultradian hypersecretion of proopiomelanocortin peptides by the isolated anterior and intermediate pituitary.

Studies were performed to determine whether the isolated ovine anterior and intermediate pituitary might rhythmically secrete three POMC peptides, ACTH, ir-beta-endorphin (ir-beta-EP), and ir-alpha-melanocyte stimulating hormone (ir-alpha-MSH) in vivo. When blood was taken at 10-min intervals from four ewes with hypothalamo-pituitary-disconnection (HPD), a distinct POMC-peptide and cortisol ultradian rhythm was noted. A comparison of the four HPD ewes with five nonstressed hypothalamopituitary-intact (HPI) ewes revealed that the mean plasma levels of the three POMC-peptides and cortisol were increased, the mean ACTH and ir-alpha-MSH pulse amplitudes were increased, and the mean ir-beta-EP and ir-alpha-MSH interpulse intervals were decreased. When four HPI ewes were subjected to a mild stress, plasma POMC-peptide and cortisol levels increased significantly when compared with the five unstressed HPI animals. In addition, the ACTH and cortisol pulse amplitudes increased and the ir-beta-EP and ir-alpha-MSH interpulse intervals decreased. Although plasma ACTH levels in the stressed HPI and HPD ewes were comparable, mean plasma cortisol levels were 2-fold greater in the stressed HPI animals. To determine whether the ACTH hypersecretion in the HPD ewe might reflect a net reduction in hypothalamic inhibitory influence over ACTH secretion, we examined the effects of dopamine (DA), somatostatin (SS-14), and rat atrial natriuretic peptide [rANF(1-28)] on the secretion of ACTH from cultured ovine anterior pituitary cells. DA and SS-14 did not exert a discernible effect on basal, CRF-, or arginine vasopressin (AVP)-stimulated ACTH secretion. Although basal ACTH secretion was unaffected by rANF(1-28) (10(-12)-10(-8) M), a significant inhibition of CRF- and AVP-stimulated ACTH release was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗
PubMed1975

The effect of reserpine on hypothalamo-pituitary-adrenocortical function in the rat.

1. The effect of reserpine on hypothalamo-pituitary-adrenocortical (HPA) function in the rat was investigated by the use of direct and indirect indices of pituitary adrenocorticotrophic activity. 2. Administration of a single dose of the drug induced prolonged hypersecretion of corticotrophin (ACTH). 3. Corticotrophin release in response to the drug no longer occurred after repeated daily injections, indicating that some form of 'adaptation' occurred. 4. The increase in HPA activity normally caused by exposure to cold was prevented by reserpine once 'adaptation' to the drug had been produced. 5. Inhibition of stress-induced ACTH release was due neither to depletion of pituitary stores of the hormone, nor to a corticosteroid feedback effect.

Adrenal Cortex↗
PubMed1982

Corticotropin releasing factor (CRF)-stimulation test in normal controls and patients with disturbances of the hypothalamo-pituitary-adrenal axis.

Intravenous application of 100 micrograms synthetic ovine corticotropin releasing factor (CRF) led to stimulation of ACTH-secretion in nine normal controls, with a maximum 30 min after CRF. Cortisol, corticosterone, cortisone and 11-deoxycortisol increased with a maximum at 60 min after CRF, whereas no rise was seen in aldosterone, 11-deoxycorticosterone, 17-alpha-hydroxyprogesterone, progesterone, DHEA-S and testosterone. The specificity of CRF-stimulation was also shown by unchanged TSH, LH, FSH, hGH, prolactin and thyroid hormone levels, als well as unchanged insulin and gastrin levels. No serious side-effects were observed during the test period and afterwards. CRF-tests were performed in ten patients with disturbances of the hypothalamo pituitary adrenal axis (HPAA). Preliminary findings show hyperresponsiveness of ACTH in all situations of ACTH-hypersecretion (two patients with Cushing's disease, one patient with Nelson's syndrome, and one with Addison's disease). In contrast, one patient with successful microadenomectomy showed no response of ACTH to CRF, whereas in another patient with a macroadenoma ACTH and cortisol-levels still increased postoperatively. Divergent patterns in ACTH-responsiveness to CRF were seen in four patients with secondary adrenal insufficiency, allowing the localization of the defect. These data point to the possible importance of the "CRF-test" as a differential diagnostic tool and prognostic factor in diseases of the HPAA.

Adrenal Cortex Hormones↗
PubMed1986

Cushing disease: successful preoperative lateralization of an ACTH-producing pituitary microadenoma by simultaneous bilateral inferior petrosal venous sinus sampling with corticotropin-releasing hormone stimulation.

A 5 10/12-year-old girl with clinical and laboratory signs of endogenous hypercortisolism had evidence of ACTH hypersecretion in a standardized dexamethasone suppression test but had surprisingly low plasma ACTH concentrations before and after ovine corticotropin releasing hormone (oCRH) stimulation. To establish the diagnosis of pituitary disease and to localize the suspected microadenoma, we performed bilateral simultaneous inferior sinus petrosus blood sampling under CRH stimulation (oCRH 1 microgram/kg as an i.v. bolus). No major side effects were noted. Inferior petrosal blood ACTH concentrations did not differ from peripheral blood under basal sampling conditions but were higher in the effluent of the left half of the pituitary 5 min after oCRH stimulation. During transsphenoidal exploration of the sella an ACTH-producing microadenoma was removed from the left portion of the anterior pituitary gland. Signs of hypercortisolism remitted after surgery. Simultaneous bilateral sinus petrosus blood sampling under oCRH stimulation is a useful lateralization procedure even with small ACTH-producing adenomas. This technique may help to avoid unsuccessful surgical exploration in children with Cushing disease.

Adenoma↗
PubMed2001

[Cushing's disease in the 90's: a review].

Since 1932 when Cushing's disease has been described, several important advances have been made in diagnosis and management. However several points remain obscure and there is no general agreement among authors. An accurate biological diagnosis is one of the difficulties found when we face a patient with hypercortisolism. In addition, corticotropin dependent syndrome should be distinguished from the independent one, as well as identifying the source of ACTH hypersecretion. The main problem in Cushing's disease is to localise the secreting adenoma and at the moment there is not any diagnostic method with absolute sensibility and specificity. Magnetic Resonance Imaging shows a sensibility of 77% and 87% especificity; inferior petrosal sinus sampling may help in localising the side, where the adenoma lies, although an appropriate technique is mandatory. New developing techniques, such as intraoperative doppler and assessment of ACTH levels in the peripituitary veins may help us in localising the source of ACTH hypersecretion. Sometimes the adenoma cannot be identified and a surgical exploration of the pituitary is required. If an adenoma is found, a 89% probility of curation has been reported; on the contrary, incomplete tumor removal, no tumor found at surgery, or the presence of the so-called corticotrop hyperplasia where followed of bad results and may explain the failed surgery. Then, hypofisectomy, hemi-hypofisectomy, radiotherapy, photon knife or gamma knife, may be of help in the control of this condition. We reviewed the recent literature and analysed the diagnostic strategies and teatments currently available for this illness. In addition we propose an algohritm for diagnosis and treatment and analyze our results in a consecutive series of 38 patients.

Adrenocorticotropic Hormone↗
PubMed2002

[Multihormonal bilateral petrosal sinus sampling in Cushing's disease: radiological, surgical and pathological correlations].

Multihormonal bilateral petrosal sinus sampling (BPSS) has been proposed to improve corticotroph microadenomas prediction of lateralisation. Few series have simultaneously compared data of pituitary MRI, surgical findings and multihormonal BPSS. Seven patients (6F/1M) with Cushing's disease, mean age at diagnosis of 35 years (range 24-55) were prospectively studied to compare radiological and multihormonal BPSS data with surgical and pathological findings. In untreated patients, simultaneous measures of ACTH, TSH and prolactine (PRL) were done at time 0, 7, 15, 22 minutes after CRH (500 microgram) and TRH (200 microgram) stimulation. An intersinus gradient of 1.4 was considered as a lateralisation. All microadenomas were identified during surgery, diameters ranged from 2 to 7 mm. All patients were in long-term surgical remission. Pathological studies confirmed a tumoral tissue with ACTH immunostaining in 6/7 cases and PRL in 3/7 cases. Pituitary MRI correctly identified tumors in 4 cases, the remaining tumors were not seen. Basal and stimulated intersinus gradients of ACTH, TSH and PRL were homolateral in 6/7 cases and were coincident with surgical findings in 4/7 cases. The other three cases were contralateral to MRI and surgical data. In conclusion, simultaneous gradient of ACTH, PRL and TSH did not improve lateralisation prediction in this series. Hormonal hypersecretion was homolateral in six cases whereas pathological studies demonstrated a mixed secretion in only three cases. A preferential pituitary draining could explain these discordances. Data from our series and from others (done with CRH stimulation and ACTH-PRL measures) strongly suggest a paracrine interaction between tumoral and normal pituitary tissue.

Adenoma↗
PubMed2006

Ectopic ACTH-secreting syndrome: a single center experience report with a high prevalence of occult tumor.

BACKGROUND: Differentiation between the two forms of ACTH-dependent Cushing's syndrome is a challenging task. Although the majority of these cases will be diagnosed as Cushing's disease secondary to an ACTH-secreting pituitary adenoma, 10-15% result from the ectopic ACTH secretion syndrome (EAS), which is usually due to neuroendocrine tumors. In the present study we report our experience with EAS in eight patients evaluated and treated during the past 10 years. METHODS: Our experience in the evaluation and management of EAS was retrospectively reviewed. The latter included a standard biochemical assessment (urinary free cortisol, low- and high-dose dexamethasone suppression tests), petrosal sinus sampling when indicated and imaging techniques such as pituitary MRI, total body CT and somatostatin receptor scintigraphy. RESULTS: The ectopic nature of the ACTH hypersecretion was confirmed with inferior petrosal sinus samplings in all cases. CT scanning localized a putative tumor in 6/8 patients, whereas octreotide scintigraphy was positive in only five. In all cases, the source was traced to the lungs. However, upon performing thoracotomy, a documented ACTH-secreting bronchial carcinoid tumor was found in only four patients. Thus, 4/8 patients with EAS remained "occult." All of these patients underwent adrenalectomy for hypercortisolism control. CONCLUSIONS: EAS is a rare cause of ACTH-dependent Cushing's syndrome. Truly "occult" tumors were frequent and these patients need to be under close surveillance for the detection of neuroendocrine tumors.

ACTH Syndrome, Ectopic↗
PubMed2005

Adrenocorticotropin hypersecretion and pituitary microadenoma following bilateral adrenalectomy in a patient with classic 21-hydroxylase deficiency.

Bilateral adrenalectomy is an acceptable alternative treatment in salt-wasting 21-hydroxylase deficiency when conventional steroid replacement therapy fails to control hyperandrogenism. Objections to surgical adrenalectomy have been based on surgical risk, possible loss of protective adrenal function, and the risk of ACTH-induced activation of adrenal rest tissue. We report a young female with salt-wasting CAH, who underwent bilateral adrenalectomy and developed severe hyperpigmentation, progressively marked corticotropin hypersecretion to concentrations seen in Nelson's syndrome (5,000-7,000 pg/ml), a pituitary microadenoma 5 years postoperatively, and probable ectopic adrenal rest tissue. Corticotropin concentrations failed to respond to ovine corticotropin-releasing hormone (oCRH) (1 microg/kg given as an i.v. bolus), but did suppress following both hydrocortisone administration (100 mg given as an i.v. bolus) and a low dose (0.5 mg given orally every 6 h for 48 h) dexamethasone suppression test. Patients with CAH have hyperactivity of the hypothalamic-pituitary-adrenal axis and are at risk for pituitary tumor formation.

Adenoma↗
PubMed2002

Mortality in 7B2 null mice can be rescued by adrenalectomy: involvement of dopamine in ACTH hypersecretion.

The serine protease prohormone convertase 2 (PC2), principally involved in the processing of polypeptide hormone precursors in neuroendocrine tissues, requires interaction with the neuroendocrine protein 7B2 to generate an enzymatically active form. 7B2 null mice express no PC2 activity and release large quantities of uncleaved ACTH, resulting in a lethal endocrine condition that resembles pituitary Cushing's (Westphal, C. H., Muller, L., Zhou, A., Bonner-Weir, S., Schambelan, M., Steiner, D. F., Lindberg, I. & Leder, P. (1999) Cell 96, 689). Here, we have compared the 7B2 and PC2 null mouse models to determine why the 7B2 null, but not the PC2 null, exhibits a lethal disease state. Both 7B2 and PC2 nulls contained highly elevated pituitary adrenocorticotropic hormone (ACTH); the neurointermediate lobe content of ACTH in 7B2 nulls was 13-fold higher than in WT mice; that of the PC2 null was 65-fold higher. However, circulating ACTH levels were much higher in the 7B2 null than in the PC2 null. Because hypothalamic inhibitory dopaminergic control represents the major influence on intermediate lobe proopiomelanocortin-derived peptide secretion, dopamine levels were measured, and they revealed that 7B2 null pituitaries contained only one-fourth of WT pituitary dopamine. Adrenalectomized 7B2 null animals survived past the usual time of death at 5 weeks; a month after adrenalectomy, they exhibited normal levels of pituitary dopamine, circulating ACTH, and corticosterone. Elevated corticosterone, therefore, seems to play a central role in the lethal phenotype of the 7B2 null, whereas a 7B2-mediated dopaminergic deficiency state may be involved in the actual ACTH hypersecretion phenomenon. Interestingly, adrenalectomized 7B2 nulls also developed unexpectedly severe obesity.

Adrenal Glands↗