Dysfunction in Sertoli cells participates in glucocorticoid-induced impairment of spermatogenesis.

The effect of stress on male fertility is a widespread public health issue, but less is known about the related signaling pathway. To investigate this, we established a hypercortisolism mouse model by supplementing the drinking water with corticosterone for four weeks. In the hypercortisolism mice, the serum corticosterone was much higher than in the control, and serum testosterone was significantly decreased. Moreover, corticosterone treatment induced decrease of sperm counts and increase of teratozoospermia. Increased numbers of multinucleated giant cells and apoptotic germ cells as well as downregulated meiotic markers suggested that corticosterone induced impaired spermatogenesis. Further, upregulation of macrophage-specific marker antigen F4/80 as well as inflammation-related genes suggested that corticosterone induced inflammation in the testis. Lactate content was found to be decreased in the testis and Sertoli cells after corticosterone treatment, and lactate metabolism-related genes were downregulated. In vitro phagocytosis assays showed that the phagocytic activity in corticosterone-treated Sertoli cells was downregulated and accompanied by decreased mitochondrial membrane potential, while pyruvate dehydrogenase kinase-4 inhibitor supplementation restored this process. Taken together, our results demonstrated that dysfunctional phagocytosis capacity and lactate metabolism in Sertoli cells participates in corticosterone-induced impairment of spermatogenesis.

Ectopic ACTH syndrome of different origin-Diagnostic approach and clinical outcome. Experience of one Clinical Centre.

PURPOSE: Ectopic Cushing Syndrome (EAS) is a rare condition responsible for about 5-20% of all Cushing syndrome cases. It increases the mortality of affected patients thus finding and removal of the ACTH-producing source allows for curing or reduction of symptoms and serum cortisol levels. The aim of this study is to present a 20-year experience in the diagnosis and clinical course of patients with EAS in a single Clinical Centre in Southern Poland as well as a comparison of clinical course and outcomes depending on the source of ectopic ACTH production-especially neuroendocrine tumors with other neoplasms. METHODS: Twenty-four patients were involved in the clinical study with EAS diagnosed at the Department of Endocrinology between years 2000 and 2018. The diagnosis of EAS was based on the clinical presentation, hypercortisolemia with high ACTH levels, high dose dexamethasone suppression test and/or corticotropin-releasing hormone tests. To find the source of ACTH various imaging studies were performed. RESULTS: Half of the patients were diagnosed with neuroendocrine tumors, whereby muscle weakness was the leading symptom. Typical cushingoid appearance was seen in merely a few patients, and weight loss was more common than weight gain. Patients with neuroendocrine tumors had significantly higher midnight cortisol levels than the rest of the group. Among patients with infections, we observed a significantly higher concentrations of cortisol 2400 levels in gastroenteropancreatic neuroendocrine tumors. Chromogranin A correlated significantly with potassium in patients with neuroendocrine tumors and there was a significant correlation between ACTH level and severity of hypokalemia. CONCLUSION: EAS is not common, but if it occurs it increases the mortality of patients; therefore, it should be taken into consideration in the case of coexistence of severe hypokalemia with hypertension and muscle weakness, especially when weight loss occurs. Because the diagnosis of gastroenteropancreatic neuroendocrine tumor worsens the prognosis-special attention should be paid to these patients.

Glucocorticoids and Trabecular Bone Score.

TBS (Trabecular Bone Score) is the latest tool for clinicians to evaluate bone micro-architecture based on a pixel greyscale, which is provided by lumbar dual-energy X-ray absorptiometry (DXA). Its use enhances fracture prediction in addition to DXA-BMD (Bone Mineral Density). This is independent of fracture risk assessment (FRAX) and DXA results. We present a narrative review regarding the connection between TBS and Glucocorticoids (GC), either as a drug used for different conditions or as a tumor-produced endogenous excess. TBS is a better discriminator for GC-induced vertebral fractures compared to DXA-BMD. This aspect is similarly available for patients with osteoporosis diagnosed by DXA. TBS is inversely correlated with the cumulative dose of GC (systemic or inhaled), with disease duration, and positively correlated with respiratory function in patients with asthma. Low TBS values are found in females with a T-score at the hip within the osteoporosis range, with diabetes mellitus, or who use GC. Lumbar TBS is a screening tool in menopausal women with type 2 diabetes mellitus. TBS is an independent parameter that provides information regarding skeleton deterioration in diabetic patients receiving GC therapy in a manner complementary to DXA-BMD. TBS might become an essential step regarding the adrenalectomy decision in patients with adrenal incidentaloma in whom autonomous cortisol secretion might damage bone micro-architecture. TBS currently represents a standard tool of fracture risk evaluation in patients receiving GC therapy or with endogenous Cushing's syndrome, a tool easy to be applied by different practitioners since GCs are largely used.

[Nutrition of horses with equine pituitary pars intermedia dysfunction ("Cushing's syndrome") treated with pergolid - A field study]. / Ernährung von Pferden mit Equine Pituitary Pars Interme dia Dysfunction ("Cushing-Syndrom") unter Pergolidtherapie.

OBJECTIVE AND AIM: The nutritional status of 36 patients with equine pituitary pars intermedia dysfunction (PPID) under pergolide treatment was investigated. ANIMALS, MATERIALS AND METHODS: The body condi tion score (BCS) and feeding were determined at the beginning of the study and after 60 and 120 days. Sampled blood for control of pergolid therapy were used for insulin and glucose measurement. A standardized questionnaire regarding the symptoms of the disease, including hypertrichosis and weight change, was completed by the owners. RESULTS: The mean BCS (scale of 1 = cachexia to 9 = grossly obese) was 3.1 ± 0.8 (large horses 2.7 ± 0.8, ponies 3.5 ± 0.8). The mean energy requirement of the large horses was estimated to be 74 ± 10 MJ of metabolizable energy, but the intake amounted only to 65 ± 15 MJ. There was a significant correlation between the BCS and the estimated energy intake in percent of requirements in the large horses. The energy requirements of the ponies were generally met. The patients were fed a mean of 2.0 ± 0.7 meals of roughage per day (total roughage intake per day 0.2-2.1 kg/100 kg body weight) and a maximum of one meal of concentrates. Sixteen ponies and one large horse did not receive any concentrates, whereas five ponies and 14 horses were fed concentrates (mean amount for ponies 0.15 kg and for large horses 0.8 kg). The requirements for zinc, copper, selenium and vitamins A and E were not met in the majority of patients. Blood glucose levels were within the reference range in all samples, but insulin levels were elevated in seven animals at least at one sampling point. The serious underweight of some of the patients was not recognized as a problem by some of the owners. CONCLUSION AND PRACTICAL RELEVANCE: Owners of PPID patients need more guidance on body condition scoring, amount of feed, number of meals, and logistics of feeding to avoid malnutrition of their animals.

Resistant hypertension in an aged woman presenting with clinical features simulating ectopic ACTH syndrome--response to spironolactone--.

A 91-year-old depressed woman had resistant hypertension despite a triple combination of anti-hypertensives, including a Ca-antagonist, an angiotensin receptor blocker, and a thiazide diuretic at optimal doses. She had hypokalemic metabolic alkalosis, elevated plasma cortisol and ACTH, and elevated urinary cortisol. The high-dose dexamethasone did not suppress the elevated ACTH and cortisol. The addition of spironolactone to her previous medications controlled and normalized hypertension, hypokalemia, and hormonal abnormalities within 4 months. Her blood pressure, serum electrolytes, and the hormonal states remained normalized for more than a year thereafter. Her depressed mental state also improved after spironolactone.

Alteration of delay and trace eyeblink conditioning in fibromyalgia patients.

OBJECTIVE: Classical conditioning processes are important for the generation and persistence of symptoms in psychosomatic disorders, such as the fibromyalgia syndrome (FMS). Pharmacologically induced hyper- and hypocortisolism were shown to affect trace but not delay classical eyeblink conditioning. As previous studies revealed a relative hypocortisolism in FMS patients, we hypothesized that FMS patients also show altered eyeblink conditioning. METHODS: FMS patients (n = 30) and healthy control subjects (n = 20) matched for gender and age were randomly assigned to a delay or trace eyeblink conditioning protocol, where conditioned eyeblink response probability was assessed by electromyogram. Morning cortisol levels, ratings of depression, anxiety as well as psychosomatic complaints, general symptomatology, and psychological distress were assessed. RESULTS: As compared with healthy controls, FMS patients showed lower morning cortisol levels, corroborating previously described disturbances in neuroendocrine regulation of the hypothalamus-pituitary-adrenal axis in these patients. Trace eyeblink conditioning was facilitated in FMS patients, whereas delay eyeblink conditioning was reduced, and cortisol measures correlated significantly only with trace eyeblink conditioning. CONCLUSION: We conclude that FMS patients characterized by decreased cortisol levels differ in classical trace eyeblink conditioning from healthy controls, suggesting that endocrine mechanisms affecting hippocampus-mediated forms of associative learning may play a role in the generation of symptoms in these patients.

Kaposi sarcoma related to an ectopic hypothalamic adrenocorticotropic hormone-secreting adenoma: case report.

OBJECTIVE: We aim to report a case of Kaposi sarcoma (KS) with Cushing's syndrome caused by endogenic glucocorticoid-induced immunosuppression. CLINICAL PRESENTATION: A 43-year-old woman presented with delirium, hirsutism, fatigue, and hypertension. At the time of presentation, physical findings showed a Cushingoid appearance, with moon-like facies, hirsutism, and hyperpigmentation. Laboratory findings showed the following: adrenocorticotropic hormone, 86.7 pg/mL (normal range, 0-46 pg/mL); baseline cortisol level, 50 microg/dL (normal range, 6.2-19 microg/dL); potassium, 2.2 mEq/L (normal range, 3.5-5 mEq/L); and midnight cortisol level, 33 microg/dL. Serum cortisol levels failed to suppress after low and high doses of dexamethasone; these findings confirmed the diagnosis of ectopic adrenocorticotropic hormone production. Magnetic resonance imaging revealed a 12 x 15-mm, round, hypothalamic mass lesion in the center of the median eminence. INTERVENTION: Endoscopic biopsy from the floor of the third ventricle was performed, and pathological examination of the lesion showed a diffuse adrenocorticotropic hormone-secreting adenoma. The patient developed diffuse skin lesions that were proven to be a KS by skin biopsy while she was prepared for transcranial surgery. After surgical removal of the adenoma, she became hypocortisolemic and required cortisol replacement. Within 1 month after surgery, all KS lesions disappeared spontaneously. CONCLUSION: Excessive cortisol may induce immunosuppression. KS is one of the most common malignant tumors of patients with immunosuppression. To the best of our knowledge, this is the first case of Cushing's syndrome with KS caused by endogenous glucocorticoid-induced immunosuppression.

[Anaesthesia for patients with adrenal gland diseases]. / Anästhesie bei Erkrankungen der Nebennierenrinde--Effizientes Risikomanagement von der Prämedikation bis zum Aufwachraum.

Perioperative management of patients with adrenal gland diseases requires detailed information on the individual endocrine status and the potential complications. Typical signs of primary hyperaldosteronism (Conn's syndrome) comprise arterial hypertension, hypokalaemia and metabolic alkalosis. In such cases preoperative treatment with spironolactone is highly recommended. In patients with hypercortisolism (Cushing's syndrome) the following concomitant disorders must be considered particularly: arterial hypertension, osteoporosis, vulnerable skin, diabetes mellitus, and increased risk for infection and thromboembolism. In all patients with proven or suspected adrenocortical insufficiency (i.e. Addison's disease, after removal of a cortisol producing tumour or as the result of long-term therapy with glucocorticoids) consequent perioperative supplementation of hydrocortisone is mandatory. In patients with phaeochromcytoma hypertensive crisis and tachyarrhythmias may occur intraoperatively resulting from massive catecholamine release. Thus, preoperative treatment with the beta-antagonist phenoxybenzamine is obligatory. In contrast, nitroprusside is the substance of choice for intraoperative control of blood pressure. beta-blocking agents may be used in phaeochromocytoma but only under sufficient beta-blockade. Removal of a malignant tumour of the adrenal gland may induce massive haemorrhage, and thus anaesthetic management has to be modified.

Bone metabolism and mass in women with Cushing's syndrome and adrenal incidentaloma.

OBJECTIVE: The aim of this study was to compare bone turnover and mass in women with either Cushing's syndrome (CS) or adrenal incidentaloma (AI), which is a possible model for minimal hypersecretion of cortisol. DESIGN AND PATIENTS: We studied 15 patients with CS (seven premenopausal and eight postmenopausal women); 23 patients with AI (five premenopausal and 18 postmenopausal women) and 20 matched controls (seven premenopausal and 13 postmenopausal women). Alkaline phosphatase (ALP), bone alkaline phosphatase (bALP), osteocalcin (BGP), 24-h urinary pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) and serum and 24-h urinary calcium and phosphorus were determined in all subjects. Bone mineral density (BMD) at lumbar spine and proximal femur was measured by dual energy X-ray absorptiometry (DEXA). RESULTS: We found a significant reduction of BGP and serum phosphorus in CS and AI (P < 0.05) vs. controls and significantly lower levels of Pyr only in CS (P < 0.05) vs. AI and controls. Spinal and femoral BMD z-values were significantly lower (P < 0.05) in patients with CS (z-score: lumbar spine -1.44 +/- 1.5 and femoral neck -1.07 +/- 1; mean +/- SD) compared to AI and controls. CONCLUSIONS: Our data show that hypercortisolism reduces osteoblastic function and bone resorption and that osteocalcin can contribute to the precocious diagnosis of silent glucocorticoid excess. Patients with active CS were found to have lower BMD, particularly at vertebral level.

The role of nutritional therapy in the treatment of equine Cushing's syndrome and laminitis.

Equine Cushing's syndrome, a relatively common and complex condition, is difficult to treat with conventional medicine. Cushing's syndrome involves a hyperplasia or adenoma of the anterior pituitary gland. Biochemical alterations include increased endogenous cortisol, insulin resistance, elevated adrenocorticotrophic hormone, and decreased thyroid hormone levels. Symptoms include hirsutism with no loss of the winter coat in summer, refractory laminitis, weight problems (over- or underweight), polyuria/polydipsia (Pu/Pd), frequent infections, lowered immunity to intestinal parasites, decreased intestinal wall integrity, and infertility. Laminitis (an inflammation of the laminae of the foot) is a common and often fatal complication of Cushing's syndrome that tends to be refractory to conventional treatment. One of the most common therapies is phenylbutazone, a non-steroidal anti-inflammatory drug (NSAID) known to cause significant changes in the permeability of the intestinal wall. Recent research has shown an intestinal bacterial exotoxin to be one of the triggering factors in laminitis. By removing phenylbutazone and healing the intestinal wall, laminitis becomes more responsive to treatment. Good hoof-care combined with nutritional management and the application of other modalities, including acupuncture and Chinese and Western herbs, can complete the healing process. The successful treatment of equine Cushing's syndrome is one of the best examples of treating a disease using the holistic approach. While each case requires different combinations of modalities, the outcome is usually positive with individually selected treatments.

Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486).

An extremely ill patient, with Cushing's syndrome caused by an ACTH-secreting pituitary macroadenoma, experienced complications of end-stage cardiomyopathy, profound psychosis, and multiple metabolic disturbances. Initially treated unsuccessfully by a combination of conventional surgical, medical, and radiotherapeutic approaches, he responded dramatically to high-dose long-term mifepristone therapy (up to 25 mg/kg x d). Treatment efficacy was confirmed by the normalization of all biochemical glucocorticoid-sensitive measurements, as well as by the significant reversal of the patient's heart failure, the resolution of his psychotic depression, and the eventual unusual return of his adrenal axis to normal. His 18-month-long mifepristone treatment course was notable for development of severe hypokalemia that was attributed to excessive cortisol activation of the mineralocorticoid receptor, which responded to spironolactone administration. This case illustrates the efficacy of high-dose long-term treatment with mifepristone in refractory Cushing's syndrome. The case also demonstrates the potential need for concomitant mineralocorticoid receptor blockade in mifepristone-treated Cushing's disease, because cortisol levels may rise markedly, reflecting corticotroph disinhibition, to cause manifestations of mineralocorticoid excess.

Leptin and the pituitary.

Although leptin was originally viewed as an antiobesity hormone, it is now evident that it may have more pleiotropic actions. Experiments in rodents have shown that leptin activates the sympathetic nervous system, is involved in regulation of blood pressure, hematopoiesis, immune function, angiogenesis and brain, bone and pituitary development. Some biological effects expected based on observations in rodents, have so far not been seen in humans. Thus due to species differences in the role of leptin it is difficult to translate the data from rodents to human physiology. Hypothalamus is the primary brain site targeted by circulating leptin, secreted by fat cells. Leptin receptor has homology to members of class I cytokine receptor family, which may imply similarities in molecular events engaged by cytokines and leptin. In view of its cytokine-like properties it is likely that leptin produced and secreted outside of fat tissue i.e. in other tissues (CNS, pituitary, ovary, placenta, etc), is a paracrine regulator. Leptin receptor isoforms, long-signaling and short-nonsignaling, have been recently localized in human pituitaries. This opens the possibility of a direct action of leptin on the pituitary. However this appears to be quite complex and is species dependent. Leptin can be synthesized by normal and tumorous pituitary cells. Leptin protein expression in pituitary adenomas is decreased compared to that in normal pituitaries. Colocalization studies with leptin and anterior pituitary cells showed that 70% of ACTH cells are positive for leptin, 21% of GH cells, 29% of LH cells, 33% of FSH cells, 32% of TSH cells, 64% folliculo-stellate cells whereas very few PRL cells were positive (3%). Leptin is stored in secretory granules and secretory cells retain leptin in granules until stimulated. This follows a different secretory pathway than in adipocytes where upon synthesis leptin is immediately released. Question to be raised is does the pituitary contribute to the body leptin pool or is its action predominantly paracrine/autocrine? Clinically based evidence from studies performed in patients harboring different functional pituitary tumors causing a state of hormonal hypersecretion (acromegaly, prolactinomas, Cushing's disease) or hypopituitarism (due to non-functioning pituitary adenomas), are in favor of a paracrine/autocrine role of the pituitary leptin. Most of the studies have shown that the link between leptin, body composition and hormones of the pituitary is indirect. Thus changes in levels of circulating leptin are most likely due to changes in the metabolic and hormonal milieu during the chronic course of the disease or chronic treatment. Furthermore, circadian rhythm of leptin, its pulsatility and gender difference are preserved in hypopituitarism as well as in patients with functional pituitary adenomas implying that intact hypothalamic-pituitary function is not essential for leptin's circadian rhythm.

Cortisol as a mineralocorticoid in human disease.

The type 2 isozyme of 11beta-hydroxysteroid dehydrogenase inactivates cortisol to cortisone and enables aldosterone to bind to the MR. Congenital deficiency of the enzyme results in cortisol-mediated mineralocorticoid excess and arises because of inactivating mutations in the HSD11B2 gene. Inhibition of the enzyme following licorice or carbenoxolone ingestion results in a similar, though milder phenotype and the enzyme is overwhelmed in ectopic ACTH syndrome. Loss of 11beta-HSD2 expression may be important in sodium balance and blood pressure control in some patients with renal disease. Finally, while some studies demonstrate impaired 11beta-HSD activity in broader populations of patients with hypertension, further studies are required to clarify the role of 11beta-HSD2 in 'essential' hypertension.

Drug-induced Cushing syndrome in a patient with ulcerative colitis after betamethasone enema: evaluation of plasma drug concentration.

The authors report the induction of Cushing syndrome by daily betamethasone enema in a patient with ulcerative colitis, and they determine for the first time the pharmacokinetic profile of betamethasone after rectal dosing. The authors found high plasma concentrations of betamethasone, which could have been enough to cause Cushing syndrome. Suppression of the hypothalamus-pituitary-adrenal axis disappeared after the dose schedule was changed from every day to three times a week. These findings suggest that a considerable amount of betamethasone is absorbed after rectal dosing.

Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia.

We present two patients with Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia who showed marked plasma cortisol response to lysine-8-vasopressin (LVP) injection (from 930 and 731 pmol/L to 2177 and 1920 pmol/L, respectively), while plasma ACTH levels remained undetectable. The ACTH independence of cortisol secretion in the two patients was determined from the following endocrinological findings. Plasma cortisol levels were not increased by corticotropin-releasing hormone injections and were not suppressed by high dose (16 mg) dexamethasone administrations. The plasma ACTH levels, measured by two independent sensitive immunoassays, were persistently undetectable even after corticotropin-releasing hormone injection, metyrapone administration, and bilateral adrenalectomy. The particular pathological finding of the two cases, atrophic lesions in nonnodular parts of the adrenal cortexes, also indicated ACTH independence of the macronodular hyperplasia. In vitro examination revealed a direct effect of LVP on cortisol secretion from the adrenal cells of the macronodules. We also examined seven patients with Cushing's syndrome caused by adrenal adenoma and found a statistically significant plasma cortisol response to LVP injection. The direct effect of LVP was also demonstrated in cultured adenoma cells. In conclusion, we discovered a direct adrenal effect of LVP on cortisol secretion in patients with ACTH-independent macronodular hyperplasia and, to a lesser extent, in patients with cortisol-producing adrenal adenoma. The cortisol response to LVP may serve to facilitate their diagnosis and choice of therapy.

Abnormalities of endocrine function in patients with clinically "silent" adrenal masses.

Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28-74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low-normal range. Ovine corticotropin-releasing hormone (CRH, 1 microgram/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxy-progesterone (17-OHP) levels were not different from those in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic GLUT 4 expression: a glucose- and insulin-sensing mechanism?

The insulin-regulatable glucose transporter, GLUT 4, is expressed primarily in peripheral tissues (skeletal muscle and adipose tissue). In response to insulin this transporter moves rapidly from an intracellular storage site to the plasma membrane, thus accounting for the substantial increase in glucose uptake by these tissues following insulin stimulation. The recent finding that GLUT 4 is also expressed in the hypothalamus suggests that this brain region, which is outside the blood-brain barrier and therefore sensitive to circulating insulin, may experience stimulation of glucose uptake in response to insulin. We propose that this may allow regions of the hypothalamus to respond directly to elevated blood glucose, constituting a form of metabolic regulation by allowing circulating glucose (and therefore insulin) in concert with other mechanisms to maintain blood glucose homeostasis. We consider the possible physiological role of such a mechanism and speculate that disturbances of this mechanism may occur in endocrine disease associated with insulin resistance.

A case of ruptured dissecting aneurysm 5 years after pituitary microsurgical treatment of Cushing's disease: autopsy findings in the hypothalamic-pituitary-adrenal axis.

The patient was a 26-year-old man with Cushing's disease who underwent transsphenoidal microscopic surgery for a pituitary microadenoma. His postoperative course was uneventful, but he died suddenly five years after the operation. At autopsy, a ruptured dissecting aneurysm with marked atherosclerosis was observed in the aorta. In the pituitary, a small focus of adrenocorticotropic hormone (ACTH) producing adenoma, possibly residual adenoma, was detected and Crooke's degeneration was observed in the non-tumorous pituitary gland. But immunohistochemical patterns of pituitary hormones in the non-tumorous pituitary gland were normal and the adrenal cortex was unremarkable. In the hypothalamus, corticotropin-releasing hormone immunoreactivity was not detected and arginine vasopressin was sporadically positive. Considering these findings, this patient may have developed subclinical hypercortisolism due to the residual adenoma at the time of autopsy, despite clinical remission. Cushing's syndrome is considered to be a risk factor dissecting aneurysm, and in this case the metabolic changes in Cushing's disease may have influenced the development of the dissecting aneurysm. Periodic cardiovascular re-evaluations should therefore be performed when there is clinical remission of Cushing's syndrome.

The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic-pituitary-adrenal axis in patients with Cushing syndrome.

Patients cured from endogenous Cushing syndrome usually develop postoperative adrenal suppression in the year ensuing surgery. To define whether the pituitary corticotroph is the rate limiting step in the postoperative recovery of this secondary/tertiary form of adrenal insufficiency, we examined surgically cured patients with Cushing syndrome 10 days, 3 months, and 6-12 months after surgery, by administering ovine CRH (oCRH) iv at the dose of 1 microgram/kg.h over 24 h. The pituitary corticotroph of these patients responded vigorously to oCRH, with ACTH concentrations reaching above the normal range at all three times of testing. Parallel measurements of cortisol in nonadrenalectomized patients demonstrated subnormal adrenal responsiveness at 10 days and 3 months and normalization at 6-12 months after surgery. The circadian rhythm of ACTH was maintained postoperatively at 10 days and 6-12 months, and the circadian rhythm of cortisol was also present at 6-12 months after surgery, in spite of the constant infusions of pharmacological doses of oCRH, suggesting that factors other than CRH secretion regulate this rhythm. We conclude that the corticotroph is not the rate limiting step in the recovery of the hypothalamic-pituitary-adrenal axis from glucocorticoid-induced adrenal suppression, and that the locus of the defect resides in the hypothalamic CRH neuron and/or its higher regulatory inputs.

Growth hormone releasing hormone priming increases growth hormone secretion in patients with Cushing's syndrome.

OBJECTIVE: In patients with Cushing's syndrome, decreased growth hormone (GH) secretion is observed though the basic mechanism is unknown. In states of chronic deficiency of hypothalamic growth hormone releasing hormone (GHRH) release, a blunted GH response to exogenous GHRH has been reported; such impairment can be partially normalized by repetitive GHRH administration (priming). In order to clarify whether a deficit in hypothalamic release of GHRH is the basis of the decreased GH secretion in patients with Cushing's syndrome, GHRH plus pyridostigmine tests were undertaken, both before and after GHRH priming. DESIGN: GHRH (200 micrograms/day as a single s.c. injection) was given daily over 7 days. Two pyridostigmine (120 mg p.o.) plus GHRH (100 micrograms i.v.) tests were performed before and after priming to assess GH response. PATIENTS: Eight patients (seven women, one man), with untreated Cushing's syndrome (six Cushing's disease, one autonomous bilateral adrenal hyperplasia, one adrenal adenoma), were studied. MEASUREMENTS: Plasma GH levels were measured by immunoradiometric assay. RESULTS: GHRH plus pyridostigmine-induced GH release was impaired in patients with untreated Cushing's syndrome (mean peak 5.2 +/- 1.4 mU/l, area under the curve (AUC) 472 +/- 96). Repetitive administration of GHRH over 7 days partially restored the GH response to the second pyridostigmine-GHRH test (mean peak 15.0 +/- 2.1 mU/l. AUC 1016 +/- 104), both P < 0.05. All of the eight Cushing's syndrome patients studied presented a higher GHRH plus pyridostigmine-induced GH secretion after priming. CONCLUSIONS: Repetitive administration of GHRH increases the pyridostigmine-GHRH-induced GH secretion in patients with Cushing's syndrome. This suggests that impaired hypothalamic release of GHRH is a contributing factor to the decreased GH secretion observed in chronic hypercortisolism.