MANAGEMENT OF ENDOCRINE DISEASE: Can we cure Cushing's disease? A personal view.

One of today's challenges in endocrinology is the treatment of Cushing's disease: Although pituitary surgery has the potential to 'cure' the patient and restore a completely normal pituitary adrenal axis, there are immediate failures and late recurrences that will ultimately require alternate therapeutic approaches. Their high number is in direct correlation with their serious limitations and they all appear to be 'default options'. This 'personal view' tries to shed some light on the inescapable difficulties of the current treatments of Cushing's disease and to provide some optimistic view for the future where the pituitary adenoma should be the 'reasonable obsession' of a successful therapeutist.

Effect of laparotomy on the pituitary-adrenal axis in dogs.

OBJECTIVE To assess effects of major abdominal surgery on serum cortisol and aldosterone and plasma canine ACTH (cACTH) concentrations. ANIMALS 39 healthy dogs undergoing laparotomy during veterinary student surgical laboratories. PROCEDURES Blood samples were obtained before and at completion of surgery. Serum cortisol and aldosterone and plasma cACTH concentrations were measured by use of validated radioimmunoassays. Changes in concentrations (postoperative concentration minus preoperative concentration) were calculated. Data were analyzed by use of the Wilcoxon signed rank test, Pearson correlation analysis, and Mann-Whitney rank sum test. RESULTS Cortisol, aldosterone, and cACTH concentrations increased significantly from before to after surgery. Although cortisol and aldosterone concentrations increased in almost all dogs, cACTH concentrations decreased in 6 of 32 (19%) dogs. All dogs had preoperative cortisol concentrations within the reference range, but 24 of 39 (62%) dogs had postoperative concentrations above the reference range. A correlation between the change in cACTH concentration and the change in cortisol concentration was not detected. CONCLUSIONS AND CLINICAL RELEVANCE Laparotomy caused a significant increase in serum cortisol and aldosterone concentrations. In most dogs, but not all dogs, plasma cACTH concentrations increased. Lack of correlation between the change in cACTH concentration and the change in cortisol concentration suggested that increased postoperative cortisol concentrations may have been attributable to ACTH-independent mechanisms, an early ACTH increase that caused a sustained cortisol release, or decreased cortisol clearance. Further studies are indicated to evaluate the effects of various anesthetic protocols and minimally invasive surgical techniques on the stress response.

Transphenoidal surgery without steroid replacement in patients with morning serum cortisol below 9 µg/dl (250 Nmol/l).

BACKGROUND: Adrenal insufficiency is a feared complication in patients undergoing transphenoidal surgery (TSS). Using the insulin tolerance test (ITT) for the preoperative assessment of hypothalamic-pituitary-adrenal (HPA) status is less than ideal, and the morning serum cortisol (MSC) is often used as a proxy for ITT. However, neither the ITT nor the MSC level has been validated to indicate HPA sufficiency compared to a physiological gold standard such as patients' ability to withstand transphenoidal surgery. OBJECTIVE: To evaluate the intraoperative and postoperative course of nine patients with non-ACTH-secreting pituitary adenomas who did not receive intraoperative cortisol replacement despite having a preoperative MSC below 9 µg/dl (250 nmol/l) and to compare this with a set of patients with a preoperative MSC greater than 14.5 µg/dl (400 nmol/l) and another set of patients with MSC below 9 µg/dl (250 nmol/l) who received intraoperative cortisol administration. METHODS: Preoperative and day 1 and day 2 postoperative MSC, intraoperative anesthetic record, vital signs, fluid balance, medications, and complications were recorded. RESULTS: None of the patients experienced the full syndrome of adrenal insufficiency. One patient with a preoperative MSC <9 µg/dl (250 mol/l) had isolated postoperative fatigue and required cortisol replacement. No patient suffered any life-threatening complications. There were no differences among the three groups in their intraoperative or postoperative courses when compared for intraoperative hypotension, acute blood pressure drop, and administration of vasopressors. CONCLUSION: This study suggests that TSS can be performed safely in patients with preoperative MSC less than 9 µg/dl (250 nmol/l) in closely monitored settings without intraoperative cortisol administration. Further studies are warranted.

Recovery of the hypothalamic-pituitary-adrenal axis in children and adolescents after surgical cure of Cushing's disease.

CONTEXT: Recovery of the hypothalamic-pituitary-adrenal axis (HPAA) after transsphenoidal surgery (TSS) for Cushing's disease (CD) in children has not been adequately studied. OBJECTIVE: Our objective was to assess time to recovery of the HPAA after TSS in children with CD. DESIGN AND SETTING: This was a case series at the National Institutes of Health Clinical Center. PATIENTS: Fifty-seven patients with CD (6-18 yr, mean 13.0 ± 3.1 yr) given a standard regimen of glucocorticoid tapering after TSS were studied out of a total of 73 recruited. INTERVENTIONS: ACTH (250 µg) stimulation tests were administered at approximately 6-month intervals for up to 36 months. Age, sex, pubertal status, body mass index, length of disease, midnight cortisol, and urinary free cortisol at diagnosis were analyzed for effects on recovery. MAIN OUTCOME MEASURE: The main outcome measure was complete recovery of the HPAA as defined by a cortisol level of at least 18 µg/dl in response to 250 µg ACTH. RESULTS: Full recovery was reached by 43 (75.4%) of 57 patients, with 29 of the 43 (67.4%) and 41 of the 43 (95.3%) recovering by 12 and 18 months, respectively. The overall mean time to recovery was 12.6 ± 3.3 months. Kaplan-Meier survivor function estimated a 50% chance of recovering by 12 months after TSS and 75% chance of recovering within 14 months. By receiver operating characteristic curve assessment, the cutoff of at least 10-11 µg/dl of cortisol as the peak of ACTH stimulation testing at 6 months after TSS yielded the highest sensitivity (70-80%) and specificity (64-73%) to predict full recovery of the HPAA at 12 months. Two of the four patients that recovered fully within 6 months had recurrent CD. CONCLUSIONS: Although this is not a randomized study, we present our standardized tapering regimen for glucocorticoid replacement after TSS that led to recovery of the HPAA in most patients within the first postoperative year. Multiple factors may affect this process, but an early recovery may indicate disease recurrence.

Can basal cortisol measurement be an alternative to the insulin tolerance test in the assessment of the hypothalamic-pituitary-adrenal axis before and after pituitary surgery?

BACKGROUND: The aims of this study were to evaluate the validity of preoperative basal serum cortisol levels measured in predicting preoperative adrenal insufficiency and also the validity of basal serum cortisol levels and early postoperative insulin tolerance test (ITT) in predicting postoperative adrenal insufficiency. METHODS: The study was prospectively designed and included 64 patients who underwent pituitary surgery for conditions other than Cushing's disease. An ITT was performed preoperatively, on the 6th postoperative day and at the 1st postoperative month. Basal serum cortisol levels were measured on the 2nd, 3rd, 4th, 5th, and 6th postoperative days. RESULTS: Patients with a preoperative basal cortisol level of <165 nmol/l (6 microg/dl) showed insufficient cortisol response and those with levels higher than 500 nmol/l (18 microg/dl) had sufficient cortisol response to the preoperative ITT. The positive predictive value of the ITT performed on the 6th postoperative day was 69.7%, and the negative predictive value in predicting adrenal insufficiency at the 1st postoperative month was 58%. Patients were considered to have an insufficient cortisol response to ITT at the 1st postoperative month if their basal cortisol levels were <193 nmol/l (7 microg/dl) or 220 nmol/l (8 microg/dl) or 193 nmol/l (7 microg/dl) or 165 nmol/l (6 microg/dl) or 83 nmol/l (3 microg/dl) on the 2nd-6th postoperative days respectively. CONCLUSION: Serum basal cortisol levels may be used as the first-line test in the assessment of the hypothalamic-pituitary-adrenal axis both preoperatively and postoperatively. Dynamic testing should be limited to the patients with indeterminate basal cortisol levels.

Role of the hypothalamo-pituitary-adrenal axis in the modulation of pollinosis induced by pollen antigens.

BACKGROUND: To clarify the mechanism of stress-induced modification of allergic diseases, we studied the effect of restraint stress on plasma levels of cytokines and the symptoms of pollinosis in mice. METHODS: The effects of restraint stress and the role of the hypothalamo-pituitary-adrenal axis (HPA-axis) in the development of pollen antigen-induced pollinosis were studied in control, hypophysectomized, adrenalectomized or ACTH-administered mice. Twenty days after sensitization, animals were subjected to mild restraint stress for 3 hours, and plasma levels of IFN-gamma, IL-10, and IgE were measured. We analyzed the incidence of sneezing and nasal rubbing in the sensitized animals. RESULTS: Plasma levels of IL-10 and IgE increased in the sensitized animals with a concomitant increase in the incidence of sneezing and nasal rubbing. The increases in plasma IgE, IL-10 and the incidence of sneezing and nasal rubbing were suppressed by restraint stress. Adrenalectomy increased IFN-gamma, inhibited the increase in plasma IL-10 and IgE, and suppressed the incidence of sneezing. In contrast, hypophysectomy increased plasma levels of IL-10, IFN-gamma, and IgE and the incidence of sneezing. Intraperitoneal administration of ACTH decreased IL-10 in plasma but increased IFN-gamma and suppressed the incidence of nasal rubbing. CONCLUSIONS: The present findings show that the HPA-axis and ACTH play important roles in the regulation of plasma cytokines and IgE thereby modulating symptoms of pollinosis. The results also suggest that a mild restraint stress suppresses the increase in Th2-dependent cytokines and IgE to reduce the symptoms of pollinosis.

Subclinical Cushings disease with amelioration of metabolic comorbidities after removal of pituitary tumor.

A 49-year-old woman with hypertension, obesity and impaired glucose tolerance (IGT) was admitted for evaluation of pituitary incidentaloma. Although she presented no Cushingoid feature, endocrine examination of hypothalamo-pituitary-adrenal (HPA) axis showed elevated basal plasma ACTH and cortisol levels, their lack of circadian rhythm, non-suppressibility to low-dose (1 mg) dexamethasone, and responsiveness to CRH, suggesting autonomous ACTH secretion from a pituitary tumor. She underwent transsphenoidal surgery, and was diagnosed as chromophobe adenoma with positive ACTH immunoreactivity. Postoperatively, her abnormal HPA axis was resolved, along with improvement of hypertension, obesity and IGT. Thus, her metabolic comorbidities are likely due to subclinical Cushings disease.

Relapsing acute adult epiglottitis following hypophysectomy.

Adult epiglottitis is an uncommon disease that may become fatal because of sudden airway obstruction. Recurrent adult epiglottitis has been reported rarely in the literature. We present a case of relapsing epiglottitis in a patient with corticosteroid insufficiency secondary to pituitary surgery. It is the first case to highlight this infection occurring in a relapsing manner in a patient with pituitary-adrenocortical insufficiency on long-term steroid replacement therapy.

Disruptions of the hypothalamo-pituitary-adrenal axis increase anticancer drug lethality in the rat.

We have previously shown that toxicity of the anticancer agent hydroxyurea (HU) in the rat is markedly increased by hypophysectomy or adrenalectomy. In this study, we investigated whether increased toxicity in ablated animals is a unique feature of HU or it is shared with other anticancer agents; the toxic effects of five such drugs have been compared in intact, hypophysectomized (HYX) and adrenalectomized (ADX) rats. Bis-chloroethyl-nitrosourea (BCNU, 5-10 mg/kg), busulfan (0.1-10 mg/kg), cyclophosphamide (25-125 mg/kg), 5-fluorouracil (15-75 mg/kg) and vindesine (0.1-0.5 mg/kg) were given to intact and endocrine-ablated rats, and lethality was recorded over 3 weeks. It was found that mortality was low or absent in intact rats, whereas (with the exception of HYX rats receiving the highest dose of busulfan) it was dramatically increased by both hypophysectomy and adrenalectomy. However, replacement treatments with long-acting tetracosactrin and corticosterone to HYX and ADX rats respectively afforded significant protection against BCNU toxicity only. We conclude that the integrity of the hypothalamo-pituitary-adrenal axis is needed to tolerate the toxicity of various anticancer drugs, although complex mechanisms appear to underlie such protective effect.