I. Introduction II. Definitions and Etiology III. Diagnostic Overview IV. Clinical Features V. Biochemical Diagnosis of Cushing’s Syndrome A. Cardinal features B. Urinary free cortisol (UFC) C. Low-dose dexamethasone testing D. Circadian rhythm assessment E. Cyclical Cushing’s syndrome VI. ACTH-Dependent vs. ACTH-Independent Cushing’s Syndrome VII. Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome A. Overview B. Basal testing C. Dynamic noninvasive testing D. Invasive testing VIII. Other Causes of Cushing’s Syndrome IX. Imaging A. Pituitary B. Adrenal C. Ectopic secretion X. Differentiation from Pseudo-Cushing’s States XI. Conclusions

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The Diagnosis and Differential Diagnosis of Cushing’s Syndrome and Pseudo-Cushing’s States

Summary
Background Craniopharyngiomas account for 2–5% of all primary intracranial tumours. Despite their benign histological appearance, they are often associated with an unfavourable prognosis and their optimal treatment remains controversial.

Aim  To analyse the natural history and treatment outcome of children and adults presenting to the Departments of Paediatrics and Endocrinology with craniopharyngioma between 1964 and 2003.

Patients and methods  The records of 121 patients (age range 2·5–83 years, 42 aged < 16 and 79 aged ≥ 16) were identified. The mean follow-up period since presentation was 103 months (8·6 years) (range 0·3–468 months). Sixteen patients underwent gross total removal (A), 3 gross total removal + radiotherapy (B), 51 partial removal (C), 33 partial removal + radiotherapy (D), 6 cyst evacuation alone (E) and 3 cyst evacuation + radiotherapy (F). The clinical, imaging and endocrinological data at presentation and during follow-up were analysed.

Results  Headache and visual field defects were the most common presenting clinical features (64% and 55%, respectively). Ninety-four per cent of the tumours had an extrasellar component and 23% of them were associated with hydrocephalus. There was a significant difference in the recurrence-free survival rates between groups A–D [at 10 years: 100% (A), 100% (B), 38% (C) and 77% (D), P < 0·01], which persisted even when analysing patients operated after 1980. The median time of first recurrence was 2·5 years (range 0·5–36). The peri-operative mortality of the patients who had any type of neurosurgical intervention due to recurrence was higher than that observed after primary surgery (24%vs. 1·8%) (P < 0·01). The rate of re-accumulation of the cyst fluid was 58% during the first year in patients of group E, whereas none of the subjects of group F experienced such an event during their follow-up period. There was no reversal of pre-existing pituitary hormone deficits after any surgical intervention. The probabilities of GH, FSH/LH, ACTH, TSH deficiency and diabetes insipidus at the 10-year follow-up were 88%, 90%, 86%, 80% and 65%, respectively. After excluding the non-tumour-related deaths, the 10-year survival rate following presentation was 90%. Patients with recurrence had a significantly lower probability for survival compared with those without it (at 10 years: 70%vs. 99%, P < 0·01). At the 10-year follow-up the probability of the presence of major visual field defects was 48%, hyperphagia/obesity 39%, epilepsy 12% and hemi-/monoparesis 11%. In this large series no substantial differences in the outcome of tumours diagnosed during childhood or adult life were found.

Conclusions  Craniopharyngiomas remain tumours associated with significant morbidity. Gross total removal provides favourable results in terms of recurrences. If this cannot be achieved safely, adjuvant radiotherapy is beneficial in preventing tumour re-growth. Childhood- and adult-onset lesions generally behave similarly.

Craniopharyngiomas in children and adults: systematic analysis of 121 cases with long‐term follow‐up

The past 45 yr’ experience with Cushing’s syndrome (CS) has led to the awareness of its complex nature and, by the same token, brought about an increase in the diagnostic and therapeutic dilemmas. We carried out a retrospective multicentre study on the diagnostic work-up and treatment in 426 patients with CS, subdivided as follows: 288 with Cushing’s disease (CD), 80 with an adrenal adenoma, 24 with an adrenal carcinoma, 25 with ectopic ACTH and/or CRH secretion, and 9 with ACTH-independent nodular adrenal hyperplasia. Normal urinary free cortisol (UFC) values among multiple collections were recorded in about 10% of patients with CS. In 28% of patients with ACTH-independent CS, basal ACTH concentrations were within the normal range but did not respond to CRH stimulation. Measurement of ACTH levels by immunoradiometric assay, rather than by RIA, offered a greater chance of recognizing patients with ACTH-independent CS or ectopic secretion. A 50% increase in ACTH or cortisol levels after CRH yielded a diagn...

Diagnosis and management of Cushing's syndrome : Results of an Italian multicentre study

Pituitary disease is associated with increased mortality predominantly due to vascular disease. Control of cortisol secretion and GH hypersecretion (and cardiovascular risk factor reduction) is key in the reduction of mortality in patients with Cushing's disease and acromegaly, retrospectively. For patients with acromegaly, the role of IGF-I is less clear-cut. Confounding pituitary hormone deficiencies such as gonadotropins and particularly ACTH deficiency (with higher doses of hydrocortisone replacement) may have a detrimental effect on outcome in patients with pituitary disease. Pituitary radiotherapy is a further factor that has been associated with increased mortality (particularly cerebrovascular). Although standardized mortality ratios in pituitary disease are falling due to improved treatment, mortality for many conditions are still elevated above that of the general population, and therefore further measures are needed. Craniopharyngioma patients have a particularly increased risk of mortality as a result of the tumor itself and treatment to control tumor growth; this is a key area for future research in order to optimize the outcome for these patients.

Mortality in Patients with Pituitary Disease

Objective To determine the prevalence and incidence of hypopituitarism in the general population. Population The study population comprised an average population sample of 146,000 adult inhabitants in South Galicia (northwestern Spain). The Medical Register of the General Hospital of Vigo ensured virtually complete case ascertainment for diagnosed hypopituitarism in this sample population. Only patients residing in the study area were included. The diagnosis of hypopituitarism was based on baseline and hormonal dynamic tests. Design The study comprised two cross-sectional surveys, the first from January to December 1992 and the second from January to December 1999, together with a longitudinal survey performed between January 1993 and December 1999. Main results In the first survey the prevalence of hypopituitarism was 29/100,000 (CI, 19.88-37.72), without sex differences. In the second survey, the prevalence observed was higher than in the first, 45.5/100,000 (CI, 34.92-56.08). In the second survey, which included almost all cases registered in the first study, the cause of hypopituitarism was a pituitary tumour in 61%, a non-pituitary tumour in 9% and a non-tumour cause in 30%. Around 50% of patients had 3-5 pituitary hormonal deficiencies, with LH/FSH being the most prevalent. Patients with tumour-induced hypopituitarism showed a tendency to suffer GH deficiency more frequently than those due to non-tumour causes. In the longitudinal study with a population of 1,020,764 people-years of observation, the average annual incidence rate of hypopituitarism was 4.21 cases/100,000 (CI, 2.95-5.47), with this incidence being similar for both sexes. The annual incidence of hypopituitarism remained stable during the study period. Conclusion We present for the first time data on the prevalence and incidence of hypopituitarism in the general adult population. These patients showed a tendency to suffer LH/FSH deficiency as the most prevalent hormone deficit. Furthermore, patients with hypopituitarism due to a tumour or its treatment showed a greater tendency to suffer GH deficiency than those with a non-tumour cause. These data may be useful for producing a rational programme for patients suffering from this condition and also for comparison with future data in our country and elsewhere in the world.

Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain

OBJECTIVE While inferior petrosal sinus (IPS) sampling correctly diagnoses pituitary-dependent Cushing's syndrome if a significant ratio of plasma ACTH between the IPS and the peripheral blood is demonstrated, little has been said about the significance of a negative ratio in Cushing's disease (e.g. a false-negative result). This study evaluates the results of IPS sampling in patients with Cushing's disease, and compares them with both imaging findings and transsphenoidal examination.

DESIGN The results of IPS sampling were retrospectively compared with both imaging findings and transsphenoidal examination. IPS samples were obtained before and 2, 5 and 10 minutes after intravenous administration of 100 μg of CRH.

PATIENTS Thirty-two patients with Cushing's disease were evaluated. All subsequently underwent transsphenoidal examination of the pituitary gland.

MEASUREMENTS The ratio of the ACTH concentrations at the IPS and in the peripheral blood (IPS : P ratio), and the ratio of the ACTH concentrations between the IPSs (interpetrosal ratio) were calculated. Radiographic evaluation of the pituitary gland was performed with magnetic resonance imaging (MRI, 29 cases) or computed tomography imaging (CT, 3 cases).

RESULTS Transsphenoidal examination of the pituitary gland revealed a microadenoma in 27 cases. Radiological imaging showed a signal compatible with a microadenoma in 22 cases (68.8%), and correctly located the tumour at the side found at surgery in 14 of the 22 cases with positive transsphenoidal findings (MRI 13 cases, CT 1 case, overall 63.6%). Successful bilateral catheterization was accomplished in 30 patients (93.8%). Samples before and after CRH stimulation were drawn in 24 cases. No major complications were observed with the technique. IPS catheterization correctly predicted Cushing's disease (by means of a significant IPS : P ACTH ratio) in 27 of the 30 patients (90%) with basal sampling, and in 23 of the 24 cases with samples drawn before and after CRH administration (95.8%). Taking into account the 12 patients with a lateral microadenoma shown at transsphenoidal examination, IP sinus ACTH ratio was in agreement with the side recorded by the neurosurgeon in 8/12 cases (66.7%). MRi correctly located the tumour in 8/12 patients (66.7%). One patient showed no significant IPS : P ACTH ratio in any set of samples. His MRI showed no sign of a microadenoma. Two years later, another pituitary MRI evaluation showed a midline hypodense signal. The transsphenoidal examination revealed a microadenoma and the post-operative plasma cortisol and urinary free cortisol fell to 293 nmol/l and 100 nmol/24 h, respectively.

CONCLUSIONS Only when a significant IPS : P ACTH ratio is present can Cushing's disease be established by IPS sampling. The absence of a significant IPS : P ACTH ratio does not necessarily imply ectopic secretion of ACTH, nor does it exclude Cushing's disease. The results of lateralization by IPS sampling do not remove the need for a thorough transsphenoidal examination of the contents of the sella turcica.

Petrosal sinus sampling for diagnosis of Cushing's disease: evidence of false negative results

Summary
OBJECTIVE Previous studies of preoperative pituitary function in patients with craniopharyngioma have been limited in scope and have focused on children. We have evaluated the impact of craniopharyngiomas and their surgical treatment on pituitary function In a large group of mostly adult patients.

DESIGN We performed a retrospective study of patients treated at our centre between 1980 and 1992.

PATIENTS Twenty-two men and 13 women, most of them adults, treated surgically for craniopharyngioma during the above period.

MEASUREMENTS Serum glucose, GH, LH, FSH, TSH and Cortisol were measured both before and after a combined insulin induced hypoglycaemia, GnRH and TRH test. Basal concentrations of thyroid hormones, PRL and gonadal steroids were also measured. Preoperative computed tomographic scan was performed in all patients, and a detailed study of visual function before and after surgery was available for 32 of them. Endocrine function was reevaluated post-operatively.

RESULTS In preoperative studies, 29 patients had some anterior pituitary deficit and 13 had diabetes insipidus. The most common abnormality was gonadotrophin deficiency, followed by GH deficiency. Dynamic studies suggested a hypothalamic origin for these deficits. In post-surgical evaluation, Impaired pituitary function was observed in most patients. Panhypopituitarism was present in 28 cases and diabetes insipidus in 24.

CONCLUSIONS Our report illustrates the high Incidence of endocrine deficits in patients with craniopharyngioma. Additional hypothalamic-pituitary dysfunction usually occurs following surgical treatment of these tumours.

F. Salame

Papers

Petrosal sinus sampling for diagnosis of Cushing's disease: evidence of false negative results

Hypothalamic‐pituitary dysfunction in patients with craniopharyngioma

The stress and strain pattern in the ligaments of the acromioclavicular joint using a quasi-static model.