High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas.

OBJECTIVES: Previous studies based on standard endocrine testing have shown a variable incidence of autonomous cortisol secretion (ACS) or autonomous aldosterone secretion (AAS) in patients with single adrenal adenomas (SAA). We tested whether the use of appropriate controls and modification of standard testing, aiming at eliminating interference from endogenous ACTH, reveals previously undetected subtle ACS and AAS by SAA. DESIGN: Case control study. Patients We investigated 151 patients with SAA and 72 matched controls with normal adrenal computerized tomography. MEASUREMENTS: All participants had arterial blood pressure recorded, and serum cortisol and aldosterone measured before and after intravenous administration of 250 mug of ACTH, and following dexamethasone administration. Eighty-three patients and all the controls had serum aldosterone and renin measured before and after saline infusion, and after a second saline infusion following dexamethasone administration. RESULTS: Using the mean + 2 SD values obtained from controls after dexamethasone administration and saline infusion following dexamethasone administration, normal cut-off values for cortisol (30.11 nM), aldosterone (67.59 pM), and aldosterone/renin ratio (9.74 pM/mU/l) were developed. Using these cut-off values, the estimated incidence of ACS and AAS in patients with SAA was 56.63% and 24.10%, respectively, whereas 12.05% had autonomous secretion of both cortisol and aldosterone. Systolic and diastolic arterial blood pressure correlated significantly with the aldosterone/renin ratio following AlphaCTH stimulation (P < 0.0002 and P < 0.001, respectively), and after saline infusion following dexamethasone administration (P < 0.003 and P < 0.002, respectively). CONCLUSIONS: By applying new cut-offs, ACS and AAS in patients with a SAA is very common, and aldosterone secretion correlates with arterial blood pressure.

Polycystic ovaries and the polycystic ovary syndrome phenotype in women with active acromegaly.

BACKGROUND: Previous retrospective studies have suggested that women with acromegaly may present with menstrual irregularity and symptoms/signs of hyperandogenism, a phenotype similar to that of the polycystic ovary syndrome (PCOS). OBJECTIVE: The aim of this study was to investigate prospectively the presence of the PCOS phenotype (PCOSP) and polycystic ovaries (PCO) on ultrasonography in women with active acromegaly. DESIGN: Women within the reproductive age range (21-43 years) with active acromegaly of recent onset and/or previous surgical and/or medical therapy were studied. MAIN OUTCOME MEASURES: Subjects underwent a physical examination; fasting bloods for androgens, pituitary hormones and metabolic parameters; an oral glucose tolerance test (OGTT) to estimate disease activity and insulin resistance; and a transvaginal ultrasound. RESULTS: Six women had newly diagnosed acromegaly, and eight still had active disease following previous surgical and/or medical treatment. Seven women were found to have PCO and six fulfilled the criteria for PCOSP; six of these women, five with PCOSP, had a pituitary macroadenoma. Women with PCOSP had significantly increased mean ovarian volumes and characteristic ovarian morphology compared to women without PCOSP (P < 0.05), higher levels of IGF-1 and testosterone and lower SHBG levels that did not reach statistical significance. A positive correlation between IGF-1 and mean ovarian volume was identified only in women with PCOSP (r = 0.851, P < 0.05). CONCLUSIONS: PCO and PCOSP are relatively common in women with acromegaly and may account for some of the symptoms related to gonadal dysfunction irrespective of the size of the pituitary tumour. It is likely that IGF-1 alone or in combination with GH and/or insulin resistance may be involved.

Carcinoid syndrome and carcinoid crisis secondary to a metastatic carcinoid tumour of the lung: a therapeutic challenge.

We describe a 53-year-old male patient, with a known history of metastatic carcinoid tumour of the lung, who developed a variety of symptoms of the carcinoid syndrome and subsequently a carcinoid crisis. Although bronchial carcinoid tumours are very rarely associated with symptoms of the carcinoid syndrome, a subset may develop a severe hypersecretory syndrome and exhibit an aggressive behaviour. In cases with excessive tumour load and difficult-to-control hypersecretory syndrome, management by a specialized multidisciplinary team using evidence-based regimens is mandatory to deal with the life-threatening carcinoid crisis, to improve patients' outcome and quality of life.

The diagnosis and differential diagnosis of endogenous Cushing's syndrome.

Cushing's syndrome (CS) is a physically and psychologically disabling disease associated with high morbidity resulting from inappropriate elevation of circulating free cortisol levels. The main features of CS are disturbance of the normal circadian rhythm of cortisol secretion, impairment of the normal feedback of the hypothalamo-pituitary-adrenal (HPA)-axis, and excessive integrated 24 hours cortisol secretion. All biochemical tests used for the diagnosis of CS rely upon the ascertainment of a disturbance of these features. However, the diagnosis of CS (endogenous hypercortisolism) still remains a challenge, although the evolution of several diagnostic tests has allowed diagnosis at an earlier stage. In the initial investigation of CS, tests of high sensitivity are required to identify patients at risk, which are followed by tests of high specificity to confirm the diagnosis and establish the precise aetiology. This review will discuss the various causes of endogenous CS and focus on established and evolving diagnostic procedures used for its diagnosis, as several studies with large number of patients have recently appeared in the literature validating current practice and proposing improved diagnostic algorithms.

A unique case of a benign adrenocortical tumor with triple secretion of cortisol, androgens, and aldosterone: development of multiple sclerosis after surgical removal of the tumor.

We present a 39-year old female with a benign adrenal tumor characterized by autonomous secretion of cortisol, androgens, and aldosterone. The patient presented with a 4-year history of hypertension and severe hirsutism. Baseline investigations revealed elevated testosterone, androstendione, and 17OH progesterone with normal levels of dehydroepi androsterone sulfate. CT of the adrenals revealed a 2.5 x 3.0 cm tumor with characteristics of an adenoma on the left adrenal gland. Pelvic ultrasound was normal. Further investigations revealed suppressed basal ACTH levels, loss of diurnal rhythm of cortisol, and failure to suppress on low dose dexamethasone suppression test, suggesting autonomous cortisol secretion by the tumor. She had an exaggerated response of 17OH progesterone to ACTH, implying reduced 21-hydroxylase activity. An elevated plasma aldosterone concentration to plasma renin activity ratio was suggestive of hyperaldosteronism, which was confirmed by failure of aldosterone to suppress to a formal saline infusion test. Complete clinical and biochemical remission of the disease was observed after left adrenalectomy. Histology confirmed the presence of an adrenocortical adenoma. The patient developed multiple sclerosis 6 months after the operation. The flare-up of an autoimmune disease (multiple sclerosis) postoperatively could be coincidental or possibly related to the high normalization of the high cortisol levels acting as a precipitating factor.

Recent advances in radiological and radionuclide imaging and therapy of neuroendocrine tumours.

Neuroendocrine tumours (NETs) constitute a heterogeneous group of tumours that are able to express cell membrane neuroamine uptake mechanisms and/or specific receptors, such as somatostatin receptors, which can be of great value in the localization and treatment of these tumours. Scintigraphy with (111)In-pentetreotide has become one of the most important imaging investigations in the initial identification and staging of gastro-enteropancreatic (GEP) tumours, whereas helical computed tomography (CT), magnetic resonance imaging (MRI), endoscopic and/or peri-operative ultrasonography are used for the precise localization of GEPs and in monitoring their response to treatment. Scintigraphy with (123)I-MIBG (meta-iodobenzylguanidine) is sensitive in the identification of chromaffin cell tumours, although scintigraphy with (111)In-pentetreotide may also have a role in the localization of malignant chromaffin cell tumours and medullary thyroid carcinoma; for further localization and monitoring of the response to treatment both CT and MRI are used with high diagnostic accuracy. More recently, positron emission tomography (PET) scanning is being increasingly used for the localization of NETs, particularly when other imaging modalities have failed, although its precise role and utility remain to be defined. Surgery is still the usual initial therapeutic, and only curative, modality of choice; however, the majority of NETs will require further treatment with somatostatin analogues and/or interferon; chemotherapy may be used for progressive and highly aggressive NETs, but its role has not been clearly defined. For those NETs that demonstrate uptake to a diagnostic scan with (123)I-MIBG or (111)In-octreotide, therapy with radionuclides such as (131)I-MIBG or (111)In/(90)Y-octreotide or other isotopes, presents a further evolving therapeutic modality.

GH deficiency in adults.

Until the last decade, the diagnosis of GH deficiency (GHD) in adults was only considered as a marker of hypothalamo-pituitary disease. GHD in adults is now recognized as a specific clinical syndrome associated with a cluster of cardiovascular risk factors such as altered body composition with increased body fat, insulin resistance, adverse lipid profile, reduced physical performance, reduced bone mineral density and impaired quality of life. Several randomized placebo controlled trials have now established that GH replacement can reverse some of these biological changes and improve the overall health status in GHD adults; as a consequence, GH replacement therapy has now been approved in many countries in such patients. With the advent of recombinant technology, there is a virtually unlimited, safe supply of recombinant human GH. Although GH replacement is not administered as commonly as steroid, thyroid and sex hormones in hypopituitary patients, a six-month trial of GH replacement with re-evaluation of well-being, body composition and lipid profile is currently recommended. However, there is marked individual variability in the response to GH replacement, with IGF-I being the most sensitive serum marker of GH action. Questions yet remaining to be answered relate to the role of GH replacement in cases of partial GHD and its use in the elderly population. The safety of long term replacement therapy remains an important issue, particularly in relation to the cardio-vascular system, the incidence of de novo malignant tumours and the recurrence rate of pituitary tumours. In the context of safety, it remains essential to monitor patients by means of longitudinal surveillance databases.

Spontaneous gonadotrophin deficiency recovery in an adult patient with Langerhans cell histiocytosis (LCH).

Langerhans cell histocytosis (LCH) is a rare disease which exhibits a particular predilection for pituitary involvement leading to diabetes insipidus (DI) and other anterior pituitary hormonal deficiencies that are usually permanent and unresponsive to treatment. We report a 35 year old woman with a 10 year history of multisystemic LCH who developed DI, mild hyperprolactinemia, gonadotrophin and partial growth hormone deficiency following a normal delivery that was accompanied with infundibular thickening on pituitary magnetic resonance imaging (MRI). Following several courses of glucocorticoid administration, that were not associated with any substantial improvement, the patient was started on estrogen replacement therapy and cabergoline. After a three year period free of further relapses she developed irregular uterine bleeding. Following estrogen and cabergoline discontinuation she resumed normal menstruation while a repeated MRI of the pituitary showed an almost normal infundibulum. Endocrine investigation revealed normal gonadotrophin axis and prolactin levels, while the patient continues to menstruate, every 30-40 days, ten months after the resumption of her menstrual cycle. This case demonstrates for the first time that LCH induced pituitary deficiencies can run a variable clinical course and even spontaneously recover.