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Hypercalcaemia results from the failure of renal calcium excretion to compensate increased influx of calcium into the circulation from the intestine, the kidneys and the skeleton. Hypercalcaemia is a common metabolic abnormality of varying severity that can be adequately diagnosed and treated. Primary hyperparathyroidism and malignant neoplasms are responsible for >90% of all cases. The management of hypercalcaemia depends on the underlying cause and involves approaches aiming at reducing serum calcium concentrations and correcting associated metabolic disturbances. A number of pharmacological interventions are currently available for the treatment of hypercalcaemia related to malignancy as well as other forms of hypercalcaemia. Knowledge of the pathophysiology of hypercalcaemia and of the properties of these interventions is essential for the successful management of affected individuals. We herein review available therapeutic interventions for hypercalcaemia of varying aetiology.

Context: X-linked hypophosphatemic rickets (XLH) is characterized by hypophosphatemia and growth retardation. Early diagnosis and treatment improve growth., Objective: Our objective was to describe long-term observations of a family with XLH due to a novel mutation of the PHEX gene with unusual clinical features, including normal growth., Patients: The mother and her two sons were followed in the same institution for nearly 30 yr., Results: The mother had hypophosphatemia and normal height (Z score, -0.6) without ever receiving any treatment. Her two sons achieved final heights of 183.7 cm (Z score, -0.01) and 182.7 cm (Z score, -0.18), respectively, despite late initiation of treatment with phosphate and low serum phosphate levels. In addition, they had reversible proximal myopathy that took about 7 yr to resolve in one of them. Direct sequencing of the PHEX gene revealed a new splice site mutation in intron 4 of the gene (IVS4+6T-->C) resulting in skipping of exon 4., Conclusions: Three members of a family with XLH due to a novel mutation of the PHEX gene had a normal growth pattern despite late diagnosis and treatment of the two boys and no treatment at all of their mother. The pathophysiological basis of this phenotype-genotype association warrants further investigation.

Background: Langerhans-cell histiocytosis (LCH) is a rare disease with features of chronic inflammation and it may also induce hypopituitarism, conditions associated with an increased risk of cardiovascular diseases., Aim: Cardiovascular and metabolic risk profile investigation in multisystem LCH patients with and without anterior pituitary deficiency., Design: Prospective, observational study., Methods: Fourteen adult patients with LCH, 7 with and 7 without anterior pituitary deficiency, and 42 controls matched for age, body mass index (BMI) and smoking. Cardiovascular risk factors were estimated in all subjects: glucose and lipid profile, mathematical indices of insulin resistance (IR), blood pressure, structural arterial and functional endothelial properties (intima-media thickness, brachial artery flow-mediated dilatation). Cardiovascular risk factors were estimated in the three groups studied; the effect of disease activity and/or treatment was also determined in patients with LCH., Results: Ten patients had diabetes insipidus, and 7 anterior pituitary hormone deficiencies: 8 patients had active disease and 11 had received systemic treatment. No difference was observed between the study groups in vascular parameters, in lipid profile or in blood pressure. However, the insulin resistance index GIR was decreased in patients with LCH without anterior pituitary deficiency compared to controls (P = 0.033). Three patients had impaired glucose tolerance and one diabetes mellitus type 2. These patients were older and had active disease; there was no association with hypopituitarism and/or previous treatment., Conclusion: Adults patients with LCH have abnormalities of glucose metabolism that tend to occur in patients with active disease, and may be a consequence of the pro-inflammatory state.

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.

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.

Langerhans' cell histiocytosis (LCH) is a rare disease of unknown etiology and variable biologic behavior and course. Almost every organ can be affected; however, it frequently involves the bones, lungs, skin and lymph nodes. LCH exhibits a particular predilection for involvement of the hypothalamo-pituitary axis resulting in diabetes insipidus and/or other anterior pituitary deficiencies. Although LCH can sometimes resolve spontaneously, it usually follows a chronic course and systemic treatment is mandatory for the management of multisystem disease. However, a significant number of patients will develop at least one permanent sequela as a consequence of the disease, with diabetes insipidus being the most common. A multidisciplinary approach is always needed in diagnosis, treatment and follow-up of all patients with LCH.

Langerhans cell histiocytosis is a rare, multisystem disease that shows a particular predilection for hypothalamo-pituitary axis involvement. Diabetes insipidus is the most frequent permanent consequence of Langerhans cell histiocytosis, developing in around a quarter of patients. Although the exact prevalence of anterior pituitary hormone deficiencies is not known, it is probably high and is almost always associated with diabetes insipidus. Established pituitary hormone deficiencies are mostly permanent and require prompt diagnosis and treatment, whereas continuous follow-up is needed to detect deficiencies that might evolve later during the course of the disease. Involvement of endocrine tissues other than the pituitary has also been described but is relatively rare. Further studies are needed to evaluate the effect that endocrine deficiencies exert on the overall prognosis of patients with Langerhans cell histiocytosis.

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.

Langerhans cell histiocytosis (LCH) is a rare, systemic disease caused by monoclonal expansion of dendritic cells that shows a particular predilection for the hypothalamic-pituitary system (HPS). We studied the function (anterior and posterior pituitary hormonal secretion) and morphology using magnetic resonance imaging (MRI) of the HPS in 17 adult patients (seven males, median age 35 years, range 18-59 years) with multisystem LCH. We also evaluated the evolution of structural HPS abnormalities in relation to pituitary function and response to treatment in 12 of these patients during a median follow-up period of 3.75 years (range 1.5-10 years). Of the 17 patients, 14 (82%) had abnormal HPS imaging, and 12 (70%) had more than one area involved. Lack of the bright spot of the posterior pituitary lobe was typically found in all patients with the diagnosis of diabetes insipidus (DI). Eight patients (47%) had infundibular enlargement, six (35%) pituitary infiltration, four (24%) partially or completely empty sella, three (18%) hypothalamic involvement, and two (12%) infundibular atrophy. DI was found in 16 patients (94%) and anterior pituitary hormonal deficiency (APHD) in 10 patients (59%); two patients had single (12%) and 8 (47%) multiple APHD. During the follow-up period there was improvement of the initially demonstrated HPS pathology in seven (47%) patients, and five (33%) of them had received at least one form of treatment. APHD and DI persisted in all patients except in one in whom established gonadotrophin deficiency recovered. In summary, DI and APHD are very common in patients with multisystem LCH and are almost always associated with abnormal HPS imaging.

In this study, we assessed the effects of a 4 week basic military physical training programme for male recruits of the Hellenic Air Force on the number and distribution of circulating immune cells and adrenergic and adrenocortical hormonal responses. One group of recruits (exercised, n = 48) participated in moderate intermittent physical exercise, whereas a second group (non-exercised controls, n = 9) performed only light work in the barracks. Both groups participated in the same non-physical, classroom-type training and testing. Military training by the exercised group resulted in significant increases in CD4+ T-lymphocytes, renal cortisol excretion and the urinary noradrenaline/adrenaline ratio, together with reductions in neutrophils and the neutrophil/lymphocyte ratio. In the exercised group, the urinary noradrenaline/adrenaline ratio correlated positively with the training-induced changes in CD4+ T-lymphocytes and negatively with changes in the neutrophil/lymphocyte ratio. No significant relationship was found between training-induced increases in cortisol excretion and any of the peripheral blood cell alterations. Our results indicate that 4 weeks of military training consisting of intermittent moderate exercise resulted in a significant increase in CD4+ T-lymphocytes and reduction in neutrophils. These changes were probably driven by alterations in hormonal status, including the significant impact of sympathetic nervous system activation.

The sensitivity of 99mTc-sestamibi scan in detecting parathyroid disease in primary hyperparathyroidism (PHP) is almost 90%, and therefore facilitates successful parathyroidectomy. To enhance the diagnostic accuracy of the procedure, we repeated imaging with 99mTc-sestamibi in 15 patients with PHP and an initially negative (11 patients) or weakly positive (four patients) 99mTc-sestamibi scan after the administration of 10 mg of oral alendronate for 2 months. Serum calcium, phosphate and parathormone (PTH) measurements were obtained at presentation and after 1 and 2 months' treatment with alendronate. Eight patients with an initially negative 99mTc-sestamibi scan demonstrated at least one area of uptake in the repeated scan. Six of these patients underwent surgery and obtained a biochemical cure; a single adenoma was found in four and hyperplasia in the remaining two. In all four patients with an initially weakly positive 99mTc-sestamibi scan, the repeated scan demonstrated enhanced uptake and also revealed further areas of uptake. Two of these patients underwent surgery with a biochemical cure; an adenoma was found in one and hyperplasia in another. Compared with baseline there was a significant increase in PTH but not in calcium or phosphate levels during treatment with alendronate. We suggest that, in patients with PHP and a negative or weakly positive initial 99mTc-sestamibi scan, administration of oral alendronate may be associated with a positive repeated 99mTc-sestamibi scan and can thus enhance the sensitivity of the procedure.

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.

Growth without growth hormone (GH) has occasionally been described in patients with organic pituitary pathology, and even more rarely in patients with idiopathic pituitary hormone deficiency. The mechanism of growth without GH remains a mystery. We describe a 17-year old male who grew 38.5 cm in height over a 7-year period, despite the fact that he had established panhypopituitarism. The hypopituitarism was initially attributed to a presumptive hypothalamic hamartoma which was not, however, confirmed on subsequent and prolonged follow-up. Regular endocrine evaluation confirmed persistent anterior and posterior pituitary hormonal deficiencies with severe concomitant hyperinsulinemia as shown by an exaggerated insulin response to a standard oral glucose tolerance test. In our patient, a postulated mechanism could be the severe hyperinsulinemia, acting either through the insulin and/or IGF receptors and thus potentiating the mitogenic effect. This case illustrates that final height attainment within or above target height may occur in patients with idiopathic pituitary hormonal deficiency despite persistent, severe GH insufficiency.

We describe a 57-year old female with the diagnosis of skull and meningeal Langerhans' cell histiocytosis who was treated with the combination of azathioprine and methotrexate. Although the skull lesions improved considerably on this regimen, the patient developed diabetes insipidus while the anterior pituitary function remained intact.

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.

In January 1996, during an outbreak of meningococcal disease at a Hellenic Air Force recruit center in southern Greece, we collected paired serum specimens from 55 randomly selected recruits and tested for antibodies against influenza virus types A and B. Of 55 specimens, 15 (27%) were found to be positive for recent influenza B infection, confirming previous reports that respiratory tract infection due to influenza is probably a predisposing factor for meningococcal disease.