Cristina Capatina

60 YEARS OF NEUROENDOCRINOLOGY: Acromegaly

Acromegaly (ACM) is a chronic, progressive disorder caused by the persistent hypersecretion of GH, in the vast majority of cases secreted by a pituitary adenoma. The consequent increase in IGF1 (a GH-induced liver protein) is responsible for most clinical features and for the systemic complications associated with increased mortality. The clinical diagnosis, based on symptoms related to GH excess or the presence of a pituitary mass, is often delayed many years because of the slow progression of the disease. Initial testing relies on measuring the serum IGF1 concentration. The oral glucose tolerance test with concomitant GH measurement is the gold-standard diagnostic test. The therapeutic options for ACM are surgery, medical treatment, and radiotherapy (RT). The outcome of surgery is very good for microadenomas (80-90% cure rate), but at least half of the macroadenomas (most frequently encountered in ACM patients) are not cured surgically. Somatostatin analogs are mainly indicated after surgical failure. Currently their routine use as primary therapy is not recommended. Dopamine agonists are useful in a minority of cases. Pegvisomant is indicated for patients refractory to surgery and other medical treatments. RT is employed sparingly, in cases of persistent disease activity despite other treatments, due to its long-term side effects. With complex, combined treatment, at least three-quarters of the cases are controlled according to current criteria. With proper control of the disease, the specific complications are partially improved and the mortality rate is close to that of the background population.

Pituitary apoplexy in non-functioning pituitary adenomas: long term follow up is important because of significant numbers of tumour recurrences.

Objectives  The frequency of pituitary tumour regrowth after an episode of classical pituitary apoplexy is unknown. It is thus unclear whether regrowth, if it occurs, does so less frequently than with non‐apoplectic non‐functioning pituitary macroadenomas that have undergone surgery without postoperative irradiation. This has important repercussions on follow up protocols for these patients.

The management of head-and-neck paragangliomas

Paragangliomas (PGLs) are tumours originating from neural crest-derived cells situated in the region of the autonomic nervous system ganglia. Head-and-neck PGLs (HNPGLs) originate from the sympathetic and parasympathetic paraganglia, most frequently from the carotid bodies and jugular, tympanic and vagal paraganglia, and are usually non-catecholamine secreting. Familial PGLs are considered to be rare, but recently genetic syndromes including multiple PGLs and/or phaeochromocytomas have been more thoroughly characterised. Nowadays, genetic screening for the genes frequently implicated in both familial and sporadic cases is routinely being recommended. HNPGLs are mostly benign, generally slow-growing tumours. Continuous growth leads to the involvement of adjacent neurovascular structures with increased morbidity rates and treatment-related complications. Optimal management mostly depends on tumour location, local involvement of neurovascular structures, estimated malignancy risk, patient age and general health. Surgery is the only treatment option offering the chance of cure but with significant morbidity rates, so a more conservative approach is usually considered, especially in the more difficult cases. Radiotherapy (fractionated or stereotactic radiosurgery) leads to tumour growth arrest and symptomatic improvement in the short term in many cases, but the long-term consequences are unclear. Early detection is essential in order to increase the chance of cure with a lower morbidity rate. The constant improvement in diagnostic imaging, surgical and radiation techniques has led to a safer management of these tumours, but there are still many therapeutic challenges, and no treatment algorithm has been agreed upon until now. The management of HNPGLs requires a multidisciplinary effort addressing the genetic, surgical, radiotherapeutic, oncological, neurological and endocrinological implications. Further progress in the understanding of their pathogenesis will lead to more effective screening and earlier diagnosis, both critical to successful treatment.

Current treatment protocols can offer a normal or near-normal quality of life in the majority of patients with non-functioning pituitary adenomas.

Non‐functioning pituitary adenomas (NFA) may be associated with significant morbidity. Published data on the quality of life (QoL) of patients with NFA are scarce and conflicting. In view of the discordant findings and the advances in the management of these subjects, we aimed to evaluate the QoL in patients with NFA followed up in a tertiary endocrine UK referral centre.

Diabetes Insipidus after Traumatic Brain Injury.

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in many age groups. Neuroendocrine dysfunction has been recognized as a consequence of TBI and consists of both anterior and posterior pituitary insufficiency; water and electrolyte abnormalities (diabetes insipidus (DI) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH)) are amongst the most challenging sequelae. The acute head trauma can lead (directly or indirectly) to dysfunction of the hypothalamic neurons secreting antidiuretic hormone (ADH) or of the posterior pituitary gland causing post-traumatic DI (PTDI). PTDI is usually diagnosed in the first days after the trauma presenting with hypotonic polyuria. Frequently, the poor general status of most patients prevents adequate fluid intake to compensate the losses and severe dehydration and hypernatremia occur. Management consists of careful monitoring of fluid balance and hormonal replacement. PTDI is associated with high mortality, particularly when presenting very early following the injury. In many surviving patients, the PTDI is transient, lasting a few days to a few weeks and in a minority of cases, it is permanent requiring management similar to that offered to patients with non-traumatic central DI.

SERIAL CHANGES OF LIVER FUNCTION TESTS BEFORE AND DURING METHIMAZOLE TREATMENT IN THYROTOXIC PATIENTS

OBJECTIVE Overt hyperthyroidism and methimazole (MMI) treatment are frequently associated with abnormal liver function tests (LFTs). We describe the serial changes of LFTs in MMI-treated hyperthyroid patients. METHODS We retrospectively analyzed all 77 patients presenting with newly diagnosed overt hyperthyroidism (59 Graves diseases, 11 toxic nodular goiters, 4 toxic adenomas, 3 amiodarone-induced thyrotoxicosis) between 2012 and 2014. All patients started MMI at 10 to 60 mg/day that was gradually tapered. We measured thyroid-stimulating hormone, free thyroxine, alanine aminotransferase (ALT) and aspartate aminotrasnferase (AST) at baseline and at 6 weeks, 4.5 months and 10 months after starting the MMI treatment. The concomitant medication was stable during MMI treatment. RESULTS At baseline, 25 patients (32.5%) had abnormal LFT, of which 5 had ALT or AST levels >2× the upper limit of normal (ULN). In most patients with baseline abnormal LFT, MMI treatment resulted in a normalization of serum ALT and AST. Thirteen patients with normal baseline LFT had <2× the ULN elevations of LFT sometime during treatment. There was a case of significant hepatotoxicity. During treatment, there were no significant differences in LFT levels between patients with initially normal or abnormal LFT. In a Cox proportional hazard regression model, abnormal LFT at baseline, abnormal thyroid function at the last evaluation, and MMI dose were not predictors of abnormal LFT at the final evaluation. CONCLUSION MMI treatment can induce insignificant LFT elevation, <2× the ULN. MMI can be safely administered in hyperthyroid patients with abnormal LFT, and normalization of increased AST and ALT levels should be anticipated. ABBREVIATIONS ALT = alanine aminotransferase AST = aspartate aminotransferase fT4 = free thyroxine HCV = hepatitis C virus LFT = liver function test LOCF = last observation carried forward MMI = methimazole PTU = propylthiouracil TSH = thyroid-stimulating hormone ULN = upper limit of normal.

Hypopituitarism: growth hormone and corticotropin deficiency.

This article presents an overview of adult growth hormone deficiency (AGHD) and corticotropin deficiency (central adrenal failure, CAI). Both conditions can result from various ailments affecting the hypothalamus or pituitary gland (most frequently a tumor in the area or its treatment). Clinical manifestations are subtle in AGHD but potentially life-threatening in CAI. The diagnosis needs dynamic testing in most cases. Treatment of AGHD is recommended in patients with documented severe deficiency, and treatment of CAI is mandatory in all cases. Despite significant progress in replacement hormonal therapy, more physiologic treatments and more reliable indicators of treatment adequacy are still needed.

Fracture Risk Assessment in Patients With Diabetes Mellitus

Diabetes mellitus, both type 1 and type 2 (T2DM), is associated with decreased bone strength as well as increased fracture risk. Bone mineral density is decreased in type 1 diabetes but increased in T2DM, compared with controls. This suggests alterations in bone quality are a major player in the pathogenesis of fragility fractures in patients with diabetes. The link between diabetes and bone appears to be mediated by complex pathways, including the insulin-insulin growth factors system, accumulation of advanced glycation end-products in bone collagen, microangiopathy, and increased bone marrow fat content. Bone fragility in T2DM, which is not reflected by bone mineral density and bone mass reduction, depends on deterioration of bone quality. Also, at least in T2DM, the classical diagnosis of osteoporosis by dual-energy X-ray absorptiometry and the fracture risk estimation by FRAX (fracture risk assessment tool) are only partially useful in assessing fracture risk. Trabecular bone score and trabecular bone score-adjusted FRAX offer an enhanced estimation of fracture risk in these patients. Specific risk stratification criteria are needed in the future. The development of improved methods to assess the material properties of bone to better characterize fracture risk is also a priority. Adequate glycemic control is generally associated with decreased fracture risk, with the exception of specific antidiabetics (thiazolidinediones, canagliflozin) that have been shown to have a detrimental effect. Most currently used antiosteoporotic treatments seem equally effective in diabetic patients as compared with patients without diabetes, but clinical data regarding the reduction in fracture risk specifically in patients with diabetes mellitus are lacking.

Vanishing testes syndrome-related osteoporosis and high cardio-metabolic risk in an adult male with long term untreated hypergonadotropic hypogonadism

The male hypogonadism-related bone mass loss is often under diagnosed. Peak bone mass is severely affected if the hypogonadism occurs during puberty and is left untreated. We present an interesting; almost bizarre case of a male with non-functional testes early during childhood and undiagnosed and untreated hypogonadism until his fifth decade of life. Forty six year male is referred for goitre, complaining of back pain. Phenotype suggested intersexuality: gynoid proportions, micropenis, no palpable testes into the scrotum, no facial or truncal hair. His medical history had been unremarkable until the previous year when primary hypothyroidism was diagnosed and levothyroxine replacement was initiated. Later, he was diagnosed with ischemic heart disease, with inaugural unstable angina. On admission, the testosterone was 0.2 ng/mL (normal: 1.7-7.8 ng/mL), FSH markedly increased (56 mUI/mL), with normal adrenal axis, and TSH (under thyroxine replacement). High bone turnover markers, and blood cholesterol, and impaired glucose tolerance were diagnosed. The testes were not present in the scrotum. Abdominal computed tomography suggested bilateral masses of 1.6 cm diameter within the abdominal fat that were removed but no gonadal tissue was confirmed histopathologically. Vanishing testes syndrome was confirmed. The central DXA showed lumbar bone mineral density of 0.905 g/cm2, Z-score of -2.9SD. The spine profile X-Ray revealed multiple thoracic vertebral fractures. Alendronate therapy together with vitamin D and calcium supplements and trans-dermal testosterone were started. Four decades of hypogonadism associate increased cardiac risk, as well as decreased bone mass and high fracture risk.

Vitamin D Deficiency and Musculoskeletal Function in the Elderly

ABSTRACT VITAMIN D DEFICIENCY IS ASSOCIATED WITH POOR MUSCULOSKELETAL FUNCTION IN THE ELDERLY, INCREASING THE LIKELIHOOD OF FALLS AND FRACTURES. VITAMIN D ADMINISTRATION INCREASES MUSCLE STRENGTH AT ALL LEVELS AND IMPROVES BALANCE. ACTIVE CORRECTION OF VITAMIN D DEFICIENCY IS AN ESSENTIAL MEASURE WITH CONSIDERABLE IMPACT ON THE HEALTH OF THE ELDERLY.