Psychological complications in patients with acromegaly: relationships with sex, arthropathy, and quality of life.

PURPOSE: Current treatment of acromegaly restores a normal life expectancy in most cases. So, the study of persistent complications affecting patients' quality of life (QoL) is of paramount importance, especially motor disability and depression. In a large cohort of acromegalic patients we aimed at establishing the prevalence of depression, to look for clinical and sociodemographic factors associated with it, and to investigate the respective roles (and interactions) of depression and arthropathy in influencing QoL. METHODS: One hundred and seventy-one acromegalic patients (95 women and 76 men, aged 20-85 years) among those recruited in a cross-sectional Italian multicentric study were investigated. Each patient filled in three validated questionnaires: AcroQoL, WOMAC (measuring articular pain, stiffness and functionality), and AIMS (evaluating articular symptoms and depression). RESULTS: A very high (up to 28%) depression rate was detected in acromegalic subjects. Two patients showing pathological AIMS depression scores, committed suicide during the three years observational period. In our population poor psychological status was significantly associated with female sex. Furthermore, a significant strong correlation was found between AIMS depression score and WOMAC score. Both depression and arthropathy-related motor disability turned out to independently contribute with similar strength to the impairment of QoL. CONCLUSIONS: We report a high prevalence of depression in acromegaly, which is associated with female sex and arthropathy. Both depression and arthropathy strongly and independently contribute to the impaired QoL of patients. Our study shows that assessment and monitoring of psychological status is mandatory in acromegaly, also suggesting an inexpensive tool for this assessment.

Development and Internal Validation of a Predictive Model for Adult GH Deficiency Prior to Stimulation Tests.

Background: The diagnosis of adult GH deficiency (GHD) relies on a reduced GH response to provocative tests. Their diagnostic accuracy, however, is not perfect, and a reliable estimation of pre-test GHD probability could be helpful for a better interpretation of their results. Methods: Eighty patients showing concordant GH response to two provocative tests, i.e. the insulin tolerance test and the GHRH + arginine test, were enrolled. Data on IGF-I values and on the presence/absence of other pituitary deficits were collected and integrated for the estimation of GHD probability prior to stimulation tests. Results: An independent statistically significant association with the diagnosis of GHD was found both for IGF-I SDS (OR 0.34, 95%-CI 0.18-0.65, p=0.001) and for the presence of other pituitary deficits (OR 6.55, 95%-CI 2.06-20.83, p=0.001). A low (<25%) pre-test GHD probability could be predicted when IGF-I SDS > +0.91 in the presence of other pituitary deficits or IGF-I SDS > -0.52 in the absence of other pituitary deficits. A high (>75%) pre-test GHD probability could be predicted when IGF-I SDS < -0.82 in the presence of other pituitary deficits or IGF-I SDS < -2.26 in the absence of other pituitary deficits. Conclusion: This is the first study that proposes a quantitative estimation of GHD probability prior to stimulation tests. Our risk class stratification represents a simple tool that could be adopted for a Bayesian interpretation of stimulation test results, selecting patients who may benefit from a second stimulation test and possibly reducing the risk of wrong GHD diagnosis.

Traumatic Brain Injury as Frequent Cause of Hypopituitarism and Growth Hormone Deficiency: Epidemiology, Diagnosis, and Treatment.

Traumatic brain injury (TBI)-related hypopituitarism has been recognized as a clinical entity for more than a century, with the first case being reported in 1918. However, during the 20th century hypopituitarism was considered only a rare sequela of TBI. Since 2000 several studies strongly suggest that TBI-mediated pituitary hormones deficiency may be more frequent than previously thought. Growth hormone deficiency (GHD) is the most common abnormality, followed by hypogonadism, hypothyroidism, hypocortisolism, and diabetes insipidus. The pathophysiological mechanisms underlying pituitary damage in TBI patients include a primary injury that may lead to the direct trauma of the hypothalamus or pituitary gland; on the other hand, secondary injuries are mainly related to an interplay of a complex and ongoing cascade of specific molecular/biochemical events. The available data describe the importance of GHD after TBI and its influence in promoting neurocognitive and behavioral deficits. The poor outcomes that are seen with long standing GHD in post TBI patients could be improved by GH treatment, but to date literature data on the possible beneficial effects of GH replacement therapy in post-TBI GHD patients are currently scarce and fragmented. More studies are needed to further characterize this clinical syndrome with the purpose of establishing appropriate standards of care. The purpose of this review is to summarize the current state of knowledge about post-traumatic GH deficiency.

Morning Serum Cortisol Level Predicts Central Adrenal Insufficiency Diagnosed by Insulin Tolerance Test.

INTRODUCTION: According to guidelines, a morning serum cortisol level <83 nmol/L is diagnostic for central adrenal insufficiency (CAI), a value >414 nmol/L excludes CAI, while values between 83 and 414 nmol/L require stimulation tests. However, there are no currently reliable data on morning serum cortisol for prediction of cortisol response to insulin tolerance test (ITT). OBJECTIVE: Using the receiver-operating characteristic curve analysis, the purpose of this study was to detect the morning serum cortisol cutoff with a specificity (SP) or a sensitivity (SE) above 95% that identify those patients who should not be tested with ITT. METHODS: We included 141 adult patients (83 males) aged 42.7 ± 12.3 (mean ± standard deviation) years old. Based on the serum cortisol response to ITT, patients have been divided into 2 groups: subjects with CAI (peak serum cortisol <500 nmol/L; 65 patients) and subjects with preserved adrenocortical function (peak cortisol >500 nmol/L; 76 patients). RESULTS: The best morning cortisol cutoff, in terms of SE (87.7%) and SP (46.1%), was ≤323.3 nmol/L. The cutoff of morning serum cortisol concentration that best predicted a deficient response to ITT was ≤126.4 nmol/L (SE 13.8%, SP 98.7%). The cutoff of morning serum cortisol concentration that best predicted a normal response to ITT was >444.7 nmol/L (SE 96.9%, SP 14.5%). CONCLUSIONS: This is the first study that identifies a morning serum cortisol cutoff that best predict the response to ITT in order to simplify the diagnostic process in patients with suspected CAI. A new diagnostic flow-chart for CAI is proposed.

The Cut-off Limits of Growth Hormone Response to the Insulin Tolerance Test Related to Body Mass Index for the Diagnosis of Adult Growth Hormone Deficiency.

INTRODUCTION: The diagnosis of growth hormone deficiency (GHD) in adults is based on a reduced GH response to provocative tests, such as the insulin tolerance test (ITT) and the GH-releasing hormone (GHRH) + arginine (ARG) test. However, the cut-off limits of peak GH response in lean subjects are not reliable in obese patients; this is noteworthy since adult GHD is often associated with obesity. To date, there are no ITT cut-offs related to body mass index (BMI). OBJECTIVE: We aimed to evaluate the diagnostic cut-offs of GH response to the ITT in the function of BMI. METHODS: The GH response to the ITT was studied in 106 patients with a history of hypothalamic-pituitary disease, a mean age of 48.2 ± 12.4 years, and a mean BMI of 26.8 ± 6.1 kg/m2). Patients were divided into lean, overweight, and obese groups according to their BMI. The lack of GH response to GHRH + ARG test was considered the gold standard for the diagnosis of GHD. The best GH cut-off in the ITT, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using receiver-operating characteristics curve (ROC) analysis. RESULTS: The best GH cut-off in the ITT was 3.5 µg/L in lean subjects (SE 82.1%; SP 85.7%), 1.3 µg/L in overweight subjects (SE 74.1%; SP 85.7%), and 2.2 µg/L in obese subjects (SE 90.0%; SP 50.0%). The diagnostic accuracy was 97.2, 76.5, and 76.7%, respectively. CONCLUSIONS: Our data show that the ITT represents a reliable diagnostic tool for the diagnosis of adult GHD in lean subjects if an appropriate cut-off limit is assumed. Overweight and obesity strongly reduce the GH response to the ITT, GH BMI-related cut-off limits, and the diagnostic reliability of the test.

HLA DRB1*0415: a new possible genetic susceptibility factor for Hirata's disease.

CONTEXT: Hirata's disease (HD) is a rare autoimmune cause of hypoglycemia. Patients suffering from this condition have a genetic predisposition, determined by HLA DR4, with some differences in the worldwide population. In Caucasians HLA DRB1*0403 is the most frequent susceptibility background on which some drugs play as triggers. CASE DESCRIPTION: We reported the case of a woman with several hypoglycemic episodes, characterized by high insulin and c-peptide levels. Biochemical and morphological exams excluded a neuroendocrine tumor. HD was diagnosed according to insulin autoantibodies positivity and patient's history, particularly about drugs taken. The HLA analysis revealed DRB1*0415 allele. CONCLUSIONS: We found a potential new predisposing factor for HD, HLA DRB1*0415 allele, never described before as genetic background to insulin autoimmune syndrome in Caucasians.

Progression of pituitary tumours: impact of GH secretory status and long-term GH replacement therapy.

BACKGROUND: Most patients treated for hypothalamic-pituitary tumours develop GH deficiency. Long-term GH replacement treatment in adults with a previous history of hypothalamic-pituitary tumour could represent a concern about increasing the risk of tumour enlargement or recurrence. PURPOSE: To assess the progression risk of hypothalamic-pituitary tumours according to the GH secretory status (normal GH secretion, non-treated and treated GH deficiency). and determine the predictors of neoplasm recurrence. METHODS: We retrospectively reviewed 309 patients with tumours of the hypothalamic-pituitary region (294 subjects underwent neurosurgery while 81 radiotherapy) who were followed for 9.9 ± 8.3 years. RESULTS: Out of 309 patients, 200 were affected by severe GH deficiency; 90 of these underwent GH therapy. The tumour progression rate did not differ among GH-sufficient, not-treated and treated GH-deficient patients (16.5%, 16.4%. and 10.0%, respectively). In a multivariate analysis, previous radiotherapy (HR 0.12, CI 0.03-0.52, p < 0.005) and residual tumour (HR 8.20, CI 2.38-28.29, p < 0.001) were independent predictors of recurrence. After controlling for multiple covariates, the tumour recurrence risk in GH-sufficient and GH-treated patients was similar to that observed in not-treated GH-deficient patients. CONCLUSIONS: With limitations of retrospective analysis, GH therapy is not associated with an increased progression rate of tumours of the hypotalamic-pituitary region during long follow-up, thus supporting the long-term safety of GH treatment. The only predictors of tumour recurrence appear to be the presence of residual disease and the lack of radiotherapy.

Super Giant Growth Hormone-Secreting Pituitary Adenoma in Young Woman: From Ventricles to Nose.

BACKGROUND: Giant pituitary adenomas are rare tumors that can have a devastating impact on a patient's life. They require a well-studied therapeutic approach that often combines different strategies. CASE DESCRIPTION: A 29-year-old woman was diagnosed with the largest GH-secreting pituitary adenoma reported in the literature, to the best of the author's knowledge. The tumor was removed with a combined approach: endoscopic endonasal transsphenoidal and transcortical transventricular. All available acromegaly drugs were used. After 2 surgeries, a large part of the tumor was removed. Both postoperative courses were uneventful. Because the disease was still active, medical therapy was initiated. The combination of pasireotide, pegvisomant, and cabergoline permitted satisfactory control of hormonal levels. CONCLUSIONS: Giant adenomas, >4 cm, are rare pituitary tumors. Therefore in order to achieve the best clinical results, they require complex management that involves a multidisciplinary team of ear, nose, and throat surgeons; endocrinologists; radiation therapists; ophthalmologists; and neurosurgeons.