V. Gasco

Diagnostic reliability of a single IGF-I measurement in 237 adults with total anterior hypopituitarism and severe GH deficiency

objective Within an appropriate clinical context, GH deficiency (GHD) in adults must be demonstrated biochemically by a single provocative test. Insulin‐induced hypoglycaemia (ITT) and GH‐releasing hormone (GHRH) + arginine (ARG) are indicated as the tests of choice, provided that appropriate cut‐off limits are defined. Although IGF‐I is the best marker of GH secretory status, its measurement is not considered a reliable diagnostic tool. In fact, considerable overlap between GHD and normal subjects is present, at least when patients with suspected GHD are considered independently of the existence of other anterior pituitary defects. Considering the time and cost associated with provocative testing procedures, we aimed to re‐evaluate the diagnostic power of IGF‐I measurement.

Gender- and age-related differences in the endocrine parameters of acromegaly

Acromegaly is a severe slow-developing disease associated with a poor prognosis for cardiovascular disease. To evaluate the impact of age and gender on the severity of the disease, 151 de novo patients with acromegaly (79 women, 72 men, age range 19–77 yr) were included in this open retrospective multi-center cohort study. Basal GH and IGF-I levels, GH response after glucose load and maximal tumor diameter at MRI were measured in all patients at diagnosis. Fasting GH levels and maximal tumor diameter were similar in women and men, while serum IGF-I levels were lower (664.9±24.9 vs 755.9±32 μg/l; p=0.02) and GH nadir after glucose load was higher (27.5±3.7 vs 18.5±2.2 μg/l; p=0.04) in women than in men. In both sexes, patients’ age was negatively correlated with basal and nadir GH, IGF-I levels and tumor size; fasting GH levels were positively correlated with IGF-I levels and nadir GH after glucose. No interaction between age and gender was found on biochemical and morphological parameters. At diagnosis, elderly patients with acromegaly have lower GH and IGF-I levels, lower GH nadir after glucose load and smaller adenomas than young patients. Women have lower IGF-I levels but higher GH nadir after glucose load than men. These age and gender differences should be considered to appropriately evaluate the activity of acromegaly throughout a life-span.

Growth Hormone Receptor Variants and Response to Pegvisomant in Monotherapy or in Combination with Somatostatin Analogs in Acromegalic Patients: A Multicenter Study

CONTEXT The influence of full-length GH receptor (GHR) and exon 3-deleted GHR (d3GHR) on responsiveness to pegvisomant (PEG-V) in acromegalic patients is uncertain. OBJECTIVE The aim of the study was to assess the distribution of GHR genotypes in a large series of patients on PEG-V therapy and their influence on treatment efficacy and adverse effects. DESIGN AND SETTING A cross-sectional multicenter pharmacogenetic study was conducted in 16 Italian endocrinology centers of major universities and tertiary care hospitals. PATIENTS The study included 127 acromegalic patients enrolled from 2009 to 2010 not cured by previous surgery, radiotherapy, and long-acting somatostatin (SST) analogs, treated with PEG-V. INTERVENTION AND MAIN OUTCOME MEASURE Sixty-three of 127 patients received combined PEG-V + SST analog therapy. Clinical and hormonal data at diagnosis and before and during PEG-V therapy were inserted in a database. GHR exon 3 deletion and other polymorphisms were genotyped by the coordinator center. Differences in PEG-V dosage required for IGF-I normalization and occurrence of adverse effects between carriers and noncarriers of GHR variants were evaluated. RESULTS d3GHR variants were not in Hardy-Weinberg equilibrium (P = 0.008). No association of these variants with PEG-V dose required for IGF-I normalization, adverse effects occurrence, and tumor regrowth was found in patients on PEG-V and on PEG-V + SST analog treatment. Similar data were obtained considering the GHR variant rs6180. CONCLUSIONS This study did not confirm a better response of d3GHR to PEG-V treatment in acromegaly. Other studies are needed to determine whether deviation from Hardy-Weinberg equilibrium may indicate an association of d3GHR genotype with poor response to usual treatments.

Cost-of-illness study in acromegalic patients in Italy

Introduction: acromegalic therapeutic goals are directed at removing the tumor, preventing tumor re-growth and reducing long-term morbidity and mortality. In this scenario, the acromegalic patient needs a variety of health resources (diagnostic tests, surgery, radiotherapy, specialist visits and drugs) for his/her cure, in order to decrease/stop the progression of the disease and to cure the co-morbid diseases. Lack of epidemiological data has suggested performing an Italian retrospective study aiming to assess the health resource consumption that is caused by acromegalic cure and the relative co-morbidities, in order to estimate the amount of the direct costs of acromegalic patients. Method: a retrospective study was performed on a total of 134 patients (142 patients selected, 76 in Genoa and 66 in Turin) for a period of about 7 yr preceding the enrolment date. Only direct costs were evaluated by performing an analysis on the perspective of Italian Healthcare Service (SSN). Results: the mean total direct costs for acromegaly cure ranged from 7.968,41 to 12.533,02 €/yr (p<0,01; Mann Whitney Test), respectively, for Responders and Non-Responders. The cost driver was drug (SS analogs) for acromegalic cure. The co-morbidity conditions associated to acromegalic Non-Responder patients are clearly higher than those with well-controlled disease. Conclusion: the study supports the hypothesis that controlled patients drove a saving for SSN in comparison to poor control patients that use more health resources.

Normal age-dependent values of serum insulin growth factor-I: Results from a healthy Italian population

Serum IGF-I levels were measured in 547 non-hypopituitaric, non-acromegalic healthy subjects of both sexes in Italy to develop reference values in relation to age and sex. Participant subjects were stratified in three age classes (25–39, 40–59 and ≥60 yr) and IGF-I assay was carried out by double-antibody radio immunoassay. Pearson’s correlation coefficient between age and IGF-I values was calculated by sex and predefined age ranges. IGF-I levels significantly decreased with age (p<0.001, Kruskal-Wallis test) while sex was not a significant factor. The median IGF-I levels were 206 ng/ml in the 25–39 yr range, 147 ng/ml in the 40–59 yr range and 103 ng/ml in the ≥60 yr range. Pearson’s correlation coefficient confirmed the negative correlation between age and IGF-I levels in the total sample of subjects (r=−0.529). The r coefficient between age and IGF-I levels did not differ between sexes (r=−0.570 in males and r=−0.529 in females), thus reflecting no sex-effect on IGF-I levels decline over years. No correlations were found in the 25–39 yr range (r=−0.036) or in the 40–59 yr range (r=−0.080) either, while in subjects aged >60 yr, IGF-I levels tended to further decrease with increased age (r=0.389). Ranges of normal values set at the 2.5th–97.5th percentile in the three age ranges were 95.6–366.7 ng/ml between 25 and 39 yr, 60.8–297.7 ng/ml between 40 and 59 yr and 34.5–219.8 ng/ml in subjects aged ≥60 yr. This study may contribute to the development of age-specific reference ranges for IGF-I determination in serum of normal subjects of both sexes in Italy.

Involvement of Hypothalamus Autoimmunity in Patients with Autoimmune Hypopituitarism: Role of Antibodies to Hypothalamic Cells

CONTEXT Antipituitary antibodies (APA) but not antihypothalamus antibodies (AHA) are usually searched for in autoimmune hypopituitarism. OBJECTIVE Our objective was to search for AHA and characterize their hypothalamic target in patients with autoimmune hypopituitarism to clarify, on the basis of the cells stained by these antibodies, the occurrence of autoimmune subclinical/clinical central diabetes insipidus (CDI) and/or possible joint hypothalamic contribution to their hypopituitarism. DESIGN We conducted a cross-sectional cohort study. PATIENTS Ninety-five APA-positive patients with autoimmune hypopituitarism, 60 without (group 1) and 35 with (group 2) lymphocytic hypophysitis, were studied in comparison with 20 patients with postsurgical hypopituitarism and 50 normal subjects. MAIN OUTCOME MEASURES AHA by immunofluorescence and posterior pituitary function were evaluated; then AHA-positive sera were retested by double immunofluorescence to identify the hypothalamic cells targeted by AHA. RESULTS AHA were detected at high titer in 12 patients in group 1 and in eight patients in group 2. They immunostained arginine vasopressin (AVP)-secreting cells in nine of 12 in group 1 and in four of eight in group 2. All AVP cell antibody-positive patients presented with subclinical/clinical CDI; in contrast, four patients with GH/ACTH deficiency but with APA staining only GH-secreting cells showed AHA targeting CRH- secreting cells. CONCLUSION The occurrence of CDI in patients with lymphocytic hypophysitis seems due to an autoimmune hypothalamic involvement rather than an expansion of the pituitary inflammatory process. To search for AVP antibody in these patients may help to identify those of them prone to develop an autoimmune CDI. The detection of AHA targeting CRH-secreting cells in some patients with GH/ACTH deficiency but with APA targeting only GH-secreting cells indicates that an autoimmune aggression to hypothalamus is jointly responsible for their hypopituitarism.

Three-hour spontaneous GH secretion profile is as reliable as oral glucose tolerance test for the diagnosis of acromegaly

The diagnosis of acromegaly, in an appropriate clinical context, usually relies on lack of GH suppression below 1 μg/l during OGTT coupled with elevated IGF-I levels. On the other hand, in normal subjects glucose-induced inhibition of GH secretory bursts without any further decrease of interpulse GH levels had already been shown. Based on the foregoing, we aimed to compare the diagnostic reliability of OGTT-induced GH nadir with that recorded during 3-h spontaneous GH secretion. In 59 acromegalic patients (17 male and 42 female, age, mean±SE 51.5±1.9, range 21–76 yr) and in 82 normal subjects (43 male and 39 female, age, mean±SE 35.7±1.5, range 15–72 yr) GH secretion was evaluated every 30 min from 0 to 180 min during slow saline infusion or OGTT (75 g at 0 min). A nadir GH concentration below 1 μg/l was recorded in all normal subjects either during OGTT or saline infusion if GH secretion was evaluated over 180 min. In contrast in acromegalic patients a nadir GH concentration below 1 μg/l never occurred in both conditions. This study shows that a 3-h spontaneous GH profile is as reliable as OGTT in the diagnosis of active acromegaly.

Hypopituitarism following brain injury: when does it occur and how best to test?

Aim of this review is to highlight how and when Traumatic Brain Injury (TBI) as well as Subarachnoid Haemorrhage (SAH) and primary Brain Tumours (pBT) of the Central Nervous System (CNS) can induce hypopituitarism, an under-diagnosed clinical problem. Moreover, this review aims to clarify, on the basis of the recent evidences, how these patients have to be tested for pituitary-function. Both retrospective and prospective studies recommended that patients with more severe form of Brain Injuries (BI) and in particular, those with fractures of the base of the skull or early diabetes insipidus, have to be closely monitored for signs and symptoms of endocrine dysfunction. Further studies will be crucial to raise awareness and remind physicians on the prevalence of hypopituitarism in patients with BI and to elucidate any incremental benefits these patients may receive from hormone replacement.

Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche

OBJECTIVE Premature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP. PATIENTS AND METHODS A total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects. RESULTS Baseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values <2 ng/ml (6 nmol/l). An ACTH-stimulated 17-OHP cutoff level of 14 ng/ml (42 nmol/l) identified by the receiver-operating characteristics curves showed the best sensitivity (90.9%) and specificity (100%) in distinguishing NCCAH patients. This value, while correctly identifying all unaffected children, missed 9% of affected individuals. Cortisol response to ACTH stimulation was <18.2 μg/dl (500 nmol/l) in 14 NCCAH patients (28%) and none of the heterozygotes or IPP children. Among the 55 NCCAH patients, 54.5% were homozygous for mild CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations. CONCLUSION In children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation.

Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults

OBJECTIVE Insulin tolerance test (ITT) is the test of reference for the diagnosis of adult GH deficiency (GHD), although GHRH in combination with arginine (ARG) or GH secretagogues are considered equally reliable tests. Testing with GH secretagogue alone is, anyway, a potent stimulus exploring the integrity of hypothalamic pathways controlling somatotropic function. We therefore aimed to determine the diagnostic reliability of testing with ghrelin, the natural GH secretagogue. METHODS We studied the GH response (every 15 MIN from 15 TO +120 MIN) to acylated ghrelin (1G/KG I.V. AT 0MIN) IN 78 patients with a history of pituitary disease (49 male, 29 female; age (MEANS.D.): 52.1±18.7 years; BMI: 26.7±5.3 kg/m(2)). The lack of GH response to GHRH+ARG and/or ITT was considered the gold standard for the diagnosis of GHD. The best GH cut-off to ghrelin test, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using the receiver-operating characteristic curve analysis. RESULTS The best GH cut-off to ghrelin test was 7.3 μg/l in lean subjects (SE 88.2%, SP 90.9%), 2.9 μg/l in overweight subjects (SE 92.6%, SP 100%) and 0.6 μg/l in obese subjects (SE 50%, SP 100%). The diagnostic accuracy was 89.3, 94.1 and 62.5% respectively. CONCLUSIONS Our data show that testing with acylated ghrelin represents a reliable diagnostic tool for the diagnosis of adult GHD, in lean and overweight subjects, if appropriate cut-off limits are assumed. Obesity strongly reduces GH response to ghrelin, GH weight-related cut-off limit and diagnostic reliability of the test.