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BackgroundSome cases of apparently idiopathic GH deficiency (GHD) may be caused by pituitary autoimmunity.ObjectiveTo study the variations in pituitary function and antipituitary antibodies (APA) from childhood to transition age in patients with apparently idiopathic GHD.DesignWe conducted a longitudinal study.Patients and methodsPituitary function and APA detection by immunofluorescence were investigated in 24 childhood patients with isolated GHD before starting recombinant GH therapy and after the stopping of this therapy in transition age. Sera of patients positive for APA were processed by double immunofluorescence to identify their pituitary target.ResultsAt diagnosis, 16 out of 24 patients were APA positive targeting only somatotrophs (group 1), while the remaining eight were APA negative (group 2). When retested off therapy, 12 out of 16 patients in group 1 persisted being APA positive, while the remaining four became negative with recovery of pituitary function. All patients in group 2 persisted being APA negative but still showing GHD. Of the 12 patients persistently APA positive, eight with confirmed GHD showed APA still targeting somatotrophs, whereas four showed APA targeting only gonadotrophs associated with isolated hypogonadotropic hypogonadism (HH).ConclusionPatients with APA at middle but not at high titer in childhood may show a remission of autoimmune GHD in childhood after GH replacement therapy. As APA may shift their target in transition period, an early characterization of APA by double immunofluorescence is advisable in APA positive GHD patients showing delayed puberty, to allow an early diagnosis and an appropriate therapy, thus preventing the progression toward HH.

Purpose: This publication reviews the accepted knowledges and the findings still discussed on several features of autoimmune hypophysitis, including the most recently described forms, such as IgG4 and cancer immunotherapy- related hypophysitis. Methods: The most characteristic findings and the pending controversies were derived from a literature review and previous personal experiences. A single paragraph focused on some atypical examples of the disease presenting under confounding pretences. Results: Headache, visual field alterations and impaired pituitary secretion are the most frequent clinical findings of the disease. Pituitary biopsy, still considered the gold diagnostic standard, does not always receive consent from the patients. The role of magnetic resonance imaging is limited, as this disease may generate images similar to those of other diseases. The role of antipituitary and antihypothalamus antibodies is still discussed owing to methodological difficulties and also because the findings on the true pituitary antigen(s) are still debated. However, the low sensitivity and specificity of immunofluorescence, one of the more widely employed methods to detect these antibodies, may be improved, considering a predetermined cut-off titre and a particular kind of immunostaining. Conclusion: Autoimmune hypophysitis is a multifaceted disease, which may certainly be diagnosed by pituitary biopsy. However, the possible different clinical, laboratory and imaging features must be considered by the physician to avoid a misdiagnosis when examining a possibly affected patient. Therapeutic choice has to be made taking into account the clinical conditions and the degree of hypothalamic-pituitary involvement, but also considering that spontaneous remissions can occur.

Type IIIb polyglandular autoimmune disease comprises autoimmune thyroid disease (HT) and chronic atrophic gastritis (AIG). Hypergastrinemia, secondary to AIG, predisposes to gastric enterochromaffin-like cell (ECL) hyperplasia, a preneoplastic condition. We evaluated the prevalence of AIG, hypergastrinemia and ECL hyperplasia in HT patients. A secondary end-point was to assess the efficacy of treatment with a somatostatin analogue in HT patient with ECL hyperplasia. From 2009 to 2011, 146 HT patients were enrolled in a prospective study. All cases underwent hormonal profile, and parietal cell antibody (PCA), gastrin, and chromogranin A (CgA) serum level assays. Selected patients with elevated gastrin and CgA levels underwent gastro esophageal endoscopy (EGDS). Patients positive for ECL hyperplasia received Octreotide LAR 30 mg/28 days for 12 months. Gastrin and CgA assays were repeated every three months and EGDS after one year. The results show that gastrin and CgA were significantly higher than normal in 17/115 (14.7%) patients. Seven more HT had isolated PCA positivity and in the 17 PCA positive patients histology diagnosed AIG, corpus prevalent, with mild to moderate atrophy. Diffuse ECL hyperplasia of the gastric body was present in three subjects, one of them presenting a type-1 carcinoid. Gastrin and CgA levels were significantly reduced (p

Context: Antipituitary antibodies (APA) recognizing GH-secreting cells may indicate an autoimmune pituitary involvement in adults with idiopathic GH deficiency (IGHD). Objective: We aimed 1) to investigate the presence of APA in prepubertal children with IGHD or idiopathic short stature (ISS), identifying the pituitary hormone-producing cells targeted by APA; and 2) to verify whether in patients with ISS the presence of APA could predict the development of GHD. Design: We performed a cross-sectional and partially longitudinal cohort study. Setting: The study was performed at the Endocrinology Unit and Pediatric Unit of the Second University and University Federico II of Naples, respectively. Patients: Twenty-six children with IGHD (group 1), 60 children with ISS (group 2), 33 children with GHD caused by lesions/abnormalities of the hypothalamus or pituitary (group 3), and 40 controls participated in the study. Nineteen children of group 2 were reevaluated after 2 yr. Main Outcome Measures: IGF-I levels, GH secretion, and APA (by indirect immunofluorescence) were evaluated in all participants. Results: At study entry, APA recognizing GH-producing cells were detected in seven of 26 children in group 1 and in 14 of 60 in group 2. Two years later, all eight initially APA-positive and all 11 APA-negative of the 19 reevaluated patients persisted positive and negative, respectively. The reevaluation of GH secretion in these patients revealed the development of GHD in all but one of the APA-positive children but in none of the APA-negative ones. Conclusions: IGHD in children can be frequently associated with APA targeting GH-secreting cells; thus, the detection of APA in children with ISS could identify those prone to develop GHD.

Recently, an increased incidence of central diabetes insipidus (CDI) in pregnancy, and less frequently in thepost partumperiod, has been reported, most probably favoured by some conditions occurring in pregnancy. This study was aimed at investigating the influence of pregnancy on a pre-existing potential/subclinical hypothalamic autoimmunity. We studied the longitudinal behaviour of arginine–vasopressin cell antibodies (AVPcAbs) and post-pituitary function in two young women with a positive history of autoimmune disease and presence of AVPcAbs, but without clinical CDI, and who became pregnant 5 and 7 months after our first observation. The behaviour of post-pituitary function and AVPcAbs (by immunofluorescence) was evaluated at baseline, during pregnancy and for 2 years after delivery. AVPcAbs, present at low/middle titres at baseline in both patients, showed a titre increase during pregnancy in one patient and after delivery in the other patient, with development of clinically overt CDI. Therapy with 1-deamino-8-d-arginine vasopressin (DDAVP) caused a prompt clinical remission. After a first unsuccessful attempt of withdrawal, the therapy was definitively stopped at the 6th and the 7th month ofpost partumperiod respectively, when AVPcAbs disappeared, accompanied by post-pituitary function recovery, persisting until the end of the follow-up. The determination of AVPcAbs is advisable in patients with autoimmune diseases planning their pregnancy, because they could be considered good predictive markers of gestational orpost partumautoimmune CDI. The monitoring of AVPcAb titres and post-pituitary function during pregnancy in these patients may allow for an early diagnosis and an early replacement therapy, which could induce the disappearance of these antibodies with consequent complete remission of CDI.

Lymphocytic hypophysitis (LYH) is an uncommon autoimmune disease in which the pituitary gland is infiltrated by lymphocytes, plasma cells and macrophages and its function is usually impaired. It has to be suspected in pregnant women and in women with recent delivery presenting with hyperprolactinemia, headache, visual field alterations and changes of one or more pituitary hormone secretions with secondary impairment of related peripheral target glands, especially when associated with other autoimmune endocrine or non-endocrine disorders. It can also occur less frequently in prepubertal or post-menopausal women and in men. Headache, visual field impairment and more rarely diplopia are due to extrasellar pituitary enlargement with optic chiasma compression and/or to invasion of cavernous sinuses. Among the 'isolated' pituitary hormone deficiencies, ACTH deficit is usually the earliest and most frequent hormonal impairment and in rare cases can induce an acute secondary hyposurrenalism as the first sign of the disease, with high mortality in affected patients. Histopathological findings from pituitary biopsy show lymphoplasmacytic infiltrate with lymphoid aggregates surrounding atropic acini of pituitary cells; immunohistochemical analysis shows numerous mast cells randomly distributed and also localized in the vicinity of capillaries, suggesting a possible influence on capillary permeability and angiogenesis, thus favoring the inflammatory and immunological aggression against pituitary cells. Nuclear magnetic resonance imaging shows uniform sellar floor depression and an extrasellar symmetrical pituitary enlargement, usually displacing the optic chiasma, which shows a rapid homogeneous enhancement after gadolinium also involving the adjacent dura (dural tail). Antipituitary antibodies have been detected in several patients with LYH but their role needs to be clarified. Since a possible spontaneous remission can occur, a careful follow-up is required in subclinical patients without important hyposurrenalism or symptomatic extrasellar expansion. Medical (immunosuppressive, replacement and antiprolactinemic) and neurosurgical (decompression) treatments are needed in clinical symptomatic patients.

The role of antipituitary antibodies (APA) in autoimmune pituitary diseases still needs to be clarified. The aim of this study was 2-fold: first, to investigate the presence of APA in adults with idiopathic or acquired GH deficiency (GHD) and in adults with autoimmune endocrine diseases; and second, to evaluate whether in autoimmune endocrine patients APA titer is correlated to the pituitary function and particularly to GH secretion. We studied 12 adults with isolated and apparently idiopathic GHD who were treated with recombinant GH in childhood (group 1a), 14 patients with adult GHD secondary to surgery for pituitary and parasellar tumors (group 1b), and 180 patients with organ-specific autoimmune diseases (group 2). APA were evaluated by indirect immunofluorescence. In all APA-positive patients and in 20 APA-negative patients of group 2, GH secretion was investigated by testing its response to insulin-induced hypoglycemia (insulin tolerance test) and, when impaired, also to arginine. APA were found (at high titers) in 4 of 12 patients of group 1a (33.3%) but were absent in all patients in group 1b. APA were also found in 40 of 180 patients of group 2 (22.2%), 35 of them at low titers (group 2a) and 5 at high titers (group 2b). Twenty of the 140 autoimmune endocrine APA-negative patients studied (group 2c) and all APA-positive patients at low titers (group 2a) had normal pituitary function. Conversely, all APA-positive patients at high titers (groups 1a and 2b) had a severe isolated GHD. An inverse correlation between APA titers and GH peak serum response to insulin tolerance test in autoimmune endocrine patients was observed. Our results suggest that APA, when detected at high titers, may be considered a good diagnostic tool to highlight the possible occurrence of GHD in adults with autoimmune endocrine diseases. Moreover, they may indicate an autoimmune pituitary involvement in adults with apparently idiopathic GHD, suggesting that the prevalence of autoimmune GHD is much higher than that so far considered.

Diagnosis of autoimmune central diabetes insipidus (CDI) is based on the presence of autoantibodies to AVP-secreting cells (AVPcAb) or the coexistence of other autoimmune polyendocrine syndromes; moreover, it can be also suggested by the presence of lymphocytic infundibulo-neurohypophysitis, evidenced by biopsy of pituitary stalk and/or by pituitary stalk thickening on magnetic resonance imaging (MRI). However, so far, in clinical CDI patients with lymphocytic infundibulo-neurohypophysitis, AVPcAb have not been investigated and in those with or without autoimmune polyendocrine syndromes (APS), longitudinal studies on the behavior of AVPcAb alone, or of both AVPcAb and hypothalamic pituitary imaging on MRI are lacking. Aim of this work was to investigate in these patients the occurrence of AVPcAb (by indirect immunofluorescence) and of pituitary stalk thickening (by MRI) and their longitudinal changes during a follow-up period. We studied 22 patients, aged 29-53, with APS and complete CDI, grouped as follows: 10 with recent onset (< or =1.5 yr) of CDI (group 1a) and 12 with CDI of long-term duration (> or = 7 yr) (group 1b); moreover, a group of 13 patients with apparent idiopathic CDI of recent onset (

Traumatic brain injury (TBI) has been recently recognized as a common cause of pituitary dysfunction. However, there are not sufficient numbers of prospective studies to understand the natural history of TBI induced hypopituitarism. The aim was to report the results of five years' prospective follow-up of anterior pituitary function in patients with mild, moderate and severe TBI. Moreover, we have prospectively investigated the associations between TBI induced hypopituitarism and presence of anti-hypothalamus antibodies (AHA) and anti-pituitary antibodies (APA). Twenty five patients (20 men, five women) were included who were prospectively evaluated 12 months and five years after TBI, and 17 of them also had a third-year evaluation. Growth hormone (GH) deficiency is the most common pituitary hormone deficit at one, three, and five years after TBI. Although most of the pituitary hormone deficiencies improve over time, there were substantial percentages of pituitary hormone deficiencies at the fifth year (28% GH, 4% adrenocorticotropic hormone [ACTH], and 4% gonadotropin deficiencies). Pituitary dysfunction was significantly higher in strongly AHA- and APA-positive (titers ≥1/16) patients at the fifth year. In patients with mild and moderate TBI, ACTH and GH deficiencies may improve over time in a considerable number of patients but, although rarely, may also worsen over the five-year period. However in severe TBI, ACTH and GH status of the patients at the first year evaluation persisted at the fifth year. Therefore, screening pituitary function after TBI for five years is important, especially in patients with mild TBI. Moreover, close strong associations between the presence of high titers of APA and/or AHA and hypopituitarism at the fifth year were shown for the first time.

Antipituitary antibodies (APA) but not antihypothalamus antibodies (AHA) are usually searched for in autoimmune hypopituitarism.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.We conducted a cross-sectional cohort study.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.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.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.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.

ObjectiveCurrent data clearly demonstrate that sports-related chronic repetitive head trauma due to boxing might result in hypopituitarism. However, the mechanism of sports-related traumatic brain injury-induced pituitary dysfunction is still unclear. In order to understand whether autoimmune mechanisms could play a role in the pituitary dysfunction due to sports-related head trauma, we investigated the presence of antipituitary antibodies (APAs) and antihypothalamus antibodies (AHAs) in amateur boxers.Patients and designSixty-one actively competing (n=44) or retired (n=17) male boxers (mean age, 26 years; range, 17–53) who had been evaluated regarding pituitary functions previously were included in the study. In all boxers and in 60 age/sex-similar normal controls, AHAs and APAs were investigated by an indirect immunofluorescence method.ResultsAHAs were detected in 13 of 61 boxers (21.3%), and APAs were detected in 14 of 61 boxers (22.9%), but in none of the normal controls. Pituitary dysfunction was significantly higher in AHA-positive boxers (46.2%) than in AHA-negative boxers (10.4%) (P=0.003). There was a significant association between AHA positivity and hypopituitarism due to boxing (odds ratio: 7.37, 95% confidence interval 1.8–30.8). There was no significant association between APA positivity and hypopituitarism.ConclusionsThis study demonstrates for the first time the presence of AHAs and APAs in boxers who were exposed to sports-related head trauma. Moreover, the present investigation provides preliminary evidence that AHAs are associated with the development of pituitary dysfunction in boxers, thus suggesting that autoimmunity may have a role in the pathogenesis.

CONTEXT: Antipituitary antibodies (APA) are frequently present in patients with autoimmune polyendocrine syndrome (APS). DESIGN: The aim was to evaluate the predictive value of APA for the occurrence of hypopituitarism. A total of 149 APA-positive and 50 APA-negative patients with APS and normal pituitary function were longitudinally studied for 5 yr. METHODS: APA, by indirect immunofluorescence, and anterior pituitary function were assessed yearly in all patients. The risk for developing autoimmune pituitary dysfunction was calculated using survival and multivariate analysis. RESULTS: Hypopituitarism occurred in 28 of 149 (18.8%) APA-positive patients but in none of the 50 APA-negative patients. The immunostaining pattern in APA-positive patients involved either isolated pituitary cells [type 1 pattern; n=99 (66.4%)] or all pituitary cells [type 2 pattern; n=50 (33.6%)]. All patients developing pituitary dysfunction throughout the study span had a type 1 pattern. Kaplan-Meier curves for cumulative survival showed a significantly higher rate for developing hypopituitarism in relation to positive APA tests (P

ObjectiveTraumatic brain injury (TBI) is a devastating public health problem that may result in hypopituitarism. However, the mechanisms responsible for hypothalamic–pituitary dysfunction due to TBI are still unclear. Although the antibodies against neurons have been demonstrated in injured animal studies, investigations regarding the occurrence of antipituitary antibodies (APAs) in patients with TBI are lacking in the literature. In order to investigate whether autoimmune mechanisms could play a role in the pituitary dysfunction after TBI, we have planned this study aimed at investigating the presence of APA at the third year of TBI and association between the TBI-induced hypopituitarism and APA.Patients and designTwenty-nine (25 males and 4 females; age 36.5±2.3 years) patients who had completed a 3-year follow-up after TBI were included in the present study. APA and pituitary function were evaluated in all the patients 3 years after TBI; moreover, APAs were tested also in sera of 60 age-/sex-matched normal controls. The APAs were investigated by an indirect immunofluorescence method.ResultsAPAs were detected in 13 out of the 29 TBI patients (44.8%), but in none of the normal controls. Pituitary dysfunction development ratio was significantly higher in APA-positive patients (46.2%) when compared with APA-negative ones (12.5%; P=0.04). There was a significant association between APA positivity and hypopituitarism due to TBI (odds ratio: 2.25, 95% confidence intervals 1.1–4.6). Moreover, there was a significant positive correlation (r=0.74, P=0.004) between APA titer ratio and peak GH response to GHRH+GH related peptide (GHRP)-6 test, suggesting that high APA titers were associated with low GH response to GHRH+GHRP-6 test.ConclusionsThis study shows for the first time the presence of the APA in TBI patients 3 years after head trauma. Moreover, present investigation indicates preliminary evidence that APA may be associated with the development of TBI-induced pituitary dysfunction, thus suggesting that autoimmunity may contribute in the development of TBI-induced hypopituitarism. The presence of the association between APA and TBI-induced hypopituitarism may provide a new point of view in this field and promote further clinical and experimental studies.

ObjectiveWhile anti-pituitary antibodies (APAs) were detected in some patients with Sheehan's syndrome (SS) suggesting an autoimmune pituitary involvement in the development of their hypopituitarism, hypothalamic cell anti-hypothalamus antibodies (AHAs) have not been investigated so far.DesignThe aim of this study was to evaluate the presence of AHA and APA in SS patients to verify whether an autoimmune hypothalamic–pituitary process can contribute to their late hypopituitarism.MethodsTwenty women with SS with a duration of disease ranging from 3 to 40 years (median 25.5 years) were enrolled into the study. Out of 20 patients, 12 (60%) had panhypopituitarism and the others had partial hypopituitarism well corrected with appropriate replacement therapy. None of them had clinical central diabetes insipidus. AHA and APA were investigated by immunofluorescence method in all patients. In addition, a four-layer immunofluorescence method was used to verify whether AHA immunostained vasopressin-secreting cells (AVP-c) or not.ResultsAHAs were found in 8 out of 20 (40%) and APAs in 7 out of 20 (35%) patients with titers ranging from 1:32 to 1:128 and 1:16 to 1:32 respectively; however, in none of these positive patients AHA immunostained vasopressin cells. None of controls resulted positive for both antibodies.ConclusionsPatients with SS, even many years after the onset of SS, can show antibodies to pituitary and/or hypothalamic but not AVP-secreting cells. Antibodies to unknown hypothalamic cells (releasing factor-secreting cells) other than APAs suggest that an autoimmune process involving both the hypothalamus and pituitary gland may contribute to late pituitary dysfunction in SS patients.

J Clin Endocrinol Metab. 2007 Feb;92(2):604-7. Epub 2006 Nov 7. Antipituitary antibodies against gonadotropin-secreting cells in adult male patients with apparently idiopathic hypogonadotropic hypogonadism. De Bellis A, Sinisi AA, Conte M, Coronella C, Bellastella G, Esposito D, Pasquali D, Ruocco G, Bizzarro A, Bellastella A. SourceDepartment of Clinical and Experimental Medicine and Surgery F Magrassi, A Lanzara, Second University of Naples, Naples, Italy. annamaria.debellis@unina2.it Abstract CONTEXT: Hypogonadotropic hypogonadism (HH) can occur at any stage of life as an isolated congenital or acquired abnormality or within a more generalized pituitary or hypothalamic impairment. However, the defect in patients with idiopathic HH is still unknown. OBJECTIVE: The aim of this study was to investigate the prevalence of antipituitary antibodies (APA) in a group of HH patients with or without Kallmann's syndrome and to characterize their pituitary target. DESIGN: We conducted a cross-sectional cohort study. SETTING: The study was performed at the Endocrinology Unit of the Second University of Naples. PATIENTS: Twenty-one HH patients with normal sense of smell (group 1), 10 patients with Kallmann's syndrome (group 2), 13 patients with HH associated with other pituitary hormone deficiencies (group 3), and 50 normal controls were studied. MAIN OUTCOME MEASURES: APA were evaluated in patients and in controls by indirect immunofluorescence. Moreover, a magnetic resonance imaging (MRI) of the hypothalamic-pituitary region was performed in all three groups of patients. RESULTS: APA were detected at high titer in eight out of 21 patients in group 1 (38%) and in five of 13 in group 3 (38.4%), and at low titers in two out of 10 in group 2 (20%) and in three of 50 controls (6%). In patients of group 1, APA immunostained selectively gonadotropin-secreting cells, whereas in those of group 3, they immunostained other pituitary hormone-secreting cells also. None of patients in group 1 showed alterations on MRI, whereas all patients in group 2 showed aplasia/hypoplasia of the olfactory bulbs/tracts and/or of olfactory sulci. Among the five APA-positive patients in group 3, three had normal MRI, one had findings of empty sella, and one had findings of autoimmune hypophysitis. CONCLUSIONS: Our results suggest that some apparently idiopathic cases of HH, both isolated and associated with other pituitary impairment, can be caused by an early autoimmune process involving the gonadotrophs at pituitary level. Future longitudinal studies are needed to clarify the natural history of this process and the possible effect of early corticosteroid therapy.

Coeliac disease (CD) is usually associated with impaired growth in children. A gluten-free diet (GFD) induces a catch-up growth with the recovery of height in about 2 years. AIM AND DISCUSSION: The lack of the height improvement has been related to growth hormone (GH) secretion impairment. CD is an autoimmune disease often associated with other endocrine and non-endocrine autoimmune disease. The aim of this study was to evaluate antipituitary autoantibodies (APA) and antihypothalamus autoantibodies in CD children with poor clinical response to a GFD and growth hormone deficiency (GHD). We diagnosed CD on the basis of specific antibodies and endoscopic biopsies in 130 patients aged 1-15 years. Seven CD children, without catch-up growth after at least 12-months GFD, were tested for GH secretion and, in five out of seven patients, the diagnosis of GHD was made in the absence of metabolic and systemic diseases.APA and antihypothalamus antibodies were detected by the indirect immunofluorescence method in the seven CD children without catch-up growth factor and in 25 CD children without growth impairment matched for sex and age, and in 58 healthy children as control groups. APA resulted positive at high titres in four out of five CD-GHD patients and were also positive at low titres (1:8) in three of only CD children and in two out of 58 controls. Hypothalamic-pituitary magnetic resonance imaging (MRI) was normal in all patients except in one with cystic pineal. APA have been previously detected not only in adults with GHD, but also in idiopathic GHD children, suggesting the occurrence of an autoimmune hypophysitis in these patients.In our study, the presence of APA in CD children without catch-up growth after GFD seems to be able to identify an autoimmune form of hypophysitis involving the somatotrophs cells.

Primary adrenal insufficiency (PAI) is clinically evident in one in 8000 individuals. A correct etiological classification is critical for correct disease management. To update the diagnostic criteria for the etiological classification of PAI, a multicentric network was established in Italy, and 222 patients with PAI were studied. Both 21-hydroxylase and adrenal cortex autoantibodies (21OHAb and ACA, respectively) were tested in two independent laboratories on coded samples and found in 65-66% and 58-61% of cases, respectively. Autoimmune polyendocrine syndrome I was diagnosed in 11 of the 222 patients. Of the remaining 211 patients, 38 (18%) had a nonautoimmune form of PAI. In 145 subjects (65%), the presence of adrenal autoantibodies, without signs of other forms of PAI, led to a diagnosis of autoimmune Addison's disease. In six cases (3%), PAI remained idiopathic. Logistic regression analysis showed a 92.2-92.7% probability of correct reclassification for the two 21OHAb assays and 84.5-85.9% for the ACA assays. We conclude that the simultaneous presence of both 21OHAb and ACA permits unambiguous diagnosis of autoimmune Addison's, whereas subjects with low antibody titers should undergo both instrumental and biochemical tests to exclude other causes of PAI. Lastly, we developed a comprehensive flowchart for the classification of PAI for use in routine clinical practice.

Central diabetes insipidus (CDI) is a rare hypothalamus-pituitary disease due to the deficiency of arginine vasopressin (AVP) synthesis from the hypothalamus and/or secretion from the neurohypophysis. The etiology of CDI is unknown in over one third of cases, classified as idiopathic CDI. The aim of this study was 2-fold: 1) to evaluate the occurrence of circulating autoantibodies to AVP-secreting cells (AVPcAb), and 2) to correlate it to clinical (sex, age of disease onset, disease duration, and degree), immunological (clinical history of autoimmune diseases and presence of related organ-specific autoantibodies), and radiological features (neurohypophyseal bright spot, pituitary stalk thickening, and empty sella) in a large cohort of patients with apparently idiopathic CDI or CDI of known etiology. To this purpose, 150 patients with CDI were studied: 64 idiopathic, 6 familial, 12 associated to granulomatous diseases, and 68 secondary to cranial trauma, tumor, or surgery. AVPcAb were measured by an indirect immunofluorescence method. AVPcAb were found in 23.3% of CDI patients: 21 idiopathic (32.8%) and 14 nonidiopathic (16.3%; chi(2) = 13.1; P < 0.001). AVPcAb were independently associated with age less than 30 yr at disease onset (P = 0.001) in patients with idiopathic CDI and with history of autoimmune diseases (P = 0.006 and P = 0.02, respectively) and radiological evidence of pituitary stalk thickening (P = 0.02 and P = 0.003, respectively) in both idiopathic and nonidiopathic CDI. The likelihood of autoimmunity in one patient with apparently idiopathic CDI with age of disease onset less than 30 yr was 53%, it increased to 91% when history of autoimmune diseases was associated and to 99% when pituitary stalk thickening was further associated. In conclusion, autoimmunity is associated with one third of patients with apparently idiopathic CDI, which should therefore be classified as autoimmune CDI. Autoimmune CDI is highly likely in young patients with a clinical history of autoimmune diseases and radiological evidence of pituitary stalk thickening. Conversely, autoimmunity probably represents an epiphenomenon in patients with nonidiopathic CDI.

Subclinical Addison's disease is characterized by the presence of adrenal autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21OHAb) with or without adrenal function failure. In our previous longitudinal study some patients with high titers of ACA and at stage 2 of subclinical adrenocortical failure showed disappearance of ACA with recovery of normal adrenocortical function after corticosteroid treatment for Graves' ophthalmopathy. To investigate whether corticosteroid-induced modification of the adrenal autoimmune markers can also involve 21OHAb and to evaluate whether the remission of subclinical adrenocortical failure can persist over a long period of time, we followed-up for 100 months the levels of 21OHAb and ACA as well as the metabolic markers of adrenal function in one patient with Graves' ophthalmopathy and at stage 2 of subclinical adrenocortical failure before and after corticosteroid therapy. A 34-yr-old woman with Graves' disease and active ophthalmopathy who was found to be positive for ACA and to have high PRA, low aldosterone levels, and normal basal ACTH and cortisol levels, but impaired cortisol response to ACTH was studied. The patient was treated with oral corticosteroid therapy for 6 months. After corticosteroid therapy, 21OHAb, initially positive, became negative in concomitance with the disappearance of ACA and the restoration of normal adrenal function. The disappearance of both 21OHAb and ACA and their prolonged absence during the follow-up suggest that corticosteroid treatment can induce long-term remission of subclinical adrenal insufficiency and prevent the onset of the clinical phase of the disease. Our pilot study may pave the way to future trials aimed at preventing the onset of the clinical signs of Addison's disease in ACA/21OHAb-positive patients.

Serum autoantibodies against eye muscle antigens are closely linked with thyroid-associated ophthalmopathy (TAO), although their significance is unclear. The two antigens that are most often recognized are eye muscle membrane proteins with molecular masses of 55 and 64 kDa, as determined from immunoblotting with crude human or porcine eye muscle membranes. We cloned a fragment of the 55-kDa protein by screening an eye muscle expression library with affinity-purified anti-55 kDa protein antibody prepared from a TAO patient’s serum. A complementary DNA (cDNA) encoding a novel protein, which we have called G2s, was sequenced on both strands, and its size was 411 bp. The open reading frame of G2s corresponded to a 121-amino acid peptide with a size of 1.4 kb. Using the rapid amplification of 5′-cDNA ends technique we were able to clone an additional 0.3 kb of the protein. G2s did not share significant homologies with any other entered protein in computer databases and had one putative transmembrane domain. Using the 1.4 kb cDNA as probe in Northern blotting of a panel of messenger ribonucleic acids prepared from human tissues, the parent protein was shown to correspond to a large molecule of about 5.8 kb with a calculated molecular mass of approximately 220 kDa, consistent with earlier immunoblot studies performed in the absence of reducing agents. G2s was strongly expressed in eye muscle, thyroid, and other skeletal muscle and to a lesser extent in pancreas, liver, lung, and heart muscle, but not in kidney or orbital fibroblasts. We tested sera from patients with Graves’ hyperthyroidism with and without ophthalmopathy and from control patients and subjects for antibodies against a G2s fusion protein by immunoblotting and enzyme-linked immunosorbent assay. In immunoblotting, antibodies reactive with G2s were identified in 70% of patients with TAO of less than 3 yr duration, 53% with TAO of more than 3 yr duration, 36% with Graves’ hyperthyroidism without evident ophthalmopathy, 17% with Hashimoto’s thyroiditis, 3% with type 1 diabetes, 23% with nonimmunological thyroid disorders, and 16% of normal subjects. The prevalences, compared to normal values, were significant for the two groups of patients with TAO, but not for the other groups. Tests were positive in 54% of patients with active TAO, 33% with chronic ophthalmopathy, 36% with Graves’ hyperthyroidism, 54% with Hashimoto’s thyroiditis, 23% with type 1 diabetes, and in 11% of normal subjects using enzyme-linked immunosorbent assay. The antibodies predicted the development of the ocular myopathy subtype of TAO in six of seven patients and the congestive ophthalmopathy subtype in seven of eight patients, respectively, with Graves’ hyperthyroidism studied prospectively during and after antithyroid drug therapy. Antibodies reactive with G2s may be early markers of ophthalmopathy in patients with Graves’ hyperthyroidism. Because G2s is expressed in both thyroid and eye muscle, immunoreactivity against a shared epitope in the two tissues may explain the well known link between thyroid autoimmunity and ophthalmopathy.

Cytoplasmic autoantibodies to vasopressin-cells (AVPcAb) have been detected not only in patients with overt central diabetes insipidus (CDI), but also in patients with endocrine autoimmune diseases without CDI. This suggests that complete CDI can be preceded by a preclinical stage. Among 878 patients with endocrine autoimmune diseases without CDI, 9 patients found to be AVPcAb positive and 139 AVPcAb-negative controls were enrolled in this open prospective study. They were evaluated for AVPcAb and posterior pituitary function at least yearly for about 4 yr (range, 37‐ 48 months); during this span, magnetic resonance imaging (MRI) of posterior pituitary and stalk was performed only in the AVPcAb-positive patients. Five of the 9 AVPcAb-positive patients had normal posterior pituitary function at study entry. They were AVPcAb positive throughout the follow-up period. At later stages of the study, 3 of them developed partial CDI, and 1 developed complete CDI. The remaining 4 patients showed impaired response to the water deprivation test at study entry and were diagnosed as having partial CDI. Two of them agreed to receive desmopressin replacement for 1 yr. After this treatment, the patients became negative for AVPcAb and displayed normal posterior pituitary function until the end of the follow-up. Conversely, the 2 untreated patients with partial CDI remained AVPcAb positive. One of them developed overt CDI. None of the controls became AVPcAb positive or developed CDI. The normal hyperintense MRI signal of the posterior pituitary, present at study entry, persisted subsequently in all 9 AVPcAb-positive patients, including those developing overt CDI, only disappearing in the late phase of complete CDI. In asymptomatic subjects, the monitoring of AVPcAb, but not MRI, seems to be useful to predict a progression toward partial/overt CDI. Early desmopressin therapy in patients with partial CDI could interrupt or delay the autoimmune damage and the progression toward clinically overt CDI. (J Clin Endocrinol Metab 84: 3047‐3051, 1999)

It is commonly recognized that a few patients with Graves’ disease (GD) develop an overt ophthalmopathy, although most of them show subclinical extraocular muscle enlargement by appropriate imaging techniques. At present, it is not possible to identify the subgroup of GD patients with subclinical retroorbital connective involvement. Recently, it has been shown that increase of soluble intercellular adhesion molecule-1 (sICAM-1) serum levels is correlated to clinical activity score in active Graves’ ophthalmopathy (GO) patients with or without hyperthyroidism, suggesting that sICAM-1 serum values could reflect the degree of ocular inflammatory activity. The aim of this longitudinal study was to evaluate sICAM-1 serum levels in GD patients without clinical ophthalmopathy and to assess their possible relationship with occurrence of GO. We measured sICAM-1 serum levels in 103 initially hyperthyroid GD patients without clinical ophthalmopathy and in 100 healthy subjects. All patients were treated with methimazole for 2 yr. Sera were collected from all patients before treatment and then monthly for the first 6 months of therapy, every 2 months in the following 6 months, and finally at the end of the follow-up study. Patients developing GO were excluded from the follow-up at the onset of ophthalmopathy. During the follow-up 17 GD patients (16.5%, group 1) developed overt eye involvement (14 as active inflammatory ophthalmopathy and 3 as ophthalmopathy without clinical retroorbital connective inflammation) and 86 (83.5%, group 2) did not. At start of the study, the mean of sICAM-1 serum concentrations did not differ significantly between the 2 groups, but it was significantly higher than in controls in both groups. No significant correlation between serum sICAM-1 concentrations and free thyroid hormone levels was found in the 2 groups of patients. During the follow-up study, a further increase of sICAM-1 serum levels was observed in 12 of the 14 patients (85.7%) of group 1 who developed active inflammatory ophthalmopathy not only at the onset but also before clinical GO appearance. On the contrary, the 3 patients of group 1 that developed ophthalmopathy without clinical retroorbital inflammation did not show any further increase of sICAM-1 levels at every time of follow-up in comparison with the starting values, even if their sICAM-1 levels were always higher than in normal controls. Finally, group 2 patients showed significantly decreased sICAM-1 levels throughout the follow-up period when compared with the starting values, although they were still significantly higher than in controls. These results indicate that a further increase of sICAM-1 serum levels before the onset of clinical ophthalmopathy may be a marker of subclinical retroorbital connective inflammation in GD patients. Therefore, our study suggests that serial determinations of sICAM-1 serum levels could help to identify and trace at the right time those GD patients prone to developing active inflammatory ophthalmopathy.

The authors have dosed by radioimmunoassay the rT3 concentrations in the amniotic fluid of 12 normal pregnant women and of 25 women with high risk pregnancies at the same period of gestation. The average of the rT3 concentrations in the amniotic fluid of pregnant women affected by diabetes mellitus, EPH gestosis and with foetal growth, retardation, are not different from those found in the control group. In the patients affected by Rh isoimmunization, the rT3 levels are remarkably higher than those found in the control group. The rT3 highest levels found in the amniotic fluid of pregnant women affected by Rh isoimmunization could be due. 1) to a decreased transformation of rT3 in rT2 for an accentuated alteration of the sulphydryl groups: 2) to a need of blocking the pathway's conversion of T4 in T3 (hormone with great catabolic effect) in these foetuses already presenting an accentuated catabolism for the chronic hemolytic enemy and for the severe hepatic alterations.

With this study, the Authors, have demonstrated that atropine has an inhibiting action on the hypophysis response and that such inhibition is correlated to the length of time between the i.m. injection of anticholinergic and the intravenous administration of TRH. Such results make believe that in human, as in the animal the cholinergic system plays a role, maybe important, in the prolactin release.