Elena Pane

Antipituitary antibodies after traumatic brain injury: is head trauma-induced pituitary dysfunction associated with autoimmunity?

OBJECTIVE Traumatic 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 DESIGN Twenty-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. Results APAs 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. CONCLUSIONS This 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.

Predictive Role of the Immunostaining Pattern of Immunofluorescence and the Titers of Antipituitary Antibodies at Presentation for the Occurrence of Autoimmune Hypopituitarism in Patients with Autoimmune Polyendocrine Syndromes over a Five-Year Follow-Up

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<0.005), pattern of immunostaining (P<0.0001), and APA titers (P<0.000001). Cox regression analysis in APA-positive patients with a type 1 pattern demonstrated a significantly (P<0.0001) higher risk for the onset of hypopituitarism in relation to increasing titers of APA. CONCLUSIONS APA measurement by immunofluorescence may help to predict the occurrence of hypopituitarism but only when considering the immunostaining pattern and their titers. Combined evaluation of these parameters allows identifying patients at higher risk for pituitary autoimmune dysfunction, thus requiring a strict pituitary surveillance to disclose a preclinical phase of hypopituitarism and possibly interrupt therapeutically the progression to clinically overt disease.

Detection of antipituitary and antihypothalamus antibodies to investigate the role of pituitary or hypothalamic autoimmunity in patients with selective idiopathic hypopituitarism

Objective  Antipituitary (APA) but not antihypothalamus antibodies (AHA) have been investigated in patients with idiopathic hypopituitarism. This study searched for APA and AHA in some of these patients to investigate whether pituitary or hypothalamic autoimmunity could play a role in their pituitary dysfunction.

Immunological and clinical aspects of lymphocytic hypophysitis

LYH (lymphocytic hypophysitis) is an autoimmune disease of the pituitary gland which can present with varying degrees of pituitary hormonal impairment and/or with symptoms related to pituitary enlargement. In this review, we provide an overview of the epidemiology, diagnosis, pathogenesis, treatment, and the role of organ-specific and antipituitary antibodies as potential markers of LYH. In addition, although the mechanisms underlying LYH are not completely understood, the role of prolactin, which plays an important part in maintaining immune system homoeostasis and is increased in the disease, is considered.

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.

Autoimmunity as a possible cause of growth hormone deficiency

A possible autoimmune aggression to pituitary somatotrophs has been suggested by the occurrence of antipituitary antibodies (APA) directed against GH-secreting cells in some cases of GH deficiency (GHD) both in adults and in children and in some patients with autoimmune poliendocrine syndrome. We also detected APA in some patients with idiopathic short stature (ISS) and suggested that the presence of these antibodies could identify those of them prone to develop GHD. In fact, patients with ISS, resulted positive for APA at the first observation, during a longitudinal follow-up showed an impaired GH response to the stimuli in subsequent years suggestive of acquired GHD. Also in such patients we demonstrated that the target of APA were the somatotrophs and that an autoimmune attack to these cells may be the underlying cause of hormonal impairment in several children with GHD positive for APA. In this connection we suggested that in these patients an early iso-hormonal therapy with recombinant GH may be useful to interrupt or delay the progression towards a clinical GHD.

Simultaneous evaluation of the circulating levels of both Th1 and Th2 chemokines in patients with autoimmune Addison's disease

Background: Chemokines play a key role in the recruitment of the immune cells into the autoimmune process. Thus, the simultaneous evaluation of circulating levels of Th1-related chemokines, such as CX chemokine ligand 10 (CXCL10) and macrophage inflammatory proteins 1α (CCL3/MIP-1α), and Th2-related chemokines, such as macrophage inflammatory proteins 1 β (CCL4/MIP-1β) could be useful in the approach to some autoimmune diseases, including autoimmune Addison’s disease (AAD). Aim: To evaluate plasmatic levels of MIP-1 α, MIP-1β, CXCL10 and adrenocortical antibodies in patients with AAD under treatment with corticosteroids. Patients and methods: Twelve women and 5 men (group 1) were divided in 2 subgroups: 9 subsjects with isolated AAD (group 1a) and 8 with AAD associated with chronic autoimmune thyroiditis (group 1b). MIP-1α, MIP-1β and CXCL10 were evaluated in the serum of all patients and in 20 healthy controls, using a system for microarray suspension. Results: The levels of MIP-1α, MIP-1β and CXCL10 resulted significantly increased vs controls (p<0.001). An inverse significant correlation between the serum levels of MIP-1β and the duration of the disease was observed. Conclusion: High levels of MIP-1α and MIP-1β associated with increased levels of CXCL10 in AAD seem to indicate a role of these chemokines in the autoimmune pathology of adrenal gland through the recruitment in loco of Th1 and Th2 cells. The simultaneous measurement of Th1-related chemokines (CXCL10 and MIP-1α) and of Th2-related chemokine MIP-1β in the serum of patients with AAD would sustain a novel preliminary hypothesis on the immune microenvironment of chronic autoimmune inflammation within adrenal glands.

Seasonal variations of plasma gonadotropin, prolactin, and testosterone levels in primary and secondary hypogonadism: Evidence for an independent testicular role

Background: Seasonal hormonal rhythmicity of the hypothalamic-pituitary-gonadal axis may influence reproductive and sexual activity in mammals. Aim: To investigate whether pituitary-gonadal axis secretion seasonality occurs in men with primary and secondary hypogonadism and whether a hierarchical machinery regulates these variations. Subjects and methods: Six adult males with Klinefelter’s syndrome (KS), eight with idiopathic normosmic hypogonadotropic hypogonadism (HH) and ten sex- and age-matched healthy controls were studied longitudinally for one year. Every three months, three plasma samples for assay of testosterone, LH, FSH, and prolactin were drawn and the mean value was used for statistical analysis. Results: Healthy males showed a significant seasonality in LH (zenith in spring) and testosterone (zenith in autumn) but not in FSH and prolactin concentrations. Patients with KS and those with HH showed a seasonal rhythmicity only of testosterone values, even if with small amplitude, with the zenith in spring and summer respectively. Conclusion: The lack of dependence of testosterone on gonadotropin variations in normal men and the persistence of seasonal testosterone but not gonadotropin variations both in primary and secondary hypogonadism seem to indicate a possible independent testicular regulation of this seasonality. The shift of testosterone peak in hypogonadal men with respect to controls suggests that LH variations could play a synchronizing, rather than pace-making, role in seasonal testosterone variations. Since hormonal seasonality may also influence gonadal activity in humans, replacement therapy in hypogonadism should be aimed also at restoring a normal seasonal rhythmicity of pituitary-gonadal hormone concentrations.