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.

Antipituitary antibodies against gonadotropin-secreting cells in adult male patients with apparently idiopathic hypogonadotropic hypogonadism.

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.

Antipituitary antibodies recognizing growth hormone (GH)-producing cells in children with idiopathic GH deficiency and in children with idiopathic short stature.

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.

Characterization of antipituitary antibodies targeting pituitary hormone-secreting cells in idiopathic growth hormone deficiency and autoimmune endocrine diseases.

OBJECTIVE: In order to investigate whether somatotrophs are the target of antipituitary antibodies (APA) in adult patients with growth hormone deficiency (GHD), we studied the sera of 37 APA positive patients. PATIENTS: Patients were grouped as follows: nine patients with APA at high titre (> 1 : 8) affected by apparently idiopathic GHD; four of them (group 1a) with isolated GHD diagnosed during childhood and five with GHD diagnosed during adulthood associated with autoimmune endocrine diseases (group 1b), and 28 patients with autoimmune endocrine diseases without pituitary impairment, previously found positive for APA at low titre (1 : 8, group 2). MEASUREMENTS: APA were evaluated by a four-layer double indirect immunofluorescence technique. RESULTS: In group 1a patients, APA immunostained exclusively GH-producing cells. In group 1b patients, APA were directed not only to GH- but also to other pituitary hormone-producing cells. In group 2 patients, APA were directed selectively to PRL-producing cells and rarely to some GH-producing cells. CONCLUSIONS: In the present study, we demonstrated that GH-secreting cells are the target of the autoimmune reaction in autoimmune GHD and that the immunostaining of only the somatotrophs is typical of isolated GHD. In contrast, the finding of diffuse staining of APA indicates the need to search for other autoimmune diseases. Finally, the presence of APA at low titre directed against PRL-secreting cells in patients with autoimmune endocrine diseases in the absence of pituitary impairment, seems to be only a nonspecific marker of pituitary autoimmunity. A longitudinal study would be useful to clarify the relationship between the different pituitary cell involvement and the natural history of pituitary dysfunction in autoimmune hypophysitis.

Lymphocytic hypophysitis: a rare or underestimated disease?

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.

Relationship between longitudinal behaviour of some markers of eye autoimmunity and changes in ocular findings in patients with Graves' ophthalmopathy receiving corticosteroid therapy.

OBJECTIVE: To investigate whether variations over time of TSH-receptor antibodies (TRAb) and antibodies against G2s (G2sAb) and extraocular muscles (EMAb) can predict worsening of ophthalmopathy in Graves' patients treated with intravenous glucocorticoid (IVGC) therapy. PATIENTS: Of 65 consecutive patients with treated Graves' disease and severe and active ophthalmopathy (GO) chosen to undergo IVGC treatment, only 57 patients, persistently euthyroid under methimazole therapy, were studied longitudinally for ocular parameters, TRAb, G2sAb and EMAb before therapy, at the end of therapy and, subsequently, every month for 21 months. MEASUREMENTS: TRAb was detected by radioimmunoassay (RIA), G2sAb by enzyme-linked immunosorbent assay (ELISA) and EMAb by indirect immunofluorescence. RESULTS: Forty-three out of 57 patients (75.4%, group 1) responded positively to therapy [improvement in diplopia and decrease in proptosis and clinical activity score (CAS)] but 14 (24.6%) did not (group 2). During follow-up after IVGC therapy, 12 out of 43 patients in group 1 (28%) showed a worsening in GO (group 1a), while 31 (72%) had stable ocular conditions or further improvement (group 1b). At the start of the study, TRAb, G2sAb and EMAb were not significantly different among the three groups. At the end of IVGC therapy TRAb levels decreased significantly with respect to starting values in all three groups of patients, whereas G2sAb and EMAb decreased significantly in groups 1a and 1b but not in group 2. During the subsequent follow-up, 10 patients in group 1a one/two months before and all 12 patients at the time of GO worsening showed an increase in G2sAb and EMAb but not in TRAb, which were consistently absent or present at low titre in all patients in this group. In group 1b TRAb, G2sAb and EMAb further decreased or became negative during the follow-up period. In all patients, TRAb were positively correlated with both CAS and proptosis only at the start of the study; by contrast, a significant correlation between both G2sAb and EMAb and diplopia was observed in groups 1a and 1b at all the times during the study, except one/two months before the worsening of GO in group 1a. CONCLUSIONS: Our results indicate that TRAb, G2sAb and EMAb can be considered sensitive markers of Graves' ophthalmopathy during the initial stages of ophthalmopathy, but that only G2sAb and EMAb seem to be good predictive markers of the outcome in patients after corticosteroid therapy. Thus, taking into account the cost/benefit ratio, a longitudinal evaluation of either EMAb or G2sAb could be useful in monitoring the intravenous glucocorticoid therapy in patients with severe and active ophthalmopathy to predict a possible worsening of Graves' ophthalmopathy.

Antipituitary antibodies in adults with apparently idiopathic growth hormone deficiency and in adults with autoimmune endocrine diseases.

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.

Steroid-cell autoantibodies are preferentially expressed in women with premature ovarian failure who have adrenal autoimmunity.

OBJECTIVE: To determine the prevalence of steroid-cell autoantibodies, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) antibodies, 17alpha-hydroxylase (17alpha-OH) antibodies, and P450 side-chain cleavage antibodies in premature ovarian failure. DESIGN: Cross-sectional, observational study. SETTING: Academic research hospitals. PATIENT(S): Eighty-one women with premature ovarian failure, 20 women with Addison disease not associated with premature ovarian failure, 42 women with type 1 diabetes mellitus, and 90 healthy women. MAIN OUTCOME MEASURE(S): Serum levels of steroid-cell autoantibodies, 17alpha-OH antibodies, P450 side-chain cleavage antibodies, and 3beta-HSD antibodies. RESULT(S): Steroid-cell autoantibodies were present in none of 57 women with isolated premature ovarian failure or premature ovarian failure plus nonadrenal autoimmune disease and in 21 of 24 (87%) women with Addison disease-related premature ovarian failure. 17alpha-Hydroxylase antibodies and P450 side-chain cleavage antibodies were significantly more frequent in women positive for adrenal autoantibodies than in those negative for adrenal autoantibodies (50% vs. 0% and 71% vs. 2%, respectively). The presence of 17alpha-OH antibodies or P450 side-chain cleavage antibodies was strongly associated with presence of steroid-cell autoantibodies. Two of 24 (8%) women with Addison disease-related premature ovarian failure and 1 of 57 (2%) women with isolated premature ovarian failure or premature ovarian failure plus nonadrenal autoimmune disease were positive for 3beta-HSD antibodies. None of 20 adult women with autoimmune Addison disease and none of 42 adult women with type 1 diabetes mellitus not associated with premature ovarian failure was positive for 3beta-HSD antibodies. CONCLUSION(S): Markers of steroid-cell autoimmunity are found only rarely in idiopathic premature ovarian failure not associated with Addison disease. Most women with Addison disease-related premature ovarian failure were positive for steroid-cell autoantibodies, 17alpha-OH antibodies, or P450 side-chain cleavage antibodies. 3beta-Hydroxysteroid dehydrogenase antibodies do not appear to be a major marker of steroid-cell autoimmunity.