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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0040
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 7 2484-2489
Copyright © 2006 by The Endocrine Society

EXTENSIVE CLINICAL EXPERIENCE

Antipituitary Antibodies Recognizing Growth Hormone (GH)-Producing Cells in Children with Idiopathic GH Deficiency and in Children with Idiopathic Short Stature

Annamaria De Bellis1, Mariacarolina Salerno1, Marisa Conte, Concetta Coronella, Gilda Tirelli, Marina Battaglia, Valentina Esposito, Giuseppe Ruocco, Giuseppe Bellastella, Antonio Bizzarro and Antonio Bellastella

Department of Clinical and Experimental Medicine and Surgery (A.D.B., M.C., C.C., G.T., M.B., G.R., G.B., A.Bi., A.Be.), "F. Magrassi, A. Lanzara", Second University of Naples, and Department of Pediatrics (M.S., V.E.) Federico II University, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Annamaria De Bellis, Chair of Endocrinology, Second University of Naples, Via S. Pansini, 5, 80131 Naples, Italy. E-mail: annamaria.debellis{at}unina2.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE DETECTION OF organ-specific antibodies has been considered the hallmark of diagnosis of autoimmune endocrine diseases (1, 2). In fact, the presence of serum, organ-specific antibodies allowed us to classify some endocrine diseases, namely Addison’s disease and central diabetes insipidus, previously considered idiopathic, among the autoimmune diseases (3, 4, 5). Antipituitary antibodies (APA) have been detected in serum of some patients with idiopathic hypopituitarism, suggesting an autoimmune pathogenesis in these cases (6, 7, 8, 9, 10). Concerning this, Bottazzo et al. (11) detected APA immunostaining exclusively GH-producing cells in a girl with Turner’s syndrome and partial GH deficiency (GHD), suggesting that autoimmunity could play an etiological role in some cases of GHD. Recently, we demonstrated that the detection of APA at high titers may contribute to diagnosing GHD in adults with autoimmune endocrine diseases, although it may indicate an autoimmune pituitary involvement in adults with apparently idiopathic GHD (IGHD) (12). Subsequently, using a four-layer indirect immunofluorescence, we were able to demonstrate that GH-secreting cells are the main target of these antibodies in these latter patients (13). Taking into account that all our APA-positive adult patients with IGHD previously investigated had a well known past history of childhood-onset GHD in the absence of hypothalamic-pituitary diseases (12, 13), we decided to search for these antibodies also in children with IGHD. Thus, we planned this study aimed to 1) investigate the presence of APA in prepubertal children with IGHD and in prepubertal children with idiopathic short stature (ISS); 2) identify in possible APA-positive patients whether somatotrophs or other pituitary hormone-producing cells are targeted by these antibodies; and 3) verify whether patients with apparently ISS positive for APA could develop GHD.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Starting in 2002, 26 children with IGHD (group 1: age range, 5.0–8.5 yr; 12 females and 14 males) and 60 children with ISS (group 2: age range, 5.0–8.1 yr; 33 females and 27 males) diagnosed at the Endocrine Unit and Pediatric Endocrinology Unit of Second University and Federico II University of Naples, respectively, were studied. To avoid interferences caused by pubertal growth, medications, or diseases, only children that had no clinical signs of puberty and were free from chronic diseases and drugs were enrolled into this study. The diagnosis of IGHD had been established on the basis of the following criteria: short stature [age and sex-adjusted height < 2 SD score (SDS)], reduced growth velocity (<25th centile), delayed skeletal development, and blunted GH response (<10 µg/liter) to two different pharmacological stimulation tests. In all patients of group 1, GH peak was less than 5 µg/liter and IGF-I levels were below the normal range for age and sex, suggesting the diagnosis of complete GHD. Patients with ISS presented with the following characteristics: height less than 2 SDS, growth velocity less than 25th centile, delayed skeletal development, and normal GH response (>10 µg/liter) at least to one of two different pharmacological tests; in 10 of them, IGF-I levels were below the normal range for age and sex. Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region and basal and dynamic secretion of other pituitary hormones were normal in all patients of groups 1 and 2. Nineteen patients of group 2 who kept on attending our units as outpatients were submitted to a new auxological and hormonal evaluation 2 yr after the first observation.

Moreover, 33 children with GHD secondary to destructive lesions or development abnormalities of the hypothalamus or pituitary (group 3) were also studied; finally, sera from 40 normal children matched for sex and age were used as controls for detecting APA.

Parents of all patients gave informed consent to the study, which was approved by the local ethical committee.

Immunological evaluation

At study entry, APA were evaluated in all children in groups 1, 2, and 3 and in normal controls. APA were also evaluated 2 yr later in 19 patients of group 2. APA were detected by an indirect immunofluorescence method on cryostat sections of young baboon pituitary gland as previously described (12). In particular, fluorescein isothiocyanate (FITC)-conjugated goat antihuman IgG sera were used to detect the presence of APA, and then positive serum samples were tested with FITC-goat antihuman IgG, IgM, and IgA sera separately. We considered positive only specimens with a titer of at least 1/8. In sera that were APA positive, antibodies against single pituitary hormone-producing cells were determined by a four-layer double-immunofluorescence technique as previously described (13, 14). In particular, the same cryostat section, in a first immunostaining step, was tested against the patient’s serum and then FITC-goat antihuman Ig sera and in a second immunostaining step against rabbit sera anti-GH, -ACTH, -TSH, -prolactin (PRL), -LH, and -FSH, separately followed by rhodamine-goat sera antirabbit IgG. The different color of anti-Ig conjugate against the human serum and against the animal serum, respectively green (FITC) and red (rodhamine), allows direct assessment of whether the patient’s serum and the animal’s serum stain the same or different pituitary cells.

Hormone assays

GH values were determined by immunoradiometric assay using commercial kits. The stimulatory tests used were the arginine test (dose, 0.5 g/kg body weight up to a maximum of 30 g) and the insulin tolerance test (dose, 0.05–0.1 IU/kg body weight). IGF-I values were measured by immunoradiometric assay using commercial kits.

Statistical analysis

Data are expressed as mean ± SD, unless otherwise specified. Nonparametric tests were used because of the non-Gaussian distribution of the data. Differences between the frequencies were evaluated by {chi}2 test. Differences among the groups were evaluated by the Kruskal-Wallis and Mann-Whitney U tests. Comparison within each group was performed using the Wilcoxon signed-ranks test. A value of P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The characteristics of children in groups 1, 2, and 3 and normal controls are illustrated in Table 1Go. Growth velocity, height (SDS), and IGF-I levels in group 1 were significantly lower than in group 2 (P < 0.001).


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  		TABLE 1. Characteristics of the children with IGHD (group 1), ISS (group 2), or secondary GHD (group 3) and normal controls at the start of the study

 
The behavior of APA in the three groups of patients and in normal controls is depicted in Fig. 1Go.


Figure 1
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  		FIG. 1. APA in children with IGHD (group 1), ISS (group 2), and GHD secondary to lesion/abnormalities of hypothalamus or pituitary (group 3) and in healthy controls at start of the study.

 
None of the normal controls and none of patients in group 3 were APA positive. APA were observed in seven of 26 (27%) children with GHD and in 14 of 60 (23%) children with ISS with titers ranging from 1/32 to 1/128 and from 1/16 to 1/64, respectively, but without significantly different prevalence between the two groups. Immunofluorescence pattern was characterized by an intracytoplasmic staining in some pituitary cells. By a four-layer double-immunofluorescence method, APA did not immunostain ACTH-, TSH-, LH-, and FSH-producing cells, but they did selectively stain GH-producing cells (Fig. 2Go, a and b) and only rarely some PRL-producing cells. In regard to families of APA-positive patients, autoimmune endocrine or nonendocrine diseases were present in parents or first-degree relatives of three of the seven GHD APA-positive and eight of the 14 ISS initially APA-positive children.


Figure 2
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  		FIG. 2. Immunofluorescence in cryostat sections of young baboon anterior pituitary gland tested against serum of a child with GHD in a primary step, adding FITC-goat sera antihuman Ig (a) and in a second immunostaining step adding rabbit antisera anti-GH followed by rhodamine-goat sera antirabbit IgG (b).

 
APA-positive and APA-negative children with both GHD and ISS were compared with respect to their characteristics (Table 2Go). In particular, no significant differences in height and growth velocity were observed between APA-positive and APA-negative patients with GHD, whereas APA-positive children with ISS showed height and growth velocity significantly lower than APA-negative patients of the same group, without any significant difference with respect to patients with GHD. Moreover, ISS APA-positive children had IGF-I levels significantly lower than APA-negative ones. In detail, 10 of 14 APA-positive children showed low levels of IGF-I, whereas all APA-negative children had normal IGF-I levels. The comparison between the results at yr 0 and at yr 2 of APA, auxological parameters, IGF-I levels. and GH response to two tests in the 19 reevaluated children with ISS are summarized in Table 3Go. This group consisted of 11 initially APA-negative and eight initially APA-positive children that kept on attending our units as outpatients, allowing an immunological and hormonal reevaluation 2 yr after the first observation.


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  		TABLE 2. Comparison between characteristics of APA-positive and APA-negative patients with IGHD (group 1) and patients with ISS (group 2) at the start of the study

 

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  		TABLE 3. Evaluation of APA, height, growth velocity, GH response to two stimuli, and IGF-I levels at the start of the study (A) and 2 yr after the first observation (B) in 19 children with ISS divided as follows: 11 initially APA-negative patients and eight initially APA-positive patients

 
These patients persisted in the prepubertal stage 2 yr later. The 11 initially APA-negative patients persisted negative 2 yr later, without significant differences in height and growth velocity with respect to their starting values; moreover, GH peaks after stimuli did not differ between 0 and 2 yr, remaining more than 10 µg/liter; moreover, IGF-I levels significantly increased (P = 0.001) at the second observation, achieving the normal range in all of them.

Instead, in all eight initially APA-positive patients, these antibodies significantly increased at yr 2 (P = 0.008), with titers ranging from 1/32 and 1/128 (Table 3Go), and recognized selectively GH-producing cells and only rarely some PRL-producing cells. These APA-positive patients did not show significant variations in height and growth velocity with respect to the baseline values. The IGF-I levels did not change at yr 2, remaining constantly below the normal range in all eight patients. Finally, in APA-positive patients, GH response to the stimuli significantly decreased at yr 2 (P = 0.008), becoming less than 10 µg/liter in seven of them, thus indicating a progression toward a GHD, whereas in all 11 APA-negative patients, as specified above, GH response remained more than 10 µg/liter, confirming the diagnosis of ISS. MRI of the hypothalamic-pituitary region was normal in all of them.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Lymphocytic hypophysitis (LYH) could impair pituitary hormone secretion in adult patients (12, 15, 16, 17, 18). In particular, GHD isolated or associated with other pituitary hormone impairment could be secondary to LYH (10, 19, 20). Histopathological study by pituitary biopsy is considered the gold standard for the diagnosis of LYH even in the absence of MRI findings suggestive of the disease. APA detection could be helpful for diagnosing particular forms of LYH, with normal MRI characteristics or when pituitary biopsy cannot be performed (21, 22). So far, studies evidencing the relationship between GHD and LYH in children are lacking (11, 23). The first important result emerging from our study is that APA against GH-producing cells are present at high titer (≥1/16) in 27% of children with apparently IGHD but are absent in secondary forms of GHD. These results indicate that, in childhood, an autoimmune aggression to somatotrophs may frequently be the underlying cause of hormonal deficit in some children with apparently IGHD and that this autoimmune process, also following the results of our previous study in adults (12, 13), may probably extend to the adulthood period for determining a possible LYH. The absence of significant alterations on pituitary MRI does not impugn these assumptions. In fact, MRI alterations are more frequent in adults than in children with LYH (21, 22, 23, 24). Indeed, in later stages, GHD is frequently accompanied by MRI characteristics of empty sella syndrome, indicating in such a case a partial atrophy of the pituitary gland (22, 24, 25, 26). Thus, even if the gold diagnostic tool remains the pituitary biopsy (not very feasible in children and not authorized by the parents of our patients), the detection of APA against GH-secreting cells by a four-layer double-indirect-immunofluorescence method may be considered a sensitive and specific immunological marker of primary autoimmune process against somatotrophs, and it seems a better tool than MRI to identify autoimmune forms of GHD among a heterogeneous group of children with IGHD.

The second important result of our study regards the detection of APA in some children with ISS. Mauerhoff et al. (23) reported the presence of APA in 5% of 397 sera of children with ISS, but these antibodies reacted with isolated cells in the anterior pituitary, immunostaining PRL-secreting cells in the majority of patients and GH-secreting cells in only three patients. In our patients with ISS, APA against GH-producing cells have been detected at high titer in 23% of them. Interestingly, ISS children showed a statistically similar prevalence of these antibodies with respect to patients with IGHD. However, APA-positive children with ISS had auxological characteristics and levels of IGF-I significantly lower than the APA-negative ISS children, whereas no significant differences were evidenced between APA-positive and APA-negative IGHD children.

It has been reported that some children with ISS may show low IGF-I levels, growth failure, and decrease of growth velocity similar to patients with GHD (27, 28, 29). Our results suggest that APA-positive children with ISS could be considered as an initial autoimmune form of GHD in whom the GH reserve is still normal. In particular, we hypothesize that the autoimmune aggression to somatotrophs, evidenced by the presence of APA against GH-producing cells, can affect in an early stage the GH secretion rate with consequent reduction of IGF-I even with GH response to the stimuli still normal; thus, the reduction of IGF-I should explain the impairment of the auxological parameters (27). Instead, the overlapping auxological characteristics in APA-positive and APA-negative IGHD children can be caused by the common impaired GH secretion independently from the presence or absence of APA. However, the occurrence of different types of antibodies, harmless in some children and pathogenic in others, cannot be excluded.

Another crucial message of our study emerges from the reevaluation of APA and of auxological and hormonal characteristics in some children with ISS 2 yr after the first observation. Our results suggest that the presence of APA could identify in children with ISS those prone to develop GHD. In fact, all eight initially APA-positive patients persisted as APA positive with additional increases of their titer, and they showed an impairment of GH response to the stimuli 2 yr after the first observation, suggesting the occurrence of GHD in these patients. Instead, all 11 initially APA-negative patients persisted as APA negative with a normal GH response to two tests at the second observation, confirming the previous diagnosis of ISS. The increase of APA titers at the second observation in the eight ISS initially APA-positive patients, associated in seven of them with an impaired GH response to the two stimuli, is in accordance with our previous studies demonstrating that the transition phase from the preclinical to the clinical stage of some autoimmune diseases is characterized by an elevation of antibody titers (30, 31, 32).

Even if this study has to be followed by longitudinal studies on a more numerous population with ISS, we hypothesize that the natural history of autoimmune GHD may be to evolve through two functional phases both characterized by the presence of antibodies against GH-producing cells: a first stage, characterized by the presence of antibodies against GH-producing cells, decreased growth velocity, and frequently low IGF-I levels but normal GH response to the stimuli, which can be followed by a second stage characterized by the increase of these antibodies, decrease of growth velocity and of IGF-I levels, and onset of impaired GH response to the stimuli.

At present, the design of our study does not allow us to establish the predictive and/or pathogenic role of APA. However, in other autoimmune diseases, intracytoplasmic organ-specific autoantibodies, such as islet-cell antibodies and adrenal cortex antibodies, released by the damaged cells could be considered, when present at high titer, good predictive markers of clinical type 1 diabetes mellitus and clinical Addison’s disease, respectively, even without having a pathogenic role (30, 32, 33). Thus, we suggest that, like for these above-mentioned organ-specific antibodies, the detection of APA may be of good clinical utility, especially when pituitary biopsy is not consented to and MRI is inconclusive, because it can contribute to diagnosing autoimmune GHD occurring in children with apparently IGHD and to predict a possible development of GHD in those with ISS.

In conclusion, our results suggest that several cases of apparently idiopathic GHD in children could be caused by an autoimmune process involving the somatotrophs, which can be revealed by the detection of APA at high titer immunostaining GH-secreting cells. Also, in children with ISS, the detection of APA against GH-producing cells may help to identify those of them prone to develop a GHD. However, the presence in the literature of only a few prepubertal cases and the lack of pituitary biopsy in our children suggest caution against generalization of our conclusions.


   Footnotes
 
This work was supported in part by grants from Ministero Università Ricerca Scientifica e Tecnologica (Prin 2004062075 to A.Be.).

First Published Online April 18, 2006

1 A.D.B and M.S. have contributed equally to the manuscript. Back

Abbreviations: APA, Antipituitary antibodies; FITC, fluorescein isothiocyanate; GHD, GH deficiency; IGHD, idiopathic GHD; ISS, idiopathic short stature; LYH, lymphocytic hypophysitis; MRI, magnetic resonance imaging; PRL, prolactin; SDS, SD score.

Received January 9, 2006.

Accepted April 7, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Roitt IM, Doniach D, Campbell PN, Hudson RV 1956 Autoantibodies in Hashimoto’s disease. Lancet 2:820–822[CrossRef]
  2. Vandewalle CL, Falorni A, Svanholm S, Lenmark A, Pipeleers DG, Gorus FK 1995 High diagnostic sensitivity of glutamate decarboxylase autoantibodies in insulin-dependent diabetes mellitus with clinical onset between age 20 and 40 years. The Belgian Diabetes Registry. J Clin Endocrinol Metab 80:846–851[Abstract]
  3. Betterle C, Dal Pra C, Mantero F, Zanchetta R 2002 Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 23:327–364[Abstract/Free Full Text]
  4. De Bellis A, Colao A, Bizzarro A, Di Salle F, Coronella C, Solimeno S, Vetrano A, Pivonello R, Pisano G, Lombardi G, Bellastella A 2002 Longitudinal study of vasopressin-cell antibodies and of hypothalamic-pituitary region on magnetic resonance imaging in patients with autoimmune and idiopathic complete central diabetes insipidus. J Clin Endocrinol Metab 87:3825–3829[Abstract/Free Full Text]
  5. Pivonello R, De Bellis A, Faggiano A, Di Salle F, Peretta M, Di Somma C, Perrino S, Altucci P, Bizzarro A, Bellastella A, Lombardi G, Colao A 2003 Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology. J Clin Endocrinol Metab 88:1629–1636[Abstract/Free Full Text]
  6. Pouplard A 1982 Pituitary autoimmunity. Horm Res 16:289–297[Medline]
  7. Crock PA, Salvi M, Miller A, Wall J, Guyda H 1993 Detection of anti-pituitary autoantibodies by immunoblotting. J Immunol Methods 162:31–40[CrossRef][Medline]
  8. Maghnie M, Lorini R, Severi F 1994 Antipituitary antibodies in patients with pituitary abnormalities and hormonal deficiency. Clin Endocrinol (Oxf) 40:809–810[Medline]
  9. Sauter NP, Toni R, McLaughlin CD, Dyess EM, Kritzman J, Lechan RM 1990 Isolated adrenocorticotropin deficiency associated with an autoantibody to a corticotroph antigen that is not adrenocorticotropin or other proopiomelanocortin-derived peptides. J Clin Endocrinol Metab 70:1391–1397[Abstract]
  10. Bensing S, Kasperlik-Zaluska AA, Czarnocka B, Crock PA, Hulting A 2005 Autoantibodies against pituitary proteins in patients with adrenocorticotropin-deficiency. Eur J Clin Invest 35:126–132[CrossRef][Medline]
  11. Bottazzo GF, McIntosh C, Stanford W, Preece M 1980 Growth hormone cell antibodies and partial growth hormone deficiency in a girl with Turner’s syndrome. Clin Endocrinol (Oxf) 12:1–9[Medline]
  12. De Bellis A, Bizzarro A, Conte M, Perrino S, Coronella C, Solimeno S, Sinisi AM, Stile LA, Pisano G, Bellastella A 2003 Antipituitary antibodies in adults with apparently idiopathic growth hormone deficiency and in adults with autoimmune endocrine diseases. J Clin Endocrinol Metab 88:650–654[Abstract/Free Full Text]
  13. De Bellis A, Bizzarro A, Perrino S, Coronella C, Conte M, Pasquali D, Sinisi AA, Betterle C, Bellastella A 2005 Characterization of antipituitary antibodies targeting pituitary hormone-secreting cells in idiopathic growth hormone deficiency and autoimmune endocrine diseases. Clin Endocrinol (Oxf) 63:45–49[CrossRef][Medline]
  14. Bottazzo GF, Pouplard A, Florin-Christensen A, Doniach D 1975 Autoantibodies to prolactin-secreting cells of human pituitary. Lancet 2:97–101[Medline]
  15. Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S 1995 Lymphocytic hypophysitis: clinicopathological findings. J Clin Endocrinol Metab 80:2302–2311[Abstract]
  16. Cheung CC, Ezzat S, Smyth HS, Asa SL 2001 The spectrum and significance of primary hypophysitis. J Clin Endocrinol Metab 86:1048–1053[Abstract/Free Full Text]
  17. Beressi N, Beressi JP, Cohen R, Modigliani E 1999 Lymphocytic hypophysitis. A review of 145 cases. Ann Intern Med 150:327–341
  18. Caturegli P, Newschaffer C, Olivi A, Pomper MG, Burger PC, Rose NR 2005 Autoimmune hypophysitis. Endocr Rev 26:599–614[Abstract/Free Full Text]
  19. Crock PA 1998 Cytosolic autoantigens in lymphocytic hypophysitis. J Clin Endocrinol Metab 83:609–618[Abstract/Free Full Text]
  20. O’dwyer DT, Smith AI, Matthew ML, Andronicos NM, Ranson M, Robinson PJ, Crock PA 2002 Identification of the 49-kDa autoantigen associated with lymphocytic hypophysitis as {alpha}-enolase. J Clin Endocrinol Metab 87:752–757[Abstract/Free Full Text]
  21. Bellastella A, Bizzarro A, Coronella C, Bellastella G, Sinisi AA, De Bellis A 2003 Lymphocytic hypophysitis: a rare or underestimated disease? Eur J Endocrinol 149:363–376[Abstract]
  22. De Bellis A, Bizzarro A, Bellastella A 2005 Pituitary antibodies and lymphocytic hypophysitis. Best Pract Res Clin Endocrinol Metab 19:67–84[Medline]
  23. Mauerhoff T, Mirakian R, Bottazzo GF 1987 Autoimmunity and the pituitary. In: Doniach D, Bottazzo GF, eds. Endocrine and other organ-oriented autoimmune disorders. Baillière’s clinical immunology and allergy. Vol. 1. London: WB Saunders; 217–235
  24. Chelaifa K, Bouzaidi K, Harzallah F, Menif E, Ben Messaoud M, Turki I, Slim R 2002 Lymphocytic hypophysitis. J Neuroradiol 29:57–60[Medline]
  25. Levine SN, Benzel EC, Fowler MR, Shroyer 3rd JV, Mirfakhraee M 1988 Lymphocytic adenohypophysitis: clinical, radiological, and magnetic resonance imaging characterization. Neurosurgery 22:937–941[Medline]
  26. Klein J, Fehm HL 2005 Unusual presentation of hypophysitis preceding an empty sella in a 75-year-old woman. Neuro Endocrinol Lett 26:757–758[Medline]
  27. Rogol AD, Blethen SL, Sy JP, Veldhuis JD 2003 Do growth hormone (GH) serial sampling, insulin-like growth factor-I (IGF-I) or auxological measurements have an advantage over GH stimulation testing in predicting the linear growth response to GH therapy? Clin Endocrinol (Oxf) 58:229–237[CrossRef][Medline]
  28. Saenger P 1998 Growth hormone and idiopathic short stature: it is too soon to call it a mis-trial. Eur J Endocrinol 138:258–261[CrossRef][Medline]
  29. Badaru A, Wilson DM 2004 Alternatives to growth hormone stimulation testing in children. Trends Endocrinol Metab 15:252–258[Medline]
  30. De Bellis A, Bizzarro A, Rossi R, Paglionico VA, Criscuolo T, Lombardi G, Bellastella A 1993 Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies. J Clin Endocrinol Metab 76:1002–1007[Abstract]
  31. De Bellis A, Colao A, Di Salle F, Muccitelli VI, Iorio S, Perrino S, Pivonello R, Coronella C, Bizzarro A, Lombardi G, Bellastella A 1999 A longitudinal study of vasopressin cell antibodies, posterior pituitary function, and magnetic resonance imaging evaluations in subclinical autoimmune central diabetes insipidus. J Clin Endocrinol Metab 84:3047–3051[Abstract/Free Full Text]
  32. De Bellis A, Falorni A, Laureti S, Perrino S, Coronella C, Forini F, Bizzarro E, Bizzarro A, Abbate G, Bellastella A 2001 Time course of 21-hydroxylase antibodies and long-term remission of subclinical autoimmune adrenalitis after corticosteroid therapy: case report. J Clin Endocrinol Metab 86:675–678[Abstract/Free Full Text]
  33. Srikanta S, Ganda OP, Rabizadeh A, Soeldner JS, Eisenbarth GS 1985 First-degree relatives of patients with type I diabetes mellitus. Islet-cell antibodies and abnormal insulin secretion. N Engl J Med 313:461–464[Abstract]



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A. De Bellis, A. A. Sinisi, M. Conte, C. Coronella, G. Bellastella, D. Esposito, D. Pasquali, G. Ruocco, A. Bizzarro, and A. Bellastella
Antipituitary Antibodies against Gonadotropin-Secreting Cells in Adult Male Patients with Apparently Idiopathic Hypogonadotropic Hypogonadism
J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 604 - 607.
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S. Bensing, S. O. Fetissov, J. Mulder, J. Perheentupa, J. Gustafsson, E. S. Husebye, M. Oscarson, O. Ekwall, P. A. Crock, T. Hokfelt, et al.
Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1
PNAS, January 16, 2007; 104(3): 949 - 954.
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