Subclinical central hypothyroidism in patients with hypothalamic-pituitary disease: does it exist?

Central hypothyroidism (CH) is characterized by decreased thyroid hormone production due to insufficient stimulation of an otherwise normal thyroid gland by TSH. In patients with established hypothalamic-pituitary disease, a low FT4 concentration is considered highly specific, although poorly sensitive, for the diagnosis of CH. That would be comparable to diagnosing primary hypothyroidism in patients at risk only when serum FT4 concentrations are below the reference range, missing all patients with subclinical primary hypothyroidism and preventing proper therapy in patients in which thyroxine replacement is clearly beneficial. Cardiac time intervals, especially the isovolumic contraction time (ICT), have been considered the gold standard of peripheral thyroid hormone action. Using Doppler echocardiography, we have previously shown a very high proportion of prolonged ICT in patients with hypothalamic-pituitary disease and serum FT4 levels indistinguishable from controls. As ICT decreased/normalized after thyroxine-induced increases in FT4 concentrations within the normal reference range, prolonged ICT was considered a bona fide diagnostic biomarker of subclinical CH. Those findings challenge the usual interpretation that FT4 concentrations in the mid-reference range exclude hypothyroidism in patients with hypothalamic-pituitary disease. Rather, subclinical central hypothyroidism, a state analogous to subclinical primary hypothyroidism, seems to be frequent in patients with hypothalamic-pituitary disease and normal FT4 levels. They also challenge the notion that thyroid function is usually the least or the last affected in acquired hypopituitarism. The relevance of Doppler echocardiography to correctly diagnose and monitor replacement therapy in both clinical and subclinical forms of CH should improve quality of life and decrease cardiovascular risk, as already demonstrated in patients with clinical and subclinical primary hypothyroidism.

Comparison of a combination test (1 µg ACTH test plus glucagon test) versus 1 µg ACTH test and glucagon test in the evaluation of the hypothalamic-pituitary-adrenal axis in patients with pituitary disorders.

OBJECTIVE: To investigate whether a combination of the low-dose (1 µg) adrenocorticotropin (ACTH) stimulation test and glucagon stimulation test (GST) could overcome the problem of equivocal results with the GST or ACTH test alone in patients with pituitary disorders. METHODS: The study included 41 adult patients with pituitary disorders and 20 healthy subjects who underwent evaluation of cortisol response to ACTH, GST, and a combination of both tests. Blood samples for cortisol measurement were obtained at baseline and 30, 60, 90, and 120 minutes after intravenous administration of ACTH 1 µg and 90, 120, 150, 180, 210, and 240 minutes after subcutaneous injection of glucagon 1 mg. The combination test was performed by injecting ACTH 1 µg at the 180-minute time point of the GST, with blood samples for cortisol measurement obtained at 210 and 240 minutes. RESULTS: Overall, 28 patients with normal cortisol response to both tests also had a normal cortisol response to the combination test. Ten patients with adrenal insufficiency in both tests also had adrenal insufficiency in the combination test, including a patient who had a peak cortisol value of 12.4 µg/dL (which is the cutoff value for the combination test). Two patients with adrenal insufficiency in the ACTH stimulation test and one patient with adrenal insufficiency in the GST had normal cortisol responses to the combination test. CONCLUSION: By using an appropriate cutoff value, the combination test may offer additional information in patients with equivocal results in the GST and ACTH stimulation test.

Rathke's cleft cyst infections and pituitary abscesses: case series and review of the literature.

PURPOSE: Pituitary abscesses (PAs) are a rare clinical entity which may arise from normal pituitary tissue or underlying lesions within the gland. Rathke's cleft cysts (RCCs) are not commonly associated with the development of PA. METHODS: Retrospective chart review of three patients with PAs within RCCs at a single university center and review of the literature. RESULTS: Three cases are reported. The first case presented with fever and headache and a history of prior surgery due to RCC and a recent respiratory tract infection. The second case had a history of recent skin infections and presented with sudden onset headache and hypopituitarism. In the third case, chronic visual field impairment prompted an ophthalmologic evaluation resulting in a diagnosis of an adenoma and an infected RCC. In all three cases, an endoscopic endonasal approach was performed to drain infected tissue and allowed microbiological identification of gram-positive cocci, followed by treatment with antibiotics for at least three weeks. Cases in the literature are scarce and the diagnosis is usually made intraoperatively due to non-specific manifestations and imaging. PAs arising from underlying pituitary lesions are less common than primary PAs. Differential diagnosis should include pituitary apoplexy, hypophysitis and other cystic lesions. CONCLUSION: PAs occurring in RCCs are infrequent. Clinical manifestations are commonly subacute, without septic symptoms. Imaging is usually non-specific. Preoperative diagnosis is infrequent and a broad differential diagnosis should be considered. Empirical antimicrobial therapy should be initiated and adjusted after obtaining cultures to reduce the rate of recurrence and improve clinical outcomes.

Comparison of a combination test (1 µg ACTH test plus glucagon test) versus 1 µg ACTH test and glucagon test in the evaluation of the hypothalamic-pituitary-adrenal axis in patients with pituitary disorders

ABSTRACT Objective To investigate whether a combination of the low-dose (1 µg) adrenocorticotropin (ACTH) stimulation test and glucagon stimulation test (GST) could overcome the problem of equivocal results with the GST or ACTH test alone in patients with pituitary disorders. Subjects and methods The study included 41 adult patients with pituitary disorders and 20 healthy subjects who underwent evaluation of cortisol response to ACTH, GST, and a combination of both tests. Blood samples for cortisol measurement were obtained at baseline and 30, 60, 90, and 120 minutes after intravenous administration of ACTH 1 μg and 90, 120, 150, 180, 210, and 240 minutes after subcutaneous injection of glucagon 1 mg. The combination test was performed by injecting ACTH 1 µg at the 180-minute time point of the GST, with blood samples for cortisol measurement obtained at 210 and 240 minutes. Results Overall, 28 patients with normal cortisol response to both tests also had a normal cortisol response to the combination test. Ten patients with adrenal insufficiency in both tests also had adrenal insufficiency in the combination test, including a patient who had a peak cortisol value of 12.4 µg/dL (which is the cutoff value for the combination test). Two patients with adrenal insufficiency in the ACTH stimulation test and one patient with adrenal insufficiency in the GST had normal cortisol responses to the combination test. Conclusion By using an appropriate cutoff value, the combination test may offer additional information in patients with equivocal results in the GST and ACTH stimulation test.

Evaluation of dynamic testing for pituitary pars intermedia dysfunction diagnosis in donkeys.

BACKGROUND: Endocrine disorders are common in donkeys. Pituitary pars intermedia dysfunction (PPID) is thought to be a frequent disturbance in donkeys due to their longevity. However, information on PPID dynamic testing in donkeys is lacking. OBJECTIVES: The objective of this study was to evaluate the previously described guidelines for PPID diagnosis in horses in donkeys with suspicion of PPID. STUDY DESIGN: Prospective experimental study. METHODS: Eighty donkeys were evaluated for PPID suspicion based on clinical signs and baseline adrenocorticotropic hormone (ACTH) concentrations. Six mix-breed donkeys (one jack and five non-pregnant jennies) fulfilling inclusion criteria were subjected to dexamethasone suppression test (DST), thyrotropin-releasing hormone stimulation test (TRH) and combined DST-TRH challenge. Tests were interpreted according to guidelines for PPID diagnosis in horses. RESULTS: Donkeys fulfilling inclusion criteria were diagnosed with PPID by TRH stimulation test (six of six). Both DST (three of six) and DST-TRH (4/6) challenges failed to detect those animals and showed conflicting results. Similarly, cortisol basal concentrations were not consistent with PPID suspicion. MAIN LIMITATIONS: Characterisation of seasonal and geographical location effect on baseline ACTH concentrations and response to TRH is compelling in this species. Further studies with a larger number of donkeys are needed. CONCLUSIONS: This is the first study in donkeys to evaluate common dynamic tests used for PPID diagnosis in horses. Preliminary results agree with the guidelines for PPID diagnosis in horses and baseline ACTH measurement followed by TRH challenge are recommended tests for diagnosis of PPID in donkeys.

Infundibuloneurohipofisitis: caso clínico y revisión de la literatura / Infundibuloneurohypophysitis: clinical report and literature review

Infundibuloneurohypophysitis is a rare condition, which is part of the group of hypophysitis, of relatively recent description (1993). The main clinical manifestation is diabetes insipidus, whose natural evolution is towards chronicity. The differential diagnosis with other thickening of the hypophysial stem is very important, where the clinic, imaging, laboratory and eventually biopsy are a main support for a correct diagnosis. We present a clinical case that shows the usual picture of infundibuloneurohypophysitis, and illustrates the imaging evolution in a female patient, with diabetes insipidus as the main clinical manifestation

Reappraisal of serum insulin-like growth factor-I (IGF-1) measurement in the detection of isolated and combined growth hormone deficiency (GHD) during the transition period / Reavaliação da dosagem sérica do fator de crescimento insulina-símile-1 (IGF-1) para o diagnóstico da deficiência isolada e combinada de hormônio de crescimento no período de transição

OBJECTIVE: To evaluate the accuracy of serum IGF-1 in the detection of isolated (IGHD) or combined growth hormone deficiency (CGHD) at the transition phase. SUBJECTS AND METHODS: Forty nine patients with GHD during childhood [16 with IGHD (10 men) and 33 with CGHD (24 men); age 23.2 ± 3.5 yrs.] were submitted to an insulin tolerance test (ITT) with a GH peak < 5 µg/L used for the diagnosis of GHD at the transition phase. Pituitary function and IGF-1 measurements were evaluated in the basal sample of the ITT. Transition patients were reclassified as GH-sufficient (SGH; n = 12), IGHD (n = 7), or CGHD (n = 30). RESULTS: Five (31%) patients with IGHD and 32 (97%) with CGHD at childhood persisted with GHD at retesting. One patient with IGHD was reclassified as CGHD, whereas 3 patients with CGHD were reclassified as IGHD. Mean GH peak was 0.2 ± 0.3 µg/L in the CGHD, 1.3 ± 1.5 µg/L in the IGHD, and 18.1 ± 13.1 µg/L in the SGH group. Serum IGF-1 level was significantly higher in the SGH (272 ± 107 ng/mL) compared to IGHD (100.2 ± 110) and CGHD (48.7 ± 32.8) (p < 0.01). All patients reclassified as CGHD, 86% reclassified as IGHD, and 8.3% reclassified as SGH had low IGF-1 level, resulting in 97.3% sensitivity and 91.6% specificity in the detection of GHD at the transition period; the cutoff value of 110 ng/mL showed 94.5% sensitivity and 100% specificity. Mean IGF-1 values did not differ in IGHD or CGHD associated with one, two, three, or four additional pituitary deficiencies. CONCLUSION: IGF-1 measurement is accurate to replace ITT as initial diagnostic test for IGHD and CGHD detection at the transition phase.

OBJETIVO: Avaliar a acurácia da dosagem sérica de IGF-1 no diagnóstico da deficiência de hormônio de crescimento isolada (DGHI) ou combinada (DGHC) na fase de transição. SUJEITOS E MÉTODOS: Quarenta e nove pacientes com DGH na infância [16 DGHI (10 homens) e 33 DGHC (24 homens); idade 23,2 ± 3,5 anos] realizaram teste de tolerância à insulina (TTI), com pico de GH < 5 µg/L considerado diagnóstico de DGH na transição. Função hipofisária e níveis de IGF-1 foram determinados na amostra basal do TTI e os pacientes foram reclassificados em GH suficientes (SGH; n = 12), DGHI (n = 7) ou DGHC (n = 30). RESULTADOS: Cinco (31%) pacientes com DGHI e 32 (97%) com DGHC na infância persistiram com DGH no reteste. Um paciente com DGHI foi reclassificado como DGHC e três com DGHC como DGHI. Os picos médios de GH foram 0,2 ± 0,3 µg/L (DGHC), 1,3 ± 1,5 µg/L (DGHI) e 18,1 ± 13,1 µg/L (SGH). O nível médio de IGF-1 foi maior no grupo SGH (272 ± 107 ng/mL) comparado com DGHI (100,2 ± 110) e DGHC (48,7 ± 32,8) (p < 0,01). IGF-1 baixo foi observado em todos os pacientes reclassificados como DGHC, 86% dos DGHI e 8,3% dos SGH, resultando em sensibilidade de 97,3% e especificidade de 91,6% para detecção de DGH na transição; valor de corte de 110 ng/mL mostrou 94,5% sensibilidade e 100% especificidade. O nível médio de IGF-1 foi similar nos pacientes com DGHI ou DGHC com uma, duas, três ou quatro deficiências hipofisárias associadas. CONCLUSÃO: A dosagem sérica de IGF-1 mostrou-se acurada para substituir o TTI na detecção tanto de DGHI como DGHC na transição.

Reappraisal of serum insulin-like growth factor-I (IGF-1) measurement in the detection of isolated and combined growth hormone deficiency (GHD) during the transition period.

OBJECTIVE: To evaluate the accuracy of serum IGF-1 in the detection of isolated (IGHD) or combined growth hormone deficiency (CGHD) at the transition phase. SUBJECTS AND METHODS: Forty nine patients with GHD during childhood [16 with IGHD (10 men) and 33 with CGHD (24 men); age 23.2 ± 3.5 yrs.] were submitted to an insulin tolerance test (ITT) with a GH peak < 5 µg/L used for the diagnosis of GHD at the transition phase. Pituitary function and IGF-1 measurements were evaluated in the basal sample of the ITT. Transition patients were reclassified as GH-sufficient (SGH; n = 12), IGHD (n = 7), or CGHD (n = 30). RESULTS: Five (31%) patients with IGHD and 32 (97%) with CGHD at childhood persisted with GHD at retesting. One patient with IGHD was reclassified as CGHD, whereas 3 patients with CGHD were reclassified as IGHD. Mean GH peak was 0.2 ± 0.3 µg/L in the CGHD, 1.3 ± 1.5 µg/L in the IGHD, and 18.1 ± 13.1 µg/L in the SGH group. Serum IGF-1 level was significantly higher in the SGH (272 ± 107 ng/mL) compared to IGHD (100.2 ± 110) and CGHD (48.7 ± 32.8) (p < 0.01). All patients reclassified as CGHD, 86% reclassified as IGHD, and 8.3% reclassified as SGH had low IGF-1 level, resulting in 97.3% sensitivity and 91.6% specificity in the detection of GHD at the transition period; the cutoff value of 110 ng/mL showed 94.5% sensitivity and 100% specificity. Mean IGF-1 values did not differ in IGHD or CGHD associated with one, two, three, or four additional pituitary deficiencies. CONCLUSION: IGF-1 measurement is accurate to replace ITT as initial diagnostic test for IGHD and CGHD detection at the transition phase.

Pituitary autoimmune disease: nuances in clinical presentation.

Pituitary autoimmune disease is considered an autoimmune organ-specific disorder, characterized by a pituitary infiltration of lymphocytes, macrophages, and plasma cells that could lead to loss of pituitary function. Hypophysitis may be secondary to systemic diseases or infections. Primary pituitary hypophysitis is classified into lymphocytic, granulomatous, xanthomatous, mixed forms (lymphogranulomatous, xanthogranulomatous), necrotizing and IgG4 plasmacytic, according to the histological findings. Concerning lymphocytic hypophysitis (LH), it is characterized by lymphocytic infiltration and can be subclassified according to the affected area on: lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis and lymphocytic panhypophysitis. LH had always been considered a rare disease. Nevertheless, with improved imaging techniques, especially magnetic resonance imaging (MRI), LH diagnosis has been increased. This disease usually affects young women during pregnancy or postpartum period with headache, visual impairment, ACTH deficiency and a homogenous sellar mass with thickening of pituitary stalk in MRI. Definitive diagnosis depends on histopathological evaluation; nevertheless, a presumptive diagnosis could be done in a typical case. As no specific autoantigen was identified in LH, there is no antipituitary antibody (APA) method available for helping diagnosis. However, APA used in some centers for research could support an autoimmune origin for some hypopituitarism previously named as idiopathic, confirming nuances in clinical presentation of pituitary autoimmune disease. Therapeutic approach should be based on the grade of suspicious and clinical manifestations of LH.

Panhipopituitarismo y diabetes insípida secundarios a hipofisitis linfocitaria en una paciente con trisomia 12p / Panhypopituitarism and diabetes insipidus secondary to a lymphocytic hypophysitis in one patient with trisomy 12p

Lymphocytic hypophysitis (LH) is an uncommon inflammatory disease of the hypophysis. It's female to male ratio of appearance is 9:1. Pregnant women are more affected during the third trimester of pregnancy or postpartum. Clinical and radiological presentation can simulate a hypophyseal adenoma. We report a nonpregnant 13 years old adolescent, with a trisomy 12p, with panhypopituitarism, diabetes insipidus and a selar tumor. It was necessary to differentiate between a germinoma and a LH. The latter was confirmed with the hypophyseal biopsy.

Central hypothyroidism and hypophysitis during treatment of chronic hepatitis C with pegylated interferon alpha and ribavirin.

Thyroid dysfunction is a known complication of interferon treatment in patients with hepatitis C virus (HCV) infection. Other uncommon endocrine complications have been reported during the treatment of viral hepatitis with IFN-alpha, such as hypopituitarism. A 54-year-old female patient with chronic hepatitis C began treatment with pegylated (PEG)-IFN-alpha 2a 180 mug/week plus ribavirin 1,000 mg/day. At week 20 of treatment, her routine laboratory control showed low levels of thyroid-stimulating hormone (TSH) and free serum thyroxine. This was confirmed at week 24, and other laboratory values showed low levels of adrenocorticotrophic hormone (ACTH). A T1-weighted magnetic resonance imaging scan demonstrated high intensity of the anterior pituitary gland and enhancement after intravenous administration of gadolinium. Hypophysitis with hypothalamic-pituitary dysfunction and secondary or central hypothyroidism was diagnosed on the basis of the clinical features, endocrinological assessment, immunological markers and imaging studies. Twenty-four weeks after stopping treatment, HCV RNA was negative by polymerase chain reaction and alanine aminotransferase values were below the upper limits of normal, and ACTH and thyroid values remained within the reference values. This is the first report of central hypothyroidism and hypophysitis during treatment with PEG-IFN-alpha plus ribavirin, and may be included in the potential list of side effects of the combination treatment.

Fast acquisition sagittal T1 magnetic resonance imaging (FAST1-MRI): a new imaging approach for the diagnosis of growth hormone deficiency.

Routine magnetic resonance imaging (MRI) is an established standard method to investigate the etiology of pituitary insufficiency. Among the anatomic abnormalities usually observed, ectopic hyperintense signal on T1 sequence is the most frequently associated with pituitary dysfunction. We developed a new protocol (FAST1-MRI) which is able to detect anatomic hypothalamic-pituitary abnormalities with 100% concordance when compared to the routine MRI protocol. FAST1-MRI takes only 3.25 minutes, and is performed without contrast, sedation or anesthesia. We studied 17 controls and 31 patients with growth hormone (GH) deficiency (18/31 with abnormal MRI). Patients with ectopic hyperintense signal were shorter in height, had lower IGF-I and IGFBP-3 levels, and reduced GH response after clonidine. In conclusion, we describe a new simplified MRI protocol that we propose should be used in the diagnosis of GH deficiency.

Infundibulo neurohipofisitis linfoplasmocitaria con compromiso quiasmatico e hipotalamico. Presentacion de un caso / Linfoplasmocitary infundibulohipophisitis with chiasmal and hypothalamic involvement. Case presentation

Objective: to present a 38 year old female patient, with central diabetes insipidus, panhipopituitarims, and severely impaired vision. Description: magnetic resonance imaging demonstrated a large mass involving the hypothalamus, infundibulum, optic nerves, and chiasm. Intervention: at surgery the optic pathways were found to be grossly involved within the inflammatory mass. Histological examination demonstrated anonspecific, mixed inflammatory infiltrate, composed predominantly of lymphocytes and plasma cells. She responded dramatically to dexamethasone, with mass reduction on serial imaging studies and vision improvement. In addition, she received hormone replacement therapy. Infundibulohypophisitis is a rare disease. Surgical biopsy and dexamethasone were an effective treatment (AU)

Glucagon stimulation test for the diagnosis of GH deficiency in adults.

The insulin tolerance test (ITT) is considered the test of choice for the diagnosis of GH deficiency (GHD). However, in patients with contraindications to ITT, alternative provocative tests must be used with appropriate cut-offs. The glucagon stimulation test has proved to be a safe, low-cost and effective means of stimulating GH secretion, and therefore can be considered as a suitable alternative to the ITT. We have studied the GH response to the glucagon test in 33 patients with known pituitary disease, 12 males and 21 females, aged between 21 and 60 yr (41.18 +/- 9.47 yr); 5 had isolated GHD and 28 had panhypopituitarism. We also evaluated a control group of 25 individuals, matched for age and sex (8 males and 17 females), aged between 20 and 60 yr (39.28 +/- 12.10 yr). They were selected via the ITT if their peak GH response was > 5.0 ng/ml. GH peak after glucagon was significantly lower in the group of patients compared to the control group (0.49 +/- 0.85 vs 8.69 +/- 5.85 ng/ml, p = 0.0001). Receiver-operating characteristic (ROC) plot analyses of the control and GHD group showed an area under the curve of 0.982 for GH peak response to glucagon. The response value of 3.0 ng/ml showed the best pair of sensitivity (97%)/specificity (88%), and was chosen as the cut-off defining GHD. After evaluation of positive predictive values (PPV) and negative predictive values (NPV) through simulation of different prevalences of the disease, we concluded that the cut-off point of 3.00 ng/ml maximizes both PPV and NPV (100%). In conclusion, we have shown that the glucagon stimulation test has a good performance and great diagnostic accuracy for the diagnosis of GHD.

Primary pituitary abscess: case report.

Pituitary abscesses are potentially life-threatening lesions if not appropriately diagnosed and treated. The authors have operated on more than five hundred cases of pituitary tumors and only one represented a case of pituitary abscess. A 35-year-old woman was investigated for chronic frontal headache. CT scan showed a cystic sellar lesion with ring enhancement after contrast injection leading to an initial diagnosis of pituitary adenoma. She underwent a sublabial transsphenoidal approach to the pituitary gland. After dural opening, purulent material was obtained and no tumor or other associated lesion was detected. There was no evidence of current or previous septicemic illness, meningitis, cavernous sinus thrombosis or sinus infection. Cultures were negative. She was put on antibiotics and discharged after 4 weeks. Nowadays, 10 years after treatment, she is doing well, with no anterior pituitary hormone deficit. MRI shows a partially empty sella without residual lesion and the pituitary stalck is in the midline. The early diagnosis and adequate treatment of this life-threatening lesion may result in excellent prognosis.