Abstract Posttraumatic stress disorder (PTSD) disrupts hypothalamic-pituitary-adrenal (HPA) axis function. Given the established role of HPA axis hormones in regulating bone metabolism, we tested the hypothesis that traumatic stress has a negative impact on bone development. We employed a variant single prolonged stress (SPS) model in which several stressors were applied to three week old C57BL/6J mice. Compared to the controls, the stressed mice showed increased freezing behavior reminiscent of PTSD symptoms. At two weeks, bone mineral content (BMC), bone area (B area) and bone mineral density (BMD) in total body based on dual-energy x-ray absorptiometry (DXA) analysis were reduced by 10.2%, 7.0% and 3.6%, respectively. Micro-CT analysis of the metaphyseal region of the excised tibia revealed that SPS caused a deterioration of trabecular architecture with trabecular number (Tb.N), BV/TV, connectivity density (Conn-Den) decreasing 12.0%, 18.9%, 23.3% and trabecular spacing (Tb.Sp), structure model index (SMI) increasing 13.9%, 21.8%, respectively. Mechanical loading increased the cross sectional area in the mid-shaft region of the loaded right vs. unloaded left tibia by 7.6% in the controls, and 10.0% in the stressed mice. Therefore, SPS applied to pre-pubertal young mice produced strong negative impact on both bone mass acquisition and trabecular architecture. Mechanical loading can be employed to increase bone size, a parameter related to bone strength, in normal as well as stressed conditions.

Context:

The clinical effectiveness of ablative radioiodine treatment of thyroid tumors is limited by the availability of the sodium iodide symporter (NIS) at the plasma membrane to uptake (131)I. A significant proportion of well-differentiated thyroid tumors are unable to concentrate sufficient radioiodine for effective therapy, and in other tumor models such as breast, where radioiodine uptake would be an attractive therapeutic option, uptake is insufficient.

Objective.

Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is over-expressed in multiple cancers, and significantly decreases NIS expression at the plasma membrane. The goal of this study was to identify a method by which PBF repression of NIS may be overcome in human tumors.

Results.

We now identify PBF as a tyrosine phospho-protein which specifically binds the proto-oncogene tyrosine-protein kinase Src in mass spectrometry, GST-pull-down and co-immunoprecipitation assays. Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in plasma membrane retention and a markedly reduced ability to bind NIS. The Src inhibitor PP1 inhibits PBF phosphorylation in multiple cell lines in vitro, including human primary thyroid cells. Of direct clinical importance to the treatment of thyroid cancer, PP1 stimulates iodide uptake by transfected NIS in TPC1 thyroid carcinoma cells and entirely overcomes PBF repression of iodide uptake in human primary thyroid cells.

Conclusions.

We propose that targeting PBF phosphorylation at residue Y174 via tyrosine kinase inhibitors may be a novel therapeutic strategy to enhance the efficacy of ablative radioiodine treatment in thyroid and other endocrine and endocrine-related tumors.

Nasal hamartomas are rare congenital lesions. We describe a case of nasal hamartoma associated with pituitary duplication and other midline anomalies. A 40-year-old female with a history of breast cancer presented with nasal obstruction. Computed tomography and magnetic resonance imaging revealed a mass arising from the nasal septum, as well as duplication of the pituitary and a skull base canal that extended from the margin of the left pituitary fossa to the nasal mass. The mass was subsequently resected via a transnasal endoscopic approach and histology confirmed the presence of hamartoma. Nasal hamartomas are benign lesions that can be associated with other midline anomalies, such as duplicated pituitary, and can be managed conservatively.

BACKGROUND:

The significance of pituitary stalk thickening (PST) on magnetic resonance imaging (MRI) is often unclear. We evaluated presenting symptoms, MRI findings, clinical course, and outcome predictors of patients with PST.

PROCEDURE:

We used a computerized search of the medical record from 1995 to 2008 to identify patients with PST without pituitary mass on MRI. Baseline and follow-up MRIs were reviewed in a blinded fashion. Relevant clinical data were abstracted.

RESULTS:

69 patients with reported PST and adequate imaging for review were identified; 42 met study criteria. Median age at first abnormal MRI was 13.6 years (range: 0.8-19.7); 43% were male. Median follow-up was 3.4 years (range 0-12.8). Patients with diabetes insipidus (DI) were significantly more likely to have a neoplastic process than those without (P = 0.0008). Of 16 patients with DI, 8 (50%) had a neoplastic process, including germ cell tumor (n = 4), Langerhans cell histiocytosis (n = 3), and lymphoma (n = 1). Among patients with DI, 7 (44%) also developed anterior pituitary hormone dysfunction (APD), either at presentation or on pre-biopsy follow-up, including 6/8 patients with stalk neoplasm and only 1/8 patients with non-neoplastic PST (P = 0.04). Twenty-six patients presented without DI; none was found to have neoplasm of the stalk except one patient with craniopharyngioma. Progression of PST on follow-up imaging was significantly associated with a subsequent neoplastic diagnosis (P = 0.04).

CONCLUSION:

Patients with PST without DI are unlikely to have a neoplastic process. Among patients with DI, APD or progressive stalk increase over time are predictive of neoplasia. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.

Background/Aims:

Central hypothyroidism (CH) in children is rare and may be due to a variety of genetic defects. Most of these defects, but not all, are associated with additional pituitary hormone deficits. In a young child presenting with CH, it is important to determine whether additional pituitary hormone deficiencies are present, but this may be difficult to establish clinically.

Methods:

We describe the clinical characteristics of two young siblings, aged 6 months and 2 years, presenting with isolated CH. Whole exome sequencing was performed to determine the genetic basis of isolated CH.

Results:

A homozygous frameshift mutation of PROP1 (296delGA) was identified in both probands. Defects in PROP1 cause progressive deficiency of multiple pituitary hormones. Based on this genetic diagnosis, further clinical testing was performed that demonstrated growth hormone deficiency in one sibling.

Conclusions:

PROP1 deficiency may present as isolated CH at a very young age. In disorders with multiple potential causative genes, whole exome sequencing may facilitate rapid genetic diagnosis and lead to important changes in clinical management.

The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand for the growth hormone secretagogue receptor (GHSR-1a). Since its discovery tremendous research efforts have been directed at unraveling ghrelin's mechanisms of action, revealing that ghrelin is a pleiotropic hormone implicated in myriad of molecular signaling mechanisms. Accordingly, ghrelin is the only known circulating peripheral hormone with the ability to promote a positive energy balance by stimulating food intake while decreasing energy expenditure and body fat utilization. Moreover, beyond its ability to promote the release of growth hormone from the anterior pituitary, ghrelin stimulates gut motility and gastric acid secretion, modulates sleep, taste sensation and behavior, and regulates glucose metabolism. Due to ghrelin's ability to promote body weight gain and adiposity via centrally mediated signaling mechanisms, modulation of the endogenous ghrelin system is considered a promising strategy to treat individuals with pathologically reduced body weight, such as patients with anorexia nervosa or cachexia. The aim of this chapter is to summarize the current knowledge of how ghrelin affects systemic energy metabolism.

Hypopituitarism has been widely described in adults after traumatic brain injury (TBI); however, the available data in pediatric populations are scarce. Here, we report the results of a prospective, long-term study in children, adolescents and young adults. STUDY GROUP: Thirty-seven children (age, 2 mo to 19.9 yr) out of 51 eligible patients were followed for 1 yr. Clinical and baseline endocrine variables were assessed in all 3 and 12 mo after TBI; children ≥ 6 y underwent two stimulation tests (glucagon stimulation and megatest).

RESULTS:

In the group ≥ 6 y, 11/23 patients (47.8%) had a subnormal GH peak 3 mo after TBI that persisted in 8/23 patients (34%) after one year. The GH response showed no correlation with injury severity (GCS, Marshall classification). Growth velocity was normal in all patients, except for one. Body mass index (BMI) SDS increased significantly in the group with low GH response. A suboptimal cortisol was observed in 10/23 subjects, which normalized in all but three, one year thereafter. All patients but one showed a pubertal response to GnRH testing. No clinical or hormonal abnormalities were detectable in children < 6 yr.

CONCLUSION:

Our results recommend to prospectively follow children after TBI; firstly because the impairment of pituitary function can not be predicted, and secondly, to avoid the potential consequences of pituitary dysfunction. Prospective clinical trials are needed before recommending a systematic screening after TBI, and/or GH therapy either in postpubertal children or in prepubertal children who grow normally. This article is protected by copyright. All rights reserved.

Hypogonadotropic hypogonadism (HH) or secondary hypogonadism is defined as a clinical syndrome that results from gonadal failure due to abnormal pituitary gonadotropin levels. HH may result from either absent or inadequate hypothalamic GnRH secretion or failure of pituitary gonadotropin secretion. Several congenital and acquired causes, including functional and organic forms, have been associated with this condition. One important aspect of the HH diagnosis is that it may reflect the presence of a tumor of the hypothalamic pituitary region or even a systemic disease. On the other hand, functional forms of HH, characterized by a transient defect in GnRH secretion, are relatively common in women, in response to significant weight loss, exercise, or stress leading to hypothalamic amenorrhea. HH is typically characterized by low circulating sexual steroids associated with low or inappropriately normal gonadotropin levels. The precise and early diagnosis of HH can prevent negative physical and psychological sequelae, preserve normal peak bone mass, and restore the fertility in affected patients.

Orbital invasion by pituitary tumors is rare. To the best of the authors' knowledge, adrenocorticotrophin (ACTH)-secreting pituitary tumors with orbital invasion have not been described in MEDLINE indexed literature. The authors report 2 cases of ACTH-secreting tumors with orbital invasion. One patient had a history of endoscopic transsphenoidal subtotal resection of an ACTH-secreting tumor and presented with recurrence in the orbit. The second patient had a long history of visual loss considered to be secondary to glaucoma. Neuroimaging revealed a destructive mass involving the sella turcica with extension in the right orbit. Debulking of the mass was performed via a transsphenoidal approach, and histopathology revealed an ACTH-secreting adenoma. ACTH-secreting adenoma should be considered in the differential of tumors involving the sella turcica with orbital invasion.

Autoimmune hypophysitis (AH) is commonly believed to be a rare chronic inflammatory condition of the pituitary gland. In clinical practice, however, the disease is often seen indeed. It typically presents with hypopituitarism and pituitary mass found by MRI. We report here unusual presentations of two females with AH followed by empty sella syndrome. The two females, aged at 64 and 57-years-old, presented with anterior pituitary dysfunction, diplopia and diabetes insipidus. By MRI the two patients shared the common characteristics with diffuse homogenous contrast enhancement of the gland and increased stalk thickness. After a long period treatment with glucocorticoids, empty sella was eventually detected by MRI.