PITUITARY DEFICIENCY FOLLOWING TRAUMATIC BRAIN INJURY IN EARLY CHILDHOOD: A REVIEW OF THE LITERATURE.

UNLABELLED: AIMS OF REVIEW: the intent of the current manuscript is to critically review the studies on pituitary gland dysfunction in early childhood following traumatic brain injury (TBI), in comparison with those in adults. Search of the literature: The MEDLINE database was accessed through PubMed in April 2015. Results were restricted to the past 15 years and English language of articles. Both transient and permanent hypopituitarisms are not uncommon after TBI. Early after the TBI, pituitary dysfunction/s differ than those occurring after few weeks and months. Growth hormone deficiency (GHD) and alterations in puberty are the most common. After the one to more years of TBI, pituitary dysfunction tends to improve in some patients but may deteriorate in others. GH deficiency as well as Hypogonadism and thyroid dysfunction are the most common permanent lesions. Many of the symptoms of these endocrine defects can pass unnoticed because of the psychomotor defects associated with the TBI like depression and apathy. Unfortunately pituitary dysfunction appear to negatively affect psycho-neuro-motor recovery as well as growth and pubertal development of children and adolescents after TBI. Therefore, the current review highlights the importance of closely following patients, especially children and adolescents for growth and other symptoms and signs suggestive of endocrine dysfunction. In addition, all should be screened serially for possible endocrine disturbances early after the TBI as well as few months to a year after the injury. Risk factors for pituitary dysfunction after TBI include relatively serious TBI (Glasgow Coma Scale score < 10 and MRI showing damage to the hypothalamic pituitary area), diffuse brain swelling and the occurrence of hypotensive and/or hypoxic episodes. IN CONCLUSION: There is a considerable risk of developing pituitary dysfunction after TBI in children and adolescents. These patients should be clinically followed and screened for these abnormalities according to an agreed protocol of investigations. Further multicenter and multidisciplinary prospective studies are required to explore in details the occurrence of permanent pituitary dysfunction after TBI in larger numbers of children with TBI. This requires considerable organisation and communication between many disciplines such as neurosurgery, neurology, endocrinology, rehabilitation and developmental paediatrics.

The infundibulo-tuberal syndrome caused by craniopharyngiomas: clinicopathological evidence from an historical French cohort (1705-1973).

PURPOSE: Infundibulo-tuberal syndrome groups endocrine, metabolic and behavioral disturbances caused by lesions involving the upper neurohypophysis (median eminence) and adjacent basal hypothalamus (tuber cinereum). It was originally described by Henri Claude and Jean Lhermitte in 1917, in a patient with a craniopharyngioma. This study investigates the clinical, pathological and surgical evidence verifying the infundibulo-tuberal syndrome caused by craniopharyngiomas (CPs). METHODS: A systematic retrospective review of craniopharyngiomas reported in French literature between 1705 and 1973 was conducted. A total of 128 well described reports providing a comprehensive clinical and pathological description of the tumors were selected. This series represents the historical French cohort of CPs reported in the pre-CT/MRI era. RESULTS: Three major syndromes caused by CPs were categorized: pituitary syndrome (35%), infundibulo-tuberal syndrome (52%) and hypothalamic syndrome (49%). CP topography was significantly related to the type of syndrome described (p < 0.001). Infundibulo-tuberal syndrome occurred in CPs which replaced or invaded the third ventricle floor. In contrast, the majority of sellar/suprasellar CPs growing below the third ventricle showed a pituitary syndrome (82%). Cases with hypothalamic syndrome were characterized by anatomical integrity of the pituitary gland and stalk (p = 0.033) and occurred predominantly in adults older than 41 years old (p < 0.005). Among infundibulo-tuberal symptoms, abnormal somnolence was not related with the presence of hydrocephalus. All squamous-papillary CPs presented psychiatric disturbances (p < 0.001). CONCLUSION: This historical CP cohort evidences a clinical-topographical correlation between the patient's type of syndrome and the anatomical structures involved by the tumor along the hypophysial-hypothalamic axis.

Analysis of the hypothalamus in a case of X-linked lissencephaly with abnormal genitalia (XLAG).

X-linked lissencephaly with abnormal genitalia (XLAG) is characterized by lissencephaly, absent corpus callosum and ambiguous genitalia. We examined hypothalamic dysfunctions in a XLAG case with a novel mutation of the ARX gene, and performed immunohistochemical evaluation of the diencephalons in autopsy brain. A 1-year-old boy showed intractable epilepsy, persistent diarrhea and disturbed temperature regulation. This case had abnormalities in circadian rhythms and pituitary hormone reserve test. He died of pneumonia. The globus pallidus and subthalamic nucleus was not identified, and the putamen and thalamus were dysplasic. The suprachiasmatic nucleus was absent. A few neurons immunoreactive for vasopressin seemed to form the ectopic supraoptic-like nucleus. The diencephalons were disturbed differently in each sub-region, and the changes may be related to various hypothalamic dysfunctions.

Pubertal impairment in Nhlh2 null mice is associated with hypothalamic and pituitary deficiencies.

Pubertal development is impaired in mice lacking the basic helix-loop-helix transcription factor Nhlh2. The mechanisms underlying changes in reproduction in Nhlh2-deficient mice (Nhlh2(-/-)) are unclear. Here we show that hypothalamic GnRH-1 content is reduced in adult Nhlh2(-/-) mice as is the number of GnRH-1 neurons localized to mid- and caudal hypothalamic regions. This reduction was detected postnatally after normal migration of GnRH-1 neurons within nasal regions had occurred. Phenotype rescue experiments showed that female Nhlh2(-/-) mice were responsive to estrogen treatment. In contrast, puberty could not be primed in female Nhlh2(-/-) mice with a GnRH-1 regimen. The adenohypophysis of Nhlh2(-/-) mice was hypoplastic although it contained a full complement of the five anterior pituitary cell types. GnRH-1 receptors (GnRHRs) were reduced in Nhlh2(-/-) pituitary gonadotropes as compared with wild type. In vitro assays indicated that Nhlh2 expression is regulated in parallel with GnRHR expression. However, direct transcriptional activity of Nhlh2 on the GnRHR promoter was not found. These results indicate that Nhlh2 plays a role in the development and functional maintenance of the hypothalamic-pituitary-gonadal axis at least at two levels: 1) in the hypothalamus by regulating the number and distribution of GnRH-1 neurons and, 2) in the developing and mature adenohypophysis.

Hypothalamic-pituitary dysfunction in critically ill patients with traumatic and nontraumatic brain injury.

BACKGROUND: A significant number of studies have shown that critically ill patients with brain injury (BI) frequently exhibit abnormal pituitary hormonal responses during the immediate postinjury period. DISCUSSION: The elucidation of endocrine alterations depends on the criteria used, the diagnostic tests applied, and the timing of testing in relation to BI. The pattern of the detected hormonal abnormalities shows considerable variability. Altered endocrine responses are due mostly to hypothalamic changes rather than to pituitary dysfunction. Several studies have examined the correlation between hormonal alterations and BI severity, but the results are inconsistent. Furthermore, it remains currently unclear whether and how pituitary abnormalities adversely affect the clinical course of BI patients during the period of critical illness. On the basis of current knowledge, with the exception of clinically significant relative adrenal deficiency and diabetes insipidus, the other endocrine alterations do not seem to require any therapeutic intervention in severely ill BI patients. It is also uncertain whether hormonal abnormalities detected in the early post-BI period persist for the rest of these patients' lives. CONCLUSIONS: In view of current evidence indicating a high incidence of pituitary dysfunction even years following BI it is recommended that repetition of endocrine evaluation should be performed during the rehabilitation phase in all patients.

The midnight to morning urinary cortisol increment is an accurate, noninvasive method for assessment of the hypothalamic-pituitary-adrenal axis.

The optimal method for assessing the hypothalamic-pituitary-adrenal axis (HPA) remains controversial. The insulin tolerance test (ITT) is considered the gold standard, but is invasive and potentially dangerous. The short Synacthen test (SST) is the most commonly used alternative, but its concordance with the ITT is poor. Using sleep as a reliable stimulus to ACTH release, we proposed that the increment in urinary cortisol levels between midnight and waking could provide a noninvasive, physiological means for the assessment of the HPA axis. Double voided urine samples were collected at home at midnight and waking in 40 patients with pituitary disease and 40 controls. Cortisol and creatinine levels were measured, and the cortisol/creatinine (Cort/Cr) ratio was calculated. The Cort/Cr increment was defined as the morning Cort/Cr ratio minus the midnight Cort/Cr ratio. The Cort/Cr increment of the patients was compared to the results of their ITT or SST. Using the results from the 40 controls, a normal Cort/Cr increment was defined as greater then 9. The positive predictive value of a Cort/Cr increment for the diagnosis of HPA insufficiency was 95%. These findings suggest that the midnight to morning Cort/Cr increment is a reliable, noninvasive alternative to the ITT/SST for assessment of the HPA.

Magnetic resonance and the diagnosis of short stature of hypothalamic-hypophyseal origin.

Magnetic resonance imaging was performed in 23 patients with short stature (7 had multiple pituitary hormone defect, 11 had isolated growth hormone deficiency and 5 had normal variant short stature) to investigate if there is a relation between magnetic resonance findings and results of endocrine tests. Magnetic resonance imaging of patients with multiple pituitary hormone deficiency or with serious isolated growth hormone deficiency (growth hormone < 3 micrograms/l) revealed an interrupted pituitary stalk and ectopic neurohypophysis or a mass. In patients with less serious isolated growth hormone deficiency (growth hormone > 3 micrograms/l) or with normal variant short stature, the technique revealed a normal or hypoplastic hypophysis. Magnetic resonance appears to be a useful second-level diagnostic tool in defining the type of alteration in growth defects of endocrine origin.

Hypothalamopituitary deficiency and precocious puberty following hyperhydration in diabetic ketoacidosis.

We report on a 5-year-old child who survived an intracerebral crisis, following ketoacidosis-revealing diabetes (DKA), with visual impairment due to a vascular occipital lesion. Two and 4 months after the initial episode, a unique hypothalamopituitary disorder consisting in GH, ACTH, TSH deficiencies and central precocious puberty, was detected. Cranial magnetic resonance images showed no visible lesion in the hypothalamopituitary region. The most likely hypothesis is the ischemia of hypothalamopituitary and occipital regions following possible cerebral edema after hyperhydration. She survived with low visual acuteness and received a combined replacement therapy for the neuroendocrinological deficiencies. This case emphasizes that the rehydration at the initial period of DKA is critical, especially when risk factors for cerebral edema are present (young age, marked hyponatremia). The neuroendocrinological consequences of acute cerebral edema are rare, but physicians must be attentive in survivors of these accidents.

[Effect of L-DOPA administration on brain bioelectrical activity in hypothalamo-hypophyseal diseases]. / Vliianie vvedeniia L-DOFA na bioélektricheskuiu aktivnost' golovnogo mozga bol'nykh s gipotalamo-gipofizarnymi zabolevaniiami.

The influence of the L-DOPA preparation on the bioelectrical activity of the brain was studied in 15 patients with Itsenko-Cushing's disease and in 12 patients with diencephalic obesity. L-DOPA administration caused an increase of the theta-rhythm index in the anterior leads in comparison with the initial recording, although the periods of detection of this elevation differed in various patients. No changes of the character of the EEG recording during the test with L-DOPA in comparison with the background recording was revealed in the patients with Itsenko-Cushings disease.

Thyrotrophin releasing hormone--TSH.

The major determinant of serum TSH and its response to TRH is the interaction of TRH and the thyroid hormones (principally T3) at the level of the thyrotroph. Small changes in thyroid hormone levels within the normal range can produce marked alteration in thyrotroph sensitivity to TRH. Elevated serum TSH is of great diagnostic value in suspected primary hypothyroidism. The demonstration of a normal TSH response to TRH is valuable in excluding the diagnosis of hyperthyroidism, whereas a suppressed response is of lesser value in diagnosis, although characteristic of the hyperthyroid state. TSH responses to TRH are of limited value in the differentiation of hypothalamic from pituitary lesions, and cannot always be correlated with clinical or biochemical thyroid status.

[Correlation of hydrocortisone and corticosterone content in assessing the functional state of the adrenal cortex in varying forms of hypercorticism]. / Sootnoshenie soderzhaniia gidrokortizona i kortikosterona pri otsenke funktsional'nogo sostoianiia kory nadpochechnikov u bol'nykh s razlichnymi formami giperkortitsizma.

Separate determination of hydrocortisone and corticosterone in the blood of patients with the hypercorticism symptom-complex showed that elevation of the corticosteroid concentration could occur on account of similar elevation of the concentration of both hormones, or one of the hormones alone. Analogous data were observed in patients after ACTH administration. Dexamethasone administration caused a reduction of the hydrocortisone and corticosterone concentration in patients with Itsenko-Cushing's disease, but to a lesser degree than in healthy individuals. Administration of the preparation to the patients with juvenile dyspituitrism decreased the cortizol level, but corticosterone chiefly; as to the patients with the hypothalamic syndrome--only the cortizol level was reduced, the level of corticosterone remaining unchanged. Thus, the evidence obtained before and after the administration of the ACTH preparations and dexamethasone permitted to assess the adrenal cortex function more fully and to defect disturbances of the corticosteroid secretion of interest of the understanding of the clinical symptoms of the disease.

Correlation between integrated LH and FSH levels and the response to luteinizing hormone relasing factor (LRF).

Integrated blood plasma levels of LH and FSH and their response to the iv administration of 100 mug synthetic LRF were studied in 29 normal subjects, 12 women with Stein-Leventhal syndrome, 8 subjects with primary gonadal failure, 7 women with Sheehan's syndrome, 20 subjects with pituitary tumors, 10 subjects with idiopathic gonadotropin deficiency and 5 subjects with hypothalamic tumors. Within each group there was considerable variation in the response of LH and FSH levels to LRF. In each group there was a statistically significant positive correlation between basal integrated gonadotropin levels and the response of the levels to LRF. Both within groups and between groups, the best indicator of the response to LRF was the basal levels of FSH and LH. In subjects with hypogonadotropic hypogonadism there was no significant difference in mean basal LH levels and mean response to LRF between patients with primarily pituitary disease (pituitary tumors or Sheehan's syndrome) and conditions which might represent hypothalamic disease (hypothalamic tumors or idiopathic gonadotropin deficiency). The response to an acute, single, injection of LRF appears to more directly reflect basal gonadotropin levels rather than disease category.

PIP: The diagnostic value of LRF was assessed by measuring the response of plasma levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) to a single iv injection of synthetic LRF in 29 normal subjects, 12 women with Stein-Leventhal syndrome, 8 patients with primary gonadal failure, 7 women with Sheehan's syndrome, 20 patients with pituitary tumors, 10 subjects with idiopathic gonadotropin deficiency, and 5 patients with hypothalamic tumors. The response of plasma LH and FSH levels to LRF varied considerably within each group. Each group showed a positive correlation between basal LH and FSH levels and the response to LRF. There was no marked difference in basal LH values and the mean response to LRF between patients with pituitary tumors of Sheehan's syndrome and patients with hypothalamic tumors or idopathic gonadotropin deficiency. It is concluded that the response to a single, acute iv injection of LRF provides little information of disease states beyond that provided by basal gonadotropin levels.

[Neuroaminergic control of anterior pituitary secretions (author's transl)]. / Contrôle neuroaminergique des sécrétions antéhypophysaires

The demonstration and identification of monoamines and of aminergic tracts in the central nervous system has permitted a study of their role in the control of the liberation of hypothalamic releasing hormones. Knowledge of the role of these hypothalamic neurohormones in the release of pituitary hormones is at present under study. The role of monoamines in the control of pituitary hormone functions depends narrowly on pharmacological methods intervening either in the synthesis of neuroamines or in their action on a specific receptor. The authors consider successively the implication of monoamines in the control of liberation of ACTH, GH, TSH, prolactin and gonadotropic hormones. The role of aminergic mechanisms in the physiology of pituitary releasing hormones forms an integral part of homeostasis. Knowledge of these mechanisms leads to a clinical study of their role in disorders of hypothalamo-pituitary function.