Pitfalls in the lab assessment of hypopituitarism.

The diagnostic approach to hypopituitarism involves many disciplines. Clinical symptoms rarely are specific. Imaging techniques are helpful but cannot prove the specific functional defects. Therefore, the definitive diagnosis of pituitary insufficiency is largely based on laboratory tests. However, also laboratory methods come with inherent limitations, and it is essential for the clinician to know and recognize typical pitfalls. Most factors potentially impairing the quality of hormone measurements are introduced in the preanalytical phase, i.e. before the hormones are measured by the laboratory. For example, the timing of blood drawing with respect to circadian rhythm, stress, and medication can have an influence on hormone concentrations. During the actual analysis of the hormones, cross-reactions with molecules present in the sample presenting the same or similar epitopes than the intended analyte may affect immunoassays. Interference can also come from heterophilic or human anti-animal antibodies. Unexpected problems can also be due to popular nutritional supplements which interfere with the measurement procedures. An important example in this respect is the interference from biotin. It became only clinically visible when the use of this vitamin became popular among patients. The extreme serum concentrations reached when patients take it as a supplement can lead to incorrect measurements in immunoassays employing the biotin-streptavidin system. To some extent, hormone analyses using liquid chromatography mass spectrometry (LCMS) can overcome problems, although availability and cost-effectiveness of this method still imposes restrictions. In the post-analytical phase, appropriateness of reference intervals and cut-offs with respect to the specific analytical method used is of outmost importance. Furthermore, for interpretation, additional biological and pharmacological factors like BMI, age and concomitant diseases must be considered to avoid misinterpretation of the measured concentrations. It is important for the clinician and the laboratory to recognize when one or more laboratory values do not match the clinical picture. In an interdisciplinary approach, the search for the underlying cause should be initiated.

A rare endocrine cause of ventricular tachycardia: a case series of two patients and a literature review.

Sheehan's syndrome is a type of hypopituitarism caused by massive uterine bleeding and hypovolaemic shock after or during delivery. Heart involvement has been documented sporadically among the various clinical manifestations of Sheehan's syndrome but life-threatening arrhythmias are infrequent. Here, we report on two rare cases of ventricular tachycardia caused by Sheehan's syndrome. Both female patients were diagnosed with Sheehan's syndrome 30 years previously, due to massive postpartum bleeding. Both of them terminated hormone replacement therapy recently. Both patients presented with torsade de pointes. The electrocardiogram showed prolonged QT interval. In addition to potassium supplementation and anti-arrhythmia therapy, steroids and thyroid hormone replacement therapy were employed, QT-interval prolongation and T-wave inversion were normalised, and implantable cardioverter defibrillator implantation was avoided. One of the patients was recovering well at the one-year follow up and the other patient was in a coma at the time of this report. We also review the literature for cases of Sheehan's syndrome presenting with ventricular tachycardia.

Hypothalamitis and pituitary atrophy.

Hypothalamitis is a rare inflammatory disorder involving the hypothalamus and classified as primary, or isolated, and secondary hypothalamitis. Secondary hypothalamitis although very rare is more common than the primary one and may occur in patients affected by autoimmune diseases such as autoimmune hypophysitis, systemic autoimmune diseases, infective diseases in patients affected by immune-deficit, paraneoplastic encephalitis, or in patients treated with immune checkpoint inhibitors. In accordance with the rarity of this disease, diagnosis and management of hypothalamitis prove to be challenging. The diagnosis requires a high index of clinical suspicion. The main symptoms may be: various degrees of hypopituitarism, neuropsychiatric and behavioral disorders, and disturbances of autonomic and metabolic regulation. Magnetic resonance images play a crucial role in the diagnosis of hypothalamitis and in the exclusion of a neoplastic lesion. Therapeutic management should be oriented according to the disease etiology. In most cases, after ruling out infective hypothalamitis, the mainstay of therapy consists of immunosuppressive treatment. Great attention should be paid to hormonal replacement therapy, if partial or total hypopituitarism is present, in particular in patients affected by diabetes insipidus, central hypoadrenalism and hypothyroidism. According to the complexity of this disease, a multidisciplinary approach is strongly advocated to reach an early diagnosis and an integrated therapy.

A novel diagnostic tool for the evaluation of hypothalamic-pituitary region and diagnosis of growth hormone deficiency: pons ratio.

Backgrounds Limitations in the evaluation of the pituitary size and changes according to pubertal status make its validity questionable. Recently, in a small-scale study, pons ratio (PR) has been suggested as a more sensitive tool for diagnosis and etiological evaluation of growth hormone deficiency (GHD). The aim of the study is to evaluate the diagnostic value of PR in the diagnosis of GHD. Methods We retrospectively evaluated the pituitary magnetic resonance imaging (MRI) of 133 patients with a diagnosis of GHD. Primary axis (PA) was assigned as a line crossing the mid-sagittal dorsum sella and fourth ventricle. PR was defined as the pons height above the PA divided by total pons height. The PR of patients with GHD was compared to subjects without GHD. Results Study included 133 patients with GHD and 47 controls. In total, 121 (91%) patients had isolated GHD and 12 (9%) patients had multiple pituitary hormone deficiency. The PR of the patient group (mean: 0.32 ± 0.89; range: 0.14-0.63) was significantly higher than controls (mean: 0.26 ± 0.067; range 0.19-0.44) (p: 0.000). The optimal cut-off value of PR for GHD diagnosis was 0.27 (sensitivity 71% specificity 56%). There was a negative correlation between anterior pituitary height (APH)-SDS and PR (p: 0.002; r: -0.27). APH was increased, but PR remained unchanged in pubertal patients (p: 0.089). Conclusions PR measurement is a noninvasive, practical method with a cost-benefit clinical value. As it is not affected by pubertal status, PR is potentially a more sensitive tool for evaluation of pituitary gland in GHD patients compared to APH.

Hypopituitarism Presenting as Adrenal Insufficiency and Hypothyroidism in a Patient with Wilson's Disease: a Case Report.

Wilson's disease typically presents symptoms associated with liver damage or neuropsychiatric disturbances, while endocrinologic abnormalities are rare. We report an unprecedented case of hypopituitarism in a patient with Wilson's disease. A 40-year-old woman presented with depression, general weakness and anorexia. Laboratory tests and imaging studies were compatible with liver cirrhosis due to Wilson's disease. Basal hormone levels and pituitary function tests indicated secondary hypothyroidism and adrenal insufficiency due to hypopituitarism. Brain MRI showed T2 hyperintense signals in both basal ganglia and midbrain but the pituitary imaging was normal. She is currently receiving chelation therapy along with thyroid hormone and steroid replacement. There may be a relationship between Wilson's disease and hypopituitarism. Copper deposition or secondary neuronal damage in the pituitary may be a possible explanation for this theory.

Hypothalamic-pituitary sarcoidosis with vision loss and hypopituitarism: case series and literature review.

PURPOSE: Hypothalamic-pituitary (HP) neurosarcoidosis (NS) accounts for 0.5 % cases of sarcoidosis and 1 % of HP masses. Correlative data on endocrine and neurological outcomes is lacking. METHODS: Retrospective case series and literature review of presentation, treatment and outcome of HP NS. RESULTS: Our series includes 4 men, ages 34-59, followed for a median of 7.3 years (range 1.5-17). All had optic neuropathy, multiple pituitary hormone abnormalities (PHAs) and other organ involvement by sarcoidosis (lung, sino-nasal, brain/spine and facial nerve). Two patients had central diabetes insipidus and one impaired thirst with polydipsia. After treatment with high-dose glucocorticoids, optic neuropathy improved in one case and stabilized in the others. After treatment, HP lesions improved radiologically, but PHAs persisted in all cases. Review of four published series on HP NS in addition to ours yielded 46 patients, age 37 ± 11.8 years, 65 % male. PHAs consisted of anterior hypopituitarism (LH/FSH 88.8 %, TSH 67.4 %, GH 50.0 %, ACTH 48.8 %), hyperprolactinemia (48.8 %) and diabetes insipidus (65.2 %). PHAs were the first sign of disease in 54.3 % patients. Vision problems occurred in 28.3 % patients, but optic neuropathy was not well documented in previous series. Most patients (93.5 %) received high-dose glucocorticoids followed by taper; 50 % also received other immunomodulators, including methotrexate, mycophenolate mofetil, cyclosporine, azathioprine, infliximab and hydrochloroquine. Only 13 % patients showed improvement in PHAs. All-cause mortality was 8.7 %. CONCLUSION: HP NS is a serious disease requiring multidisciplinary treatment and lifelong follow-up. Prospective multicentric studies are needed to determine a more standardized approach to HP NS and outline predictors of disease outcome.

Anatomy, Physiology, and Laboratory Evaluation of the Pituitary Gland.

The pituitary gland functions prominently in the control of most endocrine systems in the body. Diverse processes such as metabolism, growth, reproduction, and water balance are tightly regulated by the pituitary in conjunction with the hypothalamus and various downstream endocrine organs. Benign tumors of the pituitary gland are the primary cause of pituitary pathology and can result in inappropriate secretion of pituitary hormones or loss of pituitary function. First-line management of clinically significant tumors often involves surgical resection. Understanding of normal pituitary physiology and basic testing strategies to assess for pituitary dysfunction should be familiar to any skull base surgeon.

Heterozygous defects in PAX6 gene and congenital hypopituitarism.

BACKGROUND: The prevalence of congenital hypopituitarism (CH) attributable to known transcription factor mutations appears to be rare and other causative genes for CH remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements could be one of the molecular mechanisms participating in its etiology, especially in syndromic cases. OBJECTIVE: To identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH. SUBJECTS AND METHODS: We enrolled 88 (syndromic: 30; non-syndromic: 58) Japanese CH patients. We performed an array comparative genomic hybridization screening in the 30 syndromic CH patients. For all the 88 patients, we analyzed PAX6 by PCR-based sequencing. RESULTS: We identified one heterozygous 310-kb deletion of the PAX6 enhancer region in one patient showing isolated GH deficiency (IGHD), cleft palate, and optic disc cupping. We also identified one heterozygous 6.5-Mb deletion encompassing OTX2 in a patient with bilateral anophthalmia and multiple pituitary hormone deficiency. We identified a novel PAX6 mutation, namely p.N116S in one non-syndromic CH patient showing IGHD. The p.N116S PAX6 was associated with an impairment of the transactivation capacities of the PAX6-binding elements. CONCLUSIONS: This study showed that heterozygous PAX6 mutations are associated with CH patients. PAX6 mutations may be associated with diverse clinical features ranging from severely impaired ocular and pituitary development to apparently normal phenotype. Overall, this study identified causative CNVs with a possible role in the etiology of CH in <10% of syndromic CH patients.

Alternative causes of hypopituitarism: traumatic brain injury, cranial irradiation, and infections.

Hypopituitarism often remains unrecognized due to subtle clinical manifestations. Anterior pituitary hormone deficiencies may present as isolated or multiple and may be transient or permanent. Traumatic brain injury (TBI) is recognized as a risk factor for hypopituitarism, most frequently presenting with isolated growth hormone deficiency (GHD). Data analysis shows that about 15% of patients with TBI have some degree of hypopituitarism which if not recognized may be mistakenly ascribed to persistent neurologic injury and cognitive impairment. Identification of predictors for hypopituitarism after TBI is important, one of them being the severity of TBI. The mechanisms involve lesions in the hypothalamic-pituitary axis and inflammatory changes in the central nervous system (CNS). With time, hypopituitarism after TBI may progress or reverse. Cranial irradiation is another important risk factor for hypopituitarism. Deficiencies in anterior pituitary hormone secretion (partial or complete) occur following radiation damage to the hypothalamic-pituitary region, the severity and frequency of which correlate with the total radiation dose delivered to the region and the length of follow-up. These radiation-induced hormone deficiencies are irreversible and progressive. Despite numerous case reports, the incidence of hypothalamic-pituitary dysfunction following infectious diseases of the CNS has been underestimated. Hypopituitarism usually relates to the severity of the disease, type of causative agent (bacterial, TBC, fungal, or viral) and primary localization of the infection. Unrecognized hypopituitarism may be misdiagnosed as postencephalitic syndrome, while the presence of a sellar mass with suprasellar extension may be misdiagnosed as pituitary macroadenoma in a patient with pituitary abscess which is potentially a life-threatening disease.

ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies.

We describe a previously unreported syndrome characterized by secondary (post-natal) microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract in a highly consanguineous family with six affected children. Homozygosity mapping and exome sequencing revealed a novel homozygous frameshift mutation in the basic helix-loop-helix transcription factor gene ARNT2 (c.1373_1374dupTC) in affected individuals. This mutation results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. We also show expression of ARNT2 within the central nervous system, including the hypothalamus, as well as the renal tract during human embryonic development. The progressive neurological abnormalities, congenital hypopituitarism and post-retinal visual pathway dysfunction in affected individuals demonstrates for the first time the essential role of ARNT2 in the development of the hypothalamo-pituitary axis, post-natal brain growth, and visual and renal function in humans.

Hypothalamic/pituitary morbidity in skull base pathology.

In this article the epidemiology, pathophysiology, clinical presentation, investigation, management, and prognosis of hypopituitarism and hypothalamic dysfunction, arising from skull base pathologies and treatment of these conditions, are reviewed and discussed. The clinical question: "What is the consequence of pituitary hypofunction in young patients (ie, craniopharyngioma)?" is answered based on information provided in the review.

Neuroimaging in posttraumatic hypopituitarism.

Posttraumatic hypopituitarism is the failure of the hypothalamic-pituitary axis secondary to traumatic brain injury. It can clinically present as decreased muscle mass, concentration, libido, and fertility. It can also present as increased fatigue, depression, and cognitive deficits. In addition, electrolyte abnormalities such as hyponatremia can occur in hypopituitarism. As a result of heightened awareness of posttraumatic hypopituitarism, it is a phenomenon that is becoming more commonly diagnosed. Posttraumatic hypopituitarism is a diagnosis based on clinical evaluation, laboratory testing, and neuroimaging. Of the radiological techniques, magnetic resonance imaging is the preferred technique to image the pituitary gland. This article contains coronal and sagittal magnetic resonance imaging of the posterior fossa, illustrating the normal hypothalamus and pituitary gland as well as adjacent structures. The sequential enhancement pattern of the normal pituitary gland is consistent with its vascular supply. A colored illustration was created to display the vascular supply to the hypothalamus, pituitary stalk, and pituitary gland.

Developmental disorders of the hypothalamus and pituitary gland associated with congenital hypopituitarism.

The pituitary gland is a complex organ secreting six hormones from five different cell types. It is the end product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of congenital hypopituitarism. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism or more complex disorders such as septo-optic dysplasia and holoprosencephaly. However, the overall incidence of mutations in known transcription factors in patients with hypopituitarism is low, indicating that many genes remain to be identified; characterization of these will further elucidate the pathogenesis of this complex condition and also shed light on normal pituitary development and function.

Kickboxing sport as a new cause of traumatic brain injury-mediated hypopituitarism.

OBJECTIVE: Traumatic brain injury, which is a frequent and a worldwide important public health problem, may result in pituitary dysfunction. Concussion, a common type of lesion after traumatic brain injury, is an injury associated with sports including boxing and kickboxing. Kickboxing is one of the most popular martial arts and approximately 1-million people around the world participate in kickboxing sport. Head is the most common site of injury in amateur and professional kickboxers. Pituitary consequences of chronic repetitive head trauma in kickboxing have not been investigated until now. Therefore, the present study was designed to investigate the pituitary function in both retired and active amateur kickboxers. PATIENTS AND DESIGN: Twenty-two amateur kickboxers who have boxed in national and international championships (16 men, 6 women) with a mean age of 27.3 +/- 7.1 years, and 22 age- and sex-matched healthy controls were included in the study. Basal hormone levels were obtained from the participants. To assess GH-IGF-I axis, GHRH + GHRP-6 test and glucagon stimulation tests were used. Hypothalamo-pituitary-adrenal axis was assessed by glucagon stimulation test. RESULTS: When mean basal hormone levels were compared between kickboxers and the controls, IGF-I level was significantly lower in kickboxers (P < 0.05). Five (22.7%) and two (9.1%) of the 22 kickboxers had GH deficiency had ACTH deficiency, respectively. There were significant negative correlations between IGF-I levels and age, duration of sports and number of bouts (P < 0.05). CONCLUSIONS: Present data clearly demonstrate for the first time that amateur kickboxing is a novel cause of hypopituitarism and kickboxers are at a risk for hypopituitarism especially isolated GH deficiency. Therefore, participants of the combative sports who were exposed to chronic repetitive head trauma need to be screened.

Growth hormone deficiency in the adult.

Growth hormone deficiency (GHD) in adults may be of either adult or childhood onset and may occur as isolated GHD or as multiple hormone deficiencies. Adult-onset GHD (AoGHD) usually results from damage to the pituitary gland or hypothalamus. GH is frequently undetectable in normal subjects and thus GHD cannot be distinguished from the normal state using a single random GH measurement. In general, a stimulation test is required to recognize GHD. Insulin tolerance test (ITT) has been considered the gold standard by the most important scientific societies, although alternative tests, in particular GHRH plus arginine have been proposed as valuable alternative to ITT. The clinical syndrome associated with AoGHD is characterized by a wide array of symptoms and important chronic complications, such as cardiovascular complications, which may be responsible for an increased mortality. The rationale for GH replacement in adults GHD patients is justified by the beneficial effects on some clinical end-points, such as quality of life (QoL) and cardiovascular risk factors, whereas the effects on mortality risk are still controversial. Over the recent years, guidelines on the use of rhGH as a substitution treatment in adult hypopituitarism have been issued by international (Growth hormone research society-GRS, Endocrine Society) and relevant national (National Institute of Clinical Excellence-UK, NICE) institutions. The aim of the paper is to review and discuss these guidelines.

Hypopituitarism in childhood and adolescence following traumatic brain injury: the case for prospective endocrine investigation.

Pituitary dysfunction is now well recognised after traumatic brain injury (TBI) in adults; however, little except anecdotal evidence is known about this potential complication in childhood and adolescence. Histopathological evidence exists for both hypothalamic and pituitary damage, but few data specific to children have been published. We review the available paediatric data, which shows that after both mild and severe TBI, hypopituitarism may occur, with GH and gonadotrophin deficiencies appearing to be most common. Precocious puberty has also been documented. Road-traffic accidents, falls, sport and child abuse are the most common aetiological factors for paediatric TBI. There are no published data on the incidence or prevalence, neither within a population of children with TBI, of hypopituitarism, nor on its natural history or response to hormone replacement. We urge paediatric endocrinologists, in collaboration with adult endocrinologists, to perform formal prospective research studies in patients suffering from TBI to clarify these questions.

Primary hypothalamic lymphoma with panhypopituitarism presenting as stiff-man syndrome.

We report an unusual case of primary hypothalamic lymphoma with hypopituitarism presenting as Stiff-man syndrome (SMS). A 64-year-old man was hospitalized due to a 3-week history of general weakness, anorexia, vomiting, weight loss, and muscle pain and spasms precipitated by motion and tactile stimuli resulting in muscle stiffness and difficulty in mobility. Physical examination revealed normal sensorimotor function and reflexes, except for bitemporal visual field defect. Routine laboratory and gastrointestinal examinations provided no remarkable clues. Endocrine assessment revealed low levels of morning cortisol, thyroxine, and anterior pituitary hormones but an increase in prolactin level. The patient's muscle pain and stiffness improved dramatically within 2 days after hydrocortisone therapy and thyroxine replacement. Magnetic resonance imaging (MRI) of the brain confirmed an 18-mm enhancing hypothalamic tumor with optic chiasm involvement, which proved to be a B-cell lymphoma. The results of the extensive studies for systemic lymphoma were negative, suggesting a primary hypothalamic lymphoma. The tumor regressed completely and was invisible on MRI scan after adjuvant radiotherapy. The patient's condition was satisfactory and there was no recurrence of SMS during the 2-year follow-up period. This case demonstrated that primary hypothalamic lymphoma complicated with adrenal insufficiency may manifest as SMS. Early diagnosis and prompt intervention can lead to a favorable outcome and reduce morbidity.

Magnetic resonance imaging of the hypothalamus-pituitary unit in childrensuspected of hypopituitarism: who, how and when toinvestigate.

The magnetic resonance (MR) identification of pituitary hyperintensity in the posterior part of the sella has been the most striking recent finding contributing to the diagnosis of "idiopathic" and permanent GH deficiency (GHD). Moreover, advancements in DNA technology have shed new light on the study of the genetic causes of hypopituitarism. Abnormalities in two genes, the GH-N encoding the GH and the GHRH receptor (GHRH-R), have been identified, while mutations in five other gene-encoding transcription factors such as Pit-1, Prop-1, Hesx-1, Lhx-3 and Lhx-4 involved in anterior pituitary development, have also been described. MR imaging shows marked differences in pituitary morphology indicating different GHD etiologies and different prognoses. Ectopic posterior pituitary is a specific marker of permanent GHD. These patients do not have Pit-1, Prop-1, or Lhx-3 mutations and should be carefully monitored for evolving pituitary hormone defects, though they do not require GH re-evaluation in adulthood; selected cases may have Hesx-1 or Lhx-4 mutations. MR evidence of normal or small anterior pituitary gland, enlarged empty sella, pituitary hyperplasia and/or intrasellar or suprasellar mass when associated with combined pituitary hormone deficiency call for molecular analysis of Pit-1, Prop-1, Hesx-1, or Lhx-3. Limitation of neck rotation and Chiari-I malformation may suggest Lhx-3 or Lhx-4 mutations (exceedingly rare). In "idiopathic" isolated GHD, evidence of normal anterior or small anterior pituitary size with normal location of posterior pituitary and normal connection between the hypothalamus and pituitary gland is suggestive of "transitory" or false positive GHD; patients with such characteristics should be re-evaluated well before reaching adult height. In selected cases, anterior pituitary height that is 2 SD below age-adjusted normal pituitary height could be suggestive of GHRH-R gene defect; it is worth pointing out that normal pituitary MR together with severe GHD has been observed, though rarely, in subjects with a genetic origin of GHD.

A case of Sheehan's syndrome with panhypopituitarism due to the impairment of both the hypothalamus and the pituitary.

Sheehan's syndrome is thought to be caused by pituitary necrosis associated with massive hemorrhage at delivery. We report here on a patient with Sheehan's syndrome, showing a rare type of panhypopituitarism suggesting dysfunction of both the hypothalamus and the pituitary. Although the basal level of plasma ACTH was normal, that of plasma cortisol was low. ACTH showed a delayed high response to CRH and a low response to insulin-induced hypoglycemia, while plasma cortisol showed a low response to CRH and no response to insulin-induced hypoglycemia. In the standard ACTH test, a normal rise of plasma cortisol was found. These results indicate that the primary site responsible for hypothalamic-pituitary-adrenocortical hypofunction may be the hypothalamus. In addition, the dysfunction of the pituitary itself is suggested by the hyposecretion of other pituitary hormones with impaired responses in their provocative tests and partially empty sella.