Posterior Pituitary Research Articles

Serial assessments of anterior pituitary hormones in a case of mixed histiocytosis representing Langerhans cell histiocytosis overlapping with Erdheim-Chester disease.

SummaryA 61-year-old man developed central diabetes insipidus caused by mixed histiocytosis (MH) representing Langerhans cell histiocytosis overlapping with Erdheim–Chester disease. Bone, skin, vascular, and retroperitoneal involvements were also observed. Dynamic hormonal testing showed normal responses for anterior pituitary hormones, except for impaired secretion of growth hormone (GH). MRI of the brain showed thickening of the pituitary stalk with slightly reduced signal hyperintensity in the posterior pituitary lobe on T1-weighted imaging. During 2 years of follow-up without radical treatment for MH, imaging studies suggested extension of vascular and retroperitoneal involvements. In contrast, brain MRI did not show any particular interval changes, except for the disappearance of hyperintense signalling in the posterior pituitary lobe. Moreover, no other anterior pituitary dysfunctions beyond GH deficiency emerged during the 2 years of follow-up. The natural history of MH in this case is described, focusing on serial assessments of pituitary functions using dynamic tests.Learning pointsErdheim–Chester disease and Langerhans cell histiocytosis overlapping as MH was described, focusing on pituitary functions.MH caused both GH deficiency and central diabetes insipidus.Despite a lack of radical therapy for MH, no other anterior pituitary dysfunctions emerged for 2 years.Radiological images showed no particular interval changes in pituitary stalk lesions, while vascular and retroperitoneal involvements extended.

Cardiovascular Neuroendocrinology: Emerging Role for Neurohypophyseal Hormones in Pathophysiology.

Arginine vasopressin (AVP) and oxytocin (OXY) are released by magnocellular neurosecretory cells that project to the posterior pituitary. While AVP and OXY currently receive more attention for their contributions to affiliative behavior, this mini-review discusses their roles in cardiovascular function broadly defined to include indirect effects that influence cardiovascular function. The traditional view is that neither AVP nor OXY contributes to basal cardiovascular function, although some recent studies suggest that this position might be re-evaluated. More evidence indicates that adaptations and neuroplasticity of AVP and OXY neurons contribute to cardiovascular pathophysiology.

Symptomatic Hyponatremia after Continuous Infusion of Vasopressin: A Case Report

Arginine Vasopressin (AVP), also known as antidiuretic hormone, is a endogenously secreted peptide by the posterior pituitary in response to hyperosmolar plasma or systemic hypoperfusion states.

3D fat-suppressed T1-weighted volume isotropic turbo spin-echo acquisition (VISTA) imaging for the evaluation of the ectopic posterior pituitary gland.

We evaluated the usefulness of fat-suppressed three-dimensional T1-weighted volume isotropic turbo spin-echo acquisition (FS 3D T1W-VISTA) imaging for the evaluation of the ectopic posterior pituitary gland (EPPG). This retrospective study included 9 patients with EPPG due to causes other than tumor. All underwent sagittal two-dimensional (2D) T1W-, FS 3D T1W-VISTA- (VISTA), and 3D T2W-driven equilibrium radiofrequency reset pulse (DRIVE) imaging. Two radiologists independently reviewed the 2D T1W- and VISTA images for their image quality and for visualization of the EPPG and of pituitary stalk transection. DRIVE findings were used as the reference standard for pituitary stalk transection. Interobserver and intermodality agreements were evaluated with the kappa (κ) coefficient. The mean grade assigned to the 2D T1W- and the VISTA imaging technique for visualization of the EPPG was assessed by the Mann-Whitney U test. Interobserver agreement for visualization of the EPPG on 2D T1W- and VISTA images was excellent (κ = 0.82 and κ = 1.00, respectively). The mean grade for EPPG visualization was significantly higher for VISTA- than 2D T1W images (p = 0.0039). FS 3D T1W-VISTA imaging is useful for the evaluation of EPPG. Conventional MRI yields insufficient information for the evaluation of the ectopic posterior pituitary gland (EPPG). The visualization of the EPPG was significantly higher for fat-suppressed three-dimensional T1-weighted volume isotropic turbo spin-echo acquisition (FS 3D T1W-VISTA) than 2D T1W images. FS 3D T1W-VISTA imaging is useful for the evaluation of the EPPG.

Identification of peripheral oxytocin-expressing cells using systemically applied cell-type specific adeno-associated viral vector.

Oxytocin is primarily synthesised in the brain and is widely known for its role in lactation and parturition after being released into the blood from the posterior pituitary gland. Nevertheless, peripheral tissues have also been reported to express oxytocin. Using systemic injection of a recombinant adeno-associated virus vector, we investigated the expression of the green fluorescent protein Venus under the control of the oxytocin promoter in the gastrointestinal tract, pancreas and testes of adult rats. Here, we confirm that the vector infects oxytocin neurones of the enteric nervous system in ganglia of the myenteric and submucosal plexuses. Venus was detected in 25%-60% of the ganglia in the myenteric and submucosal plexuses identified by co-staining with the neuronal marker PGP9.5. Oxytocin expression was also detected in the islets of Langerhans in the pancreas and the Leydig cells of the testes. Our data illustrate that peripheral administration of the viral vector represents a powerful method for selectively labelling oxytocin-producing cells outside the brain.

HYPOPITUITARISM: A CASE REPORT OF OVERLOOKED DIAGNOSIS.

Hypopituitarism, which has a number of causes, is a severe endocrine condition that needs early diagnosis and treatment to prevent serious consequences. We report a 17-year old male seen in outpatient department for lack of development of secondary sexual characters and short stature. Laboratory investigation showed low total tri-iodothyronine (T3) , low total thyroxine (T4) and slightly elevated thyroid stimulating hormone (TSH) , low basal cortisol, and normal prolactin level. The patient also had low total testosterone, low LH, and FSH values. Magnetic resonance imaging (MRI) of the pituitary revealed a hypoplastic anterior pituitary with ectopic posterior pituitary. This case highlights the notable absence of recognizing the clinical presentation of hypopituitarism which at times is nonspecic and often progress insidiously before a diagnosis is made. The case calls attention to importance of thorough history taking, attention, and observation in making a new diagnosis that has the potential to alter a patient's health care and quality of life.

LC–MS/MS measurement of endogenous oxytocin in the posterior pituitary and CSF of macaques: A pilot study

Oxytocin (OT) is a nanopeptide released into systemic circulation via the posterior pituitary (peripheral) and into the central nervous system via widespread OTergic pathways (central). Central OT plays a significant role in variety of functions from social and executive cognition to immune regulation. Many ongoing studies explore its therapeutic potential for variety of neuropsychiatric disorders. Measures of peripheral OT levels are most frequently used as an indicator of its concentration in the central nervous system in humans and animal models. In this study, LC–MS/MS was used to measure OT in pituitary samples collected from adult male macaque monkeys in order to explore the correlation between individual levels of OT in the CSF (central) and pituitary (peripheral). We quantified individual differences in the levels of OT in the pituitaries (44−151 ng/mg) and CSF (41−66 pg/mL) of these monkeys. A positive correlation between these two measures was identified. These preliminary results allow for future analyses to determine whether LC–MS/MS measures of peripheral OT can be used as markers of OT levels in the brain of nonhuman primates that serve as valuable models for many human neuropsychiatric disorders.

Mechanism, spectrum, consequences and management of hyponatremia in tuberculous meningitis.

Hyponatremia is the commonest electrolyte abnormality in hospitalized patients and is associated with poor outcome. Hyponatremia is categorized on the basis of serum sodium into severe (< 120 mEq/L), moderate (120-129 mEq/L) and mild (130-134mEq/L) groups. Serum sodium has an important role in maintaining serum osmolality, which is maintained by the action of antidiuretic hormone (ADH) secreted from the posterior pituitary, and natriuretic peptides such as atrial natriuretic peptide and brain natriuretic peptide. These peptides act on kidney tubules via the renin angiotensin aldosterone system. Hyponatremia <120mEq/L or a rapid decline in serum sodium can result in neurological manifestations, ranging from confusion to coma and seizure. Cerebral salt wasting (CSW) and syndrome of inappropriate secretion of ADH (SIADH) are important causes of hyponatremia in tuberculosis meningitis (TBM). CSW is more common than SIADH. The differentiation between CSW and SIADH is important because treatment of one may be detrimental for the other; evidence of hypovolemia in CSW and euvolemia or hypervolemia in SIADH is used for differentiation. In addition, evidence of dehydration, polyuria, negative fluid balance as assessed by intake output chart, weight loss, laboratory evidence and sometimes central venous pressure are helpful in the diagnosis of these disorders. Volume contraction in CSW may be more protracted than hyponatremia and may contribute to border zone infarctions in TBM. Hyponatremia should be promptly and carefully treated by saline and oral salt, while 3% saline should be used in severe hyponatremia with coma and seizure. In refractory patients with hyponatremia, fludrocortisone helps in early normalization of serum sodium without affecting polyuria or functional outcome. In SIADH, V2 receptor antagonist conivaptan or tolvaptan may be used if the patient is not responding to fluid restriction. Fluid restriction in SIADH has not been found to be beneficial in TBM and should be avoided.

Prevalence and Characterization of Brain and Pituitary Abnormalities in Children with Pituitary Dysfunction

Introduction: Imaging studies help identify structural abnormalities associated with pituitary dysfunction, such as Ectopic Posterior Pituitary (EPP). Aim: To detect the prevalence of IGHD or CPHD in children with EPP, the association between the location of EPP and pituitary dysfunction; and, to determine the prevalence of brain and pituitary abnormalities detected by MRI. Methods: A retrospective chart review of MRI reports at St. Christopher’s Hospital for Children (SCHC) from 2006-2018 that were found to have EPP. Pituitary hormone function was evaluated in the majority. Results: 66 patients, age of (8.31±6.26) included. Of those, 26 patients had EPP. The prevalence rate of documented pituitary dysfunction was higher in patients with EPP (95%). Of the 26 patients with EPP, age (5.98±5.18 yrs) 20 patients had an endocrine evaluation. Of the 20 children, 14 had CPHD and 4 had IGHD. Patients with EPP were classified into 3 groups (upper, middle &amp; lower). Of the 21 patients with upper EPP, 17 (100%) were found to have pituitary dysfunction (14 with CPHD, 3 with IGHD). Of the 4 children with middle EPP, 1 had pituitary dysfunction which was IGHD. Diabetes insipidus was not identified in any of the children. Patients with CPHD had higher prevalence of EPP (73.7%) as compared to those with IGHD (21.1%). Conclusion: Our study supports previous reports that CPHD and IGHD are frequent in patients with EPP. No cases of DI have been reported in children with EPP. No CPHD was reported in middle/lower but IGHD was found in the middle EPP group.

Diabetes insipidus secondary to sellar/parasellar lesions.

Diabetes insipidus (DI) is a well-recognised transient or permanent complication following transsphenoidal surgery for pituitary adenomas or other sellar/parasellar lesions. However, data regarding the prevalence of pre-operative DI in sellar/parasellar lesions other than pituitary adenomas are scarce. We systematically reviewed the existing data for defining the prevalence of DI before any treatment in adult patients with sellar/parasellar lesions, excluding pituitary adenomas and metastatic lesions. In total, 646 patients with sellar/parasellar lesions presenting with DI at diagnosis were identified. The most common pathologies of sellar/parasellar lesions presenting with DI at diagnosis were lymphocytic hypophysitis (26.5%), craniopharyngiomas (23.4%), Langerhans's cell histiocytosis (18.9%) and Rathke's cleft cyst (12.7%), accounting for the vast majority (more than 80%) of these lesions. Overall, DI at diagnosis was found in 23.4% of all patients with sellar/parasellar lesions, albeit with a wide range from 10.6% to 76.7%, depending on the nature of the pathology. The highest prevalence of DI was found in less commonly encountered lesions namely germ-cell tumours (76.7%), abscesses (55.4%) and neurosarcoidosis (54.5%), each accounting for less than 3% of all sellar/parasellar lesions. Most DI cases (68.8%) were associated with anterior pituitary hormonal deficiencies, in contrast to pituitary adenomas that rarely present with DI. The enlargement and enhancement of the pituitary stalk were the most common findings on magnetic resonance imaging besides the loss of the high signal of the posterior pituitary on T1-weighted images. Resolution of DI spontaneously or following systemic and surgical management occurred in 22.4% of cases. Post-operative DI, not evident before surgery, was found in 27.8% of non-adenomatous sellar/parasellar lesions, and was transient in 11.6% of them. Besides distinctive imaging features and symptoms, early recognition of DI in such lesions is important because it directs the diagnosis towards a non-adenomatous sellar/parasellar tumour and the early initiation of appropriate treatment.

Arginine vasopressin-Venus reporter mice as a tool for studying magnocellular arginine vasopressin neurons

Arginine vasopressin (AVP) synthesized in the magnocellular neurons of the hypothalamus is transported through their axons and released from the posterior pituitary into the systemic circulation to act as an antidiuretic hormone. AVP synthesis and release are precisely regulated by changes in plasma osmolality. Magnocellular AVP neurons receive innervation from osmosensory and sodium-sensing neurons, but previous studies showed that AVP neurons per se are osmosensitive as well. In the current study, we made AVP-Venus reporter mice and showed that Venus was expressed exclusively in AVP neurons and was upregulated under water deprivation. In hypothalamic organotypic cultures from the AVP-Venus mice, Venus-labeled AVP neurons in the supraoptic and paraventricular nuclei survived for 1 month, and Venus expression was upregulated by forskolin. Furthermore, in dissociated Venus-labeled magnocellular neurons, treatment with NaCl, but not with mannitol, decreased Venus fluorescence in the soma of the AVP neurons. Thus, Venus expression in AVP-Venus transgenic mice, as well as in primary cultures, faithfully showed the properties of intrinsic AVP expression. These findings indicate that AVP-Venus mice as well as the primary hypothalamic cultures could be useful for studying magnocellular AVP neurons.

Diabetes Insipidus: Pathogenesis, Diagnosis, and Clinical Management.

Diabetes insipidus (DI) is an endocrine condition involving the posterior pituitary peptide hormone, antidiuretic hormone (ADH). ADH exerts its effects on the distal convoluted tubule and collecting duct of the nephron by upregulating aquaporin-2 channels (AQP2) on the cellular apical membrane surface. DI is marked by expelling excessive quantities of highly dilute urine, extreme thirst, and craving for cold water. The two main classifications of DI are central diabetes insipidus (CDI), characterized by a deficiency of the posterior pituitary gland to release ADH, and nephrogenic diabetes insipidus (NDI), characterized by the terminal distal convoluted tubule and collecting duct resistance to ADH. The two less common classifications include dipsogenic DI, characterized by excessive thirst due to a low osmotic threshold, and gestational DI, characterized by increased concentration of placental vasopressinase during pregnancy. Treatment of DI is dependent on the disease classification, but severe complications may arise if not tended to appropriately. The most important step in symptom management is maintaining fluid intake ahead of fluid loss with emphasis placed on preserving the quality of life. The most common treatment of CDI and gestational DI is the administration of synthetic ADH, desmopressin (DDAVP). Nephrogenic treatment, although more challenging, requires discontinuation of medications as well as maintaining a renal-friendly diet to prevent hypernatremia. Treatment of dipsogenic DI is mainly focused on behavioral therapy aimed at regulating water intake and/or administration of antipsychotic pharmaceutical therapy. Central and nephrogenic subtypes of DI share a paradoxical treatment in thiazide diuretics.

Increased oxytocin release precedes hyponatremia after pituitary surgery

PurposeThe syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a well-known complication of transsphenoidal pituitary surgery, related to inappropriate secretion of arginine vasopressin (AVP). Its diagnosis is based on hyponatremia, with a peak of occurrence around day 7 after surgery and, to date, no early marker has been reported. In particular, copeptin levels are not predictive of hyponatremia in this case. Oxytocin (OXT) is secreted into the peripheral blood by axon terminals adjacent to those of AVP neurons in the posterior pituitary. Besides its role in childbirth and lactation, recent evidences suggested a role for OXT in sodium balance. The contribution of this hormone in the dysnatremias observed after pituitary surgery has however never been investigated.MethodsWe analyzed the urinary output of OXT in patients subjected to transsphenoidal pituitary surgery.ResultsWhile OXT excretion remained stable in patients who presented a normonatremic postoperative course, patients who were later diagnosed with SIADH-related hyponatremia presented with a significantly increased urinary secretion of OXT 4 days after surgery.ConclusionTaken together, these results show for the first time that urinary OXT output remains normally stable after transsphenoidal pituitary surgery. OXT excretion however becomes abnormally high on or around 4 days after surgery in patients later developing hyponatremia, suggesting that this abnormal dynamics of OXT secretion might serve as an early marker for transsphenoidal surgery-related hyponatremia attributed to SIADH.

The Same Magnocellular Neurons Send Axon Collaterals to the Posterior Pituitary and Retina or to the Posterior Pituitary and Autonomic Preganglionic Centers of the Eye in Rats

In rats, some parvocellular paraventricular neurons project to spinal autonomic centers. Using the virus tracing technique, we have demonstrated that some magnocellular paraventricular neurons, but not supraoptic neurons, also project to autonomic preganglionic centers of the mammary gland, gingiva, or lip. A part of these neurons has shown oxytocin immunoreactivity. In the present experiment, we have examined whether the same magnocellular neuron that sends fibers to the retina or autonomic preganglionic centers of the eye also projects to the posterior pituitary. Double neurotropic viral labeling and oxytocin immunohistochemistry were used. After inoculation of the posterior pituitary and the eye with viruses, spreading in a retrograde direction and expressing different fluorescence proteins, we looked for double-labeled neurons in paraventricular and supraoptic nuclei. Double-labeled neurons were observed in non-sympathectomized and cervical-sympathectomized animals. Some double-labeled neurons contained oxytocin. After the optic nerve was cut, the labeling did not appear in the supraoptic nucleus; however, it could still be observed in the paraventricular nucleus. In the paraventricular nucleus, the double-labeled cells may be the origin of centrifugal visual fibers or autonomic premotor neurons. In the supraoptic nucleus, all double-labeled neurons are cells of origin of centrifugal visual fibers.

The evaluation of pituitary damage associated with cardiac arrest: An experimental rodent model

The pituitary gland plays an important endocrinal role, however its damage after cardiac arrest (CA) has not been well elucidated. The aim of this study was to determine a pituitary gland damage induced by CA. Rats were subjected to 10-min asphyxia and cardiopulmonary resuscitation (CPR). Immunohistochemistry and ELISA assays were used to evaluate the pituitary damage and endocrine function. Samples were collected at pre-CA, and 30 and 120 min after cardio pulmonary resuscitation. Triphenyltetrazolium chloride (TTC) staining demonstrated the expansion of the pituitary damage over time. There was phenotypic validity between the pars distalis and nervosa. Both CT-proAVP (pars nervosa hormone) and GH/IGF-1 (pars distalis hormone) decreased over time, and a different expression pattern corresponding to the damaged areas was noted (CT-proAVP, 30.2 ± 6.2, 31.5 ± 5.9, and 16.3 ± 7.6 pg/mg protein, p < 0.01; GH/IGF-1, 2.63 ± 0.61, 0.62 ± 0.36, and 2.01 ± 0.41 ng/mg protein, p < 0.01 respectively). Similarly, the expression pattern between these hormones in the end-organ systems showed phenotypic validity. Plasma CT-proAVP (r = 0.771, p = 0.025) and IGF-1 (r = −0.775, p = 0.024) demonstrated a strong correlation with TTC staining area. Our data suggested that CA induces pathological and functional damage to the pituitary gland.

Effect of oxytocin on lipid accumulation under inflammatory conditions in human macrophages

Introduction and aimsOxytocin (OT) is a neuropeptide hormone secreted by the posterior pituitary gland. Deficits in OT action have been observed in patients with behavioral and mood disorders, some of which correlate with an increased risk of cardiovascular disease (CVD). Recent research has revealed a wider systemic role that OT plays in inflammatory modulation and development of atherosclerotic plaques. This study investigated the role that OT plays in cholesterol transport and foam cell formation in LPS-stimulated THP-1 human macrophages. MethodsTHP-1 differentiated macrophages were treated with media, LPS (100 ng/ml), LPS + OT (10 pM), or LPS + OT (100 pM). Changes in gene expression and protein levels of cholesterol transporters were analyzed by real time quantitative PCR (RT-qPCR) and Western blot, while oxLDL uptake and cholesterol efflux capacity were evaluated with fluorometric assays. ResultsRT-qPCR analysis revealed a significant increase in ABCG1 gene expression upon OT + LPS treatment, compared to LPS alone (p = 0.0081), with Western blotting supporting the increase in expression of the ABCG1 protein. Analysis of oxLDL uptake showed a significantly lower fluorescent value in LPS + OT (100pM) -treated cells when compared to LPS alone (p < 0.0001). While not statistically significant (p = 0.06), cholesterol efflux capacity increased with LPS + OT treatment. ConclusionWe demonstrate here that OT can attenuate LPS-mediated lipid accumulation in THP-1 macrophages. These findings support the hypothesis that OT could be used to reduce pro-inflammatory and potentially atherogenic changes observed in patients with heightened CVD risk. This study suggests further exploration of OT effects on monocyte and macrophage cholesterol handling in vivo.

Chapter 16 - Neuroimaging of central diabetes insipidus

Central diabetes insipidus (CDI) occurs secondary to deficient synthesis or secretion of arginine vasopressin peptide from the hypothalamo-neurohypophyseal system (HNS). It is characterized by polydipsia and polyuria (urine output >30mL/kg/day in adults and >2l/m2/24h in children) of dilute urine (<250mOsm/L). It can result from any pathology affecting one or more components of the HNS including the hypothalamic osmoreceptors, supraoptic or paraventricular nuclei, and median eminence of the hypothalamus, infundibulum, stalk or the posterior pituitary gland. MRI is the imaging modality of choice for evaluation of the hypothalamic-pituitary axis (HPA), and a dedicated pituitary or sella protocol is essential. CT can provide complimentary diagnostic information and is also of value when MRI is contraindicated. The most common causes are benign or malignant neoplasia of the HPA (25%), surgery (20%), and head trauma (16%). No cause is identified in up to 30% of cases, classified as idiopathic CDI. Knowledge of the anatomy and physiology of the HNS is crucial when evaluating a patient with CDI. Establishing the etiology of CDI with MRI in combination with clinical and biochemical assessment facilitates appropriate targeted treatment. This chapter illustrates the wide variety of causes and imaging correlates of CDI on neuroimaging, discusses the optimal imaging protocols, and revises the detailed neuroanatomy required to interpret these studies.

A transgenic pig model expressing a CMV-ZsGreen1 reporter across an extensive array of tissues.

Since genetic engineering of pigs can benefit both biomedicine and agriculture, selecting a suitable gene promoter is critically important. The cytomegalovirus (CMV) promoter, which can robustly drive ubiquitous transgene expression, is commonly used at present, yet recent reports suggest tissue-specific activity in the pig. The objective of this study was to quantify ZsGreen1 protein (in lieu of CMV promoter activity) in tissues from pigs harboring a CMV-ZsGreen1 transgene with a single integration site. Tissue samples (n=35) were collected from neonatal hemizygous (n=3) and homozygous (n=3) piglets and ZsGreen1 abundance was determined via immunoblotting. ZsGreen1 was detected in all tissues, except hypothalamus, kidney cortex and oviduct. The expression patterns of homozygous and hemizygous piglets were similar (P>0.05). However, quantification revealed that ZsGreen1 protein levels were tissue-specific. Within neural/endocrine tissues, ZsGreen1 abundance was highest in the anterior pituitary gland, intermediate in the cerebellum and lowest in the cerebrum, spinal cord and posterior pituitary (P<0.05). In the digestive system, ZsGreen1 was more abundant in the salivary gland than esophagus, stomach, pancreas, duodenum, jejunum, ileum, spleen, colon, gallbladder and liver (P<0.05). Interestingly, ZsGreen1 amounts also differed within an organ (i.e., the right ventricle had 3-fold higher levels than the other heart chambers; P<0.05). These results provide useful information for the use of the CMV promoter to drive transgene expression in the pig. Moreover, this swine model represents a novel resource of ZsGreen1-labeled organs and a valuable tool to advance genome editing research.

Factors influencing growth in children with growth hormone deficiency - a case-control study.

To assess the response of South Indian children with growth hormone deficiency (GHD) to growth hormone therapy, optimal duration of therapy for good catch up, and factors determining the response of our children to growth hormone therapy. We conducted acase control study at apaediatric endocrine unit of atertiary paediatric hospital. Children diagnosed with growth hormone deficiency were initiated on GH (cases) or followed up without GH therapy (controls). Detailed clinical, biochemical, radiological, and treatment parameters were recorded at baseline and follow-up. Data were analysed using IBM SPSS version 21. We enrolled 23 subjects in group I (cases who received GH) and group II (controls with untreated children), and both the groups were comparable at baseline. Group I (-4.12 ±1.7 to -2.81 ±1.52) had significant height increase on follow-up after GH therapy compared to group II (-3.55 ±1.7 to -3.51 ±1.52) (p>0.05). Growth velocity in group I (13.25 ±5.6 cm/year, SD score 4.55 ±5.42) was significantly higher compared to group II (3.4 ±1.8 cm/year, SD score -1.62 ±2.38). Duration of growth hormone therapy, presence of ectopic posterior pituitary, and BA: CA ratio independently impacted the growth velocity SD scores. Kaplan Meier analysis curve showed 15 months of GH therapy was needed to attain aheight within ±2 SD of the target height. Early diagnosis, pre-pubertal status, delayed bone age, and presence of ectopic posterior pituitary on MRI are determinants of abetter response. Growth hormone must be administered for at least 15 months for catch up height SDs within target height SD range.

Chapter 2 - Vasopressin and oxytocin beyond the pituitary in the human brain

Vasopressin and oxytocin are primarily synthesized in the magnocellular supraoptic and paraventricular nuclei of the hypothalamus and transported to the posterior pituitary. In the human, an extensive accessory magnocellular neuroendocrine system is present with contact to the posterior pituitary and blood vessels in the hypothalamus itself. Vasopressin and oxytocin are involved in social and behavioral functions. However, only few neocortical areas are targeted by vasopressinergic and oxytocinergic nerve fibers, which mostly project to limbic areas in the forebrain, where also their receptors are located. Vasopressinergic/oxytocinergic perikarya in the forebrain project to the brain stem and spinal cord targeting nuclei and areas involved in autonomic functions. Parvocellular neurons containing vasopressin are located in the suprachiasmatic nucleus and synchronize the activity of the pacemaker in this nucleus. From the suprachiasmatic nucleus fibers project to the parvocellular part of the paraventricular nucleus, where preautonomic neurons project to the intermediolateral nucleus in the thoracic spinal cord, from where the superior cervical ganglion is reached whose noradrenergic fibers terminate in the pineal gland to stimulate melatonin secretion at night. The pineal gland is also innervated by vasopressin- and oxytocin-containing fibers reaching the gland via the "central innervation" in the pineal stalk, which might be involve in an annual regulation of melatonin secretion.