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Adipsic diabetes insipidus (ADI) is a rare disorder consisting of central diabetes insipidus (CDI) and a deficient or absent thirst response to hyperosmolality. Patients with ADI experience marked morbidity and mortality. Diagnosis and management of these patients is quite challenging, even in expert hands. In this review, we aim to provide an updated overview of this difficult clinical scenario. We conducted a PubMed search for articles related to ADI. The search terms \"adipsia,\" \"adipsic,\" \"thirst,\" and \"diabetes insipidus\" were used to identify relevant literature. ADI has been described in only approximately 100 patients. This rarity has limited the quality and quantity of literature to case reports, case series, and expert opinion. Diagnosis focuses on confirmation of CDI followed by documenting subnormal or completely absent thirst in response to a hypertonic stimulus. Among the described patients with ADI, the majority experience morbidity (e.g., severe hypernatremia, sleep apnea, venous thromboembolism [VTE], and obesity) and an increased mortality risk. Management focuses on frequent reassessment of daily prescribed water intake with fixed antidiuretic therapy (desmopressin) and comorbidity screening. The complexity of patients with ADI provides a difficult challenge for clinicians. Prompt recognition of thirst disorders in patients with CDI should lead to appropriately regimented management strategies and can result in safe outpatient care for these unique patients.

In the fasted and the streptozotocin (STZ)-induced diabetic male rat, hypothalamic growth hormone (GH)-releasing hormone (GHRH) mRNA levels, and pulsatile GH release are decreased. These changes are believed to be due to a rise in hypothalamic neuropeptide Y (NPY) that inhibits GHRH expression. To directly test if NPY is required for metabolic regulation of hypothalamic neuropeptides important in GH secretion, NPY, GHRH and somatostatin (SRIH) mRNA levels were determined in fasted (48 h) and STZ-treated wild-type (NPY +/+ ) and NPY-knockout (NPY –/– ) mice by ribonuclease protection assay. In addition, pituitary receptor mRNA levels for GHRH (GHRH-R), ghrelin (GHS-R) and SRIH (sst2) were assessed by RT-PCR. Under fed conditions the GH axis of NPY +/+ and NPY –/– did not differ. In the NPY +/+ mouse, fasting resulted in a 23% weight loss and >250% increase in NPY mRNA accompanied by a significant reduction in both GHRH and SRIH mRNA. These changes were associated with increases in pituitary expression of GHRH-R and GHS-R and a concomitant suppression of sst2. In the NPY –/– mouse, fasting also resulted in a 23% weight loss and comparable changes in GHRH-R and sst2, but failed to alter GHRH, SRIH and GHS-R mRNA levels. Fasting resulted in an overall increase in circulating GH, which reached significance in the fasted NPY –/– mouse. Induction of diabetes in NPY +/+ mice, using a single, high-dose, STZ injection (150 mg/kg), resulted in modest weight loss (5%), and a 158% increase NPY expression which was associated with reciprocal changes in pituitary GHS-R and sst2 expression, similar to that observed in the fasted state, but no change in hypothalamic GHRH or SRIF expression was observed. Induction of diabetes in NPY +/+ and NPY –/– mice, using a multiple, low-dose, STZ paradigm (5 consecutive daily injections of 40 mg/kg), did not alter body weight, hypothalamic neuropeptide expression or pituitary receptor expression, with the exception that sst2 mRNA levels were suppressed and GH levels did rise in the NPY –/– mouse. These observations demonstrate that NPY is not required for basal regulation of the GH axis, but is required for fasting-induced suppression of GHRH and SRIH expression, as well as fasting-induced augmentation of pituitary GHS-R mRNA. In contrast to the rat, fasting clearly did not suppress circulating GH levels in mice, but resulted in an overall rise in mean GH levels, similar to that observed in other mammalian species. The fact that many of the fasting-induced changes in the GH axis were observed in the high-dose STZ-treated mice, but were not observed in the multiple, low-dose paradigm, suggests STZ-mediated modulation of GH axis function is dependent on the severity of the catabolic state and not hyperglycemia.

Familial isolated pituitary adenoma (FIPA), defined as the occurrence of at least two cases of pituitary adenoma in a family that does not exhibit features of syndromic diseases, such as Carney complex or Multiple Endocrine Neoplasia type 1 or 4, is a rare autosomal dominant disease with low penetrance. About 20 % of the families with FIPA harbor inactivating mutation in aryl hydrocarbon receptor-interacting protein gene ( AIP ) associated with loss of heterozygosity of the same genetic locus (11q13) in the tumor. Rarely different types of extra-pituitary tumors have been described in the setting of AIP mutation-positive FIPA. We present the case of a patient who was diagnosed with acromegaly due to the AIP mutation c.241C>T (p.R81X) at the age of 34 years, and treated by transsphenoidal surgery. At the age of 43 years she was diagnosed with a meningioma, and at age 46 had recurrence of the somatotropinoma. Genetic studies demonstrated loss of the normal allele (by sequencing and microsatellite analysis) in DNA from the pituitary adenoma but not from the meningioma, suggesting a selective involvement of AIP mutation in the pathogenesis of the pituitary adenoma, and a casual association with the meningioma. Further investigations are required to define the exact role of AIP in non-pituitary tumorigenesis.

Several classes of pharmacological agents are approved for the medical therapy of acromegaly, including dopamine agonists, somatostatin analogs and a growth hormone receptor antagonist. Pegvisomant, a growth hormone receptor antagonist, suppresses IGF-1 levels into the normal range in over ninety percent of patients. However, increased tumor volume was reported in patients receiving pegvisomant who had not received prior radiotherapy. To describe two patients with acromegaly who developed significant tumor enlargement on pegvisomant and discuss the potential mechanisms involved. Both patients received long-acting somatostatin analog (octreotide) therapy subsequent to incomplete transsphenoidal tumor resection. Octreotide did not normalize GH/IGF-1 levels in either patient but did control tumor mass size. Pegvisomant therapy was initiated after discontinuing octreotide. Both patients exhibited suppression of IGF-1 into the normal range during pegvisomant therapy. However, significant tumor enlargement occurred in both. Potential mechanisms for tumor enlargement include the natural tendency of the tumor to grow with time, discontinuation of tumor suppressive effects of the somatostatin analog, or a direct effect of pegvisomant. The presumed mechanism of tumor enlargement is by loss of the inhibitory effect on tumor growth when IGF-1 levels are reduced. This could also explain the increase in circulating GH levels in patients with acromegaly receiving pegvisomant; patient 1 demonstrated an 18-fold increase in circulating GH levels while receiving the drug. The mechanisms of tumor enlargement in patients with acromegaly on pegvisomant are likely multifactorial. Patients, especially those who have not received prior radiotherapy, should be closely monitored for tumor enlargement.

To evaluate the pharmacokinetics, efficacy, and safety of a subcutaneous octreotide hydrogel implant in patients with acromegaly. In 2 phase II open-label randomized studies, patients aged ≥ 18 years with confirmed acromegaly and octreotide responsiveness received one or two 52 mg hydrated implants (52 mg study) or a hydrated or nonhydrated 84 mg implant (84 mg study) inserted subcutaneously in the upper arm. Implants were removed after 6 months. The 84 mg study assessed pharmacokinetics in patients with undetectable baseline octreotide concentrations. Both studies assessed efficacy (serum growth hormone [GH], insulin-like growth factor 1 [IGF-1]) and safety (adverse events, physical examination, clinical chemistry). Eleven patients received 1 (n = 5) or 2 (n = 6) 52 mg implants; 34 received a hydrated (n = 17 [safety]; n = 16 [efficacy analysis]) or nonhydrated (n = 17) 84 mg implant. With the nonhydrated versus hydrated 84 mg implant, mean maximum serum concentration (Cmax) and mean area under the drug concentration versus time curve from time 0 to 6 months were decreased (P = 0.002 and P = 0.03, respectively) and mean time to Cmax was increased (P = 0.002). In both studies, IGF-1 and GH declined in month 1 and were significantly suppressed during the 6-month treatment versus baseline (P<0.001). With the 52 mg and 84 mg implants, respectively, 3 of 11 patients (27%) and 17 of 33 patients (52%) achieved IGF-1 normalization and 8 of 11 patients (73%) and 13 of 33 patients (39%) exhibited GH <2.5 ng/mL; 9 of 11 patients (82%) and 11 of 34 patients (32%) experienced treatment-related adverse events, which were mainly gastrointestinal. Octreotide hydrogel implants were well tolerated and maintained stable octreotide release and suppression of IGF-1 and GH over 6 months.

Neoangiogenesis involves both bone marrow-derived myelomonocytic and endothelial progenitor cells as well as endothelial cells coopted from surrounding vessels. Cytokines induce these cells to proliferate, migrate, and exit the cell cycle to establish the vasculature; however, which cell cycle regulators play a role in these processes is largely unknown. Here, we report that mice lacking the cell cycle inhibitors p130 and p27 show defects in tumor neoangiogenesis, both in xenografts and spontaneously arising tumors. This defect is associated with impaired mobilization of endothelial and myelomonocytic angiogenic progenitors from the bone marrow. This article documents the role of these molecules in angiogenesis and further suggests that cell expansion and mobilization from the bone marrow of angiogenic precursors are separable events. angiogenesis cyclin-dependent kinase inhibitors stem cell

Both the diagnosis and therapy of patients with growth hormone deficiency have become more complex than originally anticipated. Pharmaceutical manufacturers who have established postmarketing databases should combine their efforts worldwide and design a multicenter evaluation of the long-term effects of growth hormone, and physicians should enroll patients with growth hormone deficiency in such a study.

The great majority of growth hormone (GH)-secreting pituitary tumors are sporadic, though a few occur with a familial aggregation, either as a component of multiple endocrine neoplasia, type 1 (MEN1) or Carney Complex, or when unassociated with other tumors, as isolated familial somatotropinomas (IFS). This report reviews the clinical and genetic information available from the 46 families reported to date with the latter syndrome. In contrast to sporadic tumors, GH-secreting tumors in IFS occur at an earlier age, especially when all affected family members are from a single generation. The IFS gene is believed to be a tumor suppressor gene, based on the presence of loss of heterozygosity. Although the gene still remains to be identified there is strong evidence for linkage to a locus of less than 10 Mb on chromosome 11q13.1-13.3.

Anterior pituitaries from the dwarf mouse strain ``little'' did not release growth hormone or accumulate adenosine 3$\\prime $, 5$\\prime $-monophosphate (cyclic AMP) in response to human and rat growth hormone-releasing factor (GRF). Dibutyryl cyclic AMP, as well as the adenylate cyclase stimulators forskolin and cholera toxin, markedly stimulated growth hormone (GH) release. The basis of the GH deficiency in the little mouse may therefore be a defect in an early stage of GRF-stimulated GH release related either to receptor binding or to the function of the hormone-receptor complex.

THE clinical features of acromegaly result directly or indirectly from sustained hypersecretion of growth hormone. 1 2 3 Somatotroph-cell adenomas, or in rare cases hyperplasia, constitute the pathologic pituitary lesions causing acromegaly. 4 , 5 Also in rare cases, acromegaly may be caused by ectopic somatotroph-cell adenomas in the sphenoid or parapharyngeal sinuses. 4 , 5 Attention has recently been focused on the elaboration of growth hormone–releasing factors by carcinoid 6 and pancreatic islet-cell tumors 7 causing acromegaly. The structure of human growth hormone–releasing factor was, in fact, first elucidated from two such pancreatic tumor extracts, which were shown to stimulate growth hormone release both in vitro and in vivo. 8 , 9 Ectopic . . .