Somatotroph-Specific Aip-Deficient Mice Display Pretumorigenic Alterations in Cell-Cycle Signaling.

Patients with familial isolated pituitary adenoma are predisposed to pituitary adenomas, which in a subset of cases is due to germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein (AIP) gene. Using Cre/lox and Flp/Frt technology, a conditional mouse model was generated to examine the loss of the mouse homolog, Aip, in pituitary somatotrophs. By 40 weeks of age, >80% of somatotroph specific Aip knockout mice develop growth hormone (GH) secreting adenomas. The formation of adenomas results in physiologic effects recapitulating the human syndrome of acromegaly, including increased body size, elevated serum GH and insulin-like growth factor 1 levels, and glucose intolerance. The pretumorigenic Aip-deficient somatotrophs secrete excess GH and exhibit pathologic hyperplasia associated with cytosolic compartmentalization of the cyclin-dependent kinase (CDK) inhibitor p27kip1 and perinuclear accentuation of CDK-4. Following tumor formation, the Aip-deficient somatotrophs display reduced expression of somatostatin receptor subtype 5 with impaired response to octreotide. The delayed tumor emergence, even with loss of both copies of Aip, implies that additional somatic events are required for adenoma formation. These findings suggest that pituitary hyperplasia precedes adenomatous transformation in somatotroph-specific Aip-deficient mice and reveal potential mechanisms involved in the pretumorigenic state that ultimately contribute to transformation.

HoxD10 gene delivery using adenovirus/adeno-associate hybrid virus inhibits the proliferation and tumorigenicity of GH4 pituitary lactotrope tumor cells.

Prolactinoma is one of the most common types of pituitary adenoma. It has been reported that a variety of growth factors and cytokines regulating cell growth and angiogenesis play an important role in the growth of prolactinoma. HoxD10 has been shown to impair endothelial cell migration, block angiogenesis, and maintain a differentiated phenotype of cells. We investigated whether HoxD10 gene delivery could inhibit the growth of prolactinoma. Rat GH4 lactotrope tumor cells were infected with adenovirus/adeno-associated virus (Ad/AAV) hybrid vectors carrying the mouse HoxD10 gene (Hyb-HoxD10) or the beta-galactosidase gene (Hyb-Gal). Hyb-HoxD10 expression inhibited GH4 cell proliferation in vitro. The expression of FGF-2 and cyclin D2 was inhibited in GH4 cells infected with Hyb-HoxD10. GH4 cells transduced with Hyb-HoxD10 did not form tumors in nude mice. These results indicate that the delivery of HoxD10 could potentially inhibit the growth of PRL-secreting tumors. This approach may be a useful tool for targeted therapy of prolactinoma and other neoplasms.

Lymphocytic hypophysitis.

BACKGROUND: Lymphocytic hypophysitis is a disorder of the pituitary gland that presents as a sellar mass lesion and/or hypopituitarism. It causes pituicyte destruction and hypopituitarism and is speculated to have an autoimmune basis. DIAGNOSIS: Lymphocytic hypophysitis should be considered in the differential diagnosis of pituitary masses and/or hypopituitarism in females who are pregnant or in the early postpartum period, especially in cases associated with other autoimmune diseases or unusual patterns of hormone deficiencies. A definitive diagnosis requires tissue biopsy. A presumptive clinical diagnosis can be made based on a history of gestational or postpartum hypopituitarism, a contrast-enhancing sellar mass with imaging features characteristic of lymphocytic hypophysitis, a pattern of pituitary hormone deficiency with early loss of adrenocorticotrophic hormone and thyroid-stimulating hormone unlike that typically found with macroadenomas, relatively rapid development of hypopituitarism and a degree of pituitary failure disproportionate to the size of the mass. Symptoms resulting from partial or panhypopituitarism occur in approximately 80% of cases and multiple deficiencies are found in approximately 75% of cases. MANAGEMENT: Appropriate management remains controversial. Corticosteroid therapy has been advocated as a means of attenuating inflammation, but given the uncertainty of its efficacy and the known adverse effects, such therapy does not seem justified for most patients. The optimal surgical strategy involves partial resection of the mass to decompress the surrounding structures. All patients with lymphocytic hypophysitis require appropriate replacement therapy for deficient hormones. Long-term follow-up is mandatory to monitor for the development of other hormonal deficits.

Advances in the treatment of prolactinomas.

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future.

Functional characterization of pendrin in a polarized cell system. Evidence for pendrin-mediated apical iodide efflux.

Pendred's syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the PDS/SLC26A4 gene that encodes pendrin. Functionally, pendrin is a transporter of chloride and iodide in Xenopus oocytes and heterologous mammalian cells and a chloride/base exchanger in beta-intercalated cells of the renal cortical collecting duct. The partially impaired thyroidal iodide organification in Pendred's syndrome suggests a possible role of pendrin in iodide transport at the apical membrane of thyroid follicular cells, but experimental evidence for this concept is lacking. The iodide transport properties of pendrin were determined in polarized Madin-Darby canine kidney cells expressing the sodium iodide symporter (NIS), pendrin, or NIS and pendrin using a bicameral system-permitting measurement of iodide content in the basal, intracellular, and apical compartments. Moreover, we determined the functional consequences of two naturally occurring mutations (L676Q and FS306>309X). In polarized Madin-Darby canine kidney cells, NIS mediates uptake at the basolateral membrane. Only minimal amounts of iodide reach the apical compartment in the absence of pendrin. In cells expressing NIS and pendrin, pendrin mediates transport of iodide into the apical chamber. Wild type pendrin also mediates iodide efflux in transiently transfected cells. In contrast, both pendrin mutants lose the ability to promote iodide efflux. These results provide evidence that pendrin mediates apical iodide efflux from polarized mammalian cells loaded with iodide. Consistent with the partial organification defect observed in patients with Pendred's syndrome, naturally occurring mutations of pendrin lead to impaired transport of iodide.

Prolactin excess: treatment and toxicity.

Dopamine agonists provide highly effective therapy for the treatment of hyperprolactinemia. As a result of their efficacy and tolerability, these agents are considered to be the initial therapy of choice in children, adolescents and adults with idiopathic hyperprolactinemia and prolactinomas. The four dopamine agonists, bromocriptine, pergolide, cabergoline and quinagolide, share a similar mechanism of action and side effect profile. Although studies of cabergoline have demonstrated the highest treatment efficacy and tolerability, all four of these agents are safe, effective and tolerable in children and adolescents. When fertility is desired, bromocriptine is generally preferable, but cabergoline is also likely safe; pergolide and quinagolide should not be used in this setting.

The novel use of very high doses of cabergoline and a combination of testosterone and an aromatase inhibitor in the treatment of a giant prolactinoma.

Most prolactinomas respond rapidly to low doses of dopamine agonists. Occasionally, stepwise increases in doses of these agents are needed to achieve gradual prolactin (PRL) reductions. Approximately 50% of treated men remain hypogonadal, yet testosterone replacement may stimulate hyperprolactinemia. A 34-yr-old male with a pituitary macroadenoma was found to have a PRL level of 10,362 micro g/liter and testosterone level of 3.5 nmol/liter. Eleven months of dopamine agonist therapy at standard doses lowered PRL levels to 299 micro g/liter. Subsequent stepwise increases in cabergoline (3 mg daily) further lowered PRL levels to 71 micro g/liter, but hypogonadism persisted. Initiation of testosterone replacement resulted in a rise and discontinuation in a fall of PRL levels. Aromatization of exogenous testosterone to estradiol and subsequent estrogen-stimulated PRL release was suspected. Concomitant use of cabergoline with the aromatase inhibitor anastrozole after resuming testosterone replacement resulted in the maintenance of testosterone levels and restoration of normal sexual function, without increasing PRL. Ultimately, further reduction in PRL on this therapy permitted endogenous testosterone production. Thus, novel pharmacological maneuvers may permit successful medical treatment of some patients with invasive macroprolactinomas.