Does preoperative somatostatin analog treatment improve surgical cure rates in acromegaly? A new look at an old question.

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Update on the treatment of pituitary adenomas: familial and genetic considerations.

peer reviewedClinically-relevant pituitary adenomas occur with a prevalence of approximately 1 per 1000 population in Belgium. Pituitary adenomas that occur in families are likely to have an important genetic pathophysiological basis. Currently about 5% of all pituitary adenoma cases have a family history of pituitary adenomas, classically due to multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Over the last decade we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes, a condition named 'familial isolated pituitary adenoma' (FIPA). Clinical features of FIPA differ from those of sporadic pituitary adenomas in that patients with FIPA are often younger and have larger tumours at diagnosis. Approximately 15% of FIPA patients have mutations in the aryl hydrocarbon receptor interacting protein gene (AIP), which indicates that FIPA may have a diverse genetic pathophysiology. In this review we examine new findings on the epidemiology of pituitary adenomas and we review familial causes of pituitary adenomas with a particular emphasis on modern clinical testing. In addition, the clinical and genetic features of FIPA are described as FIPA represents a useful framework to study the features of pituitary adenomas that occur in a familial setting

The Genetics of Growth Hormone Axis

CD-Ro

Management of acromegaly

Acromegaly is caused by hypersecretion of growth hormone and resultant overproduction of insulin-like growth factor-1 and is associated with increased mortality and morbidity. Successful treatment modalities have been developed and are used in a multistep approach allowing normal life expectancy as well as improved quality of life in an increasing number of patients

Medical management of pituitary gigantism and acromegaly

peer reviewedAcromegaly and pituitary gigantism are two related clinical manifestations of chronic growth hormone (GH) and insulin-like growth factor 1 (IGF-1) hypersecretion, usually from a pituitary adenoma. Management of acromegaly is guided by consensus reports based on accumulated clinical trials, in which medical therapies including somatostatin analogs, the GH receptor antagonist pegvisomant, and dopamine agonists play a key role alongside neurosurgery. Pituitary gigantism represents a severe subtype of acromegaly, as it affects children/adolescents whose growth plates have not fused. Apart from the risk of increased final adult height, patients with pituitary gigantism also have relatively aggressive and treatment resistant disease. This phenotype is driven by the presence of genetic mutations in nearly 50% of pituitary gigantism cases, including AIP mutations, X-linked acrogigantism syndrome, and McCune-Albright syndrome. This chapter assesses the consensus medical therapy of acromegaly and highlights specific aims and challenges for the effective management of patients with pituitary gigantism. © 2021 Elsevier Inc. All rights reserved

Bases moléculaires du gigantisme hypophysaire

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Presurgical Octreotide: Treatment in Acromegaly

One hundred seventy-two acromegalics who were operated on using the trans-sphenoidal approach underwent long-term follow-up evaluation. Sixty-four received 100 micrograms octreotide subcutaneously three times daily: for 3 to 6 weeks before surgery in 14 patients (group 1); and for 3 to 9 months in 41 and for 13 to 39 months in nine (n = 50, group 2). In 18 group 2 patients, the dose was increased stepwise to 500 micrograms three times daily because of incomplete suppression of growth hormone (GH)/insulin-like growth factor-1 (IGF-1). Tumor shrinkage was seen in 60% within 3 weeks, being nearly maximal by 3 to 4 months. More group 2 patients had greater than 25% tumor shrinkage (14 of 48 v 1 of 14 in group 1). Clinical response was excellent or good in 89%. Decrease in soft-tissue swelling and weight loss, and improved vitality, performance, carbohydrate metabolism, and cardiovascular function, facilitated anesthetic and surgical management; tumor removal was easy in virtually all cases. In all 64 patients, GH levels decreased by > or = 50%, and to < 2 micrograms/L in three of 14 patients initially and 25 of 50 patients after more prolonged treatment. IGF-1 levels decreased to normal in seven of 14 group 1 and 31 of 50 group 2 patients. Light and electron microscopy showed that adenomatous tissue exposed to octreotide had lysosomal accumulation, amyloid deposition, mild to moderate perivascular fibrosis, and moderate size reduction in both cytoplasmic and nuclear areas, with virtually no cellular complications. Remission with enclosed adenomas was greater (p < .05) than for the 108 patients not treated with octreotide; there was no difference for invasive adenomas. Octreotide use for 3 to 4 months before surgery can be recommended

Clinical and genetic aspects of familial isolated pituitary adenomas

Pituitary adenomas represent a group of functionally diverse neoplasms with relatively high prevalence in the general population. Most occur sporadically, but inherited genetic predisposing factors are increasingly recognized. Familial isolated pituitary adenoma is a recently defined clinical entity, and is characterized by hereditary presentation of pituitary adenomas in the absence of clinical and genetic features of syndromic disease such as multiple endocrine neoplasia type 1 and Carney complex. Familial isolated pituitary adenoma is inherited in an autosomal dominant manner and accounted for approximately 2–3% of pituitary tumors in some series. Germline mutations in the aryl-hydrocarbon interacting protein gene are identified in around 25% of familial isolated pituitary adenoma kindreds. Pituitary adenomas with mutations of the aryl-hydrocarbon interacting protein gene are predominantly somatotropinomas and prolactinomas, but non-functioning adenomas, Cushing disease, and thyrotropinoma may also occur. These tumors may present as macroadenomas in young patients and are often relatively difficult to control. Furthermore, recent evidence indicates that aryl-hydrocarbon interacting protein gene mutations occur in >10% of patients with sporadic macroadenomas that occur before 30 years of age, and in >20% of children with macroadenomas. Genetic screening for aryl-hydrocarbon interacting protein gene mutations is warranted in selected high-risk patients who may benefit from early recognition and follow-up

Concepts actuels de l'hyperaldostéronisme primaire

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miR-34a is upregulated inAIP-mutated somatotropinomas and promotes octreotide resistance

Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and have a heavy treatment burden. Growth hormone (GH)-secreting PAs (somatotropinomas) cause acromegaly-gigantism. Genetic forms of somatotropinomas due to germlineAIPmutations (AIPmut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigated the role of miRNA dysregulation inAIPmut+ vsAIPmut- PA samples by array analysis. miR-34a and miR-145 were highly expressed inAIPmut+ vsAIPmut- somatotropinomas. Ectopic expression ofAIPmut (p.R271W) inAip(-/-)mouse embryonic fibroblasts (MEFs) upregulated miR-34a and miR-145, establishing a causal link betweenAIPmut and miRNA expression. In PA cells (GH3), miR-34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR-145 moderately affected proliferation and apoptosis. Moreover, high miR-34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR-34a expression significantly blunted octreotide-mediated GH inhibition and antiproliferative effects. miR-34a directly targetsGnai2encoding G alpha i2, a G protein subunit inhibiting cAMP production. Accordingly, G alpha i2 levels were significantly lower inAIPmut+ vsAIPmut- PA. Taken together, somatotropinomas withAIPmutations overexpress miR-34a, which in turn downregulates G alpha i2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR-34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR-34a is a novel downstream target of mutantAIPthat promotes a cellular phenotype mirroring the aggressive clinical features ofAIPmut+ acromegaly.Peer reviewe