Page 82 - Clinical Small Animal Internal Medicine

50 Section 2 Endocrine Disease

Gene Mutation
Box 7.1 Classification of pituitary tumors in humans
VetBooks.ir by size and anatomic location in the gene in humans that encodes the GR, with a
Karl and colleagues and Lamberts described a mutation
reduction in the sites of DNA binding, while maintain­
Classification by size based on radiologic findings
ing affinity for cortisol. This de novo mutation pro­
Microadenomas Less than 10 mm diameter motes GR resistance that precedes the formation of the
Macroadenomas Equal to or greater than 10 mm corticotrophinoma.
diameter Recent studies by Teshima and colleagues, using trilos­
tane to decrease cortisol, demonstrated pituitary tumor
Classification based on radioanatomic findings growth as a consequence of a reduction in negative feed­
Stage I Microadenomas (<1 cm) without sella back. Their studies on canine ACTH tumor cells suggest
expansion that reduced negative feedback might first lead to corti­
Stage II Macroadenomas (≥1 cm); may extend above cotroph hyperplasia followed by a subsequent somatic
the sella mutation that could lead to tumor development.
Stage III Macroadenomas with enlargement and
invasion of the floor or suprasellar extension Dopaminergic Actions
Stage IV Destruction of the sella Other possibilities for a hypothalamic theory of PDH
include:
dopaminergic neurodegeneration in aged individuals
●
(GIP) receptor in the adrenal cortex. Stimulation of this ● decreased expression of the D2 dopaminergic receptor
receptor by GIP, normally released by the stomach in in the corticotroph cells, resulting in decreased dopa­
response to a meal, leads to clinical signs of hyperadreno­ minergic inhibition and subsequent hyperplasia. With
corticism in younger dogs. Occult hyperadrenocorticism this possibility, adenomas would evolve secondary to
refers to the presence of elevated adrenal steroid concen­ somatic mutations in hyperplastic cells.
trations in the absence of clinical signs and has been
best described in Scottish terriers with elevated serum The hypothalamic theory is reinforced by the recurrence
alkaline phosphatase (SAP) and vacuolar hepatopathy. of ACTH‐producing tumors following surgery or in
Atypical hyperadrenocorticism refers to animals with patients in which no tumor was found on MRI or when
clinical signs of classic hyperadrenocorticism secondary exploring the sella. Both of these scenarios suggested
to excess sex steroid production rather than excessive stimulation or lack of inhibition of ACTH‐producing
cortisol secretion. cells from higher centers (hypothalamus or hippocam­
pus). This hypothesis is also supported by the fact that
individuals with chronic stress and greater activation of
Pathogenesis the hypothalamic–pituitary–adrenal axis show cortico­
troph hyperplasia.
The pathogenesis of pituitary tumors that produce
ACTH is becoming more evident based on ongoing
studies evaluating gene and protein expression in both Monoclonal Theory
The main evidence against the hypothalamic theory is the
humans and dogs. This information will aid our under­ presence of tumor clonality in the majority of the adeno­
standing of tumorigenesis and point us toward targeted mas studied in humans. The monoclonal theory argues
specific therapies. that the adenoma occurs in the pituitary outside of other
Two theories have been put forward to explain the
development of an ACTH‐producing pituitary tumor influences and arises through the somatic mutation of a
corticotroph cell, resulting in a tumor clone. This muta­
(ACTH‐PA, corticotrophinoma):
tion precedes the clonal expansion of the tumor.
hypothalamic theory It is unknown which mutation(s) result in the develop­
●
monoclonal theory. ment of a tumor. Taking into account microadenomas
●
and macroadenomas, the existence of a variety of corti­
Hypothalamic Theory cotrophinomas is suggested. The majority of microade­
In this theory, the hypothalamus stimulates corticotrophs nomas in dogs do not progress to macroadenomas based
through enhanced secretion of corticotropin‐releasing on the low percentage of dogs that develop such tumors
hormone (CRH) and vasopressin. In addition, concur­ during treatment with adrenolytics or adrenal enzyme
rent defects in the pituitary glucocorticoid receptors blockers. Macroadenomas can display a variety of behav­
(GR) on the corticotroph cells lead to decreased negative iors, from limited growth and indolent course to more
feedback by cortisol on CRH and ACTH synthesis. aggressive behavior as seen in human patients with