The pituitary gland orchestrates our endocrine environment: it produces
hormones in response to hypothalamic factors that integrate neural inputs and its activity is balanced by the feedback action of peripheral
hormones. Disruption of this equilibrium has severe consequences that affect multiple systems and may be fatal. Genetic analysis of pituitary function led to discovery of critical
transcription factors that cause
hormone deficiencies when mis-expressed. This review will summarize recent findings that led to the first complete clinical description of inherited, isolated
corticotropin (
ACTH) deficiency (IAD) and to the first molecular mechanism for excessive
ACTH production in
Cushing's disease. Indeed, mutations in TPIT, a positive or negative regulator of cell fates for different pituitary lineages, cause neonatal IAD, a condition considered anecdotic before discovery of this
transcription factor.
Cushing's disease is caused by
corticotroph adenomas that produce excess
ACTH as a result of resistance to
glucocorticoids (Gc). Molecular investigation of the normal mechanism of Gc feedback led to identification of two essential
proteins for
pro-opiomelanocortin repression that are often mis-expressed in
corticotroph adenomas thus providing a molecular explanation for Gc resistance. These two
proteins, Brg1 and
histone deacetylase 2 (HDAC2), are involved in chromatin remodeling and may also participate in the tumorigenic process, as Brg1 is a
tumor suppressor. These recent advances have provided improved diagnosis and opened new perspectives for patient management and
therapies.