In a substantial part of adrenal
adenomas and
hyperplasias from patients with
Cushing's syndrome,
cortisol production is controlled by the expression of aberrant
hormone receptors on adrenocortical cells. We present in vivo and in vitro data of two patients with a LH-responsive
Cushing's syndrome based on
ACTH-independent bilateral adrenal
hyperplasia. Patients 1 and 2 are women who presented with
Cushing's syndrome and bilateral adrenal
hyperplasia. Endocrine testing demonstrated absence of
cortisol diurnal rhythm, insufficient
cortisol suppression after 1 mg
dexamethasone orally, and undetectable
ACTH levels in both patients. Both patients were treated by laparoscopic biadrenalectomy. In in vivo testing, in patients 1 and 2, a profound
cortisol rise was found after administration of
GnRH [change in
cortisol (Delta F), 118 and 106%, respectively], human CG (Delta F, 133 and 44%), LH (Delta F, 73 and 43%),
ACTH (Delta F, 89 and 181%), and the 5-hydroxy-tryptamine receptor type 4 (5-HT(4)) agonists
cisapride (Delta F, 141 and 148%) and
metoclopramide (Delta F, 189 and 95%). In in vitro testing, adrenal cells from patient 2 responded, in a dose-dependent fashion, with
cortisol production after exposure to human CG (Delta F, 45%),
cisapride (Delta F, 68%), and
metoclopramide (Delta F, 81%).
ACTH induced
cortisol production by cells from both patients (Delta F, 135 and 159%). In receptor studies,
LH receptor mRNA was demonstrated in adrenal tissue of both patients but also in control adrenal tissue of two patients with persisting pituitary-dependent
Cushing's syndrome treated by biadrenalectomy. In neither patient were mutations found in the
ACTH receptor gene. LH-responsive
Cushing's syndrome associated with bilateral adrenal
hyperplasia may result from aberrant (or possibly increased) adrenal
LH receptor expression. This variant is further characterized by adrenal responsiveness to
5-HT4 receptor agonists, possibly pointing to an interaction between LH and
serotonin in the regulation of
cortisol secretion. Despite the regulatory potential of LH and
5-HT4 receptor agonists on
cortisol production in our patients, their adrenals seemed to be still sensitive to
ACTH, both in vivo and in vitro.