ADRENOCORTICOTROPIN HYPERRESPONSE TO THE CORTICOTROPIN-RELEASING HORMONE-MEDIATED STIMULUS OF NALOXONE IN PATIENTS WITH MYOTONIC-DYSTROPHY

We previously showed that CRH-mediated stimuli, including exogenous CR H, cause ACTH hypersecretion in many myotonic dystrophy (DM) patients. We confirmed this by giving naloxone, a stimulator of endogenous CRH release, to a large number of DM patients and controls. DM patients, f irst degree relatives, and normal controls received iv naloxone at 140 0 h, and blood was taken for ACTH (RIA) and cortisol (high pressure li quid chromatography) measurements from 15 min before to 120 min after naloxone treatment. DM patients had basal ACTH levels approximately tw ice those of controls, and their ACTH responses were 4 times those of controls. In contrast, DM basal cortisol levels were not significantly different from those of relatives and were slightly higher than those of normal subjects. Cortisol responses were similar in the three grou ps, probably due to attenuation at high levels of adrenocortical stimu lation, although some patients with inappropriately low cortisol respo nses for their level of ACTH stimulation warrant further investigation . Nineteen of the 36 patients whose ACTH responses were greater than 3 SD above the normal mean were classed as hyperresponders. Seven patie nts, who were tested more than once, had reproducible responses relati ve to those of the normal subjects. We conclude that ACTH hypersecreti on after CRH-mediated stimuli, including naloxone, is an inherent, but variable, feature of DM, caused by expression of the genetic mutation at the anterior pituitary. The mechanism is probably a defect in the intracellular pathway initiated by CRH-receptor interaction as a resul t of abnormal levels of a cAMP-dependent kinase, DMPK, the product of the gene undergoing mutation in DM.