Androgen response to hypothalamic-pituitary-adrenal stimulation with naloxone in women with myotonic muscular dystrophy.

Myotonic muscular dystrophy (MMD) is a disease of autosomal dominant inheritance characterized by multisystem disease, including myotonia, muscle-wasting and weakness of all muscular tissues, and endocrine abnormalities attributed to a genetic abnormality causing a defective cAMP-dependent kinase. We have previously reported that MMD patients demonstrate ACTH hypersecretion after endogenous CRH release stimulated by naloxone administration while manifesting a normal cortisol (F) response. Additionally, others have reported a reduced adrenal androgen (AA) response to exogenous ACTH administration in MMD patients. As ACTH stimulates the secretion of both AAs and F, it is possible that the discordant relationship of these hormones in MMD patients results from a defect of adrenocortical ACTH receptor function or postreceptor signaling or subsequent biochemical events. Furthermore, the molecular abnormality seen in MMD patients may suggest that the mechanism underlying the frequently observed discordances in the secretion of glucocorticoids and AAs (e.g. adrenarche, surgical trauma, severe burns, or intermittent glucocorticoid administration) are explainable solely via an alteration in the function of the ACTH receptor or postreceptor signaling. To ascertain whether the responses of F and AAs to endogenous ACTH diverged in this disorder, we prospectively studied the responses of these hormones to naloxone-stimulated CRH release in nine premenopausal women with MMD and seven healthy age and weight-matched control women. After naloxone infusion (125 micrograms/kg, i.v.), blood sampling was performed at baseline (i.e. -5 min) and at 30 and 60 min. In addition to the absolute hormone level at each time, we calculated the net increment (i.e. change) at 30 and 60 min and the area under the curve (AUC) for F, ACTH, dehydroepiandrosterone (DHA), and androstenedione (A4). Consistent with our previous study, MMD patients demonstrated higher ACTH levels at all sampling times except [minud]5 min. AUC analysis revealed the ACTHAUC values were significantly higher in MMD than in control women (457 +/- 346 vs. 157 +/- 123 pmol/min.L; P < 0.03), whereas the FAUC response did not differ between MMD and controls (13860 +/- 3473 vs. 13375 +/- 3465 nmol/min.L; P > 0.5). Despite the greater ACTH secretion, the baseline circulating dehydroepiandrosterone sulfate levels were significantly lower in MMD compared with control women (18 +/- 23 vs. 61 +/- 23 mumol/L; P < 0.002). The serum concentrations of A4 at baseline, 30 min, and 60 min and DHA levels at 30 and 60 min were also significantly lower in MMD vs. control women. Additionally, the A4AUC and DHAAUC values were significantly lower in MMD patients than in controls. Furthermore, the net response of DHA at 60 min to the endogenous ACTH increase was also reduced in MMD patients compared with that in control subjects (2.3 +/- 2.1 vs. 5.6 +/- 2.6 nmol/L; P < 0.02). In conclusion, in addition to ACTH hypersecretion to CRH-mediated stimuli, these data suggest that MMD patients have a defect in the adrenocortical response to ACTH, reflected in normal F and reduced DHA and A4 secretion. Whether this defect is inherent to the disease or simply reflects adaptive changes to chronic disease remains to be demonstrated. However, it is possible that further studies of the response of MMD patients to ACTH may reveal a mechanism that explains the frequently observed dichotomy in the secretion of glucocorticoids and AAs.