Rp. Buyalos et al., ANDROGEN RESPONSE TO HYPOTHALAMIC-PITUITARY-ADRENAL STIMULATION WITH NALOXONE IN WOMEN WITH MYOTONIC MUSCULAR-DYSTROPHY, The Journal of clinical endocrinology and metabolism, 83(9), 1998, pp. 3219-3224
Myotonic muscular dystrophy (MMD) is a disease of autosomal dominant i
nheritance characterized by multisystem disease, including myotonia, m
uscle-wasting and weakness of all muscular tissues, and endocrine abno
rmalities attributed to a genetic abnormality causing a defective cAMP
-dependent kinase. We have previously reported that MMD patients demon
strate ACTH hypersecretion after endogenous CRH release stimulated by
naloxone administration while manifesting a normal cortisol (F) respon
se. Additionally, others have reported a reduced adrenal androgen (AA)
response to exogenous ACTH administration in MMD patients. As ACTH st
imulates the secretion of both AAs and F, it is possible that the disc
ordant relationship of these hormones in MMD patients results from a d
efect of adrenocortical ACTH receptor function or postreceptor signali
ng or subsequent biochemical events. Furthermore, the molecular abnorm
ality seen in MMD patients may suggest that the mechanism underlying t
he frequently observed discordances in the secretion of glucocorticoid
s and AAs (e.g. adrenarche, surgical trauma, severe burns, or intermit
tent glucocorticoid administration) are explainable solely via an alte
ration in the function of the ACTH receptor or postreceptor signaling.
To ascertain whether the responses of F and AAs to endogenous ACTH di
verged in this disorder, we prospectively studied the responses of the
se hormones to naloxone-stimulated CRH release in nine premenopausal w
omen with MMD and seven healthy age and weight-matched control women.
After naloxone infusion (125 mu g/kg, iv), blood sampling was performe
d at baseline (i.e. -5 min) and at 30 and 60 min. In addition to the a
bsolute 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). Consiste
nt with our previous study, MMD patients demonstrated higher ACTH leve
ls at all sampling times except [minud]5 min. AUC analysis revealed th
e ACTH(AUC) values were significantly higher in MMD than in control wo
men (457 +/- 346 vs. 157 +/- 123 pmol/min.L; P < 0.03), whereas the F-
AUC, response did not differ between MMD and controls (13860 +/- 3473
vs. 13375 +/- 5465 nmol/min.L; P > 0.5). Despite the greater ACTH secr
etion, the baseline circulating dehydroepiandrosterone sulfate levels
were significantly lower in MMD compared with control women (18 +/- 23
vs. 61 +/- 23 mu mol/L; P < 0.002). The serum concentrations of A4 at
baseline, 30 min, and 60 min and DHA levels at 50 and 60 min were als
o significantly lower in MMD vs. control women. Additionally, the A4(A
UC) and DHA(AUC) values were significantly lower in MMD patients than
in controls. Furthermore, the net response of DHA at 60 min to the end
ogenous ACTH increase was also reduced in MMD patients compared with t
hat 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 sti
muli, these data suggest that MMD patients have a defect in the adreno
cortical response to ACTH, reflected in normal F and reduced DHA and A
4 secretion. Whether this defect is inherent to the disease or simply
reflects adaptive changes to chronic disease remains to be demonstrate
d. 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.