Androgen Response to Hypothalamic-Pituitary-Adrenal Stimulation with Naloxone in Women with Myotonic Muscular Dystrophy

Abstract

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 g/kg, iv), blood sampling was performed at baseline (i.e. Ϫ5 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 ACTH AUC values were significantly higher in MMD than in control women (457 Ϯ 346 vs. 157 Ϯ 123 pmol/min⅐L; P Ͻ 0.03), whereas the F AUC response did not differ between MMD and controls (13860 Ϯ 3473 vs. 13375 Ϯ 3465 nmol/min⅐L; P Ͼ 0.5). Despite the greater ACTH secretion, the baseline circulating dehydroepiandrosterone sulfate levels were significantly lower in MMD compared with control women (18 Ϯ 23 vs. 61 Ϯ 23 mol/L; P Ͻ 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 A4 AUC and DHA AUC 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 Ϯ 2.1 vs. 5.6 Ϯ 2.6 nmol/L; P Ͻ 0.02).In conclusion, in addition to ACTH hypersecretion to CRH-mediated stimuli, these data suggest that MMD patients have a defect in the adrenocort...

Myotonic dystrophy type 1 with diabetes mellitus, mixed hypogonadism and adrenal insufficiency

“…Abnormal diurnal rhythm of ACTH and cortisol in DM1 have been shown in several reports ( 5 ). DM1 patients reportedly demonstrate ACTH hypersecretion after exogenous CRH stimulation and endogenous CRH release stimulated by naloxone or fenfluramine administration ( 9 ). Accordingly, ACTH hypersecretion is attributed to the CRH stimuli.…”

“…Our case also exhibited abnormal diurnal rhythm of ACTH and exaggerated ACTH secretion after CRH stimulation, indicating dysregulation of ACTH secretion, especially via CRH stimuli. Adrenal responsiveness in reported DM1 patients, on the other hand, has yielded conflicting results ( 5 , 9 ).…”

Glucocorticoid hypofunction in myotonic dystrophy

“…Se trata de un receptor de superficie que presenta 7 dominios transmembrana y está ligado a la proteína Gs, activando a la adenilato ciclasa que da lugar al aumento del segundo mensajero cAMP, cuyo efector final es una proteín-kinasa A. El defecto subyacente en el gen que codifica la DMPK dependiente de AMPc podría ser la causa de la hiporespuesta adrenal ya que largas expansiones de CTG han sido encontradas en las suprarrenales 22 . Esta hipótesis ha sido también sugerida por otros autores [23][24][25] . Otra posible explicación sería una alteración del RNA del receptor de ACTH a nivel de corteza suprarrenal ya que parece existir una alteración general del RNA nuclear en la DM1.…”