Adrenocorticotropin hyperresponse to the corticotropin-releasing hormone-mediated stimulus of naloxone in patients with myotonic dystrophy.

Abstract

We previously showed that CRH-mediated stimuli, including exogenous CRH, 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, first degree relatives, and normal controls received i.v. naloxone at 1400 h, and blood was taken for ACTH (RIA) and cortisol (high pressure liquid chromatography) measurements from 15 min before to 120 min after naloxone treatment. DM patients had basal ACTH levels approximately twice 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 groups, probably due to attenuation at high levels of adrenocortical stimulation, although some patients with inappropriately low cortisol responses 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 patients, who were tested more than once, had reproducible responses relative to those of the normal subjects. We conclude that ACTH hypersecretion 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 result of abnormal levels of a cAMP-dependent kinase, DMPK, the product of the gene undergoing mutation in DM.

Abnormal release of incretins and cortisol after oral glucose in subjects with insulin-resistant myotonic dystrophy

“…This was associated with a concomitant increase in ACTH levels in patients with long CTG repeat expansions, suggesting that alterations in ACTH reactivity and flattened diurnal rhythmicity of cortisol, as demonstrated in earlier studies (21,22), may be partly food dependent. Glucocorticoids have numerous effects on intermediary metabolism, including altered lipid metabolism, stimulation of gluconeogenesis, and inhibition of peripheral glucose utilization, and may thus contribute to insulin resistance.…”

“…However, the responses of the incretin hormones during an oral glucose tolerance test in DM1 are not known. We and others have also reported abnormal regulation of the cortisol axis in DM1 including elevated trough levels (21,22). Interestingly, increased adrenal cortex sensitivity to GIP has been demonstrated to cause food-dependent Cushing's syndrome (23), providing a potential linking mechanism between the incretin and glucocorticoid pathways to insulin resistance.…”

Glucocorticoid hypofunction in myotonic dystrophy

“…Este patrón sugiere una menor sensibilidad de la corteza suprarrenal al estímulo con ACTH que no se pone de manifiesto en respuesta al intenso estímu-lo agudo con 250 µg de ACTH ev, aunque sí se evidencia en condiciones basales y tras un estímulo más sutil como es la CRH. Jackson y col 10 al practicar el test de estí-mulo con CRH ovina, obtuvieron también valores elevados de ACTH que no conllevaban aumento en la respuesta de cortisol y Grice y col 11 hallaron idénticos resultados con la naloxona que actúa vía CRH. En nuestra opinión, y puesto que la CRH no actúa directamente sobre las suprarrenales, la menor respuesta de cortisol se debería a una menor eficacia de la ACTH tras interactuar con su receptor a nivel de corteza suprarrenal.…”

“…En los estudios de estimulación con ACTH exóge-na, la respuesta de cortisol varía entre normalidad en todos los pacientes 8 , hiporespuesta en algún caso, sin alteración clínica 6 e hiperrespuesta en presencia de largas expansiones de CTG 5 . No se han apreciado alteraciones en la respuesta del cortisol plasmático a la hipoglucemia insulínica 8 , a la metirapona 9 , a la CRH (estímulo directo 10 o indirecto 11 ) ni a la supresión con dexametasona 3 . Similar variabilidad ha ofrecido la respuesta de ACTH a las pruebas de estímulo, con resultados normales 11 o aumentados a la hipoglucemia insulíni-ca 12 , normales pero retrasados a la AVP exógena 13 y elevados a la CRH ya fuera administrada directamente 10 o estimulada indirectamente con naloxona 11 o fenfluramina 15 .…”

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

“…a defective cAMP-dependent kinase) in the anterior pituitary corticotroph or its receptor. Nonetheless, the F response to these stimuli generally remains normal (20), as does the 24-h urinary F level (20). Additionally, others have observed, in a mixed gender group of MMD patients, lower circulating concentrations of the AAs dehydroepiandrosterone (DHA) and dehydroepiandrosterone sulfate (DHS) at baseline and after the exogenous administration of ACTH (21).…”