The plasma immunoreactive adrenocorticotropin and cortisol responses to oral fenfluramine hydrochloride (1.5 mglkg body wt) or placebo were examined in 11 patients with myotonic dystrophy, 4 controls with facioscapulohumeral dystrophy, a similarly debilitating muscle wasting disease, and 14 normal controls in single-blind studies performed in mid-afternoon.Mean areas under t h e adrenocorticotropin response versus time curve were significantly greater in myotonics (2573+429 pmol.min/L) than in facioscapulohumeral dystrophy controls (6961279 pmof.min/L, P < 0.02) and normals (560f 61 pmol.min/L, P < 0.0001). Corresponding cortisol responses were significantly greater in myotonics (35757 3949 nmol.min/L) than in normals (21828f 1669 nmol.min/L, P <0.001), but not significantly greater than those in facioscapulohumeral dystrophy controls (22830k6140 nmol.min/L, P = 0.055). No stressful side-effects which could affect hormone responses, and no significant changes in blood pressure or heart rate were noted. Fenfluramine activates central serotonergic and/or noradrenergic pathways initiating secretion of corticotropin-releasing hormone and possibly arginine vasopressin. W e postulate that these fenfluramine-activated pathways a r e hyperstimulated in myotonics, leading to adrenocorticotropin and cortisol hypersecretion. This may be a manifestation of a general cell membrane defect in myotonic dystrophy. W e found a lack of correlation of a g e (and severity of disease) with adrenocorticotropin response in myotonics, and therefore, the hyperresponse may serve as a useful marker for the disease before development of other overt signs.Myotonic dystrophy (MD) is a disorder of autosomal dominant inheritance, with the genetic locus on the long arm of chromosome 19 ( I ) . I t is thc most variable in clinical presentation of the muscular dystrophies, and no primary defect or generalized abnormality has yet been identified. In preliminary studies (2) we reported hypersecretion of adrenocorticotropin (ACTH) and 8-endorphin by myotonics compared to normal controls in response to exogenous ovine corticotropin-releasing hormone (CRH) and insulin-induced hypoglycaemia. Since C R H acts directly at the corticotrope ( 3 ) , and insulin-induced hypoglycaemia causes C R H release in man (4) and increased C R H mRNA levels in rats (5), we concluded that the ACTH hypersecretion in M D is due to a defect which is elicited by CRH-corticotrope interaction.To study the hypothalamic-pituitary-adrenal axis in M D further, we examined pituitary-adrenal responses to the ACTH secretagogue, fenfluramine (fen). Fen stimulates the hypothalamic-pituitary-adrenal axis (6-8) by an incompletely understood mechanism, generally considered to be mediated by serotonin (5-HT) (9), either by a hypothalamic action to release C R H (lo), or a direct effect, regarded as less important, of 5-HT on the anterior pituitary (1 1, 12). Another interpretation suggests that the ACTH-stimulating actions of fen, while ultimately effected by C R H and/or other sec...

1. Adrenaline causes ACTH release from cultured rat pituitary corticotrophs (Vale et al. 1983) and there is evidence that it causes ACTH release in rats in vivo (Plotsky et al. 1985). 2. The present study examined the effects of intravenous adrenaline infusion with and without simultaneous administration of the known ACTH secretagogue, arginine vasopressin, in normotensive and mild essential hypertensive men on their plasma ACTH and cortisol levels. 3. Low dose adrenaline infusion (0.013 microgram/kg per min) does not cause ACTH or cortisol release, but appears to blunt the ACTH and cortisol rise caused by arginine vasopressin (0.14 pressor units/kg, i.m.).

We administered intramuscular arginine vasopressin (AVP) to ten normal controls and eight myotonic dystrophy patients. By measuring plasma AVP levels in five of the myotonics and all the normals, we showed that absorption and distribution of AVP was not delayed or significantly reduced in myotonics. The magnitude of the mean plasma adrenocorticotropin (ACTH) response to AVP in the myotonics was not different from that of normals, although it was significantly delayed (mean peak time, 37.5+/-4.9 versus 17.0 +/- 3.2 min). We propose that this delay was caused by a significantly reduced ACTH secretion rate in myotonics, because the maximum rate of detection of ACTH in plasma is reduced in myotonics (0.6 +/- 0.2 versus 1.7 +/- 0.5 pmol/L/min), whose corticotropes, while having the same capacity to respond to the AVP stimulus, are slower to attain that capacity. The mean integrated cortisol response (AUC) was significantly smaller for myotonics (8072 +/- 2017 versus 13049+/-1630 nmol.min/L). This may be due to the slower rate of ACTH delivery to the adrenal in myotonics. The timing of the adrenal response does not appear to be impaired in myotonic dystrophy, with the cortisol peak following the ACTH peak by approximately 15 min in both groups. The normal magnitude ACTH response to AVP in myotonics is in contrast to that seen to ACTH secretagogues acting via corticotropin- releasing hormone-initiated pathways, where a rapid hypersecretion is seen. We propose a mechanism of defective calcium transport to account for these observations.