High prevalence of prolonged QT interval duration in male patients with Cushing's disease.

UNLABELLED: Hypogonadal males have recently been shown to present prolonged QT interval, an electrocardiographic measure indicative of risk for fatal cardiac arrhythmias. Excess cortisol secretion induces low testosterone levels in male patients with Cushing's disease but no study has yet evaluated if this is accompanied by changes in QT interval duration. We therefore decided to evaluate whether male patients with Cushing's disease present changes in QT interval duration. QT interval was measured in electrocardiographic readings from 19 men and 35 women with Cushing's disease and age- and sex-matched controls were used for comparison. QT interval was corrected for heart rate according to Bazett's formula (QTc) and QTc >440 msec and >460 msec were taken as indicative of increased risk for torsade de pointes in men and women, respectively. Mean QTc was significantly longer in male patients compared with healthy controls (426.9±9.27 vs. 389.7±8.31, p<0.05) and 5 men with Cushing's disease presented prolonged QTc (prevalence 26%). By comparison, none of the women with Cushing's disease presented prolonged QTc. Hypokalemia and low testosterone appeared associated with long QTc. CONCLUSIONS: Male patients with Cushing's disease present prolongation of QT interval which may lead to measurements associated with high risk for ventricular arrhythmias. Both low testosterone levels and hypokalemia appear to contribute to long QT in men with Cushing's disease.

Increased prevalence of prolonged QT interval in males with primary or secondary hypogonadism: a pilot study.

Symptoms and signs of male hypogonadism span all organ systems, including the cardiovascular apparatus. The electrocardiographic QT interval reflects cardiac ventricular repolarization and, if prolonged, increases the risk of malignant arrhythmias. QT interval duration is similar in boys and girls during childhood, but shortens in males after puberty and experimental studies suggest that testosterone is a major contributor to shortening of QT interval in men. The aim of the present pilot study was to assess the duration of ventricular repolarization in adult males with primary or secondary hypogonadism. Standard ECG recordings were performed in 26 men (mean age 39.2 +/- 2.17 years) with pituitary or testicular hypogonadism and repeated in 15 patients during testosterone replacement. Twenty-six age-matched control men were also analysed. Measured QT intervals were corrected for heart rate according to Bazzett's formula (QTc = QT/radical RR interval). The prevalence of prolonged QTc was considerably higher in hypogonadal patients (four of 26 men) than in control men (none, p < 0.05) and in the general, healthy population (<2.5%). QTc interval normalized on hormone replacement therapy in the four patients presenting prolonged QTc in the hypogonadal state. Heart rate and left ventricular mass did not differ among the two groups and no known QT-prolonging factor was apparent in patients with abnormal QTc interval. In conclusion, a high number prolonged QT interval measurements was observed in hypogonadal men who may therefore be at increased risk for cardiac arrhythmias. This observation reveals an additional feature of male hypogonadism, which may benefit from testosterone replacement therapy.

Circadian blood pressure profile in patients with active Cushing's disease and after long-term cure.

Hypertension is a major feature of Cushing's disease, with the attendant increase in the rate of cardiovascular events. The circadian blood pressure profile also impacts cardiovascular risk and a few studies have shown that patients with Cushing's syndrome do not present the expected nocturnal blood pressure decrease and, further, that this alteration persists in short-range disease remission. These studies were performed by conventional discontinuous ambulatory pressure monitoring, a technique not devoid of limitations. Aim of our study was the assessment of blood pressure and heart rate profile by beat-to-beat noninvasive monitoring in twelve patients with active Cushing's disease (9 women and 3 men, age 33.3+/-2.36 years) and the assessment of its possible changes at short- (<1 year) and long-term (2-3 years) follow-up after curative surgery. No nocturnal blood pressure dipping (i.e., decrease by 10% of daytime values) was observed in 50% of patients both during active hypercortisolism and within 1 year from surgery. Recovery of blood pressure dipping profile was detected at long-term follow-up in a minority of patients. Daytime heart rate was higher in patients with active Cushing's disease and decreased over time after cure. In conclusion, patients with Cushing's disease present absent nocturnal blood pressure dipping and abnormal heart rate values which do not resolve after short-term remission of hypercortisolism and show only partial improvement in the long run. These findings identify additional cardiovascular risk factors for patients cured of Cushing's disease.

Salivary cortisol measurement in normal-weight, obese and anorexic women: comparison with plasma cortisol.

OBJECTIVE: To compare salivary, plasma and urinary free cortisol (UFC) measurements in patients with anorexia nervosa, in whom an overdrive of the hypothalamic-pituitary-adrenal (HPA) axis is well established but information on salivary cortisol is lacking, in viscerally obese patients in whom subtle abnormalities of cortisol secretion and metabolism are postulated, and in normal-weight healthy women. PARTICIPANTS AND EXPERIMENTAL DESIGN: Measurement of salivary cortisol offers a convenient way to assess the concentrations of free, biologically active cortisol in plasma in different physiopathological settings. Forty-seven drug-free, newly diagnosed women with active restrictive anorexia nervosa, 30 restrictive anorexic women undergoing chronic psychopharmacological treatment, 47 women with mild-to-moderate visceral obesity, 103 women with severe central obesity and 63 normal-weight healthy women entered the study. Salivary and blood samples were collected at 0800 h, 1700 h and 2400 h, together with three consecutive 24-h urine specimens for UFC determination. In controls and patients with anorexia nervosa (n=83), salivary and plasma cortisol were also measured after a 1-mg overnight dexamethasone suppression test (DST). In patients with anorexia nervosa, mood was rated by the Hamilton scale for anxiety and depression. RESULTS: Untreated patients with anorexia nervosa showed increased plasma and salivary cortisol and UFC concentrations (all P<0.001 compared with controls), and decreased cortisol suppression after DST in plasma and saliva (P<0.0001 and P<0.005 respectively compared with controls). These alterations were less pronounced, although still statistically significant, in treated patients with anorexia nervosa. Salivary cortisol was highly correlated with paired plasma cortisol in the whole population and after splitting the participants by group (P<0.0001). However, for plasma cortisol values greater than 500 nmol/l (the corticosteroid-binding globulin saturation point), this parallelism was lost. Taking plasma cortisol as a reference, the level of agreement for post-dexamethasone salivary and plasma cortisol was 58.9% among suppressors and 77.8% among non-suppressors (chi2 test: P<0.01). Decreased 0800 h/2400 h cortisol ratios were observed in plasma and saliva in drug-free patients with anorexia nervosa (P<0.005 and P<0.05 respectively compared with controls), and in saliva in severely obese patients (P<0.05 compared with controls). Depression and anxiety scores were unrelated to cortisol concentrations in any compartment. CONCLUSIONS: Salivary cortisol measurement is a valuable and convenient alternative to plasma cortisol measurement. It enables demonstration of the overdrive of the HPA axis in anorexia nervosa and subtle perturbations of the cortisol diurnal rhythm in women with visceral obesity. With the establishment of more specific and widely acceptable cut-off values for dynamic testing, measurement of salivary cortisol could largely replace plasma cortisol measurement.

No difference between micro- and macroprolactinomas in the prolactin responsiveness to metoclopramide and dopamine administration.

Differences between micro- and macroprolactinomas, as regards the prolactin secretory pattern in response to pharmacological challenges, have been reported in in vivo and in vitro models, and interpreted as being due to different dopaminergic regulation of prolactin release. In 32 patients with prolactin-secreting tumors, 19 with microprolactinomas and 13 with macroprolactinomas, and ten healthy volunteers, we evaluated the prolactin secretion in response to pharmacological manipulations of central dopaminergic tone. To this end, three tests were performed, in random order: (1) 4-h saline infusion; (2) 10 mg metoclopramide as i.v. bolus; (3) 4-h dopamine infusion (0.01 microgram/kg/min) with a 10-mg metoclopramide bolus given after the second hour of infusion. Dopamine infusion, compared to saline, caused a significant prolactin decrease in all the three groups of subjects, without significant difference between micro- and macroprolactinoma patients. In prolactinoma patients, administration of metoclopramide induced a significant rise in plasma prolactin which, however, was significantly lower than the one displayed by controls. Again, no difference was observed between the two groups of hyperprolactinemic patients. Dopamine infusion induced a significant and comparable increase in the prolactin response to metoclopramide in micro- and macroprolactinoma patients, while it was ineffective in control subjects. In conclusion, no differences appear to exist between micro- and macroprolactinoma patients as regards the prolactin secretory pattern during pharmacological modifications of the dopaminergic tone. A central dopaminergic defect and an increased prolactin turnover with attendant reduction of the intracellular hormone pool may both be involved in the reduced prolactin release following provocative stimuli in patients with prolactinoma.

Chronic treatment with parlodel LAR of patients with prolactin-secreting tumours. Different responsiveness of micro- and macroprolactinomas.

UNLABELLED: Forty-one patients with prolactinoma (25 micro-, 16 macroprolactinomas) were treated with a long-acting injectable preparation of bromocriptine (Parlodel LAR, Sandoz), 25-100 mg (mostly 50 mg) in every 4-8 weeks for as long as 43 months (median 19 months). The first injection caused a prompt fall of plasma PRL which reached its nadir value after 3 days. Thereafter, hormone levels remained well below initial values for 4 weeks or longer, though with the tendency, more pronounced in microprolactinoma patients, to rise again toward baseline. The prevalence of PRL normalization was greater in the macro- than in the microprolactinoma group. By repeated injections plasma PRL could be kept close to or within the normal limits in most of the patients. However, the extent of PRL inhibition was significantly greater in macro- than in microprolactinoma patients (p less than 0.01). Clinical improvement occurred in the majority of the patients, shrinkage of the tumour in 50% of them. Adverse reactions were generally mild or of moderate severity and subsided spontaneously in 24 h. They were less frequent (NS) and less severe (p less than 0.05) in macro- than in microprolactinoma patients. IN CONCLUSION: a. injectable bromocriptine (Parlodel LAR) is a highly effective preparation particularly suitable for the long-term treatment of tumourous hyperprolactinemia; b. patients with macroprolactinoma exhibit, compared with microprolactinoma patients, better responsiveness and better tolerability to injectable bromocriptine.

Comparison between a slow-release oral preparation of bromocriptine and regular bromocriptine in patients with hyperprolactinemia: a double blind, double dummy study.

The efficacy and tolerability of a slow-release preparation of bromocriptine (Parlodel SRO) were compared to those of conventional bromocriptine (Parlodel R) in a double blind, double dummy study of 12 hyperprolactinemic women (plasma PRL 81.3 +/- 4.73, ng/ml mean +/- SEM). For 2 weeks, the patients received 2.5 mg b.i.d. Parlodel R or 5 mg once daily Parlodel SRO; for the following 2 weeks, the dose of the drugs was doubled. The patients were then treated, in an open study, with 2.5-10 mg daily Parlodel SRO for 6 months. Both preparations caused a prompt and sharp PRL fall. Hormone levels remained inhibited over the whole month of observation with both preparations. Daily PRL profiles were very close with either drug although morning PRl levels were slightly higher during Parlodel SRO than during Parlodel R administration. Doubling the doses of the two drugs did not result in further significant lowering of PRL values. During the 6-month study with Parlodel SRO, plasma PRL further decreased and normalized in 11 of 12 patients. Clinical improvement occurred in the majority of cases. Tolerability of Parlodel SRO appeared to be better, though without statistically significant differences, than that of Parlodel R. Side effects were less important with the former compound in their number, severity and duration. In conclusion, thanks to its favourable pharmacological profile, Parlodel SRO appears to be a valuable alternative to regular bromocriptine in the management of hyperprolactinemia.