[The endocrinology department]. / Le Service d'Endocrinologie.

The clinical activities of the department of endocrinology encompass the care and treatment of diabetes, thyroid diseases, hypothalamo-pituitary, adrenal, gonadic and parathyroid diseases, obesity, hypercholesterolemia and paraneoplastic endocrine syndromes. These domains are briefly described. The research activities of the department have investigated the regulation of thyroid metabolism in vitro, the intrathyroid H2O2 generating system, the physiopathology of toxic thyroid nodules and the effects of ageing on the thyreotropic function of the normal ageing male. Studies of "jet lag" conditions have shed a new light on hormonal chronophysiology. Other investigations have considered the regulation of ketone body metabolism, the relationship between nutritional status and glucose metabolism, and some aspects of immunodiabetology.

[The Erasme Foundation]. / La Fondation Erasme.

Created in 1982 to encourage the scientific research in the Erasme Hospital, the Erasme Foundation has founded 174 research grants, has financially supported the building of the Cellular and Molecular Therapy Unit, and has organized more than 60 lectures in various biomedical fields.

Sporadic case of trichorhinophalangeal syndrome type III in a European patient.

Trichorhinophalangeal syndrome type III (TRP III) shares common traits with TRP I and II, including sparse hair, a "pear-shaped" nose, osteodysplasia with cone-shaped epiphyses, and autosomal dominant inheritance, but is distinguished by the presence of severe brachydactyly. TRP III was first described in 1984 in Japanese patients, one sporadic case [Sugio and Kajii, 1984: Am. J. Med. Genet. 19:741-753,1984] and two families [Niikawa and Kamei, 1986: Am. J. Med. Genet. 24:759-760; Nagaï et al., 1994: Am. J. Med. Genet. 49:278-280], and more recently in a Turkish family [Itin et al., 1996: Dermatology 193:349-352]. We report an additional observation in a patient of European descent, who presented with short stature, cone-shaped epiphyses, sparse hair, a pear-shaped nose, normal intelligence and severe brachydactyly. Neither parent had manifestations of TRP and there was no other reported case in the family, indicating a presumably fresh mutation. Our observation refines the clinical spectrum of TRP III in another ethnic background and may be of help in identifying the gene or genes for TRP syndromes.

Residual effects of a short-term intensified insulin therapy in type 2 diabetic patients with oral drug failure.

The present study was designed to evaluate the long-term effects of a short course of insulin therapy on glycaemic control in type 2 diabetic patients after failure with oral therapy. Twenty type 2 diabetic patients poorly controlled with maximal doses of sulfonylurea were given intensified insulin treatment for 12-14 days adjusted so as to achieve near normoglycaemia. They were then restarted on their previous oral medication to which one bedtime injection of NPH insulin was added if the mean diurnal glucose profile exceeded 10 mM (n = 8). At the follow up evaluation (n = 18), 6 +/- 1 months later, fasting glucose (12.3 +/- 1.1 to 8.3 +/- 0.6 mM) and HbA1c (10.2 +/- 0.5 to 8.5 +/- 0.5%) levels were significantly improved in the patients receiving a combined therapy. In the group maintained on sulfonylurea alone, fasting glucose (13.2 +/- 0.7 to 6.9 +/- 0.7 mM) and HbA1c (9.6 +/- 0.6 to 6.9 +/- 0.6%) were also significantly improved in 5 patients who had lost weight (-6 +/- 1 kg) whereas none of these parameters were significantly different from the preinsulin value in the 6 patients whose weight remained unchanged. In conclusion, the current results do not provide any evidence that short-term insulin therapy is able to reinduce the efficacy of a previously ineffective sulfonylurea treatment, on a long term basis.

Nocturnal decrease in glucose tolerance during constant glucose infusion.

Studies comparing glucose tolerance in the morning vs. that in the evening have suggested that time of day may influence glucose regulation. To examine the variation in glucose tolerance throughout the 24-h span, normal subjects were given an iv glucose infusion at a constant rate of either 5 or 8 g/kg.24 h during 30 h, and plasma levels of insulin and glucose were measured at 15-min intervals for the last 24 h of the infusion. The timing of initiation of the infusion was varied to differentiate effects of time of day from effects of duration of the infusion. A nocturnal elevation of glucose levels, culminating around midsleep and corresponding to an increase of about 15% above daytime levels, was observed in all subjects. The timing of this nocturnal maximum was not dependent on the rate of the infusion or on the time elapsed since the beginning of the infusion. Insulin levels did not show a consistent diurnal pattern. Both insulin and glucose exhibited large ultradian oscillations recurring at 100- to 150-min intervals. The amplitude of these oscillations increased with the rate of glucose infusion. These ultradian oscillations of glucose and insulin levels were temporally correlated, with a tendency for glucose pulses to lead insulin pulses by 15-30 min. These results demonstrate in normal subjects the existence of a diurnal variation in glucose tolerance distinct from the dawn phenomenon observed in diabetic subjects and indicate that spontaneous 100- to 150-min oscillations in peripheral glucose and insulin levels characterize stimulated pancreatic function, with the amplitude of the oscillations being dependent on the size of the stimulus.

Prenatal screening for gestational diabetes throughout office hours.

A group of 1666 consecutive pregnant women attending our prenatal clinic was screened for gestational diabetes (GD). Patients with risk factors (155) underwent a classical 50 g OGTT, while 1511 patients without risk factors for GD were submitted at random throughout the day to a simplified OGTT, consisting of a single blood glucose determination 1 h after the glucose ingestion. In these patients, plasma glucose 1 h after the glucose load averaged 104 +/- 1 mg/dl and exceeded 135 mg/dl in 315 patients. In the latter group, retested with a standard 50 g OGTT, 48 out of 1511 patients (3.2%) finally met the criteria for GD, while 25 patients had an abnormal OGTT in the group with risk factors. The blood glucose levels after simplified 50 g glucose load were significantly higher in the third (vs. first) trimester of pregnancy (113 +/- 1 vs. 96 +/- 1 mg/dl, p less than 0.001). A significant increase in mean glucose concentrations was also observed for those patients tested after 11 a.m. (107 +/- 1 mg/dl vs. 99 +/- 1 mg/dl prior to 11 a.m. p less than 0.001) and for the women with an ideal body weight (IBW) greater than or equal to 150% at the beginning of pregnancy (124 +/- 7 mg/dl vs. 104 +/- 1 mg/dl for less than 150% IBW, p less than 0.001). These variations in glucose tolerance, related to the time of the day, the gestational age and the body weight, are of limited amplitude and should not be considered in the determination of the cut-off point of the screening test. Glucose loading at random throughout the day is a simple and useful tool for the routine detection of unsuspected GD in pregnant patients attending prenatal clinics.

Control of circadian and episodic variations of adrenal androgens secretion in man.

The 24-h profiles of plasma cortisol (F), 11-beta-hydroxyandrostenedione (11OHAD), androstenedione (AD), dehydroisoandrosterone (DHEA) and testosterone (T) were obtained simultaneously in 11 normal males sampled at 15-min intervals. The data were submitted to a detailed quantitative analysis including the estimation of the circadian rhythm and of the episodic variations as well as the evaluation of the concomitance of episodic pulses of different hormones. A bimodal circadian rhythm was detected in the various individual profiles. The major acrophase occurred in the morning earlier for T (around 04:00 h) than for the hormones of totally or partially adrenal origin (around 07:00 h); the secondary acrophase (around 17:00 h) and the main midnight nadir were common to all hormones. The amplitude of the rhythm was highest for purely adrenal hormones (F and 11OHAD), averaging 79 and 75%, respectively, lower for hormones of mixed origin (DHEA and AD), averaging 44 and 42%, respectively, and minimal for T (22%). The possible relationship between the circadian and pulsatile variations of the various steroids was estimated in each individual by calculating Pearson's standard coefficient of variation on all pairs of hormonal profiles. A very tight relationship (r greater than 0.75; p less than 0.001) was found between the 4 adrenal hormones in each individual; a looser but significant correlation (r greater than 0.30; p less than 0.001) was also detected between T and its partial precursors (AD and DHEA) and between T and the purely adrenal hormones: F and 11OHAD (r greater than 0.30; p less than 0.01). The pulsatility of the corticotrophic axis was readily transmitted to the secretory pattern of 11OHAD, DHEA and AD. Ninety-six percent of the F pulses were reflected in at least one other hormonal profile. Finally, we showed that concomitant pulses common to the five adrenal and gonadal patterns were more frequent than would be expected on the basis of chance. These results: demonstrate a total parallelism between the long-lasting secretory events and the episodic bursts of the 4 adrenal hormones showing that the reticular and fascicular zones of the adrenal respond to pituitary control as an homogeneous structure; demonstrate the existence of a partial synchronization of adrenal and testicular pulsatile variations; suggest that, throughout the afternoon, a common mechanism may influence the slow variations of adrenal hormones and of testicular testosterone.

Prolonged pulsatile administration of ovine corticotropin-releasing hormone in normal man.

The 24-h profiles of plasma ACTH and cortisol were determined at 15-min intervals in five normal men basally and during iv bolus injections of 25 micrograms ovine corticotropin-releasing hormone (oCRH) every 4 h for 72 h. Each oCRH injection was followed by a distinct elevation of plasma ACTH and cortisol levels, with a return to basal values before the next injection. The characteristics of the ACTH and cortisol pulses induced by 25 micrograms oCRH (i.e. 0.3-0.4 micrograms/kg) were similar to those observed in other studies with 1 microgram/kg human CRH. There was no significant blunting of oCRH-induced hormonal increments in the course of the 72-h study. On each oCRH injection day, the mean 24-h cortisol level was higher than that in the basal study, but there was no increase in the mean 24-h ACTH level. During the 72-h oCRH study, the preinjection ACTH and cortisol levels exhibited a diurnal variation, indicating persistence of the circadian periodicity of pituitary-adrenal activity. There was a diurnal variation of oCRH-induced ACTH increments, with highest responses at 0700 h. A small but not significant reverse trend was apparent for cortisol increments. Spontaneous pulses of ACTH and cortisol occurred throughout the 3 days of oCRH injections, and the total number of spontaneous and oCRH-induced pulses was similar to the number of spontaneous pulses observed in the basal study. All oCRH-induced and more than 90% of spontaneous cortisol pulses occurred concomitantly with an ACTH pulse. The variability of pulse increments was greater for ACTH than for cortisol. In conclusion, prolonged pulsatile administration of oCRH did not induce pituitary desensitization and did not suppress the endogenous circadian and pulsatile ACTH and cortisol variations.

Immediate and delayed alterations of adrenocorticotropin and cortisol nyctohemeral profiles after corticotropin-releasing factor in normal man.

Intravenous injections of 50 micrograms corticotropin-releasing factor (CRF) to four normal men at 0900 and 2300 h were followed by significant plasma ACTH and cortisol elevations, without changes in GH and PRL concentrations. The responses were more easily assessed late in the evening than in the morning, when they were superimposed upon the spontaneous hormonal variations. The initial hormonal response was always followed by a period of decreased hormonal values compared to control patterns. The normal pituitary-adrenal response to CRF was blunted or abolished by prior administration of dexamethasone. These data suggest that exogenous administration or CRF-induced endogenous production of glucocorticoids modulates the sensitivity of corticotropic cells to the action of CRF. Since normal ACTH and cortisol secretory episodes are likely to obscure the effects of CRF, stimulation tests for clinical purposes should be performed during the quiescent period, i.e. late in the evening.

Effects of "jet lag" on hormonal patterns. IV. Time shifts increase growth hormone release.

Twenty-four-hour GH profiles were obtained in five normal male volunteers before travel, 1, 11, and 21 days after the Brussels-Chicago flight (time shift, 7 h); and 1, 11, and 21 days after the return flight. The westward and eastward travels involved, respectively, periods of 23 and 33 h of sleep deprivation. One year later, two of the five volunteers were submitted, in the laboratory, to an investigation mimicking the conditions of sleep deprivation undergone in the course of the eastward travel and involving two 24-h periods of blood sampling. Blood samples were drawn every 15 min, and sleep was polygraphically monitored. The amounts of GH secreted were quantified, and their relationship with the different sleep stages was analyzed. Time shifts, whether caused by "jet lag" or by sleep deprivation in the laboratory, had two effects on GH secretory patterns. First, a marked increase in GH release, due to an augmentation of the magnitude, rather than the number, of secretory spikes was observed, independently of sleep disturbances. Return to basal levels was slower after westward than after eastward travel and took at least 11 days. Second, 1 day after the eastward transportation as well as immediately after 33 h of sleep deprivation, the major GH spike, which occurred in early sleep in the other studies, was shifted to late sleep. In these investigations, the only consistent alteration of sleep was a reduction in the amount of rapid eye movement (REM) stage. The occurrence of GH spikes in sleep was significantly associated with slow wave (SW) stage. However, total amounts of GH secreted during sleep were negatively correlated with the total duration of REM stages rather than positively correlated with the total duration of SW stages. A spike by spike analysis showed that the amount of GH secreted correlates best with the ratio (SW - REM) to (SW + REM), which relates the amount of REM preceding the spike to the amount of SW during the spike and thus constitutes an indicator of the status of the REM-non-REM oscillation.

The relationship between episodic variations of plasma prolactin and REM-non-REM cyclicity is an artifact.

The concept of concomitance between nadirs and peaks of plasma levels of PRL and, respectively, rapid eye movement (REM) and non-REM stages in sleep was reevaluated using 24 nighttime profiles of plasma PRL collected at 15-min intervals and the corresponding polygraphic recordings of sleep. The subjects were 5 healthy young male adults. Data were examined using the methodology described in the original report, consisting of averaging across individual nights PRL levels during REM and non-REM sleep stages as well as using a detailed spike by spike analysis of each individual pair of hormonal and sleep profiles. We showed that in our subjects, there was no relation, other than a purely random one, between episodic PRL fluctuations in plasma and REM-non-REM cycles.

Prolactin secretion in Cushing's disease.

PRL secretion was evaluated in 11 patients with Cushing's disease (7 women, 4 men). Basal morning levels were elevated when compared to normal subjects. PRL reactivity to TRH and hypoglycemia was normal in most patients. The 24-h mean PRL levels were elevated, with partial or total alteration of the nyctohemeral rhythm. Cure of Cushing's disease by selective pituitary adenomectomy restored a normal PRL secretion.