The effects of subcutaneous administration of three doses of human growth hormone-releasing factor (hGRF-44 NH2 or hGRF) at doses of 100, 300 and 600 micrograms were studied in six normal young men. GH responses obtained with 100 and 300 micrograms were negligible. In contrast, the 600 micrograms dose gave a profile of response comparable in timing and magnitude to that obtained with i.v. hGRF at maximal effect doses (20, 80, 100 micrograms). Plasma immunoreactive hGRF levels (IR-hGRF) were compared after s.c. and i.v. hGRF. Mean maximal plasma concentrations were comparable with s.c. 600 micrograms and i.v. 20 micrograms. Peaks occurred earlier with i.v. hGRF (5 min as opposed to 15 min): however, return to undetectable values was obtained between 90 and 120 min after s.c. or i.v. injections. These data suggest a great loss of the peptide between the subcutaneous space and blood, without delayed absorption. High variability in plasma IR-hGRF concentrations between the subjects after the same s.c. doses was observed.

Ten normal young men (22-28 yr of age), within 10% of their ideal body weight, were given the four releasing hormones (TRH, 200 micrograms; GnRH, 100 micrograms; ovine corticotropin-releasing hormone, 50 micrograms; GH-releasing hormone, 80 micrograms) iv on separate days and then in combination on the same day. Plasma TSH, PRL, FSH, LH, cortisol, ACTH, and GH were measured by RIA in samples collected from 20 min before to 120 min after injection. There were no significant differences in responses to the separate and combined tests for FSH, LH, cortisol, ACTH, and GH. The plasma TSH (0.001 less than P less than 0.01) and PRL (P less than 0.001) responses were significantly higher after the combined test. The tolerance was identical to that of TRH alone. In eight patients studied after pituitary surgery, combined administration provided results comparable to those obtained after separate administration of TRH, GnRH, and insulin.

hGRF (iv 50 \ g=m\ g) was administered to 6 normal young adult males at 09.00 and 20.00 h on different days. Nocturnal GH secretion was monitored during polygraphic sleep recordings on both control nights and nights following hGRF administration. Sleep-related GH secretion and sleep parameters were not affected by diurnal hGRF administration.The close association in adult man between the occurrence of the initial episode of slow-wave sleep (SWS) and the highest peak of plasma GH concen¬ tration in a 24-h period led to the concept of sleep-related GH secretion (Takahashi et al. 1968; Sassin et al. 1969), submitted to control mecha¬ nisms probably different from those involved in day-time secretion and in pharmacologically indu¬ ced secretion (Mendelson et al. 1979). It has been reported that in man administration of GH subsequently can blunt the secretory re¬ sponse to pharmacological stimulation of GH secretion (Hagen et al. 1972) as well as sleeprelated GH secretion (Mendelson et al. 1983). This negative feedback appears, then, to be exerted at some common point of the pathways involved in the secretory mechanisms. Administration of GH in animals (Stern et al. 1975 ; Drucker-Collin et al. 1975 ; Stern & Morgane 1977) results in some changes in sleep stages with increased REM sleep and decreased SWS. In man, acute administration of GH (5 U) is followed by a decrease in SWS and an increment in REM sleep (Mendelson et al. 1980; Mendelson 1982), whereas iterative administration has no significant effect on sleep (Mendelson et al. 1983).Synthetic human growth hormone-releasing fac¬ tor (hGRF) powerfully stimulates GH release in normal young adult men (Thorner et al. 1983;Rosenthal et al. 1983;Gelato et al. 1984;Sassolas et al. 1984). This study was undertaken in order to determine whether a GH-rise, induced during day¬ time by hGRF administration, would exert an effect on the sleep-related GH secretion and on sleep stages. Materials and MethodsSix normal young men (22-26 years of age) taking no medication, within 10% of their ideal body weights, were enrolled for this study. They had given written informed consent. Protocol had been approved by our institutional Ethics Committee.The subjects were admitted to the Centre de Médecine Nucléaire (Lyon) for two trial periods at intervals of 1 week. The first period included a first control night

The dose-effect relationship of an i.v. bolus of synthetic h-GRF-44 on growth-hormone and prolactin secretion has been studied. Seven healthy adult volunteers received in a random order h-GRF-44 2.5, 5, 10, 20, 40 and 80 micrograms and a placebo. Plasma growth hormone (GH) was determined between 30 min before and 240 min after injection, the area under the curve (AUC) and the peak GH level being used to assess the response. For both parameters a dose-effect relationship was observed. Doses as low as 2.5 micrograms were capable of eliciting a rise in GH plasma levels in few patients. Above 40 micrograms the dose-effect curves tended to plateau, although the decrease in the slope of the dose-effect curve at the peak was more marked. Intersubject variability was large, so precise determination of the minimal effective dose as well as the lowest dose giving a maximal effect was not possible. The available evidence suggests that the i.v. dose of synthetic h-GRF-44 (SR 95228) which is likely to promote GH release into the blood stream in most healthy adults is within the range 40-100 micrograms. In these healthy adults unwanted effects were infrequent with these low doses. Unlike previous experience with higher doses of another synthetic h-GRF-44, prolactin secretion in this study was not affected.

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