A total of 82 patients (74 girls, 8 boys) are presently participating in an international multicentre trial for treatment of central precocious puberty (CPP) with a slow release gonadotropin-releasing hormone (GnRH) agonist depot preparation: Decapeptyl-Depot (DD). Of these patients, 53 (3 boys) were previously untreated (group 1) and 29 (5 boys) have been treated before with either a short-acting GnRH analogue or cyproterone acetate (group 2). Fifty-one patients (44 girls, 7 boys) were treated with DD for 12 months or more. Basal plasma luteinizing hormone (LH) levels decreased in both groups after 1 year of therapy. The LH response to intravenous GnRH was reduced in both groups. Basal plasma follicle stimulating hormone (FSH) levels decreased in both groups. Stimulated FSH levels were reduced in both groups after 1 year of DD treatment. Plasma oestradiol levels in the girls decreased to prepubertal levels in both groups. In all patients the clinical signs of precocious gonadarche such as breast development and menstruations (girls) and an increased testis volume (boys), did not further progress and sometimes regressed in several patients. Growth velocity decreased in the girls of group 1 from 9.0 +/- 0.72 cm/year (mean +/- SEM) in the last half-year before treatment to 6.3 +/- 0.50 in the first half-year of treatment (P less than 0.01) and to 4.5 +/- 0.23 cm/year in the second half-year (P less than 0.01). After 12 months a stabilization of growth velocity was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

ABSTRACT. As part of an ongoing international multicentre study, 19 children (14 girls, 5 boys) with central precocious puberty (CPP) were treated with a slow‐release gonadotrophin‐releasing hormone (GnRH) agonist, triptorelin, for 4 years. After 3 years of treatment, height velocity stabilized at 4.0 cm/year. Predicted adult height (mean ± SD) increased from 158.9 ± 6.8 to 164.9 ± 6.6 cm in girls (n = 14, p < 0.01), and from 174.4 ± 18.5 to 184.3 ± 17.1 cm in boys (n = 4, p < 0.05). In 12 additional girls who had started the multicentre study but discontinued triptorelin treatment after 2.2 ± 0.5 years, menses started 9.8 ± 3.7 months after cessation of treatment in all but one patient. Height velocity increased over the first 6 months after discontinuation of treatment, from 3.6 ± 0.1 to 5.4 ± 2.5 cm/year, and remained higher than pretreatment values in the second 6 months, but decreased subsequently. Bone maturation increased, and no significant improvement in predicted adult height was observed. For auxological reasons, therefore, it may be advisable to continue triptorelin treatment for as long as possible. Concomitant growth hormone (GH) therapy was initiated in three girls with CPP with height velocities of 3.2–3.6 cm/year after 3 years of treatment with triptorelin and predicted adult heights of less than the third centile for Dutch girls. Prior to the administration of GH, all patients had subnormal 24‐hour GH profiles and GH responses to arginine provocation. GH treatment increased height velocity markedly in all girls, and improved predicted adult height. It is concluded that triptorelin therapy improves predicted adult height. In children with CPP and genetic short stature, with a markedly decreased height velocity during triptorelin therapy, concomitant administration of a GnRH agonist and GH may have advantages. Further extensive studies are required.

The question as to whether treatment with short-acting or with slow-release gonadotropin-releasing hormone (GnRH) agonists has different effects on growth and bone maturation when treating girls with central precocious puberty has not yet been studied. In a meta-analysis, we compared 21 naive girls with central precocious puberty who were treated with buserelin with 22 naive girls with central precocious puberty who received Decapeptyl in depot form. Treatment lasted for at least 18 months. At the start of therapy, chronological age, bone age, growth velocity and pubertal stage in the two groups were very similar. During the first 6 months of treatment, significantly more phases of incomplete suppression of pituitary-gonadal activity occurred in the buserelin group. As a result, growth velocity and bone maturation (Δ bone age/Δ chronological age) remained significantly higher than in the Decapeptyl Depot group (p < 0.0001 and p < 0.01, respectively). In contrast to the Decapeptyl Depot group, the height standard deviation score (SDS) for bone age in the buserelin group did not change significantly in the first 6 months of treatment, and the predicted adult height decreased. Between the 6th and 18th months of therapy, the development of growth rate, Δ bone age/Δ chronological age, height SDS for bone age and predicted adult height in both groups became almost identical. However, the rate of growth and bone maturation in the buserelin group remained faster than in the Decapeptyl group, though not significantly so. The mean predicted adult height had risen significantly after 18 months in the Decapeptyl Depot group but not in the group treated with buserelin. Treatment with the slow-release GnRH agonist Decapeptyl Depot is more effective for children with central precocious puberty than therapy with the short-acting agonist buserelin, not only with regard to long-term compliance but also for auxological reasons, since Decapeptyl Depot suppresses gonadotropins and oestradiol faster and more completely at least during the first 6 months of treatment.

The auxological data of 25 patients (21 girls, 4 boys) with central precocious puberty (CPP), treated for 4 years with a slow-release gonadotropin-releasing hormone agonist [Decapeptyl-controlled release (D-CR) 3.75] every 4 weeks intramuscularly, and of 6 patients (3 girls, 3 boys), treated for 5 years, are presented. After 3 years of D-CR a stabilization of height velocity (HV) at about 4 cm/year was observed. Bone maturation (ratio of change in bone age to change in chronological age; ΔBA/ΔCA) slowed down to a mean ΔBA/ΔCA ratio of 0.5 ± 0.2 (mean ± SD) measured over 48 months. As a result, predicted adult height (PAH) improved from 156.3 ± 7.4 to 162.2 ± 6.8 cm in girls (p < 0.001) and from 174.4 ± 18.6 to 184.3 ± 17.1 cm in boys after 4 years. In the 5th year an ongoing improvement of PAH was observed. 20 additional girls discontinued D-CR for at least 12 months after treatment with D-CR for 2 years or more. In 11 girls menses started after 10.6 ± 3.1 months; 9 girls had no menarche after 12–16 months. HV increased in the first and second 6 months to a level of about 6.0 cm/year, decreased in the third 6 months after cessation to the level before discontinuing D-CR and decreased further afterwards. Bone maturation (ΔBA/ΔCA) increased progressively in the first 18 months after discontinuation, with a stabilization at about 1.3. PAH did not change in the first 12 months after discontinuation of D-CR, but showed a decrease afterwards. We conclude that D-CR treatment is very effective in the long-term suppression of gonadal activity of children with CPP resulting in a stabilization of HV and bone maturation. After treatment the resumption of gonadal activity results in progression of puberty. Preliminary auxological data suggest that the remaining growth potential may be reduced.

More than 100 patients with central precocious puberty are participating in this international multicenter study using monthly i.m. injections of the slow-release GnRH agonist Decapeptyl-Depot. In 15 patients, Decapeptyl-Depot treatment could be discontinued after 2 years of therapy. Gonadal suppression was promptly reversible in all of them, as shown by prepubertal low gonadotrophin- and sex steroid levels. Of the remaining 90 patients, 40 have been treated for more than 3 years, including 33 girls and 7 boys. Plasma levels of LH, FSH, estradiol and testosterone dropped to the prepubertal range after one month of Decapeptyl-Depot and remained there for the whole period of therapy. At start of therapy, mean chronologic age of these 40 children was 6.6 +/- 1.4 (SD) years, mean bone age 10.2 +/- 1.9 years. Mean predicted adult height increased in the boys from 173.6 +/- 13.8 (SD) cm at start of therapy to 184.6 +/- 17.0 cm after 3 years. Predicted adult height increased in girls from 158.0 +/- 12.2 to 161.0 +/- 7.5 cm. Undue side effects were not seen, long term tolerance was good. It is concluded that Decapeptyl-Depot injected i.m. every 4 weeks suppresses the pituitary-gonadal axis in children with central precocious puberty without clinical or biochemical escapes, and leads to an increase in predicted adult height by more than 3 cm in all boys and in 53% of the girls after three years of treatment.

Corticosteroid treatment of the fetus, which accelerates lung maturation, may mimic a modulating role of endogenous corticoids in normal development. To investigate this question, we determined the developmental pattern of plasma corticoids and their binding proteins in the rabbit, a commonly used species for studies of lung differentiation. The concentration of cortisol, the most potent glucocorticoid in the rabbit, was maximal at 23 days gestation (1.89 micrograms/dl), declining to 0.54 micrograms/dl at term (31 days). Levels of plasma corticosterone were always lower than those of cortisol. The adrenal content of corticoids, expressed per adrenal DNA or g BW, decreased during late gestation. Corticosteroid-binding globulin in fetal plasma decreased strikingly between day 23 (36 micrograms cortisol bound/dl) and day 31 (4.4 micrograms/dl; P less than 0.001), whereas maternal levels increased about 10-fold during this time. Free cortisol in the fetus increased between 21 and 23 days (0.041 micrograms/dl) and then decreased somewhat until after day 29 when there was an increase. To examine more directly the influence of endogenous glucocorticoids in the fetal lung, we assayed cortisol in extracts of purified lung nuclei as a reflection of receptor-cortisol complexes. The nuclear content of cortisol was constant between 23 and 30 days at levels (0.056-0.074 ng/mg DNA) comparable to those predicted from data for plasma free cortisol. Thus, in the rabbit, increases in plasma cortisol and nuclear receptor-cortisol complex are not temporally associated with the major events of lung development as in other species. We speculate that endogenous glucocorticoids may have a permissive or delayed influence on the lung during normal development in the rabbit.

Nine months' subcutaneous therapy with synthetic growth hormone releasing factor in children with short stature. Acta Paediatr Scand [Suppl] 331: 48, 1987.The growth promoting potential of GRF(l-29)NHZ was studied in nine boys with short stature over three periods of 3 months. Their short stature was due to partial hGH deficiency/hGH neurosecretory dysfunction and was diagnosed by arginine and insulin stimulation tests and hGH nocturnal profiles. Four patients (Group I) were given GRF, 3-4 pg/kg S.C. b.d. during the first period of 3 months, and after an interval of 1 month, the same dose once daily during the second treatment period of 3 months. Five patients (Group 11) were given GRF, 3'-4 pg/kg s.c., once daily during the first and b.d. during the second 3 months of therapy. After a second interval of 1 month without any GRF treatment, the third 3-month period for both groups consisted of one daily injection of GRF, 8-10 pg/kg S.C. at 19.00 hours. Total body height and lower leg length were measured by stadiometry and knemometry, respectively. GRF intravenous bolus tests were performed in each patient following fasting, before and at the end of the first and second 3-month periods. Serum IGF-1 and urinary hydroxyproline excretion were determined monthly. Stadiometric growth rate, determined over the whole study period of 11 months including the treatment-free intervals, increased from 4.92 cm/year to 5.97 cm/year (p>0.05). Mean knemometric growth rates increased from 0.28 mdweek before therapy, to 0.35 mndweek during the one iqjectiodday period at low dose, to 0.39 mndweek (p<0.05) during the b.d. period, and to 0.40 mndweek during the last 3 months of high-dose GRF given once daily. IGF-1 levels increased during GRF therapy and were highest during the high-dose period. Urinary hydroxyproline excretion and peak plasma hGH levels after intravenous GRF did not correlate with the GRF dose administered in any of the treatment phases. GRF dose and frequency of administration were probably suboptimal in this group of patients; higher dose frequencies might be necessary to achieve growth rates comparable with those observed during hGH substitution therapy.

The present study was designed to answer the following three questions: Is there any difference between the growth hormone (GH) response to i.v. injections of GHRH 1-44 by a slowly injecting hormone pump or to a s. s. or rapid i. v. injection by syringe? Do nocturnal injections of GHRH 1-44 i. v. elicit different GH levels than during daytime? Can repetitive administration of GHRH 1-44 in patient with GH deficiency induce a physiological GH pattern and thereby normalize the condition resulting from a hypothalamic defect? A rapid i. v. bolus injection of 50 micrograms GHRH 1-44 by syringe with an injection time of one second elicited in the same subject at the same time of the day a twofold greater response than a slowly injecting (60 seconds) hormone pump. In six male adult volunteers each GHRH i. v. bolus was followed by a GH secretory pulse. The GH response at night (area under the curve and peak plasma GH levels) was significantly greater than at daytime (P less than 0.05) and greater than the GH pulses measured during a spontaneous nocturnal profile (P less than 0.05). Out of six GH deficient young adult patients who had been receiving extractive GH until two years prior to the study, three responded much like the controls, the other three patients-those who lacked any spontaneous nocturnal GH peaks-had markedly lower GH levels after GHRH (P less than 0.05). However, there was a clear-cut GH release after GHRH injection in each patient.(ABSTRACT TRUNCATED AT 250 WORDS)