Long-term therapy with recombinant human growth hormone (Saizen) in children with idiopathic and organic growth hormone deficiency.

In an open-label study, 69 children with organic or idiopathic growth hormone deficiency (GHD) were treated with recombinant human growth hormone (Saizen) for an average of 64.4 mo, with treatment periods as long as 140.9 mo. Auxologic measurements, including height velocity, height standard deviation score, and bone age, were made on a regular basis. The data suggest that long-term treatment with Saizen in children with GHD results in a positive catch-up growth response and proportionate changes in bone age vs height age during treatment. In addition, long-term Saizen therapy was well tolerated, with the majority of adverse events related to common childhood disorders or existing baseline medical conditions and not to study treatment. There were no significant changes in laboratory safety data or vital signs, and no positive antibody tests for Saizen.

The not-so-good old days: working with pituitary growth hormone in North America, 1956 to 1985.

Before 1985 the use of growth hormone (GH) was governed by a philosophy of scarcity and conservation of resources. Between 1956 and 1959 human pituitary GH was shown to be effective. The competition for gland collection and extraction that followed benefited only certain patients with motivated parents and only a few investigators. To maximize gland collection, the distribution of GH for clinical investigation, and the number of patients who could be treated, the National Institutes of Health and the College of American Pathologists formed the National Pituitary Agency (NPA). In Canada a similar program was developed by the Canadian Medical Research Council. For more than 20 years the NPA supervised most of the GH treatment in the United States. Commercial pituitary GH entered the U.S. market in 1976, and competition soon appeared. Patients treated through the NPA were subjects in clinical studies for part of the first year of treatment, after which the limited availability of GH dictated treatment for only part of the year and caps on final heights. By 1984 treatment was year round and the height caps largely unenforced. In the last year of its distribution NPA GH was used in 2450 patients in the United States and commercial pituitary GH was used in 600 to 800; slightly more than 300 patients were being treated in Canada. And then, in 1985, came Creutzfeldt-Jacob disease. While the not-so-good old days are gone and need not be lamented, there remains virtue in a conservative therapeutic philosophy. If anything can be learned from the use of pituitary GH in children, it is a healthy respect for the law of unintended consequences.

Use of tissue-specific promoters in the regulation of aromatase cytochrome P450 gene expression in human testicular and ovarian sex cord tumors, as well as in normal fetal and adult gonads.

We have previously demonstrated that the tissue-specific regulation of human aromatase cytochrome P450 (P450arom) gene expression is, in part, the consequence of the use of tissue-specific promoters. Promoter I.1 (PI.1) and PI.2-specific transcripts are expressed in the placenta, whereas promoter II (PII) appears to be the only active promoter in the corpus luteum. Testicular and ovarian sex cord tumors with annular tubules (SCTATs) associated with gynecomastia in prepubertal boys and isosexual precocity in girls with Peutz-Jeghers syndrome (P-JS) have been previously reported. In the present study, we investigated the regulatory elements directing P450arom gene transcription in samples of SCTAT from three prepubertal boys and a girl with P-JS and an ovarian granulosa cell tumor from an adult woman, as well as in healthy fetal and adult testicular and ovarian tissues. Placental tissue was used as a control. Using polymerase chain reaction linked to reverse transcription and northern blotting, we determined the tissue-specific use of various P450arom promoters by analyzing specific 5'-termini from messenger RNA templates. Results indicate a universal gonadal promoter (PII) directs P450arom gene expression in healthy fetal and adult ovaries and testes, as well as in SCTAT of the P-JS and an adult ovarian granulosa cell tumor. These results are interpreted to mean that use of PII in human ovary and testis is preserved from the fetal period into adult life as well as in transformed neoplastic Sertoli and granulosa cells. On the other hand, transcripts from placenta are specific for PI.1 (and to a much lesser extent, PI.2). In SCTAT, immunoreactive P450arom is detected only in the cytoplasm of neoplastic cells, whereas the normal-appearing sex cords do not contain any immunoreactive P450arom. These results further suggest that the markedly increased aromatase expression of these transformed neoplastic cells is not a consequence of using different tissue-specific promoters. Rather it appears to involve activation (or failure of inhibition) of the upstream regulatory elements of the same promoter, which is normally functional in all gonadal tissues, namely the proximal PII.

Use of tissue-specific promoters in the regulation of aromatase cytochrome P450 gene expression in human testicular and ovarian sex cord tumors, as well as in normal fetal and adult gonads.

We have previously demonstrated that the tissue-specific regulation of human aromatase cytochrome P450 (P450arom) gene expression is, in part, the consequence of the use of tissue-specific promoters. Promoter I.1 (PI.1) and PI.2-specific transcripts are expressed in the placenta, whereas promoter II (PII) appears to be the only active promoter in the corpus luteum. Testicular and ovarian sex cord tumors with annular tubules (SCTATs) associated with gynecomastia in prepubertal boys and isosexual precocity in girls with Peutz-Jeghers syndrome (P-JS) have been previously reported. In the present study, we investigated the regulatory elements directing P450arom gene transcription in samples of SCTAT from three prepubertal boys and a girl with P-JS and an ovarian granulosa cell tumor from an adult woman, as well as in healthy fetal and adult testicular and ovarian tissues. Placental tissue was used as a control. Using polymerase chain reaction linked to reverse transcription and northern blotting, we determined the tissue-specific use of various P450arom promoters by analyzing specific 5'-termini from messenger RNA templates. Results indicate a universal gonadal promoter (PII) directs P450arom gene expression in healthy fetal and adult ovaries and testes, as well as in SCTAT of the P-JS and an adult ovarian granulosa cell tumor. These results are interpreted to mean that use of PII in human ovary and testis is preserved from the fetal period into adult life as well as in transformed neoplastic Sertoli and granulosa cells. On the other hand, transcripts from placenta are specific for PI.1 (and to a much lesser extent, PI.2). In SCTAT, immunoreactive P450arom is detected only in the cytoplasm of neoplastic cells, whereas the normal-appearing sex cords do not contain any immunoreactive P450arom. These results further suggest that the markedly increased aromatase expression of these transformed neoplastic cells is not a consequence of using different tissue-specific promoters. Rather it appears to involve activation (or failure of inhibition) of the upstream regulatory elements of the same promoter, which is normally functional in all gonadal tissues, namely the proximal PII.

Effect of somatotropin of mammalian cell origin in growth hormone deficiency.

Sixty-nine growth hormone-deficient patients were treated for 1 year with somatotropin (recombinant DNA-derived human growth hormone) produced in mouse cells. The growth velocity of the 50 patients (72%) in whom the effectiveness of this growth hormone could be evaluated increased from a mean (+/- SD) of 3.5 +/- 1.1 to 8.7 +/- 1.6. cm/y. An enhanced rate of weight gain was also observed. Bone age was not unduly accelerated. One of 66 patients developed antibodies to recombinant growth hormone, which did not affect the response to therapy. No patient developed antibodies to host cell proteins. An increased insulin response to a standard glucose load, without any change in glucose tolerance, was observed after 1 year of treatment. This authentic sequence human growth hormone preparation produced in mammalian cells is both effective and safe in the treatment of children with growth hormone deficiency.

Growth response to recombinant human growth hormone of mammalian cell origin in prepubertal growth hormone-deficient children during the first two years of treatment.

In five clinical studies performed in Austria, France, the FRG, Italy, Switzerland, the UK and the USA, 304 growth hormone (GH)-deficient children were treated with recombinant human GH (rhGH) of mammalian cell origin. Two hundred and twenty-five patients were previously untreated (naive patients), and 79 were transferred from pituitary hGH after interruption of therapy for at least 6 months (transfer patients). Two treatment protocols, differing in both dose and frequency of injections, were used: (1) a dose of 0.6 IU/kg body weight per week was administered in 3 s.c. injections to 203 patients (178 naive, 25 transfer; group 1); and (2) a dose of 0.45 IU/kg body weight per week was administered in 7 s.c. injections to 101 patients (47 naive, 54 transfer; group 2). After 1 and 2 years of treatment, 143 and 109 naive, and 51 and 46 transfer patients, respectively, were still prepubertal, and their data were analyzed for efficacy. During the 1st year of treatment, both naive and transfer patients on daily injections (group 2) demonstrated better growth than those on 3 injections per week (group 1), with height velocities (HVs) of 10.6 +/- 2.7 cm/year (group 2) versus 8.6 +/- 2.0 cm/year (group 1) for naive patients (p < 0.001), and 9.9 +/- 1.9 cm/year (group 2) versus 7.2 +/- 2.7 cm/year (group 1) for transfer patients (p < 0.001). The corresponding changes in height standard deviation score (delta H SDS) for chronological age (CA) were +1.3 +/- 0.6 (group 2) versus +0.8 +/- 0.5 (group 1) for naive patients (p < 0.01), and +1.1 +/- 0.3 (group 2) versus +0.6 +/- 0.4 (group 1) for transfer patients (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Antithyroid antibodies in Hispanic patients with type I diabetes mellitus. Prevalence and significance.

Antithyroglobulin antibodies (ATA) and antithyroid microsomal antibodies (AMA) were sought and thyroid function was determined in 90 Hispanic patients with type I diabetes mellitus followed up for up to seven years. We detected ATA in 7.5% of our patients and AMA in 34.8%. All serum samples positive for ATA also contained AMA. There was no sex difference in the prevalence of thyroid autoimmunity. A small, firm goiter was present in eight patients, one of whom developed Graves' disease. Our results suggest that a relatively high prevalence of AMA and no sex difference in thyroid autoimmunity may be unique features of Hispanic children and adolescents with type I diabetes mellitus. Such patients should be clinically evaluated for thyroid dysfunction and should be screened annually for the presence of AMA. When antibodies are present, laboratory evaluation of thyroid function should be performed frequently.

Cord serum thyroid-stimulating hormone and thyroglobulin levels decline with increasing birth weight in newborns.

Cord serum thyroglobulin (Tg) and TSH levels were related to birth weight in 3 groups of newborn infants composed of 101 infants. Serum free T3 index, free T4 index, and/or T4 also were determined. Group I consisted of normal term newborns (20 females and 19 males), whose mean +/- SD gestational ages (40.1 +/- 0.7 vs. 40.1 +/- 0.5 weeks) did not differ, but whose mean birth weights (3299 +/- 282 vs. 3757 +/- 447 g) differed significantly (P less than 0.005). In female infants, serum Tg levels (r = -0.401; P less than 0.05) and the log of TSH levels (r = -0.576; P less than 0.005) correlated negatively with birth weight, while Tg levels correlated positively with the log of TSH levels (r = 0.401; P less than 0.05). In contrast, none of these correlations was significant for male infants. However, T4 levels and birth weight correlated positively (r = 0.499; P less than 0.025) in male infants, but not in female infants. Group II consisted of newborns whose birth weights were less than 2500 g (19 females and 19 males). Mean birth weights of female (2032 +/- 301 g) and male (1850 +/- 413 g) infants did not differ significantly (P greater than 0.05). Both the Tg levels and the log of the TSH levels correlated negatively with birth weight in female (Tg, r = -0.891 and P less than 0.005; log TSH, r = 0.600 and P less than 0.005) and male (Tg, r = -0.849 and P less than 0.005; log TSH, r = -0.660; P less than 0.005) infants. Also, Tg levels correlated positively with the log of the TSH levels in female (r = 0.554; P less than 0.01) and male (r = 0.412; P less than 0.05) infants. Free T4 index levels correlated positively with free T3 index levels in female (r = 0.443; P less than 0.05) and male (r = 0.570; P less than 0.01) infants. Group III consisted of 12 normal female term newborns whose mean birth weight (3685 +/- 623 g) was not significantly (P less than 0.2) different from that of the males of group I, and 12 normal male term newborns whose mean birth weight (4104 +/- 248 g) was significantly (P less than 0.005) greater than that of the males of group I. Unlike in lower weight female or male infants, serum Tg levels did not correlate with birth weight or the log of TSH levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Ullrich-Turner syndrome associated with interstitial deletion of Xp11.4 leads to p22.31.

The full phenotype of the Ullrich-Turner syndrome (UTS) is thought to be due to loss of the short arm of X. We report a 16-year-old girl with lack of secondary sexual development, amenorrhea, and short stature. She had thyroiditis and numerous other UTS manifestations and was found to have a non-mosaic 46,X,del(Xp) chromosome abnormality. Breakpoints occurred at p11.4 and p22.31, with a loss of the intervening segment.