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Biomedical subjects

O H Pescovitz

Publications and source records attributed to O H Pescovitz.

At least 19 recordsLinked to original sources
PubMed1995

Bone mineral density during treatment of central precocious puberty.

Treatment of adults with gonadotropin releasing hormone analogs has resulted in rapid loss in bone mineral density (BMD). We measured lumbar and femoral neck BMD by dual-energy x-ray absorptiometry during 2 years of depot leuprolide therapy in 13 girls (mean age, 7.5 years; mean bone age, 10.9 years). At baseline, BMD was elevated for age and concordant with the advanced skeletal age. During therapy with gonadotropin releasing hormone analog, BMD values increased and BMD standard deviation scores for age and skeletal age did not change.

Absorptiometry, Photon↗
PubMed1995

Presence of a spermatogenic-specific promoter in the rat growth hormone-releasing hormone gene.

A GH-releasing hormone (GHRH) messenger RNA (mRNA) has been identified in hypothalamus, placenta, and testicular germ cells. The GHRH mRNA produced by spermatogenic cells is approximately 1700 nucleotides in length, whereas GHRH transcripts in hypothalamus and placenta are 750 nucleotides. To correlate the structure of testicular GHRH mRNA with cell type-specific expression, we determined its sequence. A GHRH clone isolated from a rat testicular complementary DNA library was found to be identical in the coding sequence to hypothalamic GHRH. Rapid amplification of complementary DNA ends analysis of the 5'-end of germ cell GHRH mRNA and comparison with the genomic sequence revealed that GHRH transcription in testis initiates approximately 700 basepairs 5' to transcription initiation in placenta and 10.7 kilobasepairs 5' to that in hypothalamus. Reverse transcription-polymerase chain reaction analysis of germ cell RNA using primers from testicular exons 1 and 4 demonstrated that part of the placental exon 1 sequence is contained in some testicular GHRH transcripts, as an extra exon, between testicular exon 1 and the common exon 2. This was confirmed by a Northern blot of testicular mRNA using a testicular exon 1 probe. The 5'-flanking region of the testicular GHRH gene was analyzed and found to contain a TATA-like motif and sequences homologous to spermatogenic-specific cis-acting elements. Southern blot analysis of rat liver DNA suggested that just one GHRH gene is present in rat. These results indicate that both alternative transcription initiation and splicing of the GHRH gene exist in rat testicular germ cells.

Alternative Splicing↗
PubMed1995

Precocious puberty.

The past decade has seen tremendous advances in both the diagnosis and treatment options for children with precocious puberty. Although the precise cause of CPP is still not known, long-acting GnRH analogues provide a safe and effective form of therapy. Treatment slows the progression of secondary sexual characteristics and rates of linear growth and bone maturation. Although the final verdict on how beneficial GnRH analogue therapy is in preserving the final adult height in children with precocious puberty is still not in, achieved heights are generally greater than pretreatment predicted heights. However, treatment may not be appropriate for all children with GDPP. Some children progress through puberty slowly and may not have significant compromise in final height. Furthermore, some children who come from tall families who may be subject to the same deterioration from target height as children who come from short families may not require therapy because their expected final heights may still fall within an acceptable range even if they are shorter than their siblings. Therapy offers the greatest advantage for those children in whom the onset of puberty is at a very early age, those who demonstrate rapidly accelerating bone age, or those with lower genetic height potential. In the past 3 years, the molecular mechanisms by which precocious puberty develops in children with MAS and FMPP have been elucidated. The molecular defects characterized explain the clinical manifestations. Future challenges will include the development of an effective, targeted form of therapy for gonadotropin-independent forms of precocious puberty.

Child↗
PubMed1993

A new target for growth hormone releasing-hormone action in rat: the Sertoli cell.

A GHRH-like mRNA and peptide (t-GHRH) have been detected in rat and human testis. In rat, t-GHRH mRNA is localized to developing spermatogenic cells. We predicted that the most likely target cell of t-GHRH action would be the Sertoli cell. To test this prediction, we evaluated GHRH action on Sertoli cell function. Rat GHRH at a concentration of 10 nM or 100 nM stimulated cAMP production 2-fold over control levels after a 30 min incubation. This stimulation was obliterated by preincubation with a 10-fold excess of the GHRH antagonist (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2. The effect of treatment with [His1,Nle27]GHRH(1-32)-NH2, a GHRH analog, on Sertoli cell mRNAs was also assessed. Treatment with the analog significantly increased levels of c-fos and steel factor (the product of the Steel gene, also termed SCF) mRNAs above controls, but had no effect on sulfated glycoprotein-2 mRNA. We conclude that GHRH acts via adenylate cyclase to modulate specific Sertoli cell products, possibly as part of a network of local interacting factors controlling Sertoli and germ cell function.

Adenylyl Cyclases↗
PubMed1993

Effect of deslorelin-induced pubertal delay on the growth of adolescents with short stature and normally timed puberty: preliminary results.

LH-releasing hormone agonist (LHRHa) treatment slows bone maturation and improves adult height in children with LHRH-dependent precocious puberty. To determine whether pubertal delay induced by LHRHa can enhance final height in patients with short stature and a normally timed puberty, we enrolled 43 short children (28 girls and 15 boys) in a double blind, placebo-controlled trial. Patients were assigned randomly to receive either placebo or LHRHa (deslorelin), administered sc at a dose of 4 micrograms/kg.day for a period of 4 yr. This report describes the preliminary results in 16 children who have completed 4 yr of treatment (9 patients in the deslorelin group and 7 patients in the placebo group). Predicted adult height increased significantly in the deslorelin-treated patients, by 7.6 cm compared to the pretreatment baseline and by 10.3 cm compared to that in the placebo-treated patients (P < 0.005). Four of the 16 patients received concurrent GH treatment (3 among the deslorelin-treated patients and 1 among the placebo-treated patients). Omitting these patients from the analysis did not materially affect the results: predicted adult height in the deslorelin-treated patients increased by 7.2 cm compared to the pretreatment baseline and by 10.9 cm compared to that in the placebo-treated patients (P < 0.005). We conclude that pubertal delay induced by deslorelin significantly increases predicted adult height in adolescents with short stature and a normally timed puberty. Whether deslorelin treatment will increase the final height of these patients cannot be determined until they have stopped growing.

Adolescent↗
PubMed1992

Growth hormone-releasing hormone-like messenger ribonucleic acid and immunoreactive peptide are present in human testis and placenta.

Although the sequence of human GH-releasing hormone (GHRH) has been determined, all of the information concerning gene expression has been based on pathological sources of ectopic GHRH, since the only established physiological source of GHRH in humans is the hypothalamus. We recently reported the presence of extrahypothalamic GHRH-like mRNA and immunoreactive material in rat testis and placenta. To determine if human testis and placenta also contain immunoreactive GHRH-like peptides, tissue extracts were analyzed using enzyme-linked immunosorbent assay methodology. Both tissues had detectable quantities of immunoreactive peptide recognized by a monoclonal antibody to synthetic human GHRH-(1-44) (testis, 2.4 ng/g tissue, 0.68 ng/mg protein; placenta, 2.6 ng/g tissue, 0.36 ng/mg protein). The origin of these peptides was confirmed by extracting total RNA from human testis and placenta, with analysis on Northern blots probed with riboprobes for rat hypothalamic GHRH cDNA and human pancreatic tumor GHRH cDNA. Human testis and placenta total RNA both contain an approximately 790-nucleotide RNA species similar in size to that reported in ectopic GHRH-producing human tumors. In addition, two larger hybridization signals were seen at 3000 and 4900 nucleotides. These data suggest that testis and placenta are extrahypothalamic sites of expression of the human GHRH gene. Normal expression of the GHRH gene in extrahypothalamic sites may include transcription of larger mRNA species than those observed in ectopic pathological sources of GHRH expression.

Animals↗
PubMed1991

Growth failure and decreased levels of insulin-like growth factor I in obstructive jaundice are reversed by bile diversion.

Insulin-like growth factor I (IGF-I) is one of the principal stimuli of linear growth. Growth failure in children with chronic cholestatic jaundice may be related to decreased hepatic synthesis of IGF-I. It was hypothesized that (1) biliary obstruction would lead to growth retardation and decreased circulating IGF-I levels; and (2) surgical drainage of the obstructed biliary system would reverse these effects. To test this hypothesis, the following study of male Sprague-Dawley rats (135 g; 10 animals per group) was performed. Group I underwent common bile duct ligation (CDL); group II underwent choledochoduodenostomy 2 weeks following CDL; group III were sham-operated and fed with CDL rats; and group IV were sham-operated and fed ad libitum. Daily food intake and weekly body weight were recorded. Statistical analysis was by repeated-measures analysis of variance and individual comparisons were evaluated by Student's t test. Biliary obstruction results in decreased food intake, rate of weight gain, and IGF-I levels. A significant reduction in IGF-I levels was also noted in the pair-fed sham-operated rats (group III). Relief of obstructive jaundice by surgical drainage results in a reversal of these changes. It is concluded that the growth failure and decreased IGF-I levels associated with obstructive jaundice can be reversed by surgical drainage of the obstructed biliary system and, in part, are due to inadequate nutrition.

Analysis of Variance↗
PubMed1991

Ontogeny of growth hormone releasing hormone and insulin-like growth factors-I and -II messenger RNA in rat placenta.

Hypothalamic growth hormone releasing hormone (GHRH) stimulates pituitary growth hormone secretion, which is essential for normal postnatal growth. Reports of an immunoreactive and biologically active GHRH-like peptide in placenta led us to investigate placental expression of GHRH mRNA. Placentas from d 19 gestation fetal rats were assayed for GHRH-like peptide by ELISA and for GHRH mRNA. Placenta GHRH-like peptide levels averaged 3.7 +/- 0.2 ng/g tissue. Dot-blot hybridization revealed the presence of GHRH mRNA in rat placenta in quantities greater than those of the message in rat hypothalamus. Northern gel analysis of poly-A enriched RNA was used to evaluate the specificity of GHRH mRNA hybridization and to determine the size of the placental mRNA. Placental and hypothalamic GHRH mRNA were of nearly identical size, although placental RNA had a broad band of hybridization that extended below that seen in hypothalamus. Further confirmation of homology between placental and hypothalamic GHRH mRNA was determined by an RNAse protection assay, in which a placental protected fragment was identical in size to that resulting from protection of the hypothalamic complementary RNA. The ontogeny of GHRH mRNA in rat placenta was determined by dot-blot hybridization. The message was detected at the earliest date examined, d 7, and increased more than 2-fold by d 14 and 5-fold by d 17. The ontogeny of IGF-I and IGF-II mRNA in placenta was also determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Interaction of growth hormone-releasing hormone with the insulin-like growth-factors during prenatal development in the rat.

The placenta is a chimeric organ that produces all the components of the hypothalamic-pituitary GH axis. We propose that placental GH-releasing hormone (GHRH) stimulates placental GH-like hormones which in turn stimulate production of the insulin-like growth factors (IGFs), IGF-I and IGF-II, and these placental IGFs are important for growth and development of the placenta as well as the fetus. To test this hypothesis, pregnant rats were given either GHRH antisera or preimmune sera ip from days 7-19 of gestation. Fetuses were killed on day 19, and IGF-I and IGF-II tissue and serum concentrations in the mother and fetus were measured by RIA. IGF-II receptor content was measured by Western analysis. IGF-I and IGF-II messenger (m) RNA levels were measured in the placentas as well as in the fetal livers. The GHRH antibody titer was highest at day 19 of gestation but continued to be present through day 20 of postnatal development. Although placental weights did not differ, antibody-treated animals had higher placental IGF-I and IGF-II levels (I, 108 +/- 6 (SD); II, 126 +/- 5 ng/g, respectively) vs. control animals (I, 88 +/- 2.5 (SD); II, 48 +/- 11 ng/g) in pooled specimens. The IGF-II receptor was also up-regulated in placentas from antibody-treated mothers. The fetuses of antibody-treated (A) mothers were larger than the controls (C) (A, 2.615 g; C, 2.49 g, P less than 0.05). Levels of both IGFs were significantly increased in livers of antibody treated fetuses (IGF-I: A, 15 +/- 1 (SD); C, 12 +/- 0.8 ng/g; and IGF-II: A, 295 +/- 10 (SD); C, 233 +/- 10 (SD) ng/g). In addition, the concentration of the IGF-II receptor in liver of antibody-treated fetuses was also increased. Further, pooled fetal sera from antibody-treated fetuses had higher levels of IGF-II than controls (A, 950 ng/ml; C, 700 ng/ml), and the circulating IGF-II receptor was increased as measured by Western analysis. In the liver, IGF-II mRNA levels of antibody-treated fetuses were increased to 117% of controls, whereas IGF-I mRNA levels were undetectable. The placenta showed no increase in placental lactogen or GH mRNA, whereas IGF-II and GHRH mRNA were slightly increased in antibody-treated animals. In conclusion, these data suggest that GHRH may interact with the IGFs in a different fashion during prenatal development then during postnatal development.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Effect of deslorelin dose in the treatment of central precocious puberty.

Central precocious puberty is effectively treated with long-acting LHRH analogs (LHRHas). Although at least six LHRHas have now been used in children, there have been no studies to determine the least effective dose of any of these analogs. We sought to determine the effect of decreasing an efficacious dose of deslorelin (D-Trp6-Pro9-NEt-LHRH) on basal and LHRH-stimulated gonadotropins, estradiol levels, and the rates of linear growth and skeletal maturation in subjects with central precocious puberty. Twenty-nine children with central precocious puberty were enrolled in a double blinded study. All subjects were treated for the initial 3 months with deslorelin at a dose (4 micrograms/kg.day, sc) known to suppress gonadotropins, linear growth velocity, and the rate of skeletal maturation. After 3 months, the subjects were randomly assigned to receive one of three daily sc doses of deslorelin: 4 micrograms/kg (n = 9), 2 micrograms/kg (n = 11), or 1 micrograms/kg (n = 9). They were treated at this dose in double blinded fashion for 15 months, after which time they resumed therapy at a dose of 4 micrograms/kg.day for an additional year. The children in the three groups did not differ in terms of chronological age, bone age, pretreatment growth rate, or Tanner stage at the onset of therapy. Similarly, there were no differences in the clinical and hormonal responses to the first 3 months of LHRHa therapy (4 micrograms/kg.day). During the 15-month period at the three different doses, the three dose groups could not be distinguished from each other in terms of pubertal stage, linear growth velocity, rate of skeletal maturation, sex steroid levels, mean LH or FSH levels, or peak FSH response to LHRH stimulation or to a dose of deslorelin. In contrast, the peak LH response to LHRH stimulation was highest in children treated with the lowest dose (1 micrograms/kg.day; P less than 0.025, by multiple analysis of variance). In addition, the peak LH response to a dose of deslorelin (the LHRHa test) was higher in children treated with 1 micrograms/kg.day than in those treated with 4 micrograms/kg.day (P less than 0.04). In summary, the LHRHa test is a sensitive means for detecting activation of the hypothalamic-pituitary-gonadal axis, and deslorelin at a dose of 1 micrograms/kg.day results in less gonadotropin suppression than a dose of 4 micrograms/kg.day.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed1990

Ontogeny and pituitary regulation of testicular growth hormone-releasing hormone-like messenger ribonucleic acid.

The testis is rich in central nervous system-type neuropeptides, including a GH-releasing hormone (GHRH)-like substance. We examined the ontogeny and pituitary regulation of testicular GHRH-like mRNA (t-GHRH mRNA) and compared this to expression of insulin-like growth factor-I (IGF-I) and IGF-II mRNA in developing testis. t-GHRH mRNA was measured by dot blot hybridization and quantitated using a hypothalamic GHRH cRNA standard. t-GHRH mRNA was not detectable in Northern blots in fetal testis on day 19 of gestation, but was present in low but detectable amounts in testicular dot blots on day 2 of life (0.44 pg/micrograms total RNA). Levels of the RNA increased beginning on day 21 (1.72 +/- 0.23 pg/micrograms total RNA) and reached adult levels by day 30 (4.96 +/- 0.84 pg/micrograms total RNA). The GHRH species on Northern analysis was about 1750 nucleotides at all ages examined; there was a larger species of about 3350 nucleotides seen on days 65 and 90. There was no correlation between the ontogeny of t-GHRH mRNA and either IGF-I or IGF-II mRNAs, which were maximally expressed in the testes of day 2 animals and decreased with age. To examine the influence of the pituitary gland on t-GHRH mRNA, levels of the mRNA were measured in the tests of hypophysectomized animals and age-matched controls. In animals hypophysectomized on day 21 and killed on day 42 and in animals hypophysectomized on day 42 and killed on day 63, there was marked diminution of t-GHRH mRNA (19 +/- 5% and 9 +/- 2% of age-matched controls, respectively). In contrast, in animals hypophysectomized on day 65 and killed on either day 80 or 90, there was a much smaller difference in levels of t-GHRH mRNA compared to values in control animals (73 +/- 20%). This was unlike the effect of hypophysectomy on testicular IGF-I mRNA, where uniform diminution was seen in all three groups. Because GH is important in the regulation of hypothalamic GHRH mRNA, we examined the effects of administration of recombinant human GH on the reinduction of t-GHRH mRNA after hypophysectomy and compared this to the reinduction of IGF-I mRNA. Neither t-GHRH mRNA nor testicular IGF-I mRNA increased in hypophysectomized animals treated with GH. Our results indicate that t-GHRH mRNA is developmentally regulated, and that the hypothalamic-pituitary axis is important in its expression.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Localization and growth hormone (GH)-releasing activity of rat testicular GH-releasing hormone-like peptide.

The testis contains many peptides originally described as originating in the central nervous system. The physiological function of these factors in the testis is generally unknown. We previously reported that the rat testis contains both a peptide with GH-releasing hormone-like immunoactivity (tGHRH-LI) and a mRNA species that cross-hybridizes with a hypothalamic cDNA for rat GHRH (rGHRH). The current study was designed to further characterize tGHRH-LI by determining its location within rat testis, and to evaluate whether tGHRH-LI and hypothalamic GHRH share similar biological and electrophoretic properties. Partially purified tGHRH is capable of stimulating GH secretion from cultured anterior pituitary cells in a dose-dependent manner. Testicular GHRH and rGHRH have different HPLC retention times and significantly different electrophoretic properties by Western gel analysis. The estimated size of tGHRH-LI is approximately 3.7 times that of synthetic rGHRH. Using immunohistochemistry, tGHRH-LI is localized to mature sperm forms in rat testis. We conclude that rat tGHRH-LI and rGHRH share some structural and functional properties and are probably related peptides. However, the difference in electrophoretic mobility and HPLC retention time indicates that they are not identical. The presence of tGHRH-LI in rat sperm, within the confines of the blood-testis barrier, which is generally impermeable to peptides, leads us to speculate that tGHRH serves a paracrine or autocrine role in testicular physiology.

Animals↗
PubMed1990

Precocious puberty.

The child with premature sexual development requires a thorough history, physical, and appropriate laboratory evaluation. The physician and other medical staff should remain sensitive to the family's concerns and the child's emotional adaptation. Counseling and open discussion of the psychosocial and sexual issues may greatly assist both the child and family. Making the correct diagnosis is critical to the selection of the appropriate form of therapy. Fortunately, in most cases in which therapy is warranted, it is extremely effective. In the remaining conditions, promising new forms of therapy are being investigated.

Adolescent↗