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Biomedical subjects

O H Pescovitz

Publications and source records attributed to O H Pescovitz.

At least 37 records · Page 2Linked to original sources
PubMed1997

Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adults.

To determine the effect of the GH releasing peptide (GHRP)-mimetic, MK-677, on the GH/insulin-like growth factor-I (IGF-I) axis in selected GH-deficient adults, we studied nine severely GH-deficient men [peak serum GH concentration in response to insulin-induced hypoglycemia of 1.2 +/- 1.5 micrograms/L, mean +/- SD (range 0.02-4.79)], age 17-34 yr, height 168 +/- 1.5 cm, body mass index 22.6 +/- 3.3 kg/m2, who had been treated for GH deficiency with GH during childhood. In a double-blind rising-dose design, subjects received once daily oral doses of 10 or 50 mg MK-677 or placebo for 4 days over two treatment periods separated by at least 28 days. Four subjects received placebo and 10 mg/day MK-677 in a cross-over fashion in periods 1 and 2. Five subjects received 10 mg and then 50 mg/day MK-677 in a sequential, rising-dose fashion in periods 1 and 2, respectively. Blood was collected every 20 min for 24 h before treatment and at the end of each period for GH measurement using an ultrasensitive assay. The drug was generally well tolerated, with no significant changes from baseline in circulating concentrations of cortisol, PRL, and thyroid hormones. Serum IGF-i and 24-H mean GH concentrations increased in all subjects after treatment with both 10 and 50 mg/day MK-677 vs. baseline. After treatment with 10 mg MK-677, IGF-I concentrations increased 52 +/- 20% (65 +/- 6 to 99 +/- 9 micrograms/L, geometric mean +/- intrasubject SE, P < or = 0.05 vs. baseline), and 24 h mean GH concentrations increased 79 +/- 19% (0.14 +/- 0.01 to 0.26 +/- 0.02 microgram/L, P < or = 0.05 vs. baseline). Following treatment with 50 mg MK-677, IGF-I concentrations increased 79 +/- 9% (84 +/- 3 to 150 +/- 6 micrograms/L, P < or = 0.05 vs. baseline) and 24-h mean GH concentrations increased 82 +/- 29% (0.21 +/- 0.02 to 0.39 +/- 0.04 microgram/L, P < or = 0.05 vs. baseline), respectively. Serum IGF binding protein-3 concentrations increased with both 10 mg (1.2 +/- 0.1 to 1.7 +/- 0.1 micrograms/L, P < or = 0.05) and 50 mg MK-677 (1.7 +/- 0.1 to 2.2 +/- 0.2 micrograms/L, P < or = 0.05). The GH response to MK-677 was greater in subjects who were the least GH/IGF-I deficient at baseline; by linear regression analysis the increase in 24-h mean GH concentration was positively related to both baseline 24-h mean GH concentration (r = 0.81, P = 0.009) and baseline IGF-I (r = 0.79, P = 0.01) for 10 mg MK-677. IGF-I responses were not significantly related to any baseline measurement. Fasting and postprandial insulin and postprandial glucose increased significantly after MK-677 treatment, and the clinical significance of these changes will need to be assessed in longer term studies. Oral administration of such GHRP-mimetic compounds may have a role in the treatment of GH deficiency of childhood onset.

Administration, Oral↗
PubMed1997

Spontaneous feminization in a 46,XX female patient with congenital lipoid adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein.

The most severe form of congenital adrenal hyperplasia (CAH) is lipoid CAH. It was once thought that this disease was due to mutations in the cholesterol side-chain cleavage enzyme system, thus eliminating the ability to convert cholesterol to pregnenolone, causing a complete absence of steroid hormone production. We recently showed that lipoid CAH is due to mutations in the steroidogenic acute regulatory (StAR) protein, thus preventing acutely stimulated adrenal and gonadal responses to tropic stimulation. However, this lesion may permit low levels of StAR-independent steroidogenesis to persist until the accumulation of intracellular lipid deposits destroys steroidogenic capacity. This model would predict that the steroidogenic cells of the ovaries of affected 46,XX females should remain undamaged until puberty, at which time low levels of StAR-independent estrogen biosynthesis should be detectable. We describe a 15.5-yr-old 46,XX female with a classic history of lipoid CAH who underwent spontaneous feminization and cyclical vaginal bleeding beginning at age 13. Genetic analysis of the patient and her parents showed that she was homozygous for the novel StAR frameshift mutation 261delT. This is the first adolescent female with lipoid CAH who has undergone spontaneous feminization and who has been analyzed genetically. Finding an inactive StAR gene in this patient confirms our two-hit model of the pathogenesis of lipoid CAH, in which loss of StAR activity initially preserves StAR-independent steroidogenesis, which is lost only after cells undergo chronic tropic stimulation and subsequent damage from accumulation of cholesterol esters.

Adolescent↗
PubMed1997

Testing the hypothalamic-pituitary-adrenal axis in survivors of childhood brain and skull-based tumors.

The objective of this study was to determine whether a low dose of ACTH (0.2 microg/kg) improves the sensitivity of ACTH testing in detecting hypothalamic-pituitary-adrenal (HPA) axis abnormalities in survivors of childhood brain and skull-based tumors. Twenty-two children who had undergone treatment for brain or skull-based tumors were enrolled in a prospective study to extensively evaluate the HPA axis. Five tests of the adrenal axis were evaluated in each patient, including determination of basal serum cortisol, a standard ACTH test (250-microg i.v. bolus), a low dose ACTH test (0.2 microg/kg i.v. bolus), an insulin tolerance test, and a single dose metyrapone test. Cortisol responses to both ACTH tests were nearly identical. Two patients (9%) failed the low dose ACTH test, whereas three (14%) failed the standard ACTH test; five of the children (23%) failed the insulin tolerance test, and five (23%) had abnormal responses to metyrapone. One child who initially passed the metyrapone test failed the test 19 months later after becoming symptomatic. All children with abnormal metyrapone test results had low levels of basal cortisol secretion. In this study, the low dose ACTH test did not improve the sensitivity of ACTH testing for evaluation of the HPA axis. We conclude that a single morning basal cortisol level is a good screen for testing the HPA axis in children. We recommend confirming HPA axis dysfunction with the single dose metyrapone test, although this test also has limitations.

Adrenocorticotropic Hormone↗
PubMed1997

Disorders of puberty: inactivating and activating molecular mutations.

Recent developments have increased our understanding of the molecular mechanisms that are responsible for several disorders of puberty. Specific gene mutations have been identified in three syndromes, one that is associated with delayed puberty (Kallmann syndrome) and two that are associated with precocious puberty (McCune-Albright syndrome and familial male precocious puberty). Mutations in the KAL gene have been shown to be responsible for cases of X-linked Kallmann syndrome. This gene encodes a protein that is believed to be involved in neural target recognition and protease inhibition. In McCune-Albright syndrome, heterozygous, postzygotic somatic mutations of the alpha-subunit of the stimulatory guanine nucleotide binding protein Gs have been shown to stimulate constitutive G protein activation and long-term cyclic adenosine monophosphate production. Similarly, familial male precocious puberty has been linked to gain-in-function mutations that result in increased levels of cyclic adenosine monophosphate; however, these mutations are found in the luteinizing hormone receptor gene itself. The clinical manifestations and the recent molecular advances in each of these three syndromes are explored.

Cyclic AMP↗
PubMed1996

A novel peptide from the growth hormone releasing hormone gene stimulates Sertoli cell activity.

The growth hormone releasing hormone (GHRH) gene is believed to produce a single functional peptide, GHRH (1). Although GHRH mRNA and peptide have been identified in various tissues, the only accepted function of GHRH is the stimulation of pituitary growth hormone. We have discovered that the GHRH mRNA encodes a second peptide that is abundant in testicular germ cells and specifically activates Sertoli cell expression of stem cell factor (SCF), a factor crucial for the normal progression of spermatogenesis (2). These observations suggest that the GHRH gene produces two distinct peptides, each with tissue-specific activities.

Amino Acid Sequence↗
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

Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS.

McCune-Albright syndrome (MCAS) is a sporadic disease classically including polyostotic fibrous dysplasia, café au lait spots, sexual precocity, and other hyperfunctional endocrinopathies. An activating missense mutation in the gene for the alpha subunit of GS, the G protein that stimulates cyclic adenosine monophosphate formation, has been reported to be present in these patients. The mutation is found in variable abundance in different affected endocrine and nonendocrine tissues, consistent with the mosaic distribution of abnormal cells generated by a somatic cell mutation early in embryogenesis. We describe three patients with MCAS who had profound endocrine and nonendocrine disease and who died in childhood. Two of the patients were severely ill neonates whose complex symptoms did not immediately suggest MCAS. A mutation of residue Arg201 of GS alpha was found in affected tissues from all three children. A review of the literature and unpublished case histories emphasizes the existence of other patients with severe and unusual clinical manifestations. We conclude that the manifestations of MCAS are more extensive than is generally appreciated, and may include hepatobiliary disease, cardiac disease, other nonendocrine abnormalities, and sudden or premature death.

Adolescent↗
PubMed1993

Gonadotropin-releasing hormone agonists in the treatment of girls with central precocious puberty.

The onset of puberty before the age of 8 years in a girl is considered precocious. A child who presents with premature sexual development requires a thorough history, physical examination, and appropriate laboratory evaluation. Making the correct diagnosis is crucial to the selection of the appropriate form of therapy and management. Generally, CPP is the result of premature activation of the hypothalamic-pituitary-gonadal axis and can be successfully managed with long-acting GnRH agonists. In addition, GnRH analogue therapy has been shown to be safe, effective, and reversible. Treatment has resulted in a delay in the progression of secondary sexual development, normalization of the growth velocity, slowing of the rate of bone maturation, and an increase in the predicted final adult height. The GnRH agonists are ineffective in the therapy of gonadotropin-independent precocious puberty.

Child↗
PubMed1993

Germ cell localization of a testicular growth hormone-releasing hormone-like factor.

GH-releasing hormone (GHRH)-like mRNA and immunoreactivity (t-GHRH-li) are present in the testes of rats and humans. To learn more about the physiology of t-GHRH-li mRNA, we performed a series of experiments that disrupted various testicular functions. We employed ethylene dimethanesulfonate, a Leydig cell toxin, to assess the effects of Leydig cell ablation on t-GHRH-li mRNA and protein levels in prepubertal and postpubertal male rats. The ethylene dimethanesulfonate treatment resulted in decreases in serum testosterone, but had no effect on t-GHRH-li mRNA or peptide levels. To assess the effect of GHRH on Leydig cell steroidogenesis, Leydig cells were isolated by Percoll gradient centrifugation and cultured in the presence or absence of hCG, GHRH, or hCG plus GHRH. GHRH had no effect on steroidogenesis by Leydig cells, either alone or in combination with hCG. To localize t-GHRH-li mRNA within rat testis, in situ hybridization analysis was performed on testicular sections from normal rats, using a [35S]GHRH riboprobe. Grains were detected in spermatogenic cells with the antisense probe, whereas none was detected with the sense strand (control) probe. To verify these results, Northern blot analysis of RNA from separated testicular cells was performed. t-GHRH-li mRNA was detected in spermatocytes and round spermatids and to a lesser extent in Sertoli cells, but not in elongating spermatids, Leydig cells, or peritubular myoid cells. t-GHRH-li mRNA was also not found in epididymis. Since our experiments localized t-GHRH-li mRNA to spermatogenic cells, methoxyacetic acid (MAA), a pachytene spermatocyte toxin, was administered to postpubertal rats to determine whether t-GHRH-li is expressed primarily in pachytene spermatocytes. MAA treatment caused a decrease in testicular weight, which gradually returned to control levels by 42 days. Serum FSH levels in the treated animals fluctuated over the course of the experiment, while those in control animals remained steady. However, there was no difference in testicular GHRH-li mRNA levels between control and treated animals at any treatment time. Insulin-like growth factor-I and -II mRNA levels were also unaltered by the MAA treatment. We conclude from these results that t-GHRH-li is synthesized in early spermatogenic cells, but not in mature sperm, and that testicular GHRH-li does not play a major role in steroidogenesis by the Leydig cell.

Animals↗
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↗