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Biomedical subjects

M M Grumbach

Publications and source records attributed to M M Grumbach.

At least 37 records · Page 2Linked to original sources
PubMed1995

Long-term effect of gonadotropin-releasing hormone agonist therapy on final and near-final height in 26 children with true precocious puberty treated at a median age of less than 5 years.

We report a long term study on the effectiveness of chronic GnRH agonist treatment on final or near-final height in 26 patients (20 females and six males) with true precocious puberty (TPP). This study differs from other treatment studies in that the median age at onset of therapy was 4.7 yr for females and 6.2 yr for males, the youngest cohort of treated patients reported to date. We compared patients treated with GnRH agonists who attained final or near-final height with a historical control group of untreated children with TPP (n = 116) matched for mean age of pubertal onset, etiology of TPP (idiopathic or neurogenic), rate of progression, and sex ratio. The current mean height of GnRH agonist-treated females who began therapy at more than 5 yr of age (157.6 +/- 6.6 cm) is already significantly greater than the mean final height of untreated females (152.7 +/- 8.6 cm). The current mean predicted height of the treated females is 164.6 +/- 9.7 cm. The current mean height of females whose treatment was started before 5 yr of age is greater (164.1 +/- 7.7 cm) than that of females whose treatment began after 5 yr of age (157.6 +/- 6.6 cm). The final height of untreated children whose age of sexual precocity was less than 5 yr at diagnosis is significantly less than that of treated patients who were less than 5 yr when they developed TPP (P = 0.0006). The current mean height of GnRH agonist-treated males is 166.3 +/- 12.2 cm, and the current mean predicted height is 170.8 +/- 11.3 cm. This is in sharp contrast to the mean final height of untreated males (155.6 +/- 7.7 cm). The current predicted height correlates negatively with the age at initiation of treatment and the initial bone age and positively with height SD for bone age in the agonist-treated children. The current mean height deviation from target height is significantly less in the 20 treated females (-1 SD) than in 93 untreated females (-2.4 SD; P = 0.006). The mean final height deviation from target height in 23 untreated males (-3.7 SD) is significantly greater than the current height deviation from target height in 6 treated males (-1.7 SD; P = 0.03). The salutary effects of long term GnRH agonist therapy on stature are more clear-cut in the younger treated children. Young untreated children may have the worst outcome with respect to final height.(ABSTRACT TRUNCATED AT 400 WORDS)

Body Height↗
PubMed1994

Role of MRI in the evaluation of ambiguous genitalia.

Diagnostic accuracy of magnetic resonance imaging (MRI) interpretation was assessed prospectively in patients with ambiguous genitalia or intersex problems. MRI depiction of the uterus was possible in 93%, the vagina in 95%, the penis in 100%, the testis in 88%, and the ovary in 74% of patients. The strength of MRI lies in the multiplanar capability and tissue characterization by means of T1- and T2-weighted sequences. MRI contributes to accurate morphologic evaluation of müllerian duct structures, the gonads, and the development of the phallus, all of which are essential for appropriate gender assignment and planning of surgical reconstruction.

Adolescent↗
PubMed1994

N-methyl-D-aspartate (NMDA) receptors mediate the release of gonadotropin-releasing hormone (GnRH) by NMDA in a hypothalamic GnRH neuronal cell line (GT1-1).

Previous studies demonstrated that an excitatory amino acid analog, N-methyl-D-aspartate (NMDA), stimulates GnRH secretion in the rat, prepubertal primate, and ovine fetus at the hypothalamic level. It is not known if this stimulatory effect of NMDA is mediated directly on the GnRH neurosecretory neuron. A hypothalamic GnRH neuronal cell line (GT1-1) provided a useful model system to study the effect of NMDA on GnRH release by both superfusion and static incubation techniques. Studies with GT1-1 cells indicate that GnRH neurons exhibit spontaneous autorhythmicity and function intrinsically as a neuronal oscillator for the synchronous discharge of GnRH pulses. In static incubation studies, 10(-4) and 10(-3) M NMDA increased GnRH release, whereas 10(-6), 10(-5), and 10(-2) M NMDA had no effect. A competitive NMDA receptor antagonist, AP-5 (10(-4)-10(-2) M), and a noncompetitive NMDA receptor antagonist, MK-801 (10(-12)-10(-5) M), inhibited the action of NMDA. Superfusion of GT1-1 cells after a 90-min control period followed by either continuous NMDA or intermittent NMDA (10(-4) and 10(-3) M) for 90 min increased GnRH pulse amplitude by 100-400%, but had no effect on the interpulse interval (17 min by Cluster); 10(-6), 10(-5), and 10(-2) M NMDA had no effect on either pulse amplitude or interpulse interval. MK-801 (10(-5) M) attenuated the stimulatory effect of NMDA on GnRH pulse amplitude. Incubation in glycine-free and high magnesium medium abolished the action of NMDA on GnRH release. Hybridization analysis of GT1-1 mRNA with an NMDA R1 receptor cDNA showed that this pure neuronal cell line expressed NMDA receptor transcripts observed as a 4.2-kilobase band. The results demonstrate that NMDA stimulates GnRH neurons directly to secrete GnRH through their NMDA receptors by increasing pulse amplitude without affecting pulse frequency.

Animals↗
PubMed1994

Nitric oxide synthesized by gonadotropin-releasing hormone neurons is a mediator of N-methyl-D-aspartate (NMDA)-induced GnRH secretion.

N-Methyl-D-aspartate (NMDA) directly stimulates gonadotropin-releasing hormone (GnRH) neurons to secrete GnRH. It is not known if this stimulatory effect of NMDA is mediated by NO. Northern blot analysis of the immortalized hypothalamic GnRH neuronal cells (GT1-1) mRNA with a neuronal NOS cDNA revealed this clonal cell line expressed neuronal NOS transcripts as a single 10.5-kb band. Immunoblot analysis of GT1-1 proteins with anti-neuronal NOS serum showed that the GT1-1 cells contain neuronal NOS. GT1-1 cells were used to study the effects of NO and NMDA on GnRH release. L-Arginine (10(-2) M), a precursor of NO enhances basal GnRH secretion. Both oxyhemoglobin (Hb)(10(-6)-10(-4) M), a NO scavenger and N omega-nitro-L-arginine (NNA)(10(-3),10(-2) M), a NOS inhibitor and inactivator block basal as well as NMDA-induced GnRH release. Sodium nitroprusside (SNP) (10(-4), 10(-3) M), a NO donor stimulates GnRH release, an effect inhibited by Hb. Incubation of GT1-1 cells in Ca(2+)-free medium abolished the stimulatory effect of NMDA on GnRH release. In contrast, incubation in medium with increasing concentrations of Ca2+ enhances basal GnRH release as well as augments NMDA-mediated GnRH release. The results demonstrate that L-arginine-NO pathway is functional in the GT1-1 cells and an increase in intracellular Ca2+ [Ca2+]i following NMDA receptor activation activates NOS to generate NO. We conclude that endogenous NO mediates, at least in part, basal as well as NMDA-stimulated GnRH release and may play a role as an intercellular messenger in synchronizing pulsatile GnRH release.

Amino Acid Oxidoreductases↗
PubMed1994

A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom).

We report the features of a new syndrome of aromatase deficiency due to molecular defects in the CYP19 (P450arom) gene in a 46,XX female. At birth, the patient presented with a nonadrenal form of female pseudohermaphrodism. At 17 months of age, laparotomy revealed normal female internal genital structures; the histological appearance of the ovaries was normal. FSH concentrations were markedly elevated at 9.4 ng/mL LER 869, and estrone and estradiol levels were undetectable (< 37 pmol/L). By 14 yr of age, she had failed to exhibit breast development. The clitoris had enlarged to 4 x 2 cm, and pubic hair was Tanner stage IV. The plasma concentration of testosterone was elevated at 3294 pmol/L, as was androstenedione at 9951 pmol/L. Plasma estradiol levels were below 37 pmol/L. ACTH and dexamethasone tests indicated a nonadrenal source of testosterone and androstenedione. Plasma gonadotropin levels were in the castrate range. Pelvic sonography and magnetic resonance imaging showed multiple 4- to 6-cm ovarian cysts bilaterally. Despite increased circulating androgens and clitoral growth, the bone age was 10 yr at chronologic age 14 2/12 yr. Estrogen replacement therapy resulted in a growth spurt, breast development, menarche, suppression of gonadotropin levels, and resolution of the cysts. The clinical findings suggested the diagnosis of P450arom deficiency. Analyses of genomic DNA from ovarian fibroblasts demonstrated two single base changes in the coding region of the P450arom gene, one at 1303 basepairs (C-T), R435C, and the other at 1310 basepairs (G-A), C437Y, in exon 10. The molecular genetic studies indicate that the patient is a compound heterozygote for these mutations. Expression of these mutations showed that the R435C mutation had 1.1% the activity of the wild-type P450arom enzyme, whereas the C437Y mutation demonstrated no activity. The cardinal features of this syndrome are a consequence of P450arom deficiency: 1) the fetal masculinization in this syndrome can be ascribed to defective placental conversion of C19 steroids to estrogens, leading to exposure of the female fetus to excessive amounts of testosterone; 2) the pubertal failure, mild virilization, multicystic ovaries, and hyperstimulation of the ovaries by FSH and LH are the result of the inability of the ovary to aromatize testosterone and androstenedione to estrogens; and 3) the striking delay in bone age at 14 2/12 yr supports the notion that estrogens, in contrast to androgens, are the major sex steroid driving skeletal maturation during puberty. Familial P450arom deficiency, although rare, may be more common than previously suspected.(ABSTRACT TRUNCATED AT 400 WORDS)

17-alpha-Hydroxypregnenolone↗
PubMed1993

Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries.

We identified two mutations in the CYP19 gene responsible for aromatase deficiency in an 18-year-old 46,XX female with ambiguous external genitalia at birth, primary amenorrhea and sexual infantilism, and polycystic ovaries. The coding exons, namely exons II-X, of the CYP19 gene were amplified by PCR from genomic DNA and sequenced directly. Direct sequencing of the amplified DNA from the patient revealed two single-base changes, at bp 1303 (C-->T) and bp 1310 (G-->A) in exon X, which were newly found missense mutations and resulted in codon changes of R435C and C437Y, respectively. Subcloning followed by sequencing confirmed that the patient is a compound heterozygote. The results of restriction fragment length polymorphism analysis and direct sequencing of the amplified exon X DNA from the patient's mother indicate maternal inheritance of the R435C mutation. Transient expression experiments showed that the R435C mutant protein had approximately 1.1% of the activity of the wild type, whereas C437Y was totally inactive. Cysteine-437 is the conserved cysteine in the heme-binding region believed to serve as the fifth coordinating ligand of the heme iron. To our knowledge, this patient is the first adult to have described the cardinal features of a syndrome of aromatase deficiency. Recognition that such defects exist will lead to a better understanding of the role of this enzyme in human development and disease.

Adolescent↗
PubMed1993

Hormone ontogeny in the ovine fetus. XXVII. Pulsatile and copulsatile secretion of luteinizing hormone, follicle-stimulating hormone, growth hormone, and prolactin in late gestation: a new method for the analysis of copulsatility.

To analyze the secretion patterns of LH, FSH, GH, and PRL in the late gestational sheep fetus in vivo, we measured simultaneous plasma levels of these hormones during a period of frequent sampling under basal conditions (samples every 15 min for 5 h) in 17 chronically catheterized sheep fetuses. To calculate mean plasma levels and areas under the curve, we analyzed hormone pulses and coincident pulse patterns to assess interactions between the release of these pituitary hormones. Mean plasma levels for all fetuses were: LH, 0.8 +/- 0.2 ng/ml (mean +/- SEM); FSH, 4.6 +/- 0.7 ng/ml; GH, 136.6 +/- 16.5 ng/ml; and PRL, 40.5 +/- 10.3 ng/ml. Pulse analysis detected 20 LH pulses during 5100 min of total sampling time, which gave a mean interpulse interval of 255.0 min. For GH, 37 pulses were detected; the mean interpulse interval was 129.7 min. Twenty PRL pulses yielded a mean interpulse interval of 225.0 min. FSH pulses could not be analyzed due to the long half-life of this hormone, but hormone level fluctuations were screened for maxima. A new method was developed to detect an interaction between hormone pulses. The probability of the simultaneous occurrence of hormone pulses was calculated and compared with the rate of coincidences found in the experiments. Analysis of copulsatile release of LH, GH, and PRL revealed 11 GH pulses coinciding with the LH pulses (P = 0.0020). An interaction between the pulsatile release of LH and GH can, therefore, be assumed. There was also a significant interaction between GH and PRL. Seven PRL pulses preceded the GH pulses by 15 min (P = 0.0014). In contrast, no significant copulsatile release could be observed between LH and PRL; 95.5% of LH pulses were accompanied by a maximum FSH level, suggesting an interaction between LH and FSH secretion. In summary, we show that LH, GH, and PRL (and possibly FSH) are secreted in a pulsatile fashion in the ovine fetus. Furthermore, the pulsatile releases of LH, FSH, and GH as well as GH and PRL are temporarily coupled, as demonstrated by a significant number of coincident pulses between LH/GH and GH/PRL and a high number of FSH hormone maxima concomitant with LH pulses.

Activity Cycles↗
PubMed1993

The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history.

The LHRH-secreting hypothalamic hamartoma (HH), a congenital malformation consisting of a heterotopic mass of nervous tissue that contains LHRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle, can cause true or central precocious puberty (TPP). We have suggested that it functions as an ectopic LHRH pulse generator independent of the central nervous system inhibitory mechanism that normally restrains the hypothalamic LHRH pulse generator. TPP associated with a hamartoma has all of the hormonal hallmarks of puberty, including a pubertal pattern of pulsatile LH and a pubertal plasma LH response to LHRH administration. Little is known about the natural history of HH. We present long term data on 10 children (5 females and 5 males) with TPP due to HH. Physical signs of puberty were observed at a mean age of 2.2 +/- 1.6 yr (range, 0.5-5.1). Two of 10 had a pedunculated mass, and 8 of 10 had a sessile mass. The hamartoma varied in diameter from 4-25 mm and did not change with time (3.5-8.7 yr). Four patients have a seizure disorder, 3 with gelastic seizures (1 with mental retardation) and 1 with tonic-clonic seizures. The shape of the hamartoma, sessile or pedunculated, did not correlate with the occurrence of seizures. At presentation with sexual precocity, the mean height SD for chronological age was +3.5 +/- 0.4, the mean height SD for bone age was -1.9 +/- 0.4, and the mean bone age SD for chronological age was +6.8 +/- 0.7. Baseline data were comparable to those of 10 females with idiopathic TPP. Nine of 10 HH patients and all idiopathic TPP patients were treated with a LHRH agonist. The response to therapy was excellent in both groups and indistinguishable. Nine of 10 HH children attend school regularly and, aside from those with seizures, have no neurological handicap. While surgical resection of the hamartoma has been recommended, it carries an increased risk of morbidity and mortality and, if removal is incomplete, does not arrest the sexual precocity. In our experience, LHRH agonist therapy for TPP due to HH is the preferable approach.

Child, Preschool↗
PubMed1991

Hormone ontogeny in the ovine fetus. XXVI. A sex difference in the effect of castration on the hypothalamic-pituitary gonadotropin unit in the ovine fetus.

The detection of pulsatile ovine LH (oLH) secretion in the sheep fetus by 81 days gestation (term 147 days), the suppression of fetal gonadotropin secretion by chronic administration of an LH-releasing factor agonist or antagonist, and the capacity of N-methyl; D-aspartate (a neuroexcitatory amino acid analog) to evoke a fetal oLH pulse strongly support a functional LH-releasing factor pulse-generator in the ovine fetus. In light of the sex difference in fetal gonadal function and gonadotropin secretion before day 114, we postulated that fetal castration would have a discordant effect on the pattern of gonadotropin secretion in males and females. Fetal sheep were either castrated (male = 11; female = 9) or sham operated (male = 9; female = 6) at 110-115 days gestation. Chronic indwelling arterial and venous catheters were implanted, and animals were studied for up to 30 days. During each study period fetal arterial blood samples were drawn every 15 min for 5 h and the plasma assayed for oFSH and oLH by specific RIAs. Multiple studies were performed on each fetus. In all fetuses (both intact and castrated) a decrease in oLH pulse frequency occurred after day 130. In female fetuses before day 130, castration had no effect on mean oLH pulse frequency (sham, 0.72 +/- 0.19 pulses/5 h; castrate, 0.50 +/- 0.13 pulses/5 h; P greater than 0.05). After day 130, pulsatile oLH secretion decreased in both intact and castrated female fetuses to undetectable levels during the sampling period. In contrast, castration significantly (P less than 0.001) increased mean oLH pulsatility in males before and after day 130 (less than 130 days, sham, 1.06 +/- 0.24 pulse/5 h; castrate, 2.70 +/- 0.22 pulse/5 h; greater than 130 days, sham, 0.18 +/- 0.12 pulses/5 h; castrate, 1.65 +/- 0.26 pulses/5 h). Mean oLH pulse amplitude was increased by castration only in the male fetuses (sham, 3.89 +/- 0.87 ng/ml; castrate, 6.02 +/- 0.39 ng/ml; P less than 0.05). oFSH pulses were infrequent in both sexes and not influenced by castration. The mean plasma concentration of oFSH was greater in intact female fetuses than in intact males (female, 5.65 +/- 1.15 ng/ml vs. male, 2.07 +/- 0.45 ng/ml; P less than 0.01). Castration increased the mean value for plasma oFSH in males (4.40 +/- 0.43 ng/ml; P less than 0.001) but had no effect in females (3.83 +/- 0.64 ng/ml; P greater than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Hormone ontogeny in the ovine fetus. XXV. Somatotrope desensitization to growth hormone releasing factor (GRF) independent of short-latency, ultrashortloop GH feedback.

Plasma ovine growth hormone (oGH) concentrations are strikingly elevated in the ovine fetus and decline at birth towards the low levels observed in the newborn lamb. We postulated that developmental changes in somatotrope function secondary to GH-releasing factor (GRF) desensitization and GH feedback play a role in the developmental pattern of oGH secretion and tested this hypothesis in vito in chronically catheterized ovine fetuses (123-145 days gestation; term 147 days) and newborn lambs (1-18 days). In the first set of studies, two consecutive intravenous GRF(1-44 amide) boluses (1 microgram/kg) were administered. When the GRF boluses were given 90 min apart, they elicited similar oGH responses, both in fetuses and in newborn lambs. In contrast, when the GRF boluses were given 20 min apart, a significant oGH response was evoked by the first GRF but an oGH response was not detected after the second GRF, either in fetuses or in newborn lambs. When the oGH response GRF(1-44 amide; 1 microgram/kg i.v.) was evaluated 40 min after the start of a human GH infusion (25 micrograms/kg hGH bolus followed by 0.5 microgram/kg/min hGH for 80 min, resulting in mean hGH plasma concentrations of 80 ng/ml), the exogenous hGH did not after the oGH response to GRF, either in fetuses or in newborn lambs. The present in vivo results demonstrate that the fetal and the neonatal somatotrope can be desensitized to GRF and suggest that a short-term latency, ultrashortloop GH feedback mechanism is not operative, either in the ovine fetus or in the newborn lamb.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The pubertal growth spurt in eight patients with true precocious puberty and growth hormone deficiency: evidence for a direct role of sex steroids.

The relative contributions of GH, insulin-like growth factor-I (IGF-I), estradiol, and testosterone to the pubertal growth spurt are incompletely understood. We studied 8 patients (5 girls and 3 boys) with true precocious puberty and GH deficiency due to CNS lesions to assess the role of sex steroids in pubertal growth independent of an increase in circulating GH. Included is 1 patient with an unusual hypothalamic lesion due to head trauma. A control group of 17 GH-sufficient patients with true precocious puberty (13 girls and 4 boys) was matched for chronological age. The GH-deficient girls grew at a mean velocity of 9.2 cm/yr (range, 7.2-14.4), and the boy's mean height velocity was 7.9 cm/yr (6.1-9.9). Mean bone age was advanced in the GH-deficient group (girls, +2.7 SD; boys, +2.6 SD), but not as much as the GH-sufficient controls (girls, +5.4 SD; boys, +4.3 SD). The mean concentration of plasma IGF-I was lower in the GH-deficient group than in the control group, but was greater than the mean concentration in age-matched prepubertal GH-deficient patients. Four GH-deficient patients were treated with a potent agonist of LRF. This caused suppression of gonadal sex steroid concentrations and a fall in mean height velocity from 9.1 to 4.3 cm/yr after 1 yr of therapy; however, circulating GH and IGF-I values were not uniformly altered. We conclude that a substantial pubertal growth spurt can occur in patients with true precocious puberty and GH deficiency that is dependent on gonadal sex steroids yet unaccompanied by normal pubertal levels of circulating GH or IGF-I. Reversal of this growth acceleration is possible with sex steroid suppression. The results, in light of previous in vivo and in vitro studies, suggest that the normal pubertal growth spurt is mediated in part by direct effects of sex steroids at the growth plate.

Age Determination by Skeleton↗
PubMed1989

Hormone ontogeny in the ovine fetus: XIX: The effect of a potent luteinizing hormone-releasing factor agonist on gonadotropin and testosterone release in the fetus and neonate.

To investigate further the role of the hypothalamic luteinizing hormone releasing factor (LRF) pulse generator and the pituitary LRF receptor in the regulation of gonadotropin secretion and gonadal steroidogenesis in the ovine (O) fetus and neonatal lamb, we measured the increment (the difference between the concentration of plasma LH at time 0 and peak LH) in oLH (delta oLH) and oFSH (delta oFSH) responses to a potent LRF agonist, D-Trp6Pro9NEt-LRF (LRF-A), after consecutive daily doses in 17 ovine fetuses (six females, 11 males) and in 15 neonatal lambs (six females, nine males). Seven of the lambs had been studied as fetuses. In addition, plasma concentrations of testosterone (T) and androstenedione (delta 4A) were measured in nine male fetuses. After a stimulatory response to the first dose of LRF-A, the mean delta oLH and delta oFSH responses in the 106- to 118-d gestation fetuses of both sexes were significantly suppressed by the fourth dose and in the neonatal lamb by the second dose. Suppression was sustained throughout the duration of LRF-A therapy which included the gestational interval when the fetal pituitary exhibits its greatest responsiveness to an acute dose of synthetic LRF. The duration of oLH and oFSH suppression after cessation of LRF-A therapy was studied by measuring the delta oLH and delta oFSH responses to LRF before and at intervals after LRF-A therapy. In the fetus, the delta oLH and delta oFSH responses remained significantly decreased 7-8 d after the agonist was discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Hormone ontogeny in the ovine fetus and neonatal lamb. XX. Effect of age, breeding season, and twinning on the growth hormone (GH) response to GH-releasing factor: evidence for a homeostatic role of fetal GH.

The ovine GH (oGH) response to GRF (1-44 amide) was evaluated in 74 chronically catheterized fetal and neonatal lambs. After a 1-h control period, GRF was administered iv, and the oGH response was studied during the next 60 min. The following variables were analyzed: GRF dose, fetal or neonatal age, breeding season, and singleton or multiple pregnancy. One and 10 micrograms/kg GRF elicited a similar oGH response, which was greater (P less than 0.001) than the response to 0.1 microgram/kg GRF. GRF-stimulated oGH release was strikingly age dependent. The mean peak incremental oGH response in fetuses of 89-122 days gestation (294 +/- 55 ng/ml) was higher (P less than 0.05) than that in fetuses of 127-145 days gestation (136 +/- 19 ng/ml); the fetal response was much greater (P less than 0.005) than the mean peak increment in neonatal lambs (46 +/- 7 ng/ml). A remarkable difference in basal and GRF-induced oGH secretion was observed in both fetuses and lambs of ewes bred in the normal breeding season (on-season) and those bred out of season (off-season). In the neonatal lamb, the mean basal oGH concentration was higher (P less than 0.005) in the on-season (12 +/- 2 ng/ml) than in the off-season (7 +/- 0.5 ng/ml) neonatal lambs, as was the mean peak incremental oGH response to GRF (70 +/- 12 vs. 33 +/- 7 ng/ml; P less than 0.01). In contrast, in singleton, late gestational fetuses (127-145 days), the mean basal oGH concentration was lower (P less than 0.03) in the on-season (74 +/- 9 ng/ml) than in the off-season (124 +/- 18 ng/ml) fetuses, as was the mean peak incremental oGH response to GRF (136 +/- 9 vs. 292 +/- 41 ng/ml; P less than 0.005). Further, compared to the on-season, late gestational singletons, on-season twin fetuses had higher (P less than 0.0001) basal oGH levels (199 +/- 19 ng/ml) and peak incremental oGH responses (248 +/- 11 ng/ml). Moreover, off-season twin fetuses had the highest basal GH concentrations and the most striking increment in GH concentration after GRF treatment of any of the groups. The strikingly age-dependent pattern of the GRF-induced oGH response in fetal and neonatal lambs is compatible with the concept that the inhibitory influences or their effects on the somatotrope increase gradually during late gestation and sharply at birth.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1989

Regulation of growth hormone (GH) secretion by GH-releasing factor, somatostatin, and insulin-like growth factor I in ovine fetal and neonatal pituitary cells in vitro.

Serum GH concentrations in the ovine fetus are much higher than those in the neonate, and the maximal GH response induced by GRF is 5-fold greater in the fetus than in the neonate. To clarify these in vivo observations further, we studied the effects of GRF, somatostatin (SRIF), and insulin-like growth factor I (IGF-I) on primary cultures of fetal and neonatal ovine pituitary cells. GH secretion from fetal ovine pituitary cells increased from 148 +/- 34 to 950 +/- 130 ng/10(5) cells.3 h in response to 1 nM GRF, whereas GH secretion from neonatal pituitary cells rose from 113 +/- 26 to 1221 +/- 129 ng/10(5) cells.3 h, a significantly greater response (P less than 0.001). This greater GRF-induced GH response in neonatal than fetal cells differs from the response in vivo and suggests that the increased in vivo response in the fetus is not due to inherently increased sensitivity of pituitary cells to GRF. SRIF (10 nM) decreased maximal GRF-induced GH secretion by 37 +/- 3% in fetal cells compared with 59 +/- 8% in neonatal cells (P less than 0.01). This may explain in part the decreased in vivo sensitivity to SRIF in the ovine fetus compared to that in the neonatal lamb. In fetal pituitary cells, 10 nM GRF increased ovine (o) GH mRNA from 100 +/- 14% to 145 +/- 40%, SRIF decreased oGH mRNA to 84 +/- 3%, and GRF and SRIF in combination increased fetal oGH mRNA to 126 +/- 24%. Values in neonatal pituitary cell cultures were similar (control, 100 +/- 17%; GRF, 132 +/- 6%, SRIF, 85 +/- 15%; GRF plus SRIF, 105 +/- 26%). Pretreating fetal cells with 100 nM IGF-I for 3 days reduced GRF-stimulated GH secretion from 1049 +/- 38 to 232 +/- 8 ng/10(5) cells.3 h (P less than 0.001). Similarly, IGF-I pretreatment of neonatal cells reduced GRF-stimulated GH secretion from 810 +/- 18 to 419 +/- 16 ng/10(5) cells.3 h (P less than 0.001). The mean secreted IGF-I was 0.58 U/ml (36 nM) in culture medium from neonatal cells and was unchanged by incubation for 3 days with 5 micrograms/ml hGH. Secreted IGF-I in medium from fetal cells was 0.87 U/ml (54 nM) without GH and 0.81 U/ml (51 nM) after incubation with human GH. IGF-I mRNA was present in neonatal pituitary and brain.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Hormone ontogeny in the ovine fetus and neonate. XXII. The effect of somatostatin on the growth hormone (GH) response to GH-releasing factor.

We postulated that an increase in the biological effectiveness of somatostatin (SRIF) accounts, at least in part, for the decrease in basal and GRF-induced ovine GH (oGH) secretion observed around birth in the ovine fetus and neonate. To test this hypothesis, SRIF (SRIF-14; given as 30 micrograms/kg iv bolus, followed by 2 micrograms/kg.min for 75 min) was infused into chronically catheterized fetal and neonatal lambs, and the oGH response induced by GRF [GRF-(1-44) amide; 1 microgram/kg] in the presence of exogenous SRIF was compared to the oGH response induced by GRF in saline-infused controls. In fetuses of 115-122 days gestation, SRIF had no detectable effect on the oGH response to GRF [peak incremental oGH response (mean +/- SEM), 527 +/- 124 vs. 562 +/- 103 ng/ml in controls]. In neonatal lambs (3-17 days old), SRIF completely suppressed the immediate oGH response to GRF (peak incremental response, 0.8 +/- 1.3 vs. 111 +/- 34 ng/ml in controls; P less than 0.02). In late gestational fetuses (126-139 days old), a transitional pattern was observed (peak incremental oGH response, 207 +/- 56 vs. 324 +/- 30 ng/ml in controls; P less than 0.04). In the second part of this study, we explored, in the neonatal lamb, the hypothesis that SRIF withdrawal plays a role in pulsatile GH secretion and that the amount of GRF to which the somatotrope is exposed before SRIF withdrawal is a major factor in determining the amplitude of GH bursts. SRIF (SRIF-14; a 30 micrograms/kg bolus, followed by 2 micrograms/kg.min) was infused iv for 40 min, GRF [GRF-(1-44) amide; 1 microgram/kg] was injected iv 20 min after starting the SRIF infusion, and the oGH rise after SRIF withdrawal was evaluated. In one series of controls GRF was replaced by saline, and in the other SRIF was replaced by saline. The oGH rise during recovery after SRIF alone was lower than that after the combined administration of SRIF and GRF (peak oGH increment, 8 +/- 3 vs. 38 +/- 12 ng/ml; P less than 0.04). The amplitude of the GH pulse after SRIF and GRF was similar to the immediate oGH response to GRF alone. These studies show that SRIF is unable to suppress the immediate oGH response to GRF in the ovine fetus, and that the suppressive effect of SRIF on the immediate oGH response to GRF increases gradually in late gestation and sharply at birth.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗