PubMed Health⌕ Search

Biomedical subjects

L Cuttler

Publications and source records attributed to L Cuttler.

At least 37 records · Page 2Linked to original sources
PubMed1993

Maturation of gonadotropin and sex steroid responses to gonadotropin-releasing hormone agonist in males.

We have previously demonstrated that a single dose of the GnRH agonist nafarelin stimulates both gonadotropin and sex steroid secretion in adult men and women. In order to define the maturational steps involved in this response, we tested the effect of nafarelin on LH, FSH, testosterone (T), and estradiol (E2) secretion over 24 h in four groups of males: prepubertal (P1; n = 4), early pubertal (P2; n = 8), and midpubertal boys (P3; n = 4) with variations in the timing of puberty, and normal young adult males (P4; n = 10). Nafarelin stimulated rapid gonadotropin release in all groups, but the pattern of LH response varied. In prepubertal and pubertal boys, LH levels peaked 3-4 h after nafarelin and declined by 50% or more at 24 h post nafarelin. By contrast, adults reached an initial LH peak at 1 h, and LH secretion was sustained with levels 24 h post nafarelin equivalent to those during the early response phase. Nafarelin stimulated T secretion in all groups, but the response was greatest in groups P3 and P4; the maximal incremental rise (delta) in T was 1.2 +/- 0.5, 4.4 +/- 1.0, 18.8 +/- 5.4, and 15.3 +/- 1.4 nmol/L in P1, P2, P3, and P4 males, respectively (analysis of variance: F = 14.4, P < 0.001). E2 concentrations increased much more in adults than in the other groups post nafarelin: delta E2 was 5.5 +/- 1.1, 22.1 +/- 14.7, 83.9 +/- 47.5, and 323.8 +/- 14.7 pmol/L in the P1, P2, P3, and P4 groups, respectively (F = 71.1, P < 0.001). Similarly, the delta E2/delta T ratio was significantly greater in adult males than in less mature males. This developmental pattern of response to nafarelin suggests that male pubertal maturation involves increase of the gonadotrope LH readily releasable and reserve pools. The dissociation of E2 from T responses to nafarelin during puberty suggests that aromatase activity does not fully mature in males until puberty is complete. These findings indicate that a single dose of the GnRH agonist nafarelin is a promising means of assessing the maturation of the pituitary-gonadal axis in males.

Adolescent↗
PubMed1993

The effect of isobutylmethylxanthine, forskolin, and cholera toxin on growth hormone release from pituitary cell cultures of perinatal and mature rats.

The factors that regulate growth hormone (GH) release during the perinatal period are not well understood. Circulating GH levels are markedly elevated in mammalian fetuses and newborns compared with mature animals, and the immature pituitary is highly responsive to the GH-stimulatory effect of GH-releasing factor (GHRF). The etiology of these developmental changes in GH secretion is not known. In order to investigate the mechanisms underlying GH release from immature pituitaries, we tested the effects of agents that increase intracellular cyclic adenosine 3',5' monophosphate (cAMP) production independent of the GHRF receptor on GH release from pituitaries of developing and mature rats. Pituitary cell cultures from fetal (day 20 of gestation), newborn (postnatal day 2), juvenile (postnatal day 12-15), adult male (3-4 months), and adult female (3-4 months) rats were tested with isobutylmethylxanthine (IBMX; 0.001-1.0 mM), forskolin (0.01-10 microM), and cholera toxin (0.025-25 ng/ml). IBMX, forskolin, and cholera toxin stimulated GH release in a dose-dependent manner from pituitary cultures of all age groups. However, the magnitude of the GH responses to these agents was highly age-dependent. Perinatal pituitaries exhibited markedly greater GH responses to IBMX, forskolin, and cholera toxin than did those of mature animals (P < 0.001 for age effect with each agent). GH release in response to the highest dose of IBMX (1 mM) was 301 +/- 8, 389 +/- 37, 296 +/- 33, 198 +/- 14, and 187 +/- 19% of control values from pituitary cell cultures of fetal, newborn, juvenile, adult male, and adult female rats, respectively (P < 0.001). In response to the highest dose of forskolin (10 microM) GH release was 537 +/- 46, 601 +/- 75, 274 +/- 22, 270 +/- 37, and 248 +/- 35% of control values in the same respective age groups (P < 0.001). Similarly, the highest dose of cholera toxin (25 ng/ml) stimulated GH release to 407 +/- 55, 365 +/- 43, 249 +/- 26, 186 +/- 11, and 186 +/- 1% of controls in these respective age groups (P < 0.003). The marked stimulation of GH release from perinatal pituitaries by IBMX, forskolin, and cholera toxin is consistent with the concept that cAMP is a potent mediator of GH release from immature as well as mature somatotrophs. The developmental changes in the GH secretory response to these agents further suggest that signal transduction pathways mediating GH release may undergo maturation, at least in part, at intrasomatotroph loci distal to the GHRF receptor.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Calcium signalling in single growth hormone-releasing factor-responsive pituitary cells.

The release of pituitary GH appears to be critically dependent on alterations in the free intracellular Ca2+ concentration ([Ca2+]i). However, little is known about the nature of Ca2+ signalling within normal pituitary cells. We, therefore, examined [Ca2+]i patterns in individual cultured pituicytes of adult male rats under basal conditions and in response to GH regulatory agents, using the calcium-sensitive dye fura-2 together with digital imaging microscopy. Perfusion of cultured anterior pituitary cells with GH-releasing factor (GHRF) resulted in a marked increase in [Ca2+]i in specific pituitary cells. These cells did not respond to other hypothalamic secretagogues (GnRH, TRH, or CRF), and there was no evidence of desensitization on repetitive administration of GHRF. Somatotrophs (n = 134) exhibited spontaneous oscillations of [Ca2+]i in the basal state, with considerable heterogeneity of oscillatory patterns among cells. After application of a near-maximal stimulatory dose of GHRF (1 nM), there was a striking 2.2-fold increase in the amplitude of [Ca2+]i oscillations and only a modest increase in their frequency. Forskolin (1 microM) augmented somatotroph [Ca2+]i in patterns similar to those of GHRF. Somatostatin (10 nM) abolished the [Ca2+]i response to GHRF (n = 26); this reflected a marked reduction in the amplitude of [Ca2+]i oscillations and a slight reduction in their frequency. Ca(2+)-free medium or the Ca2+ channel antagonist nimodipine (0.1-1 microM) suppressed the Ca2+ stimulatory effect of GHRF. Conversely, the Ca2+ channel agonist BAY K8644 (1 microM) strikingly augmented the GHRF-induced rise in [Ca2+]i, with a major stimulatory effect on the amplitude of [Ca2+]i oscillations and no observed effect on their frequency. In summary, GHRF and other hypothalamic secretagogues increase [Ca2+]i in pituitary cells in a highly specific manner, consistent with the known specificity of their effects on hormone release. Somatotrophs exhibit spontaneous rhythmic oscillation of [Ca2+]i in the basal state. Known regulators of GH release markedly alter the [Ca2+]i oscillatory pattern in characteristic manners, exerting predominant effects on the amplitude of [Ca2+]i pulses and lesser effects on their frequency. These striking effects of GH regulatory agents on pituitary Ca2+ signalling are consistent with the concept that modulation of [Ca2+]i is a critical mediator of somatotroph function.

Animals↗
PubMed1990

Preserving adult height potential in girls with idiopathic true precocious puberty.

We designed a prospective study of height potential in girls with idiopathic precocious puberty, comparing the presenting features of girls with and without evidence of reduced adult height potential. The 14 girls with impaired adult height prognoses (group 1) were reexamined after treatment with a gonadotropin releasing hormone agonist, nafarelin. The seven girls with the prognosis of unimpaired height (group 2) were followed without therapy. We found that the group could be distinguished at initial examination by the greater bone age/height age ratio of group 1 (mean +/- SEM: 1.4 +/- 0.06 vs 1.0 +/- 0.05; p less than 0.005) and by the greater difference between predicted height and target height in group 1. The mean predicted height in group 1 was significantly less than the mean target height (150.7 +/- 2.1 vs 165.4 +/- 3.0 cm; p less than 0.005), whereas the mean predicted and target heights in group 2 were similar (165.4 +/- 3.0 vs 164.3 +/- 2.1 cm). Initial estradiol levels were also greater in group 1 than in group 2 (21.6 vs 10.6 pg/ml; p less than 0.05), although this difference was not sustained during follow-up. In group 1, nafarelin therapy suppressed the pituitary-gonadal axis, and although there was a transient reduction in height potential in girls with the youngest bone ages during the first 6 months of therapy, 2 years of treatment slightly improved predicted heights from 150.7 +/- 2.1 to 152.7 +/- 2.0 cm (p less than 0.05). Height predictions also increased without therapy during the 2-year observation period in group 2, from 165.4 +/- 3.0 to 168.7 +/- 4.1 cm (p less than 0.05). Our data indicate that gonadotropin releasing hormone agonist therapy preserves height potential in girls with an initially impaired height prognosis, and that height potential is preserved without therapy in those with a good initial height prognosis.

Age Determination by Skeleton↗
PubMed1990

Biphasic action of forskolin on growth hormone and prolactin secretion by rat anterior pituitary cells in vitro.

To assess the role of cAMP-mediated signal transduction processes in mediation of secretagogue-stimulated GH release, we examined the dose-related effects of the diterpene adenylate cyclase activator forskolin (FSK) in primary monolayer cultures of rat adenohypophyseal cells. In cell cultures prepared from both immature (12 days old) and adult (6 weeks to 4 months old) male or female rats, the dose-related stimulation of GH release by FSK was biphasic. With increasing FSK concentrations from 0.03-3.16 microM, GH release increased progressively to maximal values of 442 +/- 19% and 303 +/- 10% of basal release in cells from immature and adult rats, respectively. FSK concentrations above 3.16 microM induced progressively diminished GH responses, with net inhibition to below basal release evident at 100 microM FSK. FSK stimulated PRL release to a lesser degree than it did GH release; the PRL response to FSK was also biphasic. When maximal stimulatory concentrations (Emax) of FSK and GH-releasing factor (GRF; 10 nM) were added in combination, the GH response was significantly less than the individual response to either secretagogue alone. In response to FSK alone, GRF alone, and FSK plus GRF, GH release was 478 +/- 7%, 583 +/- 11%, and 244 +/- 5%; 278 +/- 4%, 283 +/- 3%, and 175 +/- 2%; and 299 +/- 12%, 351 +/- 5%, and 191 +/- 17% of basal release in cells from 12-day-old, adult male, and adult female rats, respectively (P less than 0.01 for all responses to combined addition vs. the individual responses). Submaximal stimulatory concentrations of GRF added in combination with submaximal FSK elicited partially additive GH responses; the GH response to Emax GRF, on the other hand, was inhibited in a dose-related manner by all concentrations of FSK that by themselves were stimulatory. The GH responses were also suppressed when Emax FSK was added to cultured cells of 12-day-old rats in combination with Emax cholera toxin (2.5 ng/ml) or prostaglandin E2 (10 microM), agents whose actions, like that of GRF, involve adenylate cyclase activation. In contrast, FSK did not suppress but in most cases augmented the maximal GH responses to secretagogues whose action is independent of adenylate cyclase activation: (Bu)2cAMP (0.5 mM), TRH (100 nM), phorbol myristate acetate (50 nM), the Ca2+ ionophore A23187 (250 microM), and the dihydropyridine Ca2+ channel agonist BAY K8644 (10 microM). Indeed, combined addition of FSK with the latter two agents resulted in synergistic stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Ethical issues in growth hormone therapy.

Pediatricians face clinical and ethical dilemmas about therapy to augment growth in short children who do not meet classic criteria for growth hormone (GH) deficiency. Biologic norms of health are unhelpful because of the uncertain relationship between stature, GH secretion, health, and disease. Instead, we suggest that GH therapy be evaluated from the perspective of cultural norms. We compare GH therapy for short normal children with currently accepted therapies for non--life-threatening pediatric conditions such as well-child care, cosmetic therapy, treatment of psychological problems, and invasive outpatient therapy for chronic conditions. Based on this analysis, we argue that the burdens of therapy, the uncertainty about long-term risks and benefits, the unclear therapeutic end point, and the implications for child health policy place routine GH therapy for children without documented deficiency of GH secretion outside current pediatric ethical norms. Such therapy is properly administered within a comprehensive clinical research protocol.

Beauty Culture↗
PubMed1989

Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty.

We tested the hypothesis that growth hormone (GH) mediates the rise in insulin-like growth factor I (IGF-I) concentrations in children with precocious puberty. We studied three groups of patients. Group 1 included six children with GH deficiency and precocious puberty (precocious GH-deficient); group 2 included 10 GH-sufficient patients with idiopathic true precocious puberty (precocious GH-sufficient); and group 3 included 9 prepubertal children with GH deficiency (prepubertal GH-deficient). Growth rates, pubertal status, and plasma IGF-I concentrations were determined at regular intervals. The precocious children with GH deficiency had a mean (+/- SD) growth rate of 7.2 +/- 2.1 significantly below that of the precocious GH-sufficient patients (10.5 +/- 2.5 cm/yr, p less than 0.05) but above that of the prepubertal GH-deficient children (3.9 +/- 1.4 cm/yr, p less than 0.05). The mean IGF-I concentration in the precocious GH-deficient children was 0.77 +/- 0.39 U/ml, significantly lower than the mean level of 2.2 +/- 0.67 U/ml in the precocious GH-sufficient patients (p less than 0.01). However, precocious GH-deficient patients had significantly higher IGF-I values than the prepubertal GH-deficient children (0.24 +/- 0.10 U/ml, p less than 0.05). IGF-I values did not rise with the onset of precocious puberty in four of the precocious GH-deficient children evaluated before and after the development of precocious puberty. However, three patients who began GH treatment did have a rise in plasma IGF-I concentrations to levels of 1.2, 3.4, and 3.7 U/ml, respectively. These findings are compatible with the concept that sex steroids increase IGF-I levels in precocious puberty primarily by increasing GH production. A small but direct effect of sex steroids on IGF-I production may also exist. The onset of precocious puberty in children with organic GH deficiency may mask the abnormal growth pattern of these children and delay diagnosis; determinations of plasma IGF-I concentrations may be helpful in assessing the GH status of these patients.

Adolescent↗
PubMed1989

The effect of age on prostaglandin E2 stimulation of growth hormone release from cultured rat pituitary cells.

Prostaglandin E2 (PGE2) is a potent secretagogue of GH in mature mammals. Although PGs are produced by the fetus and newborn of many species, the ontogeny of PGE2's GH stimulatory effect and the interaction of PGE2 with GHRF in the developing animal are not known. We examined the effects of 0.01-10 microM PGE2 and 0.01-10 nM rat GHRF, alone and in combination, on GH release from cultured pituitary cells of 2-day(d)-old, 7-d-old, 15-d-old, and adult (3- to 4-month-old) male rats (n = 4-7 experiments/age group). The effect of PGE2 on GH release was markedly age dependent. The GH response to all doses of PGE2 over 0.01 microM was greatest in pituitary cells of adult and 15-d-old rats and least in those of 2-d-old pups. PGE2 (0.1 microM) did not cause significant GH release from pituitary cells of 2-d-old pups (110 +/- 3% of control values), but increased that from 7-d-old, 15-d-old, and adult pituitary cells to 126 +/- 8%, 155 +/- 8%, and 156 +/- 9% of respective control values (by analysis of variance: F = 7.28; P less than 0.001). PGE2 (1 microM) increased GH release to 123 +/- 8%, 145 +/- 12%, 259 +/- 24%, and 260 +/- 17% of control values from pituitary cells of these same respective age groups (F = 12.3; P less than 0.001). The highest dose of PGE2 studied (10 microM) yielded similar results. The influence of PGE1 on GH release was also age dependent and similar to that of PGE2. In contrast to PGE2, GHRF stimulated GH release most in pituitary cells of 2-d-old pups and least in those of adults, similar to our previous observations with human GHRF-40. Coincubation with PGE2 and low dose GHRF resulted in partial additivity of GH response in adult rats, but no additivity in newborn pups. These results indicate that in rats, the sensitivity of the somatotroph to PGE2 increases with advancing age after birth. The contrasting developmental patterns of somatotroph sensitivity to PGE2 and GHRF support the concept that these GH secretagogues act, at least in part, by different intracellular mechanisms, which are subject to differential rates of maturation.

Animals↗
PubMed1989

Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome.

Acromegaly and hyperprolactinemia have been reported in association with the McCune-Albright syndrome, but the pathophysiology of the GH and PRL hypersecretion that occurs in patients with this disorder has not been defined. We studied GH and PRL secretory dynamics in three patients with McCune-Albright syndrome and hypersecretion of these hormones. Each patient had excessive linear growth, glucose-non-suppressible plasma GH concentration, and GH responsiveness to TRH and GHRH. In response to exogenous GHRH, plasma GH concentrations rose approximately 2-fold in all three patients. Plasma GHRH levels were 20-40 ng/L (normal, less than 30). Study of the spontaneous GH secretory pattern in two patients indicated nocturnal augmentation of GH release. Bromocriptine therapy failed to reduce plasma GH in all patients; in one patient treatment with octreotide, a long-acting somatostatin analog, partially suppressed plasma GH and insulin-like growth factor I levels. These results suggest that hypersecretion of GH in the McCune-Albright syndrome is not due to ectopic GHRH production or autonomous somatotroph function. The results are similar to those described in classic acromegaly due to GH-secreting pituitary tumors. However, the lack of radiographic pituitary enlargement, the variable pituitary pathology reported in similar patients, and frequent concordance of GH and PRL excess suggest that the pathogenesis of this disorder may differ fundamentally from other forms of acromegaly or gigantism. The pathophysiology may reflect abnormal hypothalamic regulation and/or an embryological defect in pituitary cellular differentiation and function.

Adolescent↗
PubMed1989

A new test of combined pituitary-testicular function using the gonadotropin-releasing hormone agonist nafarelin in the differentiation of gonadotropin deficiency from delayed puberty: pilot studies.

There is evidence that the capacity to synthesize gonadotropins is less in teenage boys with gonadotropin deficiency (GD) than in those with constitutional delay of puberty (DP). We hypothesized that this might predispose the latter group to have a greater pituitary-testicular response to the potent long-acting GnRH agonist nafarelin. We evaluated GD patients 14.3-24.0 yr of age (n = 8) and prepubertal DP boys 14.8-17.6 yr of age (n = 3). In most subjects the response to nafarelin was compared to that of frequent nocturnal blood sampling for LH and testosterone levels. All subjects received a single dose of nafarelin (1.0 micrograms/kg, sc), and blood was then sampled at 0.5- to 4.0-h intervals for 24 h. Patients with GD could not be distinguished from those with DP by pubertal staging criteria or by baseline values of LH, FSH, or testosterone. Patients with GD exhibited no rise in plasma LH levels during sleep, in contrast to those with DP. All GD patients had LH and FSH responses distinctly less than those of the DP group between 3-24 h postnafarelin. The peak incremental responses of GD and DP to nafarelin were, respectively: LH, 5.5 +/- 2 3 (+/- SEM and 77.2 +/- 8.6 IU/L (P less than 0.02); FSH, 2.7 +/- 1.2 and 9.4 +/- 0.8 IU/L (P less than 0.005). Testosterone peak responses were lower as well (0.26 +/- 0.2 vs 1.6 +/- 0.5 nmol/L, P = 0.05). This pilot study suggests that the response to a single test dose of nafarelin distinguishes GD from DP in the teenage years as well as does measurement of nocturnal LH levels. The testosterone response to the GnRH agonist adds a new dimension to GnRH testing. Nafarelin also allows assessment of the bioactivity of endogenous gonadotropin, is a more potent stimulus of pituitary-testicular function than endogenous GnRH secretion, and is more cost-effective than nocturnal sampling.

Adolescent↗
PubMed1987

Evaluation of growth disorders in children.

Both pediatricians and pediatric endocrinologists are frequently required to evaluate children for possible disorders of linear growth. This article reviews the factors which influence growth as well as the etiologies of short and tall stature, and discusses the clinical and laboratory evaluation of abnormal growth. Recent developments in the evaluation of children with growth disorders are highlighted.

Adolescent↗
PubMed1986

Differential responsiveness of the somatotroph to growth hormone-releasing factor during early neonatal development in the rat.

The effects of human pancreatic GH-releasing factor-40 (hpGRF-40; 0.01-100 nM) and (Bu)2cAMP (0.015-1.5 mM) on GH release from primary monolayer cultures of pituitary cells were evaluated in rats of three age groups: postnatal days 2 and 12, and young adult males (3-4 months). Both hpGRF-40 and (Bu)2cAMP elicited a dose-related increase in GH release in cell cultures from each age group. However, the magnitude of the fractional increase over basal release was markedly age dependent. hpGRF-40-stimulated GH release (expressed as a percentage of control values) was greater in cultured cells of 2-day-old than of 12-day-old rats, which was, in turn, significantly greater than in cells of adult rats (P less than 0.001). Maximum hpGRF-40-stimulated GH release was 1058 +/- 50% of control values (+/- SE) in 2-day-old, 617 +/- 21% of control values in 12-day-old, and 405 +/- 6% of control values in adult pituitary cell cultures. The slopes of the dose-response curves differed significantly among the three age groups (P less than 0.001) and varied inversely with increasing age. GH release induced by (Bu)2cAMP was similarly age dependent; maximal stimulated release was 1073 +/- 20%, 414 +/- 4%, and 259 +/- 7% of control values in cultured cells of 2-day-old, 12-day-old, and adult rats, respectively (P less than 0.001 for age effect at each dose). As with hpGRF-40, the slopes of the dose-response curves for (Bu)2cAMP decreased with advancing age (P less than 0.001). Intracellular GH storage during culture, basal release of GH, and serum GH were also age dependent. Pooled serum GH was consistently elevated in 2-day-old rats (139 +/- 2 ng ml-1), became lower and more variable in 12-day-old rats (62 +/- 14 ng ml-1), and was even more variable in adult male rats (79 +/- 23 ng ml-1), owing to random sampling during spontaneous secretory pulses. These results indicate that the stimulatory effects of GRF and (Bu)2cAMP on GH secretion from cultured rat pituitaries vary with age; pituitary cells of newborn rats are relatively more sensitive to these secretagogues than those of adult rats. This increased responsiveness of the neonatal somatotroph to GRF may contribute to the elevation of the plasma GH concentration which is characteristic of the perinatal period in the rat.

Aging↗
PubMed1986

The effect of age on somatostatin suppression of basal, growth hormone (GH)-releasing factor-stimulated, and dibutyryl adenosine 3',5'-monophosphate-stimulated GH release from rat pituitary cells in monolayer culture.

To test the hypothesis that relative resistance of the somatotroph to somatostatin (SRIF) contributes to elevated circulating levels of GH in the newborn rat, we examined the effects of SRIF (0.1, 0.33, and 1 nM) on basal, human pancreatic GH-releasing factor-40 (hpGRF-40; 1 nM)-stimulated, and (Bu)2cAMP (0.5 mM)-stimulated GH release from pituitary cells of 2-day-old, 15-day-old, and adult Sprague-Dawley rats in monolayer culture. The effect of SRIF on basal GH release varied markedly with age. SRIF, in the doses studied, did not inhibit basal GH release (nanograms of GH per 10(5) cells/3 h) from pituitary cultures of 2-day-old rats. In those of 15-day-old rats, only the two higher doses of SRIF (0.33 and 1 nM) suppressed GH release. By contrast, in pituitary cell cultures of adult male and female rats, all doses of SRIF significantly inhibited basal GH release (P less than 0.001). Similarly, the degree of SRIF suppression of both hpGRF-40- and (Bu)2cAMP-stimulated GH release differed among the age groups. In pituitary cultures of 2-day-old rats, SRIF did not significantly inhibit stimulated GH release. In 15-day-old rat pituitary cells, SRIF inhibited GH release, but did not eradicate the stimulatory effect of hpGRF-40 or (Bu)2cAMP. By contrast, in pituitary cell cultures of adult male and female rats, SRIF completely abolished the stimulatory effect of both hpGRF-40 and (Bu)2cAMP. When expressed as a percentage of the control (or stimulated) value, GH release at each SRIF dose varied markedly with age (P less than 0.001). Furthermore, a similar age-associated trend was evident when, in a separate series of experiments (n = 37), we examined the suppressive effect of a single concentration of SRIF (0.33 nM) on (Bu)2cAMP (0.5 mM)-stimulated GH release in cultured pituitary cells of rats ranging in age from -1 (day 20 of gestation) to 78 days. The degree of suppression increased progressively with advancing age; GH release decreased from 82 +/- 2% (+/- SE) of stimulated values in cultured cells of perinatal rats to 20 +/- 1% of stimulated values in cultured cells of 78-day-old rats. There was a significant negative correlation between age and SRIF-inhibited GH release (r = -0.89; P less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1986

Ontogeny of the in vitro growth hormone stimulatory effect of thyrotropin-releasing hormone in the rat.

The ontogenic changes in the somatotroph's responsiveness to TRH were examined in enzymatically dissociated rat pituitary cells in primary monolayer culture. Exposure to TRH (10(-8) M) caused a significant increase in GH release in cultured pituitary cells from rats ranging in age from -1 day (20 days of gestational age) to 90 days. The magnitude of the response, expressed as a percent increment above control rat GH (rGH) release, rose progressively until it reached a maximum of 209 +/- 5% (mean +/- SE) on postnatal day 12. Thereafter, the response declined to values ranging from 10-30% above control rGH release. In cultured adenohypophyseal cells of rats on postnatal day 12, the effect of TRH was dose related; the effective concentration range was 10(-10)-10(-7) M, with an EC50 of 2.5 +/- 0.6 X 10(-9) M. TRH (10(-8) M) potentiated the GH stimulatory effect of a submaximally effective concentration of human GH-releasing factor-40 (hGRF-40; 10(-9) M) in cultured pituitary cells of developing rats, aged -1 to 30 days, and that of (Bu)2cAMP (5 X 10(-4) M) in cultured pituitary cells of rats aged -1 to 45 days. The rGH response to the combined addition of TRH with either hGRF-40 or (Bu)2cAMP was up to 2 times greater (P less than 0.05) than the sum of the individual responses. When the interaction of TRH (10(-8) M) with multiple concentrations of hGRF-40 (10(-10), 10(-9), and 10(-8) M) was tested in cultured pituitary cells of 4- to 36-day-old rats at 4-day intervals, synergism was least at the lowest and greatest at the highest concentration of hGRF-40; synergistic interaction decreased progressively after 20 days of age to undetectable levels by 36 days. In cultured anterior pituitary cells of 12-day-old rats, maximally stimulatory TRH (10(-7) M) potentiated the GH stimulatory effects of both hGRF-40 and (Bu)2cAMP at concentrations at the EC50 value or greater, with synergism being most pronounced at maximally effective concentrations. Whereas the GH response to the combined addition of maximal hGRF-40 (10(-7) M) and (Bu)2cAMP (1.5 X 10(-3) M) was not greater than that to maximal hGRF alone, TRH potentiated the responses to both secretagogues whether added separately or combined.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

The effect of pulsatile administration, continuous infusion, and diurnal variation on the growth hormone (GH) response to GH-releasing hormone in normal men.

To examine the relative effectiveness of GH-releasing hormone (GHRH) given either as multiple iv pulses or as a continuous iv infusion, we studied the GH response to a nearly equivalent total dose of GHRH-44 administered by both routes in a group of normal men. Further, in view of the pulsatile nature of GH secretion and its augmentation with sleep, we investigated whether a diurnal difference in GH release was present during chronic pulsatile administration of GHRH during day and night. Seven men received six GHRH pulses (1 microgram/kg, iv) at 2-h intervals during both day (0900-2100 h) and night (2100-0900 h), and four underwent nighttime placebo pulsing. Eight men received a daytime continuous GHRH infusion (0.15 microgram/kg X h for 5 h, followed by 0.75 microgram/kg X h for 5 h) and a separate 10-h placebo infusion. The GH response to a bolus dose of GHRH (1 microgram/kg, iv) was determined after both continuous GHRH and placebo infusions. No significant difference was found in the GH area response (mean +/- SEM) during total day and night GHRH pulsing periods (6095 +/- 1192 vs. 6506 +/- 1483 ng/min X ml; P = NS). GH secretion was blunted after the initial daytime GHRH pulse (P = 0.02), and only two of seven men had a GH increase after the second pulse; responsiveness was restored after the fourth pulse. In contrast, all subjects responded to the second nighttime GHRH pulse. During continuous GHRH infusions, GH secretion was unsustained and pulsatile. The incremental GH response to a single GHRH bolus dose was decreased after GHRH infusion compared to that after placebo (4.4 +/- 1.8 vs. 10.3 +/- 3.4 ng/ml; P less than 0.05). No difference was found in the total GH area response to a nearly equivalent dose of GHRH administered as either multiple pulses or continuous infusion followed by a single GHRH bolus dose. The apparent pulsatile nature of GH secretion during continuous GHRH infusion and the lack of a significant difference in the GH response to a nearly equivalent dose of GHRH administered as either multiple pulses or a continuous infusion suggest that GHRH need not be administered in a pulsatile manner to be an effective therapeutic agent for the stimulation of GH secretion in children with hypothalamic GHRH deficiency.

Adult↗
PubMed1985

Hormone ontogeny in the ovine fetus. XVIII. The effect of an opioid antagonist on luteinizing hormone secretion.

Endogenous opioid-like peptides influence gonadotropin release in adult animals and man; however, the role of these peptides in the regulation of fetal LH secretion is not known. We administered naloxone hydrochloride (1.3 mg/kg iv), a specific opioid receptor antagonist, to 22 chronically catheterized ovine fetuses of gestational ages 94-143 days (term = 147 days). As a control, each fetus also received the vehicle on a separate occasion, the sequence of the studies being randomized. After the administration of naloxone, LH secretion increased from 38.6 +/- 5.8 to 114 +/- 21 ng/h ml-1 (P less than 0.001); LH release was not affected by administration of the vehicle. Morphine (13 mg/kg) and naloxone (1.3 mg/kg) were administered together to three fetuses (gestational age 94-105 days); LH secretion was sharply reduced from 411 +/- 14.3 ng/h ml-1 after naloxone alone to 53 +/- 17.5 ng/h ml-1 after the administration of both naloxone and morphine (P less than 0.01). The response to naloxone varied with gestational age. Fetuses of 94-115 days showed a significantly higher increment in LH secretion when given naloxone (112.3 +/- 30.7 ng/h ml-1) than did older fetuses of gestational age 126-143 days (64.8 +/- 20.8 ng/h ml-1) (P less than 0.02). These findings indicate that, in the ovine fetus endogenous opioid-like peptides exert a tonic suppressive effect on LH secretion at least as early as 94 days gestation. Moreover, the effectiveness of naloxone in augmenting LH release decreases with advancing gestational age. This latter observation supports the concept that, in the ovine fetus, endogenous opioid tone is not the sole factor involved in the dampened fetal LH secretion which is characteristic of late gestation.

Animals↗
PubMed1985

Somatomedin-C levels in children and adolescents with gonadal dysgenesis: differences from age-matched normal females and effect of chronic estrogen replacement therapy.

The factors responsible for the elevation of circulating somatomedin-C/insulin-like growth factor I (Sm-C) during normal pubertal development are uncertain. To assess the role of ovarian estrogen secretion during puberty, we examined the effect of estrogen deficiency due to primary hypogonadism on Sm-C levels in late childhood and early adolescence. The concentration of immunoreactive Sm-C was measured in 36 untreated patients with gonadal dysgenesis (age, 4-16 yr); results were compared with the pattern of change in Sm-C in 153 age-matched normal girls. Between ages 4-9 yr, patients with gonadal dysgenesis had Sm-C levels similar to those in the age-matched normal subjects. In contrast to the normal girls, Sm-C levels in patients with gonadal dysgenesis did not rise after 10 yr of age and were significantly lower than those in normal girls at 11-16 yr of age. The effect of low dose estrogen therapy was assessed in eight patients with Turner's syndrome. Their Sm-C levels were measured before and during 2-12 months of treatment with ethinyl estradiol (90-220 ng/kg X day). The mean Sm-C concentration rose from 0.72 +/- 0.06 U/ml (+/- SEM) before treatment to 1.17 +/- 0.17 U/ml during estrogen treatment (P less than 0.04). In three patients who had a similar increase in Sm-C during estrogen treatment, interruption of therapy was associated with a fall in Sm-C concentrations; when estrogen therapy was reinstituted in two of these patients, Sm-C levels rose again. These results suggest that increasing endogenous estrogen production is a major determinant of the rise of circulating Sm-C that occurs during pubertal development in normal girls. Chronic estrogen deficiency, as in untreated patients with gonadal dysgenesis, is associated with failure to manifest the elevation of Sm-C that occurs during normal puberty.

Adolescent↗