Influence of testicular hormones on the somatostatin-GH system during the growth promoted transition to puberty in sheep

The aim of the present study was to investigate whether the growth promoted transition to puberty in lambs involved changes in the effects of testicular hormones on somatostatin in hypothalamic neurons and GH secretion. The study was performed in infants (9-week-old) testis-intact (TEI) and orchidectomized (ORCHX) at the sixth week of age, and pubertal lambs (16-week-old) TEI and ORCHX at the 12th week of age (n = 20). In TEI lambs, the changes included a pubertal increase in immunoreactive somatostatin in the periventricular nucleus and median eminence with simultaneous neuropeptide depletion in the median eminence, and a decrease in the percentage of the hypophyseal area (PA) occupied by GH-immunoreactive cells (P < 0.05). The mean concentration of GH in the peripheral blood plasma was greater (P < 0.001) in early infancy (5 wk), because of the greater (P < 0.0001) pulse amplitude, and then uniformly low until puberty. The postnatal increase in the body weight (BW) was prominent (P < 0.01) in middle-late infancy (9-12 wk) because of the large daily live-weight gain. After orchidectomy somatostatin was abundant. This effect on nerve terminals in the median eminence was greater (P < 0.01) in infancy and lesser (P < 0.05) in puberty. Conversely, the PA occupied by GH cells was lower in the ORCHX pubertal lambs compared to TEI lambs (P < 0.05). The GH concentration and pulse characteristics were less (P < 0.05) in the infantile and pubertal ORCHX lambs compared to the TEI lambs. However, this effect was weak (P < 0.05) until middle infancy because of no influence on the GH basal concentration, and strong (P < 0.001) after late infancy. The BW did not differ (P > 0.05) between TEI and ORCHX lambs. Findings suggest activation of GH negative autofeedback loop in middle infancy. Testicular factors may play an inhibitory role in regulating somatostatin accumulation and a stimulatory role in GH secretion until puberty. The start of puberty is related to an attenuation in the stimulatory role of gonadal factors in regulating somatostatin depletion in nerve terminals associated with an intensification of the stimulatory role of gonadal factors in regulating GH secretion. From a somatic perspective of growth rate, these mechanisms do not seem to be important. Thus, testicular factors modulate mechanisms within the somatostatin-GH system to integrate somatotropic and gonadotropic functions at the time of growth-promoted sexual maturation in sheep.     

Prenatal androgen exposure and growth and secretion of growth hormone and prolactin in ewes postweaning

Growth and secretion of growth hormone (GH) and prolactin (PRL) in ewe lambs exposed to androgen during fetal development were investigated. Testosterone cypionate was administered to the pregnant dams from approximately Days 28 to 84 of gestation. Ewe lambs from dams that received androgen exhibited masculinized external genitalia and some masculine behavioral characteristics. Intact androgenized ewe lambs grew faster (P less than 0.05) and were more efficient in conversion of food to body gain (P less than 0.05) than ewe lambs born to untreated dams over the period from 70 to 224 days of age. One-half of the ewe lambs in each group was ovariectomized at 58 days of age. Ovariectomy had no effect on subsequent growth or efficiency of growth in the control ewe lambs. However, ovariectomy of androgenized ewe lambs abolished the observed stimulated rate of growth and decreased the improvement in efficiency of food conversion. Blood samples were collected from the lambs at 85 and 136 days of age at 15-min intervals for 8 hr to determine parameters of GH and PRL secretion. Prenatal androgen exposure had no effect on any parameter of GH or PRL secretion. These data indicate that prenatal androgen exposure altered differentiation of growth potential in ewe lambs, but the growth response was not mediated through dramatic changes in secretion of adenohypophysial somatotropic hormones, GH and PRL.     

The influence of sex and gonadectomy on the growth hormone and corticosterone response to hexarelin in the rat

The present study is designed to investigate the role of sex and gonadal status in the growth hormone (GH) and corticosterone response to hexarelin (HEXA), a GH-releasing peptide, which also causes a stimulatory action on the hypothalamic-pituitary-adrenal (HPA) axis. HEXA (80 microg/Kg) was administered intracarotid to anesthetized intact or gonadectomized male (ORC) and female (OVX) middle-aged rats. The GH stimulatory response to HEXA was gender-related since the GH increase was significantly (p < 0.001) higher in intact males (area under the curve, AUC= 12560 +/- 1784 ng/ml.45 min) than in females (AUC= 4628 +/- 257 ng/ml.45 min). This sex difference does not depend on circulating gonadal steroids since it persists in ORC (AUC = 11980 +/- 1136 ng/ml.45 min) and OVX (AUC = 5539 +/- 614 ng/ml.45 min) rats. The different effects of HEXA on corticosterone secretion detected in male and female rats are probably dependent on the prevailing activity of the HPA axis. In fact, in male rats that have low basal corticosterone levels, HEXA caused an increase in corticosterone secretion, which was significantly (p< 0.05) higher in ORC than in intact rats. The increase in corticosterone secretion by HEXA both in intact and OVX females was delayed, probably due to the elevated initial corticosterone levels, which could have activated the glucocorticoid negative feedback. We suggest that gender-specific patterns in the regulation of the hypothalamus-pituitary function could be responsible for the GH and corticosterone sexually differentiated responses to HEXA.     

Morphological and functional study of the GH-immunoreactive adenohypophyseal cells in ovariectomized rats

Summary In view of the existence of a different secretion pattern of growth hormone (GH) between male and female rats, the aim of the present study was to analyse the role played by ovarian steroid hormones in the modulation of such secretion. To do so, postpuberal female rats were ovariectomized and killed at 30 days after the operation. The basal serum levels of growth hormone, together with cell area, cytoplasmic area and nuclear area of the hypophyseal somatotropic cells of normal and ovariectomized rats were compared. The results obtained show that ovariectomy induces a significant decrease (p<0.05) in the basal serum levels of GH, accompanied by an increase in cellular and cytoplasmic areas, with no significant differences in nuclear area. Overiectomy was also accompanied by an increase in reaction intensity and the number of GH-immunoreactive cells (p<0.01). These findings point to the shift towards a masculine secretory and morphological pattern following ovariectomy and supports the hypothesis that ovarian steroids intervene in the establishment of a different pattern in females compared to males.     

The effect of cyclosporine administration on growth hormone release and serum concentrations of insulin-like growth factor-I in male rats.

The aim of this work was to study the effect of cyclosporine on the somatotropic axis. Accordingly, growth hormone (GH) secretion, circulating insulin-like growth factor I (IGF-I) and IGF binding proteins (IGFBPs) in response to cyclosporin A (CsA) treatment were examined in adult male Wistar rats. Cyclosporine administration (5, 10 or 20 mg/Kg daily) over 8 days did not modify the body weight, but it did decrease serum concentration of corticosterone and increased serum IGF-I and GH levels. Rats treated with 5 and 10 mg/Kg of cyclosporine had similar levels of serum IGFBPs to control rats, but there was an increase in circulating IGFBP-3 and IGFPB-1,2 in the group treated with 20 mg/Kg of CsA. The increase in circulating GH correlates with a decrease in pituitary GH content in CsA treated rats, with no modification in hypothalamic somatostatin content, suggesting an increase in pituitary GH release. In order to test this hypothesis, anterior pituitary cell cultures were exposed to different CsA concentrations during a 4 h incubation period. Cyclosporine increased GH secretion in cultured pituitary cells (p<0.05). These data suggest that cyclosporine increases circulating IGF-I and GH by stimulating pituitary GH release.     

The consequences of altered somatotropic system on reproduction

Although the primary control of gonadotropin secretion is by the hypothalamic GnRH and the gonadal function is controlled by the pituitary gonadotropins and prolactin, the emerging evidence suggests a vital role of the somatotropic axis, growth hormone (GH), and insulin-like growth factor-I (IGF-I) in the control of the pituitary and gonadal functions. It has been shown that GH deficiency, GH resistance, and experimental alterations in IGF-I secretion modify folliculogenesis, ovarian maturation, ovulation, and pregnancy, and in the male, GH/IGF-I plays an important role in spermatogenesis and the Leydig cell function. The primary focus of this review is to examine the role of GH/ IGF-I on the onset of puberty, fertility, pituitary, and gonadal endocrine functions. A number of studies have revealed that fertility is affected in GH-deficient dwarf and in IGF-I gene-ablated mice, possibly due to subnormal function of either the pituitary gland or the gonads. In the female GH receptor gene knockout (GHR-KO) mice, there was impairment in follicular development, ovulation rate, sexual maturation, production of and responsiveness to pheromonal signals, and the corpus luteum function. In IGF-I-deficient male GHR-KO mice, puberty is delayed, spermatogenesis is affected, and neuroendocrine-gonadal function is attenuated. Similarly, in some of the human Laron syndrome patients, puberty is delayed due to GH resistance. These data suggest that, in addition to GnRH and gonadotropins, GH/IGF-I influences the pituitary and gonadal functions in animals and humans.     

Single exposure to testosterone in adulthood rapidly induces regularity in the growth hormone release process

The neonatal gonadal steroid milieu is known to be important in imprinting the striking sexual dimorphism of growth hormone (GH) secretion; however, the influence of the sex steroids on GH control in adult life and their mechanism/site of action are largely unknown. In the present study, we tested the hypothesis that testosterone (T) subserves the gender-specific regularity of the GH release process in adulthood. The approximate entropy statistic (ApEn) was used to quantify the degree of regularity of GH release patterns over time. Eighteen hours after a single subcutaneous injection of 1 mg T, both sham-operated and ovariectomized (OVX) female adult rats displayed plasma GH profiles that were strikingly similar to the regular male-like ultradian rhythm of GH secretion. The highest ApEn values, denoting greater disorderliness of GH secretion, were observed in the ovary-intact group, and T injection significantly (P < 0.001) reduced this irregularity whether or not the ovaries were present. Serial intravenous injections of GH-releasing hormone (GHRH) caused a similar increase in plasma GH levels in sham-operated females independently of time of administration. In contrast, female rats administered T exhibited a male-like intermittent pattern of GH responsiveness to GHRH, the latter known to be due to the cyclic release of endogenous somatostatin. These results demonstrate that acute exposure to T during adult life can rapidly and profoundly "masculinize" GH pulse-generating circuits in the female rat. Our findings suggest that the enhanced orderliness characteristic of the GH release process in males, compared with females, is regulated by T. We postulate that this T-induced regularity is mediated at the level of the hypothalamus by inducing regularity in somatostatin secretion, which in turn governs overall GH periodicity.     

Influence of gonadal hormones on endocrine activity of gonadotroph cells in the adenohypophysis of male lambs during the postnatal transition to puberty

Using histomorphological and functional criteria we describe the feedback mechanisms which could play a role in the regulation of the gonadotrophic axis during the postnatal transition to puberty in male lambs. The working hypothesis was that the testicular factors change the peripheral levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by influencing the synthesis rate and storage of LH and FSH in adenohypophyseal gonadotroph cells of weanling and weaned pubertal lambs. The examination was made in (i) 9-week-old infantiles, suckling lambs undergoing weaning, testis-intact (TEI) and orchidectomised (ORCHX) at the 6th week of age, and (ii) 16-week-old pubertal lambs TEI and ORCHX at the 12th week of age (n=5 per group). Changes in gonadotrophs were assayed with hybridohistochemistry, immunohistochemistry and radioimmunoassay. The percentage of the adenohypophyseal area (PA) occupied by cells containing LHβ-mRNA and FSHβ-mRNA and peripheral levels of both gonadotrophins were lower (P<0.01) in the 16-week-old TEI lambs in comparison with the 9-week-old ones. The PA occupied by cells immunoreactive for LHβ was lower (P<0.01), whereas in the case of FSH was greater (P<0.001) in the 16-week-old lambs. After orchidectomy the PA occupied by gonadotrophs stained for LHβ-mRNA was greater (P<0.01) in 16-week-old lambs. The PA occupied by LHβ-labelled cells was lower (P<0.05) in the 9-week-old ORCHX lambs, whereas in 16-week-old ones was higher (P<0.05) in comparison with the TEI lambs. The circulating LH was greater (P<0.01) in the ORCHX 9- and 16-week-old lambs compared to the TEI ones. The PA occupied by cells containing FSHβ-mRNA and the plasma FSH concentration were greater (P<0.001) after orchidectomy in lambs from both age stages. The PA occupied by FSHβ-labelled cells was greater (P<0.01) in the 9-week-old ORCHX lambs, whereas in 16-week-old ones was lower (P<0.05) compared to the lambs from TEI groups. In conclusion, in infantile lambs testicular factors may play inhibitory role in regulating FSH synthesis rate, storage and release in contrast to the stimulatory role in regulating LH storage reflected by the inhibitory role in regulating LH release. In lambs at the beginning of puberty, testicular factors may play inhibitory role in regulating LH synthesis rate, storage and release in contrast to the stimulatory role in regulating FSH storage reflected by the inhibitory role in regulating FSH synthesis rate and release. The effects of testicular hormones on the gonadotrophin storage, i.e. releasable pools in adenohypophyseal cells, are specific for both LH and FSH in lambs during the postnatal transition to puberty. Thus, the initiation of puberty in male sheep is a function of change of the inhibitory role of gonadal factors in regulating FSH storage to the stimulatory one and the stimulatory role of gonadal factors in regulating LH storage to the inhibitory one.     

Dynamic of the GRF-induced GH response in genetically obese Zucker rats: influence of central and peripheral factors

To determine the time onset of the growth hormone (GH) alteration in the genetically obese rat, we studied the in vivo and in vitro rat growth hormone releasing factor (rGRF(1-29)NH2)-induced GH secretion in 6- and 8-week-old lean and obese male Zucker rats. Under sodium pentobarbital anesthesia, rGRF(1-29)NH2 (GRF) was injected intravenously at two doses: 0.8 and 4.0 micrograms/kg b.w. Basal serum GH concentrations were similar in lean and obese age-matched animals. The GH response to both GRF doses tested was unchanged in 6-week-old obese rats as compared to their lean litter mates. In contrast, a significant decrease of the GH secretion in response to 4.0 micrograms/kg b.w. GRF was observed in the 8-week-old obese rats. The effect of GRF (1.56, 6.25 and 12.5 pM) was further studied in vitro, in a perifusion system of freshly dispersed anterior pituitary cells of lean and obese Zucker rats. Basal GH release was similar in the 6-week-old animal group. In contrast, it was significantly decreased in 8-week-old obese rats as compared to their lean litter mates. Stimulated GH response to 1.56 and 6.25 pM GRF was significantly greater in the 6-week-old obese group than in the age-matched control group. In contrast, the GH response to all GRF concentrations tested was significantly decreased in the 8-week-old obese rats as compared to their respective lean siblings. In 8-week-old obese rats, a decrease of GH pituitary content and an increase of hypothalamic somatostatin (SRIF) concentration were observed. Insulin and free fatty acid serum were significantly increased in 8-week-old obese rats. In contrast, lower insulin-like growth factor I serum levels were observed in the obese animals as compared to their lean litter mates. Finally, to further clarify the role of the periphery in the inhibition of GH secretion observed in the 8-week-old fatty rats, we exposed cultured pituitary cells of 8-week-old lean animals to 17% serum of their obese litter mates. A significant decrease of GRF-stimulated GH secretion of lean rat pituitary cells exposed to the obese serum was noted (P less than 0.05). This study demonstrates that, in the obese Zucker rat, an alteration of the GH response to GRF is evident by the 8th week of life. This defective GH secretion could be related to peripheral and central abnormalities.     

Morphometric changes in GH-immunoreactive adenohypophyseal cells induced by intraventricular administration of colchicine to adult rats.

In order to elucidate whether the gender differences observed in the somatotropic cells of adult rats are mediated by hypothalamic neuropeptides, a morphometric analysis was made of the GH-immunoreactive cells of adult rats treated intraventricularly with colchicine. The morphometric and morphological findings obtained were correlated to the basal serum levels of GH at the time of sacrifice. Treatment with colchicine was seen to increase serum GH levels; this increase was accompanied by an increase in the intensity of the reaction of the GH-cells and, morphometrically, an increase in their size due to an increase in the nuclear area, but with no significant changes in the cytoplasmic area. The results suggest that in the absence of somatostatin and GRF the basal release of GH is elevated in a similar fashion in both sexes, in turn suggesting that gonadal steroids might act at hypothalamic level on the release of somatostatin and, indirectly, on the intracellular pool of GH and hormonal secretion.     

Effect of CRF injected into the median eminence on GH secretion in female rats under different steroid status

To evaluate whether the median eminence (ME) is a site of action of CRF (corticotropin releasing factor) on GH secretion and to determine the possible role of estradiol and progesterone in modifying theses secretion, we injected CRF (0.25, 0.75, 1, and 1.5 nmol of peptide dissolved in 1 μl of water) directly into the ME in three experimental groups of rats: Long-term ovariectomized (OVX); OVX primed by estradiol (OVX±E) and OVX primed by estradiol plus progesterone (OVX±EP). Blood was collected to determine GH (30, 60, 90, and 120 min postinjection) Serum T₃, T₄, and glucose levels were measured in OVX±E rats 30 min postinjection. CRF at all doses studied significantly decreased serum GH levels in the three experimental groups. Serum T₃, T₄, and glucose levels were unchanged after CRF administration. The results suggest that: CRF inhibits “per se” GH secretion, at least in part, by a central action in the ME. The inhibitory effect of CRF on GH is independent of the estrogen/progesterone status of the animal. CRF at ME levels may participate in a variety of stress-related responses, including growth inhibition, through GH suppression.     

Isolated deficiency of immunocytochemically detected somatostatin in Snell dwarf, but not in “little,” mice

Immunocytochemical staining of the neuropeptide somatostatin was evaluated in the brains of two growth hormone-deficient mouse mutants, Snell dwarf (dw/dw), and “little” (lit/lit). In Snell dwarf mice, in which GH is undetectable, an isolated somatostatin deficiency was observed in hypothalamic median eminence and in anterior periventricular hypothalamic neurons which are afferent to median eminence, compared to somatostatin staining in normal mice of the same strain (DW/?). Somatostatin staining in all other CNS areas in dwarfs was identical to that in normal mice. In contrast, in little mice, which exhibit 5–10% of normal GH levels, somatostatin expression was comparable between mutants and normal mice (LIT/?) in all CNS areas, including median eminence-afferent neurons in anterior periventricular hypothalamus. The results suggest that expression of somatostatin in hypophysiotropic CNS is dependent upon minimal pituitary GH secretion.     

Regulation of hormone secretion in primary cell cultures of human somatotropinomas]

The effects of somatostatin and thyroliberin (thyrotropin-releasing hormone; TRH) on growth hormone (GH) and prolactin (PRL) secretion were studied in short-term (0.5-3h) or long-term (21-24h) incubations using monolayer cell cultures of somatotropin obtained from surgical material of patients with acromegaly. High sensitivity of both GH and PRL release to inhibitory action of somatostatin (10(-11) M) was established. We could not reveal the unambiguous influence of TRH on somatotropic function in the in vivo and in vitro conditions, as compared to the action of this tripeptide on PRL secretion. The results obtained permit us to propose that cell cultures of pituitary adenomata represent adequate and convenient models for studying the pathogenesis of tumor processes in the pituitary gland and for the development of new procedures of pharmacotherapy.     

The neuroendocrine events during the ovine growth-promoted maturation: the developmental importance of hypophysiotrophic action of somatostatin in ewes

The comparison of hypothalamic somatostatin (SRIH)-neuronal systems, hypophyseal somatotroph populations and growth hormone (GH) blood plasma patterns among developmental stages, from infancy until puberty, may help to describe the nature of the hypothalamo-hypophyseal mechanisms underlying the changes in GH on the systemic level leading to the somatic, that is growth and sexual maturity in sheep. The aim of this study was to elucidate (i) developmental importance of hypophysiotrophic action of SRIH, (ii) precise time of maturation of this action and (iii) photoperiodic regulation of the postnatal ontogeny in ewes. The central and peripheral activity of the SRIH-GH axis is described through a sequence of histomorphological and functional changes in Merino ewes born after the summer solstice. The actual time of puberty of these animals was delayed until the following breeding season, when the sheep were 14-month old. Histomorphometric examinations have been made in 21 infantile (preweanling, 12-week old), prepubertal (15- and 22-week old), peripubertal (30- and 52-week old) and pubertal (63-week old) ovary-intact sheep. Functional examinations of the GH plasma levels were determined every 1-2 weeks during the period from the 12th to 63rd week of age. The highest GH level was observed at the 13th week of age, on the beginning of the breeding season. The fluctuations in the GH level just after the winter and summer solstice were detected as the one and only deviation from a rule of uniformly low GH concentrations observed until puberty. The age of the fall in serum GH levels corresponded with the postweaning period and the beginning of the phase of the lower daily live-weight gains (growth rate). Thus, the development of GH secretion was finished before the 15th week of age, that is together with the ending of the transitional infantile/prepubertal period, whereas the maturational processing within the hypothalamo-hypophyseal unit prolonged after the 15th week of age until 22 weeks of age and concerned the role of SRIH as the hypophysiotrophic factor regulating somatic maturation, i.e. attenuating growth. Altogether, the pattern of GH secretion during weaning is important for the shift between infancy and prepuberty depended upon an intensive growth and defined as growth maturation. The maturation of the SRIH-GH axis is finished by 22 weeks of age, independently of photoperiodic influences, whereas the neuroendocrine mechanisms to integrate somatic, that is growth and sexual maturation, are seasonal in nature in the ewe. Our observations confirm the hypothesis of the inherent endogenous rhythm controlling somatic maturation in the sheep.     

Insights into a role of GH secretagogues in reversing the age-related decline in the GH/IGF-I axis

Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo). Hypothalamic growth hormone-releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased (P < 0.01 and P < 0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS; P < 0.001) and SS mRNA (P < 0.01), and median eminence IR-SS were found in old rats as were GHS receptor and IGF-I mRNA (P < 0.01 and P < 0.05). Hypothalamic IGF-I receptor mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or cocultured with fetal hypothalamic cells, responded to ghrelin. Only in the presence of fetal hypothalamic cells did ghrelin elevate the age-related decrease of GH secretion to within normal adult range. In old rats, growth hormone-releasing peptide-6 returned the levels of GH and IGF-I secretion and liver IGF-I mRNA, and partially restored the lower pituitary IR-GH and GH mRNA levels to those of young untreated rats. These results suggest that the aging GH decline may result from decreased GHRH function rather than from increased SS action. The reduction of hypothalamic GHS-R gene expression might impair the action of ghrelin on GH release. The role of IGF-I is not altered. The aging GH/IGF-I axis decline could be rejuvenated by GHS treatment.     

Effect of protein deficiency on some hypothalamic and pituitary hormones in growing male lambs. An immunohistochemical study

Growing male lambs were fed with diets containing 14.0, 10.8 and 7.6% protein for 3 months to determine their effects on the content of hypothalamic LHRH and SRIH and pituitary LH and GH, using immunohistochemical methods. Lowering the concentration of dietary proteins caused marked changes in the immunoreactivity of these hormones. The immunoreactive (IR) content of LHRH stored in the median eminence was enhanced, and the proportion of LH cells and their IR content increased. Opposite effects were observed in the SRIH/GH system; IR SRIH content stored in the median eminence markedly diminished, and, although hyperplasia of GH cells was observed, their IR content was diminished. This study indicates that prolonged restrictions of protein in the diet of growing male sheep affects the immunoreactive content of the investigated hormones. It seems that they suppress LHRH/LH release and augment GH release, possibly via suppression of hypothalamic somatostatin.     

Inhibition of somatotroph growth and growth hormone biosynthesis by activin in vitro

Activin-A, a homodimeric protein composed of two inhibin beta A-subunits, was first isolated from gonadal fluids based upon its ability to stimulate FSH secretion and biosynthesis, but was also observed to suppress GH secretion. The present report describes the effects of activin on the biosynthesis of GH and the proliferation of pituitary somatotrophs. In pituitary cells cultured in the presence of 0.7 nM activin for 3 days, GH secretion was decreased by 50% compared to the control value. Inhibition of GH biosynthesis, measured by quantitative immunoprecipitation of [35S]methionine-labeled cells, could be observed after 24 h of activin treatment, and maximal (70%) inhibition of GH biosynthesis was observed after 3 days. Activin inhibited basal as well as GH-releasing factor (GRF)-, glucocorticoid-, and thyroid hormone-stimulated GH biosynthesis. Inhibin, which is known to reverse the effect of activin on FSH secretion, did not reverse the effect of activin on GH biosynthesis. Treatment of somatotrophs with activin for 3 days completely inhibited the growth-promoting effect of GRF on somatotrophs. However, no effect of activin on GRF-stimulated expression of the c-fos protooncogene was observed. These data demonstrate that activin, in addition to its stimulatory effect on FSH secretion, is able to inhibit both expression of GH and growth of somatotropic cells.     

Age-related changes of the somatotropic axis in cloned Holstein calves

To determine if the development of the somatotropic axis in somatic clones (clones) is similar to that in heifers produced by artificial insemination (controls), serum samples were collected every 30 min for 6 h, once per month, for 7 mo from 4 clones generated from a 13-yr-old cow and from 4 age-matched controls. Average concentrations of growth hormone (GH) were not different between clones and controls, and GH concentrations declined over time in controls. Average concentrations of insulin-like growth factor I (IGF-I) were less in clones than controls, and IGF-I concentrations increased over time in both groups. Concentrations of IGF-binding protein 3 (IGFBP-3) were greater in controls than in clones and did not change over time. Average IGFBP-2 concentrations did not change over time and were not different between clones and controls. Clones and controls were challenged with GH-releasing hormone (GHRH) (3 microg/100 kg body weight) and somatostatin (somatotropin release-inhibiting factor [SRIF]) (1.87 and 5 microg/100 kg body weight) at 14 mo of age. GHRH-induced GH secretion was greater and SRIF inhibition of GHRH-induced GH was less in clones than in controls. We speculate that some of the differences between clones and controls in concentrations of GH, IGF-I, and IGFBP-3 may be related to the genetic merit of the animals. Although there were differences in concentrations of components of the somatotropic axis between these clones and their age-matched controls, the values recorded were all within the range reported for calves of similar ages.     

Neuroendocrine Regulation of Growth Hormone Secretion in Teleost Fishes with Emphasis on the Involvement of Gonadal Sex Steroids

In teleost fishes, growth hormone (GH) appears to play an important regulatory role in several, apparently disparate, physiological events, including reproduction, osmotic or ionic regulation, metabolism, growth and development. GH secretion is regulated by hypothalamic neuroendocrine factors that either act directly on the somatotrophic cells in the pituitary gland, or modulate the secretion or activity of other neuroendocrine factors. In addition, the degree of the neuroendocrine influence on GH release is influenced by the nutritional and reproductive state of the fish; moreover, there appear to be marked species differences in some aspects of this neuroendocrine-physiological condition relationship among fish species. Thus, the neuroendocrine control of GH secretion in fishes is complex, and still poorly understood. The neuropeptides, gonadotrophin-releasing hormone, growth hormone-releasing hormone, thyrotrophin-releasing hormone, neuropeptide Y, serotonin and pituitary adenylate cyclase-activating polypeptide have all been demonstrated to stimulate GH in fish, as has the glutamate agonist, N-methyl-d,l-aspartate. Conversely, somatostatin has a potent inhibitory action on GH release in goldfish and carp, but is less effective in salmon and trout species.This review examines the interactive nature of the neuroendocrine control of GH secretion in fishes, and the manner in which gonadal steroids, directly or indirectly, modulate GH secretion and/or the release, or the activity, of the neuroendocrine factors.     

Differentiation between the somatostatin inhibition and the post-somatostatin rebound observed on growth hormone secretion in vitro

A rebound in growth hormone secretion following somatostatin treatment has been shown in several systems where somatostatin suppresses secretion of the hormone. We have developed an in vitro system in which isolated and cultured pituitary cells were perfused after mild trypsinization. After washing, these cells retained their sensitivity and secreted growth hormone (GH) in response to physiological activators (norepinephrine, dopamine, serotonin) or inhibitors (somatostatin) as well as pharmacological activators (PGE2). The variation in GH secretion occurred within a minute after commencement of the infusion and was as rapidly reversible and repeatable minutes later. During somatostatin infusion the GH secretion was not totally suppressed (residual secretion (mean +/- S.D.) 34 +/- 7%). After the infusion a rapid rebound in GH secretion occurred, reaching levels in excess of the pretreatment value of 138 +/- 13%. This rebound effect occurred at doses higher than (10(-10)M) but not at lower doses, even when significant inhibition was observed. The inhibitory effect is of greater magnitude than the rebound effect (rebound = inhibition X 57 +/- 7% (mean +/- S.D.)). Furthermore, rebound was not enhanced by prolongation of somatostatin infusion. These latter results indicate that the rebound in secretion cannot be explained on the sole basis of storage of intracellular GH during somatostatin infusion and in fact suggest the involvement of a process of GH degradation and/or an inhibition of GH synthesis.