Role of growth hormone and prolactin in the control of reproduction: what are we learning from transgenic and knock-out animals?

Growth hormone (GH), insulin-like growth factor (IGF-I), and prolactin (PRL) can influence various aspects of reproductive functions in both females and males. However, the physiological role of PRL and the GH-IGF-I axis in the control of reproduction has been difficult to define, and the recent availability of knock-out (KO) animals allows re-examination of this issue. PRL-receptor (R)-KO and PRL-KO females are sterile because of luteal failure. In addition, these mice have severe deficits in the development of oocytes and early embryos. However, male fertility is not affected in the PRL-KO and in most of the PRL-R-KO animals. IGF-KO animals have an infantile reproductive system and are sterile. GH-R-KO mice can reproduce, but their breeding performance is reduced, particularly in females. These data indicate that IGF-I signaling is required for normal reproductive development and confirm the requirement for PRL for fertility in the female mouse. GH resistance leads to quantitative deficits in reproductive development and functions, but does not preclude fertility in either sex. We suspect that PRL and the GH-IGF-I axis provide partially overlapping (redundant) regulatory inputs to the hypothalamic-pituitary-gonadal axis, and consequently, targeted disruption of either signaling pathway has relatively mild consequences on many functions related to reproduction. Overexpression of heterologous or homologous GH in transgenic animals can lead to severe reproductive deficits, including female sterility in some of the lines. Studies in GH transgenics should allow the identification of mechanisms that mediate the effects of chronic overexposure to GH on reproduction.     

生长激素/胰岛素样生长因子1与阿尔茨海默病

生长激素／胰岛素样生长因子-1（GH／IGF-1）轴的合成、分泌、调节及生物学活性与阿尔茨海默病（AD）有密切关系。生长激素（GH）的合成和分泌受生长激素释放激素（GHRH）正向调节。GH／IGF-1轴活性下降导致一系列生理功能变化。GH／IGF-1缺乏可引起衰老及神经退行性变（AD）而导致认知功能的下降,相应激素的补给可以抑制或逆转这种认知障碍。越来越多的证据表明：GH／IGF-1参与AD型痴呆病理过程,对AD有很好的治疗应用前景。本文就生长激素／胰岛素样生长因子1在AD发病中的机理和药理学研究做一综述。     

Fertility of transgenic female mice expressing bovine growth hormone or human growth hormone variant genes

Although growth hormone (GH) exerts various direct and indirect stimulatory effects on gonadal development and function, excessive levels of GH in acromegalic patients and in transgenic animals are often associated with reproductive disorders. We have examined reproductive performance of transgenic female mice expressing the following hybrid genes: mouse metallothionein-1 (MT)/human placental GH variant (hGH.V), MT/bovine GH(bGH), and phosphoenolpyruvate carboxykinase (PEPCK)/bGH. This allowed us to evaluate the effects of chronic GH excess in three animal models and to obtain some information on the significance of the lactogenic activity of the foreign GH (hGH.V vs. bGH) and on the developmental stage of transgene expression (MT vs. PEPCK). Transgenic animals from each line had elevated plasma insulin-like growth factor-I levels and greatly increased adult body weight. Plasma bGH levels were significantly higher in PEPCK/bGH than in MT/bGH transgenic mice. Approximately 20% of transgenic MT/hGH.V and MT/bGH females and over 60% of transgenic PEPCK/bGH females were infertile. Transgenic females that did reproduce ovulated either a normal or increased number of eggs but exhibited a variety of reproductive disorders including increased interval between pairing with a male and conception, increased interval between litters, reduced number of litters, reduced fetal growth, increased pre- and postnatal mortality, and alterations in sex ratio. Among adult offspring of these females, the proportion of transgenic animals was significantly less than the expected 50%. While some characteristics (e.g., fetal crown-rump length and weight on Day 14 of pregnancy) were affected to a comparable extent in transgenic females from all three lines, MT/hGH.V and PEPCK/bGH females were, in general, more severely affected than the MT/bGH animals. Sterility of PEPCK/bGH females appeared to be due to luteal failure since treatment with progesterone led to pregnancy. Greatly increased intervals between successive litters appeared to be due to failure to mate during postpartum estrus and to sterile matings during this period. Reduced fetal size and weight may have been due to chronic glucocorticoid excess because comparable changes could be induced in normal females by injections of dexamethasone during pregnancy, and plasma corticosterone levels were previously shown to be elevated in transgenic mice from each of these lines. Comparison of these results with data obtained from matings of normal female mice to transgenic males from the same lines suggests that reduced fetal growth is due primarily to maternal genotype, while reduced "transmission" of the hybrid genes is not, and presumably reflects increased mortality of transgenic progeny at various stages of development.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differential effects of cannabinoid exposure and stress on plasma prolactin, growth hormone and corticosterone levels in male mice

Plasma prolactin (PRL) levels were reduced in stressed and non-stressed male mice after a single dose of Δ⁹-tetrahydrocannabinol (THC), the main psychoactive constituent of marihuana, while growth hormone (GH) levers were reduced only in non-stressed animals. Chronic treatment with THC did not affect PRL or GH levels under either condition. Neither acute nor repeated exposure to THC affected plasma corticosterone levels.In contrast to the affects of THC, acute exposure to cannabinol (CBN), a non-psychoactive ingredient in marihuana, increased plasma GH levels in non-stressed mice, while repeated CBN treatments reduced GH levels in stressed animals. Moreover, chronic CBN exposure resulted in decreased peripheral levels of corticosterone in both stressed and non-stressed mice, and reduced plasma PRL levels in stressed mice.Psychoactive and non-psychoactive components of marihuana can exert different effects on endocrine function and on responsivity to stress in male mice.     

Prolactin and growth hormone regulate adiponectin secretion and receptor expression in adipose tissue

Adiponectin is a hormone secreted from adipose tissue, and serum levels are decreased with obesity and insulin resistance. Because prolactin (PRL) and growth hormone (GH) can affect insulin sensitivity, we investigated the effects of these hormones on the regulation of adiponectin in human adipose tissue in vitro and in rodents in vivo. Adiponectin secretion was significantly suppressed by PRL and GH in in vitro cultured human adipose tissue. Furthermore, PRL increased adiponectin receptor 1 (AdipoR1) mRNA expression and GH decreased AdipoR2 expression in the cultured human adipose tissue. In transgenic mice expressing GH, and female mice expressing PRL, serum levels of adiponectin were decreased. In contrast, GH receptor deficient mice had elevated adiponectin levels, while PRL receptor deficient mice were unaffected. In conclusion, we demonstrate gene expression of AdipoR1 and AdipoR2 in human adipose tissue for the first time, and show that these are differentially regulated by PRL and GH. Both PRL and GH reduced adiponectin secretion in human adipose tissue in vitro and in mice in vivo. Decreased serum adiponectin levels have been associated with insulin resistance, and our data in human tissue and in transgenic mice suggest a role for adiponectin in PRL and GH induced insulin resistance.     

Differential in vivo activities of bovine growth hormone analogues

In rodents, bovine (b) growth hormone (GH) binds only to GH receptors, while human (h) GH binds to both GH and PRL receptors. The phenotypic consequences of expression of bGH and hGH in transgenic mice are different and, in some cases, opposite. In the present study, site-directed in vitro mutagenesis of the bGH gene was used systematically to eliminate its differences from hGH at one, two, three or four sites suspected of conferring lactogenic activity: D11, H18, S57 and T60, respectively (corresponding to sites 12, 19, 57 and 60 of the bGH molecule). The resulting bGH analogues were expressed in cell lines and in transgenic mice. All of the seven bGH analogues produced retained their ability to bind to GH receptors and exhibited somatogenic activity in vitro and in vivo. However, none of them were able to bind to PRL receptors or to elicit detectable lactogenic response in vitro. Transgenic animals expressing any of the generated analogues were characterized by gigantism and splanchnomegaly. The effects of expression of each of the double, triple or quadruple mutants on the seminal vesicle weight resembled the effects of wild-type hGH and differed from the effects of expression of wild-type bGH. There were differences between the effects of the expression of different bGH analogues on plasma PRL levels and on the PRL response to pharmacological blockade of catecholamine synthesis. Plasma LH levels in ovariectomized females were suppressed by several of the analogues tested, an effect not seen in animals expressing wild-type bGH or hGH. Dopamine turnover in the median eminence of male mice was also altered in animals expressing different bGH analogues but not in those expressing wild-type bGH or hGH. In ovariectomized females, the effects of different bGH analogs on the turnover of dopamine and norepine phrine in the median eminence included changes resembling those detected in animals expressing hGH, as well as alterations differing from the effects of bot h bGH and hGH.The results indicate that biological actions of these bGH analogues cannot be characterized simply in terms of enhanced or reduced somatogenic or lactogenic activity and raise a possibility that different sites, domains or features of the tri-dimensional structure of GH are involved in its actions on different cellular targets     

Single nucleotide polymorphisms in the growth hormone and insulin-like growth factor-1 genes are associated with milk production, body condition score and fertility traits in dairy cows

The somatotrophic axis (GH-IGF) is a key regulator of animal growth and development, affecting performance traits that include milk production, growth rate, body composition, and fertility. The aim of this study was to quantify the association of previously identified SNPs in bovine growth hormone (GH1) and insulin-like growth factor 1 (IGF-1) genes with direct performance trait measurements of lactation and fertility in Holstein-Friesian lactating dairy cows. Sixteen SNPs in both IGF-1 and GH1 were genotyped across 610 cows and association analyses were carried out with traits of economic importance including calving interval, pregnancy rate to first service and 305-day milk production, using animal linear mixed models accounting for additive genetic effects. Two IGF-1 SNPs, IGF1i1 and IGF1i2, were significantly associated with body condition score at calving, while a single IGF-1 SNP, IGF1i3, was significantly associated with milk production, including milk yield (means ± SEM; 751.3 ± 262.0 kg), fat yield (21.3 ± 10.2 kg) and protein yield (16.5 ± 8.0 kg) per lactation. Only one GH1 SNP, GH33, was significantly associated with milk protein yield in the second lactation (allele substitution effect of 9.8 ± 5.0 kg). Several GH1 SNPs were significantly associated with fertility, including GH32, GH35 and GH38 with calving to third parity (22.4 ± 11.3 days) (GH32 and GH38 only), pregnancy rate to first service (0.1%) and overall pregnancy rate (0.05%). The results of this study demonstrate the effects of variants of the somatotrophic axis on milk production and fertility traits in commercial dairy cattle.     

Prolactin and growth hormone in the regulation of the immune system

Evidence implicating prolactin (PRL) and growth hormone (GH) in the regulation of the immune system has been reviewed. Hypophysectomized animals have deficiencies in both cell-mediated and humoral immunological functions and either PRL or GH corrects these deficiencies. Animals administered bromocryptine, a drug that specifically blocks PRL release, have impaired immune responses similar to hypophysectomized animals, and again both PRL and GH correct these deficiencies. Genetically dwarf animals, which lack both PRL and GH, are also immunocompromised, and once again PRL and GH can correct the deficiencies. In dwarf animals, however, fewer studies have examined PRL actions. In growth-deficient children, immune function is not dramatically altered and basal secretion of GH has been reported. Very few clinical studies have examined whether PRL secretion is also deficient, and this may explain why a clear loss in immune function is not evident in growth-deficient children. In a number of species, including man, both PRL and GH stimulate thymic function and increase the secretion of thymulin, a thymic hormone. No studies, however, have reported on the effects of PRL and GH on other thymic hormones. A number of studies have reported in vitro effects of PRL and GH on cells involved with immunity, and the presence of high-affinity PRL and GH receptors have been observed on a number of these cells. The action of GH on the proliferative response of cells involved with immunity in vitro appears to be mediated by the production of insulin-like growth factor I. The effect of PRL on insulin-like growth factor I production by these cells has not been examined. One of the most consistent findings from in vitro studies is that prolactin antisera blocked a number of immune reactions. This led to the discovery that cells involved with immunity appear capable of producing PRL and GH, but the physiological significance of these observations have not been explored. There is a great need to identify the cell types responding to PRL and GH and this should be a goal of future investigations. There is also a need for investigators to be aware that both PRL and GH are involved in the regulation of the immune system and to design experiments to elucidate where each functions in the maturation cascade of cells involved with immunity. From the evidence available, it is apparent that PRL and GH have an important function in the immune system and future investigations should be directed toward elucidating their site(s) of action.     

Daily profiles of plasma prolactin (PRL), growth hormone (GH), insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), testosterone, and melatonin, and of pituitary PRL mRNA and GH mRNA in male Long Evans rats in acute phase of adjuvant arthritis

We studied the effects of adjuvant arthritis (AA) on the endocrine circadian rhythms of plasma prolactin (PRL), growth hormone (GH), insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), testosterone, and melatonin and of pituitary PRL and GH mRNA in male Long Evans rats. Groups of control and AA rats (studied 23 days after AA induction) that were housed under a 12/12 h light/dark cycle (light on at 06:00 h) were killed at 4 h intervals starting at 14:00 h. Cosinor analysis revealed a significant 12 h rhythm in PRL and PRL mRNA (p < 0.001) in controls with peaks at 14:00 h and 02:00 h, respectively. The peak at 02:00 h was abolished in the AA group resulting in a significant 24 h rhythm in parallel with that of PRL (p < 0.05) and PRL mRNA (p < 0.0001). Growth hormone showed no rhythm, but a significant rhythm of GH mRNA was present in both groups (p < 0.0001). Insulin-like growth factor-1 showed a 24 h rhythm in control but not in AA rats. The mean values of GH, GH mRNA, and IGF-1 were significantly reduced in AA. Luteinizing hormone displayed a significant 24 h rhythm (p < 0.01) peaking in the dark period in the control but not AA group. Testosterone showed in phase temporal changes of LH levels with AA abolishing the 02:00 h peak. Melatonin exhibited a significant 24 h rhythm in control (p < 0.001) and AA (p < 0.01) rats with maximum levels during the dark phase; the mesor value was higher in the AA males. These results demonstrate that AA interferes with the rhythms of all the studied hormones except the non-24 h (arrhythmic) GH secretion pattern and the rhythm in melatonin. The persistence of a distinct melatonin rhythm in AA suggests the observed disturbances of hormonal rhythms in this condition do not occur at the level of the pineal gland.     

Gender-specific alterations in gene expression and loss of liver sexual dimorphism in the long-lived Ames dwarf mice

Genetic mutations that increase lifespan in mice frequently involve alterations in the growth hormone/insulin-like growth factor-I signaling pathway. Although several of the effects of GH on gene expression are known to be sex-dependent, an understanding of the gender-specific vs. gender-independent effects of lifespan-extending mutations of the GH/IGF-I axis is currently lacking. The Ames dwarf mice (prop1(df/df)) are GH, prolactin and thyroid-stimulating hormone deficient and exhibit an increase in mean lifespan of 49% in males and 68% in females. We used oligonucleotide arrays containing over 14,000 genes to study the gender-specific vs. gender-independent effects of the prop1(df) mutation in liver of male and female Ames mice. We identified 381 gender-independent and 110 gender-specific alterations in gene expression produced by the Prop1(df/df) genotype. The gender-specific alterations corresponded to genes with a strong sexual dimorphism in wild-type mice and produced an almost complete loss of sex-specific gene expression in the liver of Ames dwarf mice: out of 123 genes that showed sexual dimorphism in wild-type mice only six maintained a gender difference in mutant mice. However, the Prop1(df/df) genotype did not introduce new sexually dimorphic patterns of gene expression in Ames dwarf mice that were not present in the wild-type animals. The gender-specific alterations accounted for a large fraction of the most significant changes in gene expression in male and female Ames mice livers and affected several metabolic processes, particularly fatty acid metabolism, steroid hormone metabolism, and xenobiotic metabolism.     

Ovariectomy during the luteal phase influences secretion of prolactin, growth hormone, and insulin-like growth factor-I in the bitch

A decline in circulating progesterone concentration plays an important role in the ethiopathogenesis of pseudopregnancy in the bitch. Because growth hormone (GH) and prolactin (PRL) are essential for normal mammogenesis and the secretion of these hormones is influenced by changes in the circulating progesterone concentration, the purpose of this study was to investigate the effects of mid-luteal phase ovariectomy on the 6-h pulsatile plasma profiles of GH and PRL and the basal plasma concentrations of GH, PRL, and insulin-like growth factor-I (IGF-I) in six beagle bitches. Ovariectomy was followed by only mild or covert signs of pseudopregnancy. The sharp decrease of the plasma progesterone concentration was accompanied by decreased basal plasma concentrations of GH and IGF-I and a rise in basal plasma PRL concentration. GH and PRL were secreted in a pulsatile fashion both prior to and after ovariectomy. The mean basal plasma GH concentration was significantly higher before ovariectomy than on days 1 and 7 after ovariectomy. The mean area under the curve above the zero level (AUC(0)) for GH was significantly higher before than at 7 days after ovariectomy. The mean area under the curve above basal level (AUC(b)) and the frequency of GH pulses at 7 days after ovariectomy were significantly higher than before and 1 day after ovariectomy. Both the mean basal plasma PRL concentration and the mean AUC(0) for PRL increased after ovariectomy. In conclusion, ovariectomy of bitches in the mid-luteal phase stops progesterone-induced GH release from the mammary gland, as evidenced by the lowering of basal plasma GH levels, the recurrence of GH pulsatility, and the lowering of circulating IGF-I levels. The sudden lowering of plasma progesterone concentration is probably a primary cause of a prolonged increase in PRL secretion. These observations underscore the importance of similar, albeit less abrupt, hormonal changes in the cyclical physiological alterations in the mammary gland and in the development of pseudopregnancy.     

Conversion of growth hormone-secreting cells into prolactin-secreting cells and its promotion by insulin and insulin-like growth factor-1 in vitro

The newly established rat pituitary cell line, MtT/S, has pituitary somatotroph (growth hormone-producing cell)-like characteristics, i.e., the cells produce growth hormone (GH), possess GH-immunopositive secretory granules, and respond to GH-releasing hormone. When MtT/S cells were cultured in regular medium no prolactin (PRL) cells were observed and PRL was not detected, by radioimmunoassay or Western blot analysis, in the medium or the cells. However, GH production and the GH cell population decreased markedly when the cells were incubated with insulin or insulin-like growth factor-1 (IGF-1). After stimulation with insulin or IGF-1 there was a 2-day lag period, then some PRL was detected in the medium; after 5 days a number of PRL cells appeared. Double immunocytochemistry indicated clearly that no cell contained both PRL and GH. These results show that insulin and IGF-1 stimulate conversion of MtT/S cell line GH cells to PRL cells. This suggests that the MtT/S cell line is an excellent model system which shows the GH-cell/PRL-cell lineage.     

Sleep in mice with nonfunctional growth hormone-releasing hormone receptors

The role of the somatotropic axis in sleep regulation was studied by using the lit/lit mouse with nonfunctional growth hormone (GH)-releasing hormone (GHRH) receptors (GHRH-Rs) and control heterozygous C57BL/6J mice, which have a normal phenotype. During the light period, the lit/lit mice displayed significantly less spontaneous rapid eye movement sleep (REMS) and non-REMS (NREMS) than the controls. Intraperitoneal injection of GHRH (50 microg/kg) failed to promote sleep in the lit/lit mice, whereas it enhanced NREMS in the heterozygous mice. Subcutaneous infusion of GH replacement stimulated weight gain, increased the concentration of plasma insulin-like growth factor-1 (IGF-1), and normalized REMS, but failed to restore normal NREMS in the lit/lit mice. The NREMS response to a 4-h sleep deprivation was attenuated in the lit/lit mice. In control mice, intraperitoneal injection of ghrelin (400 microg/kg) elicited GH secretion and promoted NREMS, and intraperitoneal administration of the somatostatin analog octretotide (Oct, 200 microg/kg) inhibited sleep. In contrast, these responses were missing in the lit/lit mice. The results suggest that GH promotes REMS whereas GHRH stimulates NREMS via central GHRH-Rs and that GHRH is involved in the mediation of the sleep effects of ghrelin and somatostatin.     

Growth hormone and proclatin in avian species

Considerable progress has been made in study of the physiology of avian growth hormone (GH) and prolactin (PRL) following their purification and the consequent development of radioimmunoassay systems. Plasma GH concentrations are consistently high in the early rapid phase of growth while PRL levels are related to both reproductive and salt/water status. In the chicken, GH secretion appears to be under dual stimulatory and inhibitory hypothalamic influences while PRL is under predominantly stimulatory control. Stress can affect both GH PRL release, normally decreasing GH and elevating PRL levels.     

Mild calorie restriction does not affect testosterone levels and testicular gene expression in mutant mice

The hypothalamic-pituitary-gonadal (HPG) axis and the somatotropic axis are influenced by nutritional factors. Calorie restriction (CR) extends lifespan but suppresses both the HPG and the somatotropic axes. Since most CR studies use a fairly severe (40%-60%) reduction of calorie intake, we hypothesized that a milder CR (20%) might not be deleterious to reproduction in male mice. To test this hypothesis, we evaluated the effects of 20% CR on testicular testosterone content and on testicular expression of genes that are relevant to testicular function and reproductive competence, including insulin-like growth factor-I, cytochrome P450 aromatase (Cyp19a1), androgen receptor, luteinizing hormone receptor, follicle-stimulating hormone receptor, cytochrome P450c17 and 3-beta-hydroxysteroid dehydrogenase/isomerase. To relate CR effects to the activity of the somatotropic axis, we have used growth hormone-resistant GHR knockout mice as well as transgenic mice overexpressing GH. Mild CR did not affect testosterone levels in testis homogenates and had little effect on expression of the examined genes in the reproductive organs. Altered activity of the GH/insulin-like growth factor-1 axis had a major impact on the parameters analyzed. The results also suggest that expression of several key genes involved in the control of testicular function is preserved under conditions of mild CR and encourage speculation that mild regimens of CR can produce longevity benefits without impairing reproduction.     

Effects of growth hormone and insulin-like growth factor-1 on hepatocyte antioxidative enzymes

The physiological decline that occurs in aging is thought to result, in part, from accumulation of oxidative damage generated by reactive oxygen species during normal metabolic processes. Elevated levels of antioxidative enzymes in liver tissues are present in the Ames dwarf, a growth hormone (GH)-deficient mouse that lives more than 1 year longer than wild-type mice from the same line. In contrast, transgenic mice that overexpress GH exhibit depressed hepatic levels of catalase and have significantly shortened life spans. In this study, we evaluated the in vitro effects of GH and insulin-like growth factor 1 (IGF-1) on antioxidative enzymes in mouse hepatocytes. Hepatocytes were isolated from wild-type mice following perfusion of livers with a collagenase-based buffer. Dispersed cells were plated on Matrigel and treated with rat GH (0.1, 1.0, or 10 microg/ml) or IGF-1 (0.5, 5.0, or 50 nM) for 24 hr. Hepatocytes were recovered and protein was extracted for immunoblotting and enzyme activity assays of catalase (CAT), glutathione peroxidase (GPX), and manganese superoxide dismutase (MnSOD). A 41% and 27% decrease in catalase activity was detected in cells treated with GH, whereas IGF-1 reduced CAT activity levels to a greater extent than GH (P < 0.0001). The activity and protein levels of GPX were also significantly depressed in cells treated with GH, whereas activity alone was decreased in cells treated with IGF-1 (P < 0.04). GH significantly suppressed MnSOD levels by 40% and 66% in 1.0 and 0.1 microg/ml concentrations, respectively. Similarly, IGF-1 decreased MnSOD protein levels (5 nM; P < 0.05). These results suggest that GH and IGF-1 may decrease the ability of hepatocytes to counter oxidative stress. In addition, these experiments provide an explanation for the differing antioxidative defense capacity of GH-deficient versus GH-overexpressing mice, and they suggest that GH is directly involved in antioxidant regulation and the aging process.     

Lactotroph hyperplasia in the pituitaries of female mice expressing high levels of bovine growth hormone

PEPCK/bGH transgenic mice have very high blood levels of foreign GH, and prominent reproductive disturbances, especially in females. To obtain a deeper insight into the causes of these abnormalities, pituitaries of PEPCK/bGH transgenics were studied by immunocytochemistry, electron microscopy and in situ hybridization (ISH) techniques. Pituitary weights were significantly reduced (P < 0.05) in transgenic males, while in transgenic females they were increased without reaching significance compared to nontransgenic controls. In both sexes, GH cells were inhibited, as previously described in other lines of GH transgenic mice. In females, PRL cells were increased by 37% compared to controls. Ultrastructurally, the lactotrophs had characteristics of stimulation and PRL mRNA was increased by 35%. In males the increase in the number of PRL immunoreactive cells was not significant, the PRL mRNA signal did not differ from controls, and there were no changes in their ultrastructure. Only in females ACTH cells were significantly reduced (P < 0.05) in number and unchanged in males; however, POMC mRNA signal was increased in both genders and reached significance (P < 0.05) in males. In females, but not in males, the percentage of LH cells was lower than in control mice. In conclusion, the high blood bGH levels induced sex related changes in transgenic mice from the present line. The infertility of PEPCK/bGH transgenic females may be attributed to lactotroph hyperplasia and marked reduction in number of gonadotrophs.     

Evidence that growth hormone exerts a feedback effect on stomach ghrelin production and secretion

Ghrelin is a recently discovered stomach hormone that stimulates pituitary growth hormone (GH) secretion potently. The purpose of these experiments was to test the hypothesis that a stomach-ghrelin-pituitary-GH axis exists in which either an elevation or reduction in systemic GH levels will exert a negative or positive feedback action, respectively, on stomach ghrelin homeostasis. In rats, GH administration decreased stomach ghrelin mRNA levels and plasma ghrelin levels significantly. In GH-releasing hormone (GHRH) transgenic mice, GHRH overexpression decreased stomach ghrelin peptide levels when compared with control mice. In aged rats (25 months) stomach ghrelin mRNA and peptide levels and plasma ghrelin levels were decreased when compared with young rats (5 months). Because GH secretion is reduced in aged rats, the elevated stomach ghrelin production and secretion may reflect a decreased GH feedback on stomach ghrelin, homeostasis, and secretion. Together, these findings suggest that endogenous pituitary GH exerts a feedback action on stomach ghrelin homeostasis and support the hypothesis that a stomach-ghrelin-pituitary GH axis exists.     

Effects of fasting on growth hormone/insulin-like growth factor I axis in the tilapia,Oreochromis mossambicus

Effects of fasting on the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis were examined in the tilapia (Oreochromis mossambicus) acclimated to fresh water. Fasting for 2 weeks resulted in significant reductions in body weight, specific growth rate and hepatosomatic index in both males and females. Significant reductions in specific growth rates were observed after 1 and 2 weeks in both sexes, although the decrease in body weight was not significant in the female. A significant reduction was also seen in the condition factor of females after 2 weeks. No change was seen in the gonadosomatic index in either sex. Two weeks of fasting also produced a significant reduction in plasma IGF-I but not in plasma GH, prolactin (PRL(188)) or cortisol. Significant reductions in the hepatic IGF-I mRNA were seen in both sexes. On the other hand, a significant increase was observed in cortisol receptor mRNA in the female liver. Plasma IGF-I levels were correlated significantly with specific growth rate, condition factor and hepatosomatic index, indicating that plasma IGF-I is a good indicator of growth in the tilapia. No change was seen in plasma glucose or osmolality after 2 weeks of fasting. During fasting, tilapia appears to convert metabolic energy from growth to basal metabolism including maintenance of ion and water balance.