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Biomedical subjects

L A Frohman

Publications and source records attributed to L A Frohman.

At least 55 records · Page 3Linked to original sources
PubMed1993

Congenital gigantism due to growth hormone-releasing hormone excess and pituitary hyperplasia with adenomatous transformation.

The cause of gigantism in most patients is a GH-secreting pituitary tumor. In this report, a case of congenital gigantism due to probable central hypersection of GH-releasing hormone (GHRH) is described. Normal at birth (4.4 kg; 53 cm), our 7-yr-old male patient grew progressively thereafter to attain a height of 182 cm and a weight of 99.4 kg at the time of our evaluation. The markedly increased baseline plasma levels of GH (730 micrograms/L) did not suppress during a standard 3-h oral glucose tolerance test, but did increase 54% after iv infusion of GHRH. Baseline plasma levels of insulin-like growth factor-I, PRL, and immunoreactive GHRH were also markedly increased. Computed imaging of the head showed a large, partially cystic sellar and suprasellar mass. Extensive imaging studies did not localize a potential source of GHRH. Preoperative treatment with octreotide and bromocriptine for 4 months resulted in a 25% reduction of suprasellar tissue mass. The pituitary tissue removed at transsphenoidal and transfrontal operations showed massive somatotroph, lactotroph, and mammosomatotroph hyperplasia. Areas of GH- and PRL-secreting cell adenomatous transformation were also evident. No histological or immunohistochemical evidence of a pituitary source of GHRH was found. The peripheral plasma immunoreactive GHRH concentration remained unaffected by pharmacological and surgical interventions. We suspect that a congenital hypothalamic regulatory defect may be responsible for the GHRH excess in this case.

Adenoma↗
PubMed1993

Stimulatory effect of thyroid hormone on growth hormone gene expression in a human pituitary cell line.

A cell line (GX) derived from a pituitary tumor of a boy with gigantism, which exhibits morphological characteristics of epithelial cells, has been established and maintained in culture for over 2 yr. Initially, GX cells secreted GH which was stimulated by T3. However, after 2 yr in culture, GH production in GX cells is no longer detectable, though GH messenger RNA (mRNA) synthesis has been maintained. The GX cell line is a somatomammotroph line as indicated by the presence of both GH and PRL mRNAs. GX cells were used to study the effect of T3 on GH gene expression. A nearly 3-fold increase in GH mRNA accumulation was observed in GX cells in response to the addition of T3 to the culture medium. This increase was also observed in serum-free medium, indicating that the effect of T3 does not require the presence of other hormones or serum factors. Neither PRL nor beta-actin mRNA accumulation was stimulated by T3 in GX cells. Nuclear runoff experiments demonstrated that the stimulatory effect of T3 on GH mRNA accumulation is related to transcriptional activation of the human GH gene.

Cell Division↗
PubMed1993

Effects of drinking water monochloramine on lipid and thyroid metabolism in healthy men.

The purpose of this study was to determine whether a 4-week consumption of 1.5L per day of drinking water containing monochloramine at a concentration of 2 ppm (ppm = mg/L) or 15 ppm under controlled conditions would alter parameters of lipid or thyroid metabolism in healthy men. Forty-eight men completed an 8-week protocol during which diet (600 mg cholesterol per day, 40% calories as fat) and other factors known to affect lipid metabolism were controlled. During the first 4 weeks of the protocol, all subjects consumed distilled water. During the second 4 weeks, one-third of the subjects were assigned randomly to drink 1.5 L per day of water containing 2 ppm of monochloramine, to drink 1.5 L per day of water containing 15 ppm monochloramine, or to continue drinking distilled water. Four blood samples were collected from each subject at the end of each 4-week study period. Subjects drinking monochloramine at a concentration of 2 ppm showed no significant changes in total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoproteins A1, A2, or B when compared to the distilled water group. Parameters of thyroid function also were unchanged by exposure to monochloramine at this concentration. However, subjects drinking monochloramine at a concentration of 15 ppm experienced an increase in the level of apolipoprotein B. Other parameters of lipid and thyroid metabolism did not change. We conclude that consumption of drinking water containing 2 ppm of monochloramine does not alter parameters of lipid and thyroid metabolism in healthy men. Consumption of water containing 15 ppm monochloramine may be associated with increased levels of plasma apolipoprotein B.

Adolescent↗
PubMed1993

Lack of effect of drinking water chlorine on lipid and thyroid metabolism in healthy humans.

Animal studies and a single human epidemiological study have suggested that chlorine in drinking water may raise the level of blood cholesterol. The purpose of this study was to determine whether a 4-week exposure to drinking water chlorine (1.5 L per day) at a concentration of 20 ppm (ppm = mg/L) under controlled conditions would alter circulating parameters of lipid metabolism in healthy humans. Thirty men and thirty women each completed an 8-week protocol during which diet (600 mg cholesterol per day, 40% calories as fat) and other factors known to affect lipid metabolism were controlled. For the first 4 weeks of the protocol, all subjects consumed distilled water. For the second 4 weeks, half of the subjects were assigned randomly to drink 1.5 L per day of chlorinated water (20 ppm), while the others continued drinking distilled water. Four blood samples were collected from each subject at the end of each 4-week study period. Compared to the control group, those subjects given chlorine showed no significant changes in total plasma cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, or apolipoproteins A1, A2, or B. There was a trend toward low serum thyroxine and triiodothyronine levels in men given chlorine, though thyroid-stimulating hormone levels were unchanged. This trend, if real, was not clinically significant. Thus, short-term exposure to chlorinated drinking water at 20 ppm appears to have no significant impact on parameters of lipid or thyroid metabolism in healthy humans.

Adolescent↗
PubMed1992

Growth hormone-releasing factor analogs with hydrophobic residues at position 19. Effects on growth hormone releasing activity in vitro and in vivo, stability in blood plasma in vitro, and secondary structure.

To test the hypothesis that replacing Ala19 in growth hormone-releasing factor (GRF) with more hydrophobic residues will increase growth hormone releasing activity, four GRF analogs were prepared and tested. The molecules were made by substituting Val, Ile, or Leu at position 19 of [Thr2,Ala15,Leu27]bGRF(1-29)NH2. The compounds were evaluated for growth hormone (GH) releasing activity in vitro (rat anterior pituitary cells) and in vivo (steers). Additionally, their half-life in vitro was determined in bovine plasma, and their secondary structure was examined by circular dichroism. In pituitary cells, peptides with substitutions at position 19 had the following potencies: Ala (native), 0.37; Val, 1.16; Ile, 0.37; Leu, 0.043. When assayed in steers as a single iv bolus, over a 2-h period, the compounds gave the following integrated GH response: Ala, 2.75; Val, 2.67; Ile, 2.57; Leu, 1.55. Only the Leu analog was statistically different from the other three (p = 0.05). In bovine plasma, the half-lives (hours) were as follows: Ala, 4.9; Val, 6.6; Ile, 12.3; Leu, 14.7. In phosphate buffer the compounds were calculated to have the following percent helical content: Ala, 26; Val, 21; Ile, 27; Leu, 32. For these analogs, helicity in aqueous buffer is inversely related to their in vitro activity. Using a linear multiple regression model, the plasma half-life of the analogs positively correlated (r2 = 0.999) with both the hydrophobicity of the residue at position 19 and the helicity of the analog. Although the Val analog had both increased inherent activity and increased plasma stability in vitro compared to the Ala analog, in this study we were unable to demonstrate an increase in activity in vivo. The in vivo GH releasing activity of the analogs was not simply related to a combination of their intrinsic GH releasing activity and their in vitro plasma half-life. This suggests that in vivo additional factors are moderating the expression of activity.

Amino Acid Sequence↗
PubMed1992

Interaction of ethanol with signal transduction mechanisms mediating growth hormone release by rat pituitary cells in vitro.

The effects of ethanol on signal transduction mechanisms of rat GH (rGH) release were investigated in primary culture of rat anterior pituitary cells. Ethanol (30, 100, and 300 mM) had no significant effect on basal rGH release or cell content after a 4-h incubation or on intracellular cAMP levels at 30 min. Ethanol did not alter rGRH (10(-11) M)-stimulated rGH release, but at concentrations of 100 and 300 mM it inhibited rGRH (10(-9) M)-stimulated rGH release by 12% (P less than 0.05) and 54% (P less than 0.01). In contrast, a dose-dependent stimulatory effect was observed on rGRH-induced cAMP accumulation. Ethanol enhanced the inhibitory effect of SRIH (10(-11) and 10(-9) M) on rGH release by up to 24% (P less than 0.01). Stimulation of rGH release by cAMP derivatives and forskolin was partially inhibited by ethanol, as was cAMP accumulation after forskolin treatment. Cholera toxin-stimulated rGH release was also inhibited by ethanol, whereas cAMP accumulation was increased. At the higher concentrations, ethanol enhanced rGH release after protein kinase-C activation by phorbol ester and after stimulation of calcium influx with Ca ionophore. No significant ethanol effect was noted on prostaglandin E2-stimulated rGH release, and ethanol did not alter rGH mRNA levels or proliferation of a pituitary somatomammotroph cell line. The results indicate that ethanol exerts multiple effects on systems mediating GH release from the pituitary in vitro. However, the inhibitory influence of ethanol on GH secretion is related primarily to the adenylate cyclase-cAMP pathway, which represents the major signal transducing system in the somatotroph.

Animals↗
PubMed1992

Inhibitory effects of ethanol on the growth hormone (GH)-releasing hormone-GH-insulin-like growth factor-I axis in the rat.

Ethanol administration decreases GH secretion in humans and experimental animals. The mechanism of these inhibitory effects was investigated by evaluating the spontaneous secretory pattern of GH in chronically cannulated unanesthetized rats, plasma insulin-like growth factor-I (IGF-I) concentrations, and hypothalamic GH-releasing hormone (GHRH) and somatostatin, and pituitary GH mRNA levels. Body weight gain was reduced in ethanol (5%)-liquid diet-fed rats (n = 6) for 6 days compared to that in both isocalorically pair-fed controls (n = 6) and ad libitum-fed animals (n = 6). Spontaneous GH secretion was markedly decreased (by 75-90%) in ethanol-fed rats compared to that in pair-fed and ad libitum-fed groups, while pulsatile pattern of GH release was preserved, with secretory bursts occurring every 180-220 min in all groups. Mean 6-h plasma GH levels in ethanol-, pair-, and ad libitum-fed animals were: 18.8 +/- 4.5, 113.3 +/- 14.9, and 179.6 +/- 30.1 ng/ml, respectively (P < 0.01, ethanol vs. each control). Plasma IGF-I concentrations were decreased in the ethanol-fed rats (338 +/- 16 ng/ml) compared to those in pair-fed (427 +/- 39 ng/ml; P < 0.05) and ad libitum-fed (769 +/- 25 ng/ml; P < 0.01) rats. Ethanol treatment decreased GHRH mRNA levels to 9% of those in ad libitum-fed (P < 0.01) and 20% of those in pair-fed (P < 0.05) animals, whereas it did not significantly alter somatostatin or GH mRNA levels. The results indicate that the effects of ethanol inhibit GH secretion primarily at the hypothalamic level, resulting in impaired GHRH gene expression. Since the GHRH-GH-IGF-I axis has an important role in growth regulation, the growth retardation seen in experimental models of alcohol abuse may be a consequence at least in part of the suppressive effects of ethanol on this axis.

Animals↗
PubMed1992

Regulation of growth hormone secretion.

The secretion of growth hormone (GH) is controlled by a complex regulatory system. The primary control is exerted by two neuroendocrine hormones, GH-releasing hormone and somatostatin, though other hypothalamic neuropeptides directly and indirectly participate in this process. The regulation of each of these neurohormones is now being clarified at both physiologic and molecular levels, as are their respective roles in the generation of pulsatile GH secretion and in GH feedback regulation. Considerable information has been amassed concerning signal transduction systems mediating the effects of hypothalamic hormones on GH secretion. Although multiple second messengers have been implicated, the adenylate cyclase-cyclic AMP-protein kinase A system appears to exert a predominant role. The developmental regulation of the somatotropes and of GH gene expression is also of importance in determining the GH responses to releasing and inhibiting hormones. The availability of several rodent strains with genetic disorders of growth associated with impaired GH secretion, along with the development of transgenic models, has permitted a more detailed analysis of the role of cytokines and growth factors on both somatotrope biology and hormone secretion. Finally, knowledge gained from studies in animals is permitting a better understanding of the mechanisms involved in physiologic GH secretion and altered GH secretion associated with specific disease states in humans.

Amino Acid Sequence↗
PubMed1992

Morphologic effects of hGRH gene expression on the pituitary, liver, and pancreas of MT-hGRH transgenic mice. An in situ hybridization analysis.

Morphologic changes in the pituitary, liver, and pancreas of mice with the metallothionein-human growth hormone--releasing hormone (MT-hGRH) transgene were analyzed by in situ hybridization histochemistry (ISH). There was progression from somatotroph hyperplasia to neoplasia in pituitaries of transgenic mice. Pituitary neoplasms were present between 9 to 12 months of age in some mice. Magnetic resonance imaging (MRI) readily identified enlarged pituitaries in MT-hGRH transgenic mice. Serum mouse GH and hGRH levels were marked elevated in MT-hGRH transgenic mice. In situ hybridization histochemistry showed mRNA for hGRH in liver, pituitary, pancreas, spleen, and in most other tissues examined. Combined ISH and immunohistochemistry in the pituitary gland showed that some of the GH cells also produced hGRH, and ultrastructural immunohistochemical analysis of pituitaries showed that GH and hGRH were localized in the same cell and within the same secretory granules. Liver cells of MT-hGRH transgenic mice showed evidence of hypertrophy, and the pancreatic islets were hyperplastic with significant increases in the islet cell areas. The morphologic changes in the liver were distinctive enough to separate control littermates from MT-hGRH transgenic mice in all cases. The enlarged pancreatic islets had increased numbers of insulin-producing cells. Immunoreactive hGRH and hGRH mRNA were both localized in islet cells, and an intense hybridization signal of hGRH mRNA, but only weak staining for hGRH protein, were detected in the liver of transgenic mice. These results indicate that excessive hGRH production leads to distinct morphologic changes in various organs in MT-hGRH transgenic mice and that there is temporal progression from hyperplasia to adenomatous somatotrophs in pituitaries with chronic stimulation by hGRH that involves paracrine, endocrine, and autocrine mechanisms.

Adenoma↗
PubMed1992

A rapid and simple method for labeling short DNA fragments using Taq polymerase.

This report describes a new method for labeling PCR-generated short length (60-120 bp) double-stranded DNA fragments for use as hybridization probes. The method utilizes gene-specific primers identical to those for PCR generation of non-radioactive DNA fragments. Radioactive probes are synthesized by Taq DNA polymerase without using PCR. Single-stranded (sense or antisense) and double-stranded probes can be individually prepared by selection of the appropriate primers. The labeling reaction reached maximum incorporation within 30 min with mean specific activities of 1.05 x 10(9) dpm/microgram (antisense single-stranded), and 1.62 x 10(9) dpm/microgram (double-stranded) were obtained using templates 69-117 of nucleotides. This method offers a simple and rapid means of generating antisense probes for Northern blot analyses and double-stranded probes for Southern blot analyses that provide highly intense signals with low background.

Animals↗
PubMed1991

A comparison of transcriptional regulatory element activities in transformed and non-transformed rat anterior pituitary cells.

Transformed (GH-3) and non-transformed (P3) rat anterior pituitary cells were compared in their ability to direct expression of plasmids containing a variety of eukaryotic transcriptional regulatory elements (TREs). These include the herpes simplex virus thymidine kinase (HSV-TK), Rous sarcoma virus long terminal repeat (RSV-LTR), simian virus 40 early (SV-40E), human cytomegalovirus immediate-early (CMV-IE) and mouse metallothionein 1 (mMT-1) TREs. Chloramphenicol acetyl transferase (CAT) gene expression served as a reporter in this study. Following transient transfection, the cell lines exhibited similar profiles of TRE utilization. In each cell line. CMV-IE was most efficient in directing reporter gene expression, although 2-fold greater activity was observed in GH-3 versus P3 cells. RSV-LTR directed gene expression was lower than that of CMV-IE while both HSV-TK and SV-40E were inactive in each cell line. Also, the mMT-1 promoter was inducible by addition of ZnCl2 to the culture media, though the level required for maximal activation differed between the two cell lines. Transfected GH-3 and P3 cells, therefore, displayed similar TRE utilization profiles yet significant differences were observed in the ability of these cell lines to respond to specific regulatory elements.

Animals↗
PubMed1991

Growth hormone and insulin-like growth factor-I measurements in high growth (hg) mice.

Effects of a recessive gene causing high growth (hg) were studied on two major components of the growth axis in mice. Plasma and pituitary levels of growth hormone and plasma levels of insulin-like growth factor I (IGF-I) were measured in three lines homozygous for hg, each compared with a control line of alike genetic background but wild type for the hg locus (Hg). Line Gh (hghg) and line GH (HgHg) are from a line which had undergone long-term selection for high postweaning weight gain; line Ch (hghg) and line CH (HgHg) were extracted from the second backcross of Gh to C57BL/6J; line L54 (hghg) was from the sixth backcross to C57BL/6J (B6) (HgHg). Pituitary GH levels and plasma IGF-I levels were measured in both sexes at 3, 4.5, 6 and 9 wk of age. Plasma growth hormone was measured in 8- to 12-wk-old males at hourly intervals from 08.00 to 17.00. Body weight in lines homozygous for hg at 6 and 9 wk of age was 10-30% greater than in control lines. The ontogeny of this increased growth depended on genetic background. Pituitary growth hormone content was 52% lower in the two hghg lines measured (lines Ch and Gh) than in control lines at 4.5, 6 and 9 wk. Plasma growth hormone levels were also much lower in hg mice, with values only 20-30% of those in their respective controls. hg lines showed consistently low plasma growth hormone levels throughout the 9 hr sampling period, while control lines expressed the characteristic pulsatile hormone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Synthesis and biological evaluation of mouse growth hormone-releasing factor.

The recently described mouse growth hormone-releasing factor (mGRF) was synthesized by the solid phase procedure, purified by 2 stages of preparative high performance liquid chromatography and fully characterized. The biologic activity of the 42-amino acid peptide (H-His-Val-Asp-Ala-Ile-Phe- Thr-Thr-Asn-Tyr- Arg-Lys-Leu-Leu-Ser-Gln-Leu-Tyr-Ala-Arg-Lys-Val-Ile-Gln-Asp-Ile-Met-Asn- Lys- Gln-Gly-Glu-Arg-Ile- Gln-Glu-Gln-Arg-Ala-Arg-Leu-Ser-OH) was assessed in primary cultures of both mouse and rat anterior pituitary cells and compared to synthetic rat (rGRF) and human (hGRF) growth hormone-releasing factors. mGRF was equipotent to rGRF in mouse somatotrophs but slightly less potent in rat somatotrophs, while hGRF was 3-5 times less potent in both rodent species.

Amino Acid Sequence↗
PubMed1991

Evidence for a defect in growth hormone-releasing factor signal transduction in the dwarf (dw/dw) rat pituitary.

Dwarf (dw/dw) rats exhibit a 40% reduction in body growth, isolated GH deficiency (less than 5% of normal pituitary content), and a decreased number of pituitary somatotrophs (15-20% of normal). Since GH-releasing factor (GRF) stimulates GH synthesis and secretion and somatotroph proliferation, and its effects are probably mediated by cAMP, we have assessed GH secretion and cAMP production in dw rat pituitaries in response to various GH secretagogues. Dispersed pituitary cells from dw rats were less sensitive (2.5-fold) to stimulation of GH secretion by GRF and showed a 25% reduction in the maximal GH response even after normalization of their reduced GH content. Intracellular cAMP was elevated 63-fold over basal levels in normal cells after 4 h in response to maximal GRF stimulation, but only 1.9-fold in dw cells, and even larger differences between the groups were found at earlier time points. The GH responses of dw cells to exogenous cAMP, however, were indistinguishable from normal. Forskolin, a direct stimulator of adenylate cyclase, elicited comparable maximal GH and cAMP responses, but an increased ED50, in dw cells. Activation of GS alpha by cholera toxin showed an increased ED50 and reduced GH and cAMP responses in dw cells, and marked decreases in these responses were observed in response to prostaglandin E1. Phorbol ester stimulation resulted in a reduced maximal GH response in dw cells without a change in sensitivity. These results provide evidence for a defect in the GRF signal transduction pathway associated with a decreased ability of GS alpha to stimulate adenylate cyclase in dw rat somatotrophs that may be causally linked to their GH deficiency.

Alprostadil↗
PubMed1991

Biosynthesis of human growth hormone-releasing hormone (hGRH) in the pituitary of hGRH transgenic mice.

We have studied the posttranslational processing of prohuman GH-releasing hormone (pro-hGRH) to the mature hormones, hGRH(1-44)-NH2 and hGRH(1-40)-OH, and its carboxyl-terminal peptide (hGCTP) in pituitary cells from transgenic mice bearing a metallothionein-hGRH fusion gene after incubation with [35S]methionine. After separation on HPLC, 35S-labeled and unlabeled hGRH in medium and cell extracts were characterized by RIA and immunoprecipitation with antisera against hGRH and against hGCTP. After a 4-h pulse, unlabeled and [35S]pro-hGRH, hGRH(1-44)-NH2, and hGRH(1-40)-OH were identified in medium and cell extracts by both RIA and immunoprecipitation with anti-hGRH serum. In cell extracts, after a 0.5-h pulse, [35S]pro-hGRH and hGRH(1-44)-NH2 but not [35S]hGRH(1-40)-OH were detectable. After a 0.5-h chase, however, 35S-labeled hGRH(1-40)-OH, pro-hGRH, and [35S]hGRH(1-44)-NH2 were all measurable. After a 4-h chase, comparable levels of [35S]hGRH(1-44)-NH2 and hGRH(1-40)-OH were present, and very little intracellular 35S-pro-hGRH remained. A progressive decrease in the ratio of immunoprecipitable pro-hGRH to mature hGRH peptides and an increase in the ratio of hGRH(1-40)-OH to hGRH(1-44)-NH2 was observed in the two chase periods. In medium, [35S]hGRH(1-44)-NH2 was detectable at all times, whereas only minimal amounts of [35S]hGRH(1-40)-OH were present. Labeled and unlabeled pro-hGRH in cell extracts was also detected with anti-hGCTP serum, and another peak, which coeluted with synthetic hGCTP, was also identified. The low molar ratio of intracellular immunoreactive hGCTP to hGRH (less than 0.02) suggests a more rapid turnover rate of hGCTP than of hGRH. These results demonstrate the processing of hGRH prohormone to both mature forms of hGRH and provide evidence that hGRH(1-40)-OH is derived from hGRH(1-44)-NH2.

Animals↗
PubMed1991

Impaired generation of cyclic adenosine 3',5'-monophosphate in a somatomammotroph cell line derived from dwarf (dw) rat anterior pituitaries.

The dwarf (dw) mutation in rats results in 40-50% growth retardation associated with a selective reduction in pituitary somatotroph number, GH content, and GH mRNA levels and a decreased GH secretory response to GH-releasing factor (GRF). Recent studies in freshly dispersed pituitary cells have provided evidence for a defect in adenylate cyclase-linked GRF signal transduction in dw somatotrophs. To further examine this defect in a more specific cell population, we developed a somatomammotroph cell line (DP) derived from anterior pituitaries of male dw rats. A similar cell line from normal rats (Po) was used as control. We studied acute GH (4-h release) and cAMP (30-min intracellular accumulation) responses to GH secretagogues known to interact with the adenylate cyclase system. Basal GH release in both cell lines was 80-130% of the cell content, thus limiting the capacity for further GH responses. GRF (10(-8) M) produced a doubling of cAMP levels in Po and DP cells (P less than 0.01), but inconsistent effects on GH release. (Bu)2cAMP (5 x 10(-3) M) increased GH secretion by 50-100% in both groups (P less than 0.01). Cholera toxin (10(-9) M) increased GH release by 50% in both Po and DP (P less than 0.01), but the cAMP response in DP cells was only half that in Po cells (P less than 0.01). Forskolin (10(-5) M), a direct stimulator of adenylate cyclase, doubled GH release in both groups (P less than 0.01). However, cAMP generation was impaired in DP, with a maximal response to forskolin less than one third that in Po (P less than 0.01). In somatotrophs, cAMP mediates not only GRF-stimulated GH release, but also GH synthesis and mitogenesis. The impairment in maximal cAMP generation in DP cells, while not affecting acute GH release, may underlie the defect in somatotroph cell number and GH content in the dw pituitary gland.

Adenylyl Cyclases↗
PubMed1991

The role of the cholinergic pathway in growth hormone feedback.

Cholinergic pathways play an important role in the regulation of GH secretion. To assess their participation in GH feedback, we investigated the effect of pyridostigmine (an acetylcholinesterase inhibitor) on plasma GH responses to GH-releasing hormone (GHRH) plus TRH, insulin hypoglycemia, and arginine as well as on the inhibition of these responses by exogenous GH. The GH response to each stimulus was inhibited by an infusion of GH (0.55 micrograms/m2/min), started 4 h earlier. Pyridostigmine (120 mg, orally), administered 30 min before the stimulus, enhanced GH responses to GHRH and insulin during both saline and GH infusions. However, GH responses during combined administration of pyridostigmine and GH were less than those during pyridostigmine alone. GH responses to arginine, in contrast, were not affected by pyridostigmine in either the absence or presence of exogenous GH. TSH responses to TRH were unaltered by either GH or pyridostigmine. Pyridostigmine enhancement of GH responses to a maximally stimulatory dose of GHRH suggests that its effect is exerted by inhibition of somatostatin release. The lack of effect of pyridostigmine on plasma GH responses to arginine suggests that arginine and pyridostigmine increase GH secretion through a common pathway. The enhancement by pyridostigmine of GH responses in both the presence and absence of exogenous GH suggests that exogenous GH and pyridostigmine exert their discordant effects on GH secretion through independent mechanisms.

Administration, Oral↗