Effects of insulin-like growth factor-I on growth hormone and prolactin secretion and cell proliferation of human somatotrophinomas and prolactinomas in vitro

OBJECTIVE IGF-I inhibits GH secretion from normal and some tumorous pituitary tissue, and has been shown to be mitogenic for gonadotrophinoma cells in vitro. It is not known whether IGF-l affects somatotrophinoma cellular proliferation or the secretion of other hormones, such as PRL and α-subunit, which are often co-secreted by these tumours. We have therefore examined the effects of IGF-l on proliferation and hormonal secretion of human somatotrophinomas and prolactinomas in vitro. DESIGN Pituitary adenoma tissue was dispersed to single cells in monolayer culture. The effects of 100 nw IGF-I on GH, PRL and α-subunit secretion were determined over 4-hour and over 4-day periods, and a 4-day dose-response study using 1–100 nM IGF-I was performed on two tumours. Adenoma cell S-phase proliferation was determined after bromodeoxyuridine Incorporation for 1 hour after 4 days, using a double immunostaining method. RESULTS Over 4 hours, 100 nw IGF-I had no effect on GH, PRL or α-subunit secretion in 7 tumours. Over 4 days, 100 nw IGF-I reduced GH secretion In 518 somatotrophinomas (range 17–84%, P < 0·05) compared to controls, with tumours responding to IGF-I having lower basal serum and in-vitro GH levels than tumours unaffected by IGF-I (P < 0·05). There was no effect on α-subunit secretion in any of the three tumours studied. PRL co-secretion was increased In 315 somatotrophinomas compared to control (20, 30 and 37%, P < 0·05), with tumours responding to IGF-I being associated with lower basal serum and in-vitro PRL levels than those tumours unaffected by IGF-I. IGF-I also increased PRL secretion in 2/2 prolactinomas (27 and 32%, P < 0·05) compared with control. GH was inhibited and PRL secretion was stimulated by 1 and 10 nw IGF-I in the two dose-response studies. The proliferative labelling index did not exceed 1·9% in any tumour and no proliferative effect was found with 100 nw IGF-I in any somatotrophinoma. CONCLUSION IGF-I inhibited tumorous GH in 62% and stimulated PRL secretion in 71 % of tumours over 4 days, without affecting α-subunit secretion or being mitogenic for somatotrophinoma cells in vitro. No hormonal effects were observed over short (4-hour) incubations. IGF-I may be a newly recognized factor directly stimulating tumorous PRL secretion.     

Inhibition of binding of ovine placental lactogen to growth hormone and prolactin receptors by monoclonal antibodies

From a single cell fusion, five stable hybridomas secreting antiovine placental lactogen (oPL) antibodies were obtained. Three of these secrete immunoglobulin (Ig)G subclass, and the other two secrete IgM class antibodies. Ascites fluids were raised in mice for each clone and were used as the antibody component for the development of solid phase RIA. Three solid-phase RIAs were successfully established using individual IgG subclass monoclonal antibodies, but the IgM class antibodies were ineffective. In all three individual solid-phase RIAs, the binding of [125I]iodo-oPL to the immobilized antibody was inhibited by unlabeled oPL, but not by ovine pituitary PRL (oPRL), ovine GH (oGH), or ovine pituitary extract. Two of the IgG subclass antibodies were able to inhibit the binding of [125I] iodo-oPL to PRL receptors(s) and to GH receptor(s) in rabbit mammary gland and liver, respectively. One of these two IgG subclass antibodies was more effective at inhibiting the binding of oPL to PRL receptor(s) in rabbit mammary gland, whereas the other one is more effective in inhibiting the binding of oPL to GH receptor(s) in rabbit liver. These antibodies, however, could only weakly inhibit the binding of [125I]iodo-oPRL to rabbit mammary gland and were ineffective in inhibiting the binding of [125I]iodo-oGH to rabbit liver. The addition of monoclonal antibodies in both radioreceptor assay (RRA) for PRL (RRA-PRL) and for GH (RRA-GH) did not affect the parallelism of the displacement curve of oPL standard. Our results suggest that oPL might contain two distinct binding sequence(s): one responsible for the binding of oPL to PRL receptor(s) and the other responsible for the binding of oPL to GH receptor(s). These two binding sequences might overlap or be located adjacent to one another. The interaction of monoclonal antibodies with these binding sequences of oPL may block the binding of oPL with PRL and GH receptor(s). Alternatively, our studies suggest that the monoclonal antibodies do not bind to hormone receptor(s)-binding sequence(s) in oPL, but the interaction between oPL and monoclonal antibody might alter the conformational structure of the oPL which will consequently lead to a lower binding of oPL to PRL and GH receptor(s).     

Administration of insulin-like growth factor-I, but not growth hormone, increases maternal weight gain in late pregnancy without affecting fetal or placental growth.

During late pregnancy in the rat, circulating levels of insulin-like growth factor-I (IGF-I) and some IGF-binding proteins (IGFBP) decline. The aim of the present study was to determine the relationship of GH to circulating IGF and IGFBP in the late-pregnant rat and to examine the effects on maternal, fetal and placental growth of preventing the decline in serum IGF and IGFBP concentrations. During the first 9 days of pregnancy, IGF-I concentrations increased from 340 to 500 micrograms/l. Recombinant human (rh) GH at 2.4 mg/kg per day and rhIGF-I at 1.4 mg/kg per day were infused into pregnant rats via osmotic mini pumps during the second half of pregnancy. After pump implantation on day 11 of pregnancy, only IGF-I infusion significantly increased circulating IGF-I. A maximum IGF-I concentration of 907 micrograms/l was measured on day 14 during treatment with IGF-I, after which the serum concentration decreased to 510 micrograms/l by day 20 of pregnancy. The serum IGFBPs were examined using a Western ligand blot technique. Infusion of neither GH nor IGF-I returned the IGFBPs to non-pregnant levels. Administration of IGF-I slightly increased IGFBP-3 and a smaller 32 kDa IGFBP at days 17 and 20 of pregnancy. Neither fetal nor placental weight was significantly different between treatment groups. However, administration of IGF-I significantly increased maternal weight gain during the 10-day treatment period.(ABSTRACT TRUNCATED AT 250 WORDS)     

The insulin-like growth factor-I generation test: peripheral responsiveness to growth hormone is not decreased with ageing

OBJECTIVE: Ageing is accompanied by a reduction in GH secretion, and a decrease in circulating IGF-I. Few data are available on whether the responsiveness of IGF-I to GH stimulation changes with age. SUBJECTS AND METHODS: Therefore we carried out multiple IGF-I generation tests in 26 healthy volunteers (16 male) of normal body mass index (BMI); nine aged 20-40 years, six aged 41-60 years, and 11 aged > 61 years. Each subject received three single doses of GH: 0.8, 2.0 and 21 IU in random order at least 4 weeks apart. Serum samples were taken 0, 18, 24, 48, 72 and 120 h following each dose of GH. RESULTS: Basal serum levels of IGF-I (P < 0.0001) and IGFBP-3 (P < 0.01) declined with age, but serum acid-labile subunit (ALS) levels did not (P = 0.2). Peak IGF-I levels (P < 0.01 for 0.8 IU and P < 0.05 for the 2 IU dose) and area under curve (AUC) IGF-I (P < 0.01 for the 0.8 IU and 2.0 IU doses of GH and P < 0.05 for the 21 IU dose) after GH administration continued to demonstrate a significant trend towards lower values with increasing age. However, the increment in IGF-I, IGFBP-3 and ALS in response to GH did not decline with age. Indeed, the increment in IGF-I after 2 IU of GH, judged by the increase from basal to peak levels, increased with advancing age (P = 0.05), and a positive relationship was seen between the increment in the area under the IGF-I curve following the 21 IU dose of GH and age (P < 0.02). CONCLUSION: These data illustrate that although activity of the GH/IGF-I axis declines with age, peripheral responsiveness to GH is not attenuated. This suggests that a decrease in GH responsiveness does not contribute to the age-related fall in circulating GH-dependent peptides. Thus, for those embarking on trials of GH therapy or GH secretagogues in the elderly, the capacity to generate IGF-I will not limit potential efficacy. Furthermore, the dose of GH replacement required for patients with organic GH deficiency is likely to be lower in the elderly compared with young adults.     

Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis

Prolactin, growth hormone and placental lactogen are members of a family of polypeptide hormones which share structural similarities and biological activities. Numerous functions have been attributed to these hormones, among which stand out their recently discovered effects on angiogenesis, the process by which new blood vessels are formed from the pre-existing microvasculature. Prolactin, growth hormone and placental lactogen, along with two non-classical members of the family, proliferin and proliferin-related protein, can act both as circulating hormones and as paracrine/autocrine factors to either stimulate or inhibit various stages of the formation and remodeling of new blood vessels, including endothelial cell proliferation, migration, protease production and apoptosis. Such opposing actions can reside in similar but independent molecules, as is the case of proliferin and proliferin-related protein, which stimulate and inhibit angiogenesis respectively. The potential to exert opposing effects on angiogenesis can also reside within the same molecule as the parent protein can promote angiogenesis (i.e. prolactin, growth hormone and placental lactogen), but after proteolytic processing the resulting peptide fragment acquires anti-angiogenic properties (i.e. 16 kDa prolactin, 16 kDa growth hormone and 16 kDa placental lactogen). The unique properties of the peptide fragments versus the full-length molecules, the regulation of the protease responsible for specific protein cleavage, the selective expression of specific receptors and their associated signal transduction pathways are issues that are being investigated to further establish the precise contribution of these hormones to angiogenesis under both physiological and pathological situations. In this review article, we summarize the known and speculative issues underlying the effects of the prolactin, growth hormone and placental lactogen family of proteins on angiogenesis, and address important remaining enigmas in this field of research.     

The glycogenic effects of placental lactogen and growth hormone in ovine fetal liver are mediated through binding to specific fetal ovine placental lactogen receptors

To examine the relative roles of placental lactogen (PL) and GH in fetal metabolism, we have examined the effects of ovine PL (oPL), ovine GH (oGH), and ovine PRL (oPRL) on glycogen metabolism in cultured ovine fetal hepatocytes and have examined the binding of these hormones to hepatic membranes from fetal and neonatal lambs. In ovine fetal hepatocytes, oPL (150 ng/ml-20 micrograms/ml) stimulated dose-dependent increases in [14C]glucose incorporation into glycogen (18-167%) and total cellular glycogen content (10-69%). oGH and oPRL also stimulated glycogen synthesis in fetal hepatocytes, but the potencies of these hormones were only 12% and 4% that of oPL. The dose-response curves of the three hormones were parallel, and their maximal effects were identical, suggesting a common mechanism of action. In hepatic membranes from fetal lambs, the maximal specific binding of [125I]oPL was 26.3% while the maximal specific binding of [125I]oGH was only 0.9-1.5%. The binding of [125I]oPL was saturable and reversible and varied with incubation time and temperature. Unlabeled oPL (1 ng/ml-5 micrograms/ml) caused a dose-dependent inhibition of the binding of [125I]oPL to fetal hepatic membranes, with half-maximal displacement of [125I]oPL by 5-7 ng unlabeled oPL/ml. oGH and oPRL caused parallel displacement of [125I]oPL, but with potencies only 2% and 0.1% that of oPL. Scatchard analysis of oPL dose-response curves indicated that the hormone bound to a single class of receptors with a dissociation constant of 1.1 X 10(-10) M. The maximal specific binding of [125I]oGH to hepatic membranes of neonatal lambs (20.1%) greatly exceeded the binding of oGH to fetal hepatic membranes. In addition, the potency of oGH in competing for [125I]oPL binding sites in neonatal liver greatly exceeded the potency of oGH in competing for [125I]oPL binding sites in fetal liver. Although the biological effects of both oPL and oGH in postnatal subprimate tissues may be mediated through binding to nonprimate GH receptors, the results of these studies suggest that the glycogenic effects of oPL in ovine fetal liver are mediated through binding to specific fetal oPL receptors. The relatively weak biological effects of oGH and oPRL in ovine fetal liver appear to be mediated through the binding of the hormones to fetal oPL receptors. The presence of specific, high affinity PL receptors in ovine fetal tissues provides a mechanism whereby oPL may function as a GH in the ovine fetus.     

New concepts: growth hormone, insulin-like growth factor-I and the kidney.

Both growth hormone (GH) and IGF-1 have major effects on normal kidney growth, structure and function and participate in the pathogenesis of certain kidney diseases. Furthermore when the kidneys fail there are profound changes in the circulating GH-IGF-1 system and the renal and systemic responses to these hormones. In this brief review we address the advances that have been made in our understanding of the relationship between growth hormone GH and IGF-1 and the kidney in health and the systemic and local perturbations that occur in kidney disease and identify key unanswered questions.     

The anterior hypothalamus provides stimulatory input to tuberoinfundibular dopamine neurons which is not mediated by prolactin

Complete or retrochiasmatic deafferentations of the mediobasal hypothalamus were made in female rats 7 days prior to experimentation in order to determine the role played by putative afferent neuronal connections (1) in maintaining the basal neuronal activity of tuberoinfundibular dopaminergic (TIDA) neurons, and (2) in the stimulatory actions of prolactin on these neurons. The neuronal activity of TIDA neurons was estimated by measuring the rates of synthesis, turnover or metabolism of dopamine (DA) in the terminals of these neurons in the median eminence. Complete deafferentation of the mediobasal hypothalamus reduced the basal rate of DA synthesis, and retrochiasmatic deafferentation decreased the rates of synthesis, turnover and metabolism of DA in the median eminence. A knife cut 1 mm rostral to the retrochiasmatic cut failed to alter basal TIDA neuronal activity. These results suggest that afferent neuronal inputs originating in or coursing through the caudal portion of the anterior hypothalamus mediate a tonic stimulatory influence on TIDA neurons in the female rat. Intracerebroventricular administration of rat prolactin or systemic administration of haloperidol (which increases circulating levels of prolactin) increased DA synthesis in the median eminence of both sham-operated rats and retrochiasmatic-deafferentated rats. Thus, the stimulatory action of prolactin was not blocked by retrochiasmatic deafferentation. In addition, elimination of the basal stimulatory action of endogenous prolactin by pretreating animals with bromocriptine reduced the rate of DA synthesis in the median eminence of both sham- and retrochiasmatic-deafferentated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Parathyroid hormone potentiates the effect of insulin-like growth factor-I on bone formation

Insulin-like growth factor-I and parathyroid hormone are both known regulators of bone formation. In this study, human recombinant IGF-I and bovine PTH (1-34) and their combination were studied for their effects in vitro on the proliferation of embryonic chick osteoblast-like cells (osteoblasts) and in vivo on bone formation in normal rats. Osteoblasts from 17-day-old chick embryos were cultured in serum-free BGJb medium containing 0.1% bovine albumin. After 2 days, IGF-I and/or PTH were added. Twenty-four hours later [3H]thymidine incorporation into trichloroacetic acid precipitable material was quantified as an index of cell proliferation. This has previously been shown to reflect actual cell division. IGF-I at doses ranging from 0.85 to 13.6 nmol/l caused a dose-dependent increase in [3H]thymidine incorporation into osteoblasts. PTH alone (10 to 1000 pmol/l) had no significant effect. However, when combined with IGF-I, PTH potentiated the mitogenic effect of IGF-I and achieved statistical significance at 30 and 100 pmol/l (p less than 0.05). This potentiation was also studied in vivo. The right hind-limbs of rats weighing 150 g were infused intra-arterially by an osmotic minipump with graded doses of IGF-I (0.1 to 0.4 nmol/day) and/or PTH (0.27 nmol/day) for 7 days. The rate of trabecular bone apposition (formation) was measured by double tetracycline labelling and compared with the contralateral uninfused limb which acted as the control. Histomorphometric data revealed that neither IGF-I nor PTH alone had a significant effect on trabecular bone apposition rate compared with control limbs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of bovine growth hormone, human placental lactogen and ovine prolactin on intestinal fluid and ion transport in the rat.

The influence of bovine growth hormone and human placental lactogen on intestinal absorption was compared with that of ovine prolactin. Administration of each of these hormones in vivo daily for 2 days, resulted in increased fluid and electrolyte transport by the rat intestine, as measured in vitro. Hypophysectomy causes a fall in fluid and ion absorption in the rat jejunum but these changes are prevented by growth hormone treatment. Bovine growth hormone and ovine prolactin produce essentially similar effects in intact rats: significant increases in fluid, sodium and calcium transport in the duodenum; in fluid, sodium and potassium transport in the jejunum; in sodium, chloride, potassium and calcium transport in the ileum. Growth hormone also significantly increased fluid, sodium and chloride transport in the colon. Treatment of hypophysectomized rats with human placental lactogen enhanced fluid and ion transport in the jejunum; however, it failed to restore normal potassium transport in the ileum and colon at the 1 mg daily dose level. Growth hormone and human placental lactogen appear to affect jejunal water and electrolyte transport in the same manner as occurs with prolactin, possibly by influencing active ion transport.     

Growth hormone and insulin-like growth factor-I stimulate hormonal function and proliferation of thymic epithelial cells.

We have investigated the role of GH and insulin-like growth factor-I (IGF-I) in controlling the secretion of thymulin, a hormone produced by thymic epithelial cells (TEC). Thymulin plasma concentrations (mean +/- SD) were increased in 21 patients with acromegaly compared to those in 30 controls, as assessed by bioassay (4.24 +/- 0.97 vs. 2.67 +/- 0.87; P less than 0.001) and RIA (561 +/- 241 vs. 315 +/- 113 pg/L; P less than 0.01). Good correlations were observed between plasma levels of thymulin and IGF-I (P less than 0.001). In vitro experiments demonstrated that both recombinant human GH and IGF-I significantly increased thymulin production in culture supernatants of normal human TEC and a rat TEC line. In parallel, IGF-I also significantly stimulated the proliferation of human TEC, as measured by bromodeoxyuridine incorporation. Additionally, the stimulatory effect of GH on thymulin production was abrogated by both an anti-IGF-I antibody and an anti-IGF-I receptor antibody. These results support a role for GH and IGF-I in the control of thymic hormonal function in man and suggest that the effect of GH may be mediated by local secretion of IGF-I within the thymus.     

Differential effect of growth hormone and insulin-like growth factor-I, insulin-like growth factor-II, and insulin on Ig production and growth in human plasma cells

The effect of human growth hormone (GH) and insulin-like growth factor- I (IGF-I), IGF-II, and insulin on human plasma cell responses was studied. GH enhanced Ig production and thymidine uptake in the human plasma cell lines, IM-9 and AF-10. IGF-I, but not IGF-II or insulin, also enhanced Ig production and proliferation in them. However, enhancement by GH was not mediated by IGF-I, because enhancement was blocked by anti-GH antibody (Ab), but not by Ab to IGF-I or IGF-I receptor. Conversely, the enhancement by IGF-I was blocked by either Ab to IGF-I or IGF-I receptor, but not by anti-GH Ab. GH and IGF-I also enhanced production of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, and IgM and thymidine uptake in PCA-1+ plasma cells generated in vitro. Again, enhancement by GH was specifically blocked by anti-GH Ab, whereas enhancement by IGF-I was specifically blocked by either Ab to IGF-I or IGF-I receptor. These results indicate that GH and IGF-I may play important roles in plasma cell responses.     

The lipolytic effects of mouse placental lactogen II, mouse prolactin, and mouse growth hormone on adipose tissue from virgin and pregnant mice

The lipolytic activities of three structurally related mouse hormones, placental lactogen II (mPL-II), GH (mGH), and PRL (mPRL), and human PL (hPL) were investigated. Adipose tissue was obtained from virgin and day 12 and day 16 pregnant mice. Lipolytic activity was assessed by the ability of the hormones to stimulate glycerol release from fat explants in the presence of dexamethasone and by the ability of the hormones to sensitize adipose tissue to the lipolytic stimulus theophylline. In the first experiment, adipose tissue explants were incubated in Krebs-Ringer buffer with 0.0, 0.1, 0.5, 1.0, 5.0, and 10.0 micrograms/ml hormone for 4 h. mGH was lipolytic at a concentration of 0.5 micrograms/ml or greater in adipose tissue from both virgin and pregnant mice. mPRL was lipolytic at a concentration of 5.0 micrograms/ml or greater in adipose tissue from virgin mice. In adipose tissue from pregnant mice mPRL was not lipolytic in day 12 tissue, but it was lipolytic at a concentration of 5.0 micrograms/ml in day 16 tissue. mPL-II and hPL did not stimulate glycerol release in mouse adipose tissue from virgin or pregnant mice. In the second experiment preincubating adipose tissue from virgin mice in the presence of 0.5 or 5.0 micrograms/ml mGH significantly increased the ability of the tissue to respond to theophylline; however, mGH did not induce this response in adipose tissue from pregnant mice, mPRL, mPL-II, and hPL did not increase theophylline-induced lipolysis in adipose tissue from either virgin or pregnant mice. These results indicate that two lipolytic mechanisms are activated in adipose tissue from mice; mGH can activate both mechanisms, whereas mPRL can activate only one.     

Characterization of immunoreactive insulin-like growth factor-I from leukocytes and its regulation by growth hormone.

In the present study, we investigated the production of insulin-like growth factor I (IGF-I) by leukocytes and its production after treatment with GH. Immunoreactive (ir) IGF-I was observed in leukocytes by direct immunofluorescence with fluorescein isothiocynate-conjugated antibodies to IGF-I. Studies using immunoaffinity purification, HPLC and a fibroblast proliferation bioassay suggests that the de novo synthesized leukocyte-derived irIGF-I is similar in mol wt, antigenicity, and bioactivity to serum IGF-I. We also evaluated the effect of GH on the production of leukocyte-derived irIGF-I. Spleen cells cultured for 24 h in the presence of exogenous GH caused a 2-fold elevation of irIGF-I as demonstrated by RIA and immunofluorescence. In order to determine if leukocyte-derived irGH can stimulate the production of irIGF-I, we cultured spleen cells for 24 h in the presence of antibodies specific for GH. The data showed a decrease in the number of cells positive for irIGF-I, suggesting that leukocyte-derived irGH may stimulate the synthesis of irIGF-I by leukocytes. We also demonstrated that exogenous IGF-I can decrease the levels of leukocyte GH-related RNA and ir protein. Taken together, our data demonstrate the synthesis and secretion of bioactive irIGF-I from leukocytes and suggest a regulatory circuit for leukocyte-derived irGH and irIGF-I within the immune system.     

Potentiation of epidermal growth factor-induced differentiation of cultured human placental cells by insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) potentiates epidermal growth factor (EGF)-stimulated placental lactogen (hPL) secretion by cultured placental cells. In this study we have examined the effects of EGF and IGF-I, alone or in combination, on the differentiation of placental cells in culture and correlated this differentiation with hPL secretion. Addition of EGF (10 ng/mL) or IGF-I (100 ng/mL) alone in serum-free medium was associated with enlargement of the BhCG-positive (differentiated cytotrophoblast marker) mononucleated trophoblast cells. Concomitant addition of IGF-I and EGF resulted in more marked enlargement of the BhCG-positive cells, aggregation of the enlarged cells, and early syncytiotrophoblast formation. Measurement of hPL in the medium revealed that the stimulatory effect (P less than 0.05) of EGF on hPL secretion by total placental cells was proportional to the stimulatory effect of EGF on cell differentiation, as revealed by the obliteration of its stimulatory effect on hPL by BhCG-positive cells. The augmented stimulatory effect of EGF on hPL secretion by all cells in the presence of IGF-I was decreased (P less than 0.05) when expressed per number of human chorionic gonadotropin (BhCG)-positive cells. The dose-response curves of hPL stimulation by IGF-I in the presence of EGF revealed that the decreased effect of IGF-I on hPL secretion by BhCG-positive-staining cells was due to the difference in magnitude (approximately 1.5 times) of stimulation of BhCG staining of and hPL secretion by the cells. These results extend our previous suggestion that IGF-I in placenta, in addition to its effect on hPL secretion, affects cell differentiation; however, the two effects may not be interdependent.     

The growth hormone/insulin-like growth factor-I axis in exercise and sport

The syndrome of adult GH deficiency and the effects of GH replacement therapy provide a useful model with which to study the effects of the GH/IGF-I axis on exercise physiology. Measures of exercise performance including maximal oxygen uptake and ventilatory threshold are impaired in adult GH deficiency and improved by GH replacement, probably through some combination of increased oxygen delivery to exercising muscle, increased fatty acid availability with glycogen sparing, increased muscle strength, improved body composition, and improved thermoregulation. In normal subjects, in addition to the long-term effects of GH/IGF-I status, there is evidence that the acute GH response to exercise is important in regulating substrate metabolism after exercise. Administration of supraphysiological doses of GH to athletes increases fatty acid availability and reduces oxidative protein loss, particularly during exercise, and increases lean body mass. Despite a lack of evidence that these metabolic effects translate to improved performance, GH abuse by athletes is widespread. Tests to detect GH abuse have been developed based on measurement in serum of 1) indirect markers of GH action, and 2) the relative proportions of the two major naturally occurring isoforms (20 and 22kDa) of GH. There is evidence that exercise performance and strength are improved by administration of GH and testosterone in combination to elderly subjects. The potential benefits of GH in these situations must be weighed against potential adverse effects.     

The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency

An extensive literature suggesting that PRL, GH, IGF-I, and thyroid hormones play an important role in immunity has evolved. Because the use of one or more of these hormones as immunostimulants in humans is being considered, it is of critical importance to resolve their precise role in immunity. This review addresses new experimental evidence from analysis of lymphocyte development and function in mice with genetic defects in expression of these hormones or their receptors that calls into question the presumed role played by some of these hormones and reveals unexpected effects of others. These recent findings from the mutant mouse models are integrated and placed in context of the wider literature on endocrine-immune system interactions. The hypothesis that will be developed is that, with the exception of a role for thyroid hormones in B cell development, PRL, GH, and IGF-I are not obligate immunoregulators. Instead, they apparently act as anabolic and stress-modulating hormones in most cells, including those of the immune system.     

Ovine placental lactogen, but not growth hormone, stimulates amino acid transport in fetal rat diaphragm

Previous studies from this laboratory indicate that ovine placental lactogen (oPL) and ovine growth hormone (oGH) stimulate amino acid transport in diaphragms of postnatal rats with equal potencies. However, in studies reported here using diaphragms from fetal rats on day 20 of gestation, oPL (2,5 and 20 micrograms/ml) stimulated a dose-dependent increase in amino acid uptake, while oGH (5,20 and 100 micrograms/ml) and rat growth hormone (rGH, 2 and 40 micrograms/ml) were without effect. The effect of oPL on fetal AIB transport was neither enhanced nor antagonized by oGH (100 microgram/ml). The magnitude of stimulation of AIB transport by oPL was comparable to that observed with insulin (100 and 1000 microU/ml). Human placental lactogen (hPL) and ovine prolactin (oPRL) had no effect on fetal AIB transport. Since oPL is present in high concentrations in fetal blood, these studies suggest that oPL may have a direct role in the regulation of fetal amino acid and protein metabolism, that oPL and oGH may bind to different receptors in fetal rat tissues, and that oPL may function as a "fetal growth hormone".