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R Barnard and M J Waters


Since Ymer & Herington (1985) refocused attention on the serum growth hormone (GH) binding protein (GHBP), it has attracted considerable research effort. Despite this, much remains to be resolved regarding its physiological function(s) and its regulation (which provides clues to function). The presence of a high affinity GHBP has significant implications for understanding the growth process, for understanding maternal control of foetal development and for attempts to enhance growth using genetically engineered GH analogues. To date, these implications have not been adequately explored.

Although there is evidence for a low affinity high capacity GHBP (Baumann & Shaw 1990), the present review will focus on the high affinity GHBP. It will summarize what is known regarding distribution, regulation and suggested roles of the high affinity GHBP. Evidence that GHBP has a significant role in the endocrinology of pregnancy and control of foetal growth will be discussed. Since progress in GHBP

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R. Barnard, P. Quirk, and M. J. Waters


A panel of monoclonal antibodies (MAbs) reactive with distinct epitopes on the rabbit liver GH receptor and rabbit serum GH-binding protein (GHBP) were tested for cross-reactivity with the GHBP from human serum. Four of seven MAbs reacted with the human serum GHBP. Immunoprecipitation of the human binding protein enabled hormonal specificity identical to that previously reported for human GH receptors to be demonstrated. Scatchard analyses of 125I-labelled human GH binding to the serum GHBP were carried out with correction made for endogenous human GH which was measured by radioimmunoassay of each serum sample. This approach yielded the first reliable estimates of the affinity and capacity of the human GHBP. The binding capacity (mean ± s.e.m.) of female sera (804±126 pmol/l; n= 6) was greater than that of male sera (505 ± 36 pmol/l; n=9; P < 0·02). The affinity of the GHBP was 0·91 ±0·10 litres/nmol (n= 15).

The presence of multiple epitopes common to the human serum GHBP and the rabbit liver GH receptor is consistent with identity between the extracellular domains of the human GHBP and the human GH receptor, as is the case for the rabbit GHBP and GH receptor.

Journal of Endocrinology (1989) 123, 327–332

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L. M. McLeay, M. A. Comeskey, and M. J. Waters


Adult sheep were infused with depilating doses of epidermal growth factor (EGF) at 4 pg/kg per h for 24 h. Food was available ad libitum during recording of integrated electromyographic (EMG) activity of the gastrointestinal tract. In comparison with control sheep infused with saline, EGF reduced the frequency of A and B sequences of contraction of the reticulum and rumen over the 24-h period, an effect attributable to the consumption of less food. During the 24-h infusion, EGF stimulated phase III migrating myoelectric complex (MMC)-like activity of the duodenum with an associated decline in the EMG of the abomasal antrum.

Infusion of EGF for 1 h at 2·5 and 5·0 μg/kg per h in fasted animals produced inhibitory effects on the frequency of A sequences of contraction of the reticulum and rumen during the infusion, and on the amplitude of the ruminal EMG during, and in the hour following, infusion. Phase III MMC-like activity of the duodenum was stimulated by EGF in fasted animals.

It is concluded that in fed sheep, depilating doses of EGF have inhibitory effects on the EMG activity of the reticulum and rumen through reductions in food consumption and by other undefined mechanisms. Additional effects of EGF on the gastrointestinal tract of sheep include stimulation of duodenal phase III MMC-like activity.

Journal of Endocrinology (1990) 124, 109–115

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P. E. Lobie, J. García-Aragón, and M. J. Waters


There is evidence that prolactin (PRL) influences gastrointestinal function. However, the sites at which prolactin exerts these effects are not known. A monoclonal antibody was therefore generated against the rabbit mammary gland prolactin receptor (MAb 218) and used to study the distribution of the prolactin receptor in the rabbit gastrointestinal tract (GIT) by immunohistochemistry. MAb 218 is an IgG 1 κprecipitating antibody which precipitates major affinity cross-linked mammary gland prolactin receptor subunits of molecular masses 45 and 80 kDa. It has an affinity of 0·8 × 109 mol/l for the prolactin receptor and does not react with GH or insulin receptors in precipitation assays. MAb 218 immunoreactivity was observed in classical prolactin target cells such as mammary gland epithelium, and this immunoreactivity was abolished by preincubation of MAb 218 with purified prolactin receptor but not by preincubation with purified GH receptor.

In the GIT, the most intense immunoreactivity was associated with the oesophageal epithelium, chief (zymogenic) cells of the fundic mucosa, pancreatic islets of Langerhans and surface epithelial cells of the duodenum and jejunum. Other specific elements of the GIT were immunoreactive at lower levels or were immunonegative. No immunoreactivity was observed in these locations with a control monoclonal antibody (MAb 50·8) of identical isotype to 218.

To support the immunohistochemical findings, rabbit gastric mucosal membranes were used to show the presence of lactogen-specific binding. Scatchard analysis of 125I-labelled human GH binding to the gastric mucosal membranes with rat prolactin as displacing ligand yielded an affinity constant (K a) of 1·0 ± 0·2 × 109 mol/l with a capacity of 3·5 ± 0·4 fmol/mg protein. Affinity cross-linking and sodium dodecyl sulphate-polyacrylamide gel electrophoresis of the gastric receptor revealed lactogenic hormone-binding subunits of molecular masses 43, 68 and 83 kDa. The 68 kDa subunit was not seen in rabbit mammary gland or ovarian tissue, and may be unique to gastric mucosa.

In conclusion, we have demonstrated the presence of a high affinity lactogenic receptor in specific epithelial cell subpopulations of the GIT. This localization of the prolactin receptor in the GIT will assist in further functional assignment of prolactin to gastrointestinal physiology.

Journal of Endocrinology (1993) 139, 371–382

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Hyperglycaemia was produced in chronically catheterized fetal lambs and pregnant ewes by the infusion of glucose into the fetus. Plasma concentrations of placental lactogen did not change significantly in either fetal or maternal circulations. Fetal and maternal hypoglycaemia was induced by administration of insulin to the fetus and ewe separately. Plasma concentrations of placental lactogen in the fetus did not change significantly but maternal plasma concentrations fell slightly after hypoglycaemia in either fetus or ewe. Plasma concentrations of placental lactogen rose in both the ewe and fetus during prolonged fasting of the ewe. These results neither confirm nor refute a role for placental lactogen in intermediary metabolism of the pregnant ewe and fetus but glucose concentration alone is unlikely to be a significant factor in the control of secretion of this hormone.

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J. R. Bourke, S. Murdoch, S. W. Manley, T. Matainaho, G. J. Huxham, and M. J. Waters


Thyrotrophin (4-256 μU/ml) promoted an increase in the rate of release of radioiodine from the organic iodine pool of cultured porcine thyroid cells in follicular formations. This action of TSH was antagonized by low concentrations of epidermal growth factor (EGF; 0·1–5 nmol/l). The maximal effect of EGF was reached by 0·5 nmol/l. EGF (0·5–5 nmol/l) also inhibited the stimulatory effect of 8-chloro cyclic AMP (0·06–1·0 nmol/l) on radioiodine turnover. Exposure of thyroid cultures to media with a calcium concentration of 17·7 μmol/l (1% of normal) resulted in a very marked increase in the rate of release of radioiodine. The effect of TSH in low-calcium media was to inhibit the increased release of radioiodine, and EGF (0·5 nmol/l) antagonized this inhibitory effect of TSH. The calcium ionophore, A23187, stimulated radioiodine release in a dose-dependent fashion, and EGF (1·7 nmol/l) inhibited this response. Fluid transport in thyroid monolayers was stimulated by prostaglandin E2 (PGE2; 1 μmol/l). EGF (5 nmol/l) also stimulated fluid transport, but antagonized the effect of PGE2 added subsequently. It was concluded that EGF exerted acute antagonistic effects on thyroid cell responses in vitro to cyclic AMP and agents promoting accumulation of cyclic AMP in time-frames too short for these inhibitory effects to be attributable to the dedifferentiative effect of the growth factor.

Journal of Endocrinology (1991) 128, 213–218

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J. R. Bourke, P. A. McGrath, G. J. Huxham, M. J. Waters, and S. W. Manley


Cultured porcine thyroid cells maintained in media containing TSH exhibited a membrane potential of −50 mV, and hyperpolarized by about 10 mV within 1 h of the addition of epidermal growth factor (EGF; 10 ng/ml). Follicle cells had depolarized to −45 mV after 4 h of exposure to EGF. Cells maintained in dibutyryl cyclic AMP (dbcAMP) did not alter their membrane potential when exposed to EGF for up to 4 h. Cultures washed to remove the TSH or dbcAMP hyperpolarized to − 75 mV within 30 min, and a reversible depolarization to − 60 mV was observed on addition of EGF. It was concluded that EGF acts as a physiological antagonist of TSH and also exerts a separate depolarizing influence on cultured thyroid cells.

J. Endocr. (1986) 109, 321–324

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G. Shaw, G. I. Jorgensen, R. Tweedale, M. Tennison, and M. J. Waters


Adult Merino ewes were infused via the jugular vein with either saline (n = 5) or epidermal growth factor (EGF) (4·2 μg/kg per h, n = 6) for 24 h in either the luteal phase or the follicular phase of the oestrous cycle and reproductive function was examined.

Infusion of EGF during the luteal phase caused no detectable change in plasma progesterone or prolactin concentrations over a 7-day period compared with the controls.

Infusion of EGF during the follicular phase suppressed the oestrous rise in plasma oestradiol. Luteinizing hormone pulse amplitude was increased and pulse frequency was decreased by the end of the infusion. All control ewes had a pro-oestrous LH surge and mated, but the LH surge and oestrus were prevented by EGF infusion. Nevertheless, plasma progesterone levels rose subsequently in the EGF-infused ewes in parallel with the control ewes, suggesting that the preovulatory follicle had luteinized. Both LH and FSH rose over the 7 days after EGF infusion to levels similar to those in ovariectomized ewes.

Thus EGF appears to inhibit follicular oestradiol production, although it does not affect luteal progesterone production or follicular luteinization. We suggest that the alteration in gonadotrophin secretion patterns results from a disturbance of feedback mechanisms between the ovary and the hypothalamopituitary axis, although a direct effect in the brain or the pituitary gland cannot yet be excluded.

J. Endocr. (1985) 107, 429–436

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P. E. Lobie, W. Breipohl, D. T. Lincoln, J. García-Aragón, and M. J. Waters


Acromegaly is characterized by coarsening of facial features, acanthosis nigricans, hypertrichosis and oily skin. To determine the site through which GH exerts these effects, we have used immunohistochemistry to localize the GH receptor/binding protein (BP) in rat, rabbit and human skin. Three monoclonal antibodies (MAb 1, 43, 263) were immunoreactive in identical locations, whereas no immunoreactivity was evident when control monoclonal antibodies (MAb 50.8 and MAb 7 (rat)) were used. Skin from neonatal and adult animals was used to determine whether GH receptor/BP expression was developmentally regulated.

Immunoreactivity of the GH receptor/BP in the three species was consistently localized in the stratum basale and stratum spinosum. Intermittent staining was observed in the stratum granulosum. Scattered basal epidermal cells often displayed more intense immunoreactivity. This distribution was observed at all maturational stages examined. Intense GH receptor/BP immunoreactivity was observed in all histological layers of the lower one-third of hair follicles and in hair matrix cells of the dermal papillae. Immunoreactivity was also detected in the outer epithelial root sheath of the upper two-thirds of hair follicles, in sebaceous glands and in fibroblasts of the connective tissue sheath surrounding the follicle. GH receptor/BP immunoreactivity was also present in the secretory duct and myoepithelial cells of human eccrine sweat glands. Fibroblasts, Schwann cells of peripheral nerve fascicles, skeletal muscle cells and adipocytes of the dermis were also immunoreactive as were medial smooth muscle and endothelial cells of arteries.

These results provide evidence that GH acts locally on the epidermis and epidermal appendages concordant with our recent localization of GH receptor/BP to epithelial cell types of the gastrointestinal and reproductive systems.

Journal of Endocrinology (1990) 126, 467–472

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F J Steyn, T Y Xie, L Huang, S T Ngo, J D Veldhuis, M J Waters, and C Chen

Pathological changes associated with obesity are thought to contribute to GH deficiency. However, recent observations suggest that impaired GH secretion relative to excess calorie consumption contributes to progressive weight gain and thus may contribute to the development of obesity. To clarify this association between adiposity and GH secretion, we investigated the relationship between pulsatile GH secretion and body weight; epididymal fat mass; and circulating levels of leptin, insulin, non-esterified free fatty acids (NEFAs), and glucose. Data were obtained from male mice maintained on a standard or high-fat diet. We confirm the suppression of pulsatile GH secretion following dietary-induced weight gain. Correlation analyses reveal an inverse relationship between measures of pulsatile GH secretion, body weight, and epididymal fat mass. Moreover, we demonstrate an inverse relationship between measures of pulsatile GH secretion and circulating levels of leptin and insulin. The secretion of GH did not change relative to circulating levels of NEFAs or glucose. We conclude that impaired pulsatile GH secretion in the mouse occurs alongside progressive weight gain and thus precedes the development of obesity. Moreover, data illustrate key interactions between GH secretion and circulating levels of insulin and reflect the potential physiological role of GH in modulation of insulin-induced lipogenesis throughout positive energy balance.