STOICHIOMETRY OF THE PULSATING GROWTH-HORMONE (GH) BINDING TO THE GH-BINDING PROTEIN AND THE TURNOVER GH-RECEPTOR

The pulsatile pattern of growth hormone (GH) secretion is synchronized with the GH-receptor (GHR) turnover and the ensuing GH-binding protein (GHBP). We investigated the effect of GH pulse frequency on the turnover of GHR, and tested the theoretical reciprocal impacts of GH, GHR, and GHBP in different species and clinical conditions. Male Sprague-Dawley rats were hypophysectomized (hypox) at 35 days of age. Two groups of 16 rats received a single or two iv injections of 10 mu g human GH (hGH) at an interval of 45 min. They were killed 45, 90, or 135 min after the single or second injection. A third group of 25 hypox rats were given continuous sc infusion of hGH for 6 days. Liver membranes were prepared for hGH somatogenic binding. A bolus of GH at 45-min intervals expedited GHR turnover, and continuous GH resulted in faster turnover cycles of 90 min. The impact of GHBP on GH bioactivity was then calculated in human serum by a rabbit liver membrane displacement assay. Bioactivity was diminished by GHBP with increasing GH levels up to a point, within the physiological range, where GH bioactivity is gradually restored. Finally, simulation calculation of the bound and free fraction of GH over a typical pulse in man and male rat showed the changing relations of free/bound GH. In man free hormone predominates most of the pulse, whereas in rat free GH comprised a smaller fraction. Thus, the reciprocal effects of GH and GHR turnover and GHBP generation, and that of GHBP on GH t(1/2) lead to self-perpetuation of high (mostly free) GH in downregulation of GHR and its turnover with resultant lower GHBP.