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 protei n (GHBP). We investigated the effect of GH pulse frequency on the turn over of GHR, and tested the theoretical reciprocal impacts of GH, GHR, and GHBP in different species and clinical conditions. Male Sprague-D awley rats were hypophysectomized (hypox) at 35 days of age. Two group s of 16 rats received a single or two iv injections of 10 mu g human G H (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 w ere given continuous sc infusion of hGH for 6 days. Liver membranes we re prepared for hGH somatogenic binding. A bolus of GH at 45-min inter vals expedited GHR turnover, and continuous GH resulted in faster turn over cycles of 90 min. The impact of GHBP on GH bioactivity was then c alculated 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 gradua lly restored. Finally, simulation calculation of the bound and free fr action of GH over a typical pulse in man and male rat showed the chang ing relations of free/bound GH. In man free hormone predominates most of the pulse, whereas in rat free GH comprised a smaller fraction. Thu s, 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 (mostl y free) GH in downregulation of GHR and its turnover with resultant lo wer GHBP.