Insulin-like growth factors and their binding proteins in plasma and milk after growth hormone-stimulated galactopoiesis in normally lactating women

Abstract

We performed a double-blind randomized placebo-controlled trial of recombinant human growth hormone (hGH) in normally lactating women (N = 8 per group) to investgate the endocrine mode of action of the galactopoietic effect of this hormone. Insulin-like growth factors I (IGF-I) and II (IGF-II) and their binding proteins (IGFBP-1, IGFBP-2 and IGFBP-3) were measured by radioimmunoassay in plasma and milk samples collected throughout the study. All assays were validated for human plasma and milk. Human GH treatment (0.1 IU·kg−1 body wt·day−1 for 7 days) increased plasma concentrations of IGF-I from 22.1±1.3 nmol/l (mean±sem) to 59.7±2.5 nmol/l (p<0.01). At the end of the study the increase in plasma IGF-I correlated significantly with the increase in milk volume (r=0.67, p<0.005, N=16). The IGF-I levels were considerably lower in milk, with 0.14±0.03 nmol/l before and 0.31±0.04 nmol/l after hGH treatment. The increase in milk IGF-I levels (134.0±14.5%) with hGH treatment was significant (p<0.01) and plasma and milk IGF-I concentrations correlated significantly when considering all samples of the study (r=0.45, p<0.001, N= 56). The concentrations of IGF-II were not changed significantly with hGH treatment in plasma (52.5±2.5 nmol/l before and 42.6±3.9 nmol/l after treatment) or milk (2.1±0.29 nmol/l before and 2.3±0.49 nmol/l after hGH treatment). The IGFBP-1 levels were not changed with hGH treatment in plasma (approximately 1.3 nmol/l) or milk (approximately 0.2 nmol/l). Although IGFBP-2 concentrations in plasma were reduced significantly (p<0.05) after hGH treatment (11.1±1.5 before and 8.4±0.9 nmol/l after hGH treatment), milk IGFBP-2 levels did not respond to hGH treatment. Milk levels were markedly higher (sevenfold) in comparison to plasma levels. Plasma IGFBP-3 showed a delayed and smaller rise with hGH treatment in comparison to the rise observed in IGF-I. However, at the end of the study the response (38.6±4.9%) to hGH was significant (p<0.01) and a significant correlation was observed also between the increase in IGFBP-3 and the increase in milk volume (r=0.55, p =0.03, N=16). Plasma IGF-I and IGFBP-3 concentrations correlated significantly when considering all samples of the study (r=0.61, p<0.001, N=63). Milk IGFBP-3 levels were approximately 100-fold lower in comparison to plasma levels and did not correlate with any other measurements. Our data show that hGH-stimulated galactopoiesis in normally lactating women is mediated by significant elevations of plasma and milk IGF-I and plasma IGFBP-3. While IGF-I may be a principal mediator of the galactopoietic effect of hGH, we cannot simply attribute the action of hGH solely to a systemic rise in IGF-I. The increase in plasma IGFBP-3 with hGH treatment suggests that IGFBP-3 could facilitate the delivery of IGF-I to the mammary gland. The high concentrations of IGFBP-2 in milk suggest that mammary epithelial IGFBP-2 may direct regional tissue distribution of IGF-I to the site of milk synthesis.