Abstract A rare 20K isoform of GH-V (here abbreviated GHv) was discovered in 1998. To date, only one research article has characterized this isoform in vivo observing that GHv treatment in male high-fat fed rats had several GH-like activities but unlike GH lacked diabetogenic and lactogenic activities and failed to increase IGF-1 or body length. Therefore, the current study was conducted to further characterize the in vivo activities of GHv in a separate species and in a GH deficient model (GH-/- mice) and with both sexes represented. GHv treated GH-/- mice had significant increases to serum IGF-1, femur length, body length, body weight and lean body mass and reduced body fat mass similar to mice receiving GH treatment. GH treatment increased circulating insulin levels and impaired insulin sensitivity, in contrast, both measures were unchanged in GHv treated mice. Since GHv lacks prolactin receptor (PRLR) binding activity, we tested the ability of GH and GHv to stimulate proliferation of human cancer cell lines and found that GHv has a decreased proliferative response in cancers with high PRLR. Our findings demonstrate that GHv can stimulate IGF-1 and subsequent longitudinal body growth in GH deficient mice similar to GH, but unlike GH, GHv promoted growth without inhibiting insulin action and without promoting growth of PRLR-positive cancers in vitro. Thus, GHv may represent improvements to current GH therapies especially for individuals at risk for metabolic syndrome or PRLR-positive cancers. growth hormone, placental growth hormone, growth hormone variant, growth hormone 2, GH-V, GH-2 This content is only available as a PDF. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)