Endocrinology 2020 Aug 1;161(8):bqaa097.https://bit.ly/3zqg6c5
This study, in a GH-deficient mouse model, shows that a 20-kDa variant of placental GH (20k-GH-V) retains the growth-promoting effects of normal pituitary-derived GH (GH-N), but with the advantages of having no diabetogenic or prolactin receptor (PRLR)-mediated tumour-promoting effects.
One of the first described actions of GH is its diabetogenic or anti-insulin activity. This diabetogenic activity was demonstrated by the Nobel Laureate, Bernardo Houssay, who showed that surgical removal of the pituitary in dogs and toads increased insulin sensitivity.
Placental GH (GH-V) differs from pituitary-secreted GH-N in 13 of the 191 amino acid residues, but the common isoforms of both share the same overall 22-kDa size. GH-V and GH-N also share the same growth promoting and insulin inhibiting effects, but lacks PRLR binding activity. In 1998, Cesar Boguszewski discovered a rare smaller 20kDa isoform of GH-V in human placenta (its mRNA lacks 45-bp in exon 3). At that time, this 20k-GH-V was shown to lack all the usual functions of GH, including the inability to generate IGF-1 and increase length in normal mice. The key finding of the current study is that this rare placental variant, 20k-GH-V, does indeed stimulate IGF-1 and length growth to a similar extent to that of GH-N, but only in GH-deficient mice, and not in normal mice. They also confirm that, regardless of underlying GH status, 20k-GH-V has no insulin inhibiting effects and did not alter proliferation of human cancer cell lines that highly exhibit PRLR.
Both GH-N and 20k-GH-V also increased circulating FSH levels. Since basal and stimulated plasma FSH levels are attenuated in GH-immunoneutralized, GH-deficient, and GH-resistant animals, and exogenous GH has been shown to increases release of FSH from rodent pituitary glands, the increase in FSH following GH treatment in GH-/- mice is expected.
GH-V is expressed in the syncytiotrophoblast and extravillous cytotrophoblast layers of the human placenta. Its levels increase throughout pregnancy and eventually replaces GH-N in the maternal circulation. Studies suggest that GH-V is an important regulator of fetal growth and development, with reduced maternal circulating concentrations in pregnancies complicated by fetal growth restriction. Unlike the pulsatile secretion pattern of GH-N, GH-V is secreted by the placenta in a tonic fashion with constant 24-hour circulating levels. Interestingly, the 20-kDa variant of pituitary GH-N has also been reported to have diminished lactogenic effects in vitro compared with 22-kDa GH-N.
In summary, 20k-GH-V is a potent stimulator of body growth, as indicated by increased IGF-1, femur length, body length, body weight, and lean body mass, and also reduces body fat mass similar to GH-N administration in a mouse model of GH deficiency. The authors argue that 20k-GH-V may allow an improved form of GH therapy, especially for GH deficient patients at risk for metabolic syndrome or PRLR-positive cancers.