Ipamorelin chronic treatment dynamically remodels somatotroph GH content and population in young female rats

Growth hormone (GH) secretion is governed by interplay between GHRH and somatostatin, yet the long-term plasticity of the somatotroph cell population in response to exogenous secretagogues remains incompletely characterised. GH secretagogues (GHS) represent a distinct pharmacological class acting through GHSR to amplify GH release, but whether chronic GHS exposure reshapes the somatotroph compartment itself — altering granule content, cell proportions, or subsequent secretory competence — was not well established. Understanding such adaptive responses is critical for evaluating the safety and efficacy of GHS-based therapeutic strategies, particularly in younger or female subjects where somatotroph dynamics may differ from adult male models. Ipamorelin, a selective pentapeptide GHS with minimal off-target secretagogue activity, provides a clean tool to probe these adaptations without the confounds of broader ACTH or prolactin stimulation seen with older GHRPs.

Young female rats received ipamorelin (Ipamorelin group), GHRH (GHRH group), or saline (control group) chronically over 21 days in vivo. Following treatment, pituitary cells were harvested and placed in 3-day basal monolayer cultures. After basal culture, cells were exposed in vitro for 4 hours to ipamorelin (10⁻⁸ M), GHRP-6 (10⁻⁸ M), or GHRH (10⁻⁸ M). Primary endpoints included the percentage of somatotroph cells, the strongly/weakly immunostaining GH cell ratio assessed by immunocytochemistry, individual intracellular GH content per somatotroph, secretory granule volume density by ultrastructural analysis, and somatotroph ultrastructure.

Ultrastructural morphology of somatotroph cells was unchanged across groups, but the volume density of secretory granules was significantly increased (p < 0.05) by prior in vivo treatment with either ipamorelin or GHRH compared to saline controls. During the 3-day basal culture period, the percentage of somatotroph cells and the strongly/weakly immunostaining GH cell ratio did not differ between any of the three groups, indicating that chronic in vivo treatment did not constitutively alter resting somatotroph composition ex vivo. However, in the Ipamorelin group only, subsequent 4-hour in vitro challenge with ipamorelin, GHRP-6, or GHRH each increased the percentage of somatotroph cells without altering the strongly/weakly immunostaining ratio — a response absent in the saline and GHRH groups.

Basal intracellular GH content over 4 hours was lower in both the Ipamorelin and GHRH groups than in the saline group, yet only in the Ipamorelin group did in vitro addition of ipamorelin (10⁻⁸ M), GHRP-6 (10⁻⁸ M), or GHRH (10⁻⁸ M) rescue and increase intracellular GH content — a priming effect unique to ipamorelin pretreatment.

Collectively, these results indicate that chronic ipamorelin selectively sensitises somatotrophs to subsequent secretagogue challenge, enhancing both cell recruitment and intracellular GH accumulation in a manner not fully replicated by chronic GHRH.