Transgenic Mice Overexpressing the Growth-Hormone-Releasing Hormone Gene Have High Concentrations of Tachykinins in the Anterior Pituitary Gland

Abstract

According to recent reports, substance P (SP) is localized in the anterior pituitary gland within subsets of thyrotropes and somatotropes, although earlier electron-microscopic studies described the presence of this tachykinin in mammotropes and gonadotropes. Transgenic mice overexpressing the growth-hormone-releasing hormone (GHRH) gene have markedly enlarged pituitary glands, due to hyperstimulation of the somatotropes. Therefore, we speculated that if somatotropes are able to synthesize tachykinins, these peptides should be greatly increased in the anterior pituitary of transgenic GHRH mice. We found that, in accordance with our working hypothesis, both SP and neurokinin A (NKA) were markedly increased in the anterior pituitary gland of male and female transgenic mice, compared with their respective normal controls. In male transgenic mice, NKA was 13.6- and SP 20.2-fold higher than in the anterior pituitary from normal mice. In female transgenic mice, NKA was 40- and SP 100-fold higher than in the anterior pituitary from normal female mice. In male transgenic mice, NKA and neuropeptide K (NPK) contents in the anterior pituitary showed no significant changes between 26 and 50 days of age but significantly increased between 50 days and 5 months of age. The concentration of NKA in the anterior pituitary did not show significant differences between 26 days and 5 months of age, but NPK concentrations in the anterior pituitary significantly decreased with age. In female transgenic mice, NKA content and concentration in the anterior pituitary increased after 35 days of age, but NPK concentrations significantly decreased after 26 days of age. Triiodothyronine markedly decreased anterior pituitary tachykinins, but ovariectomy and estrogen administration failed to significantly affect tachykinin concentrations in the anterior pituitary of transgenic mice. Tachykinin immunostaining was detected in some somatotropes, but tachykinins were also present in cells that were not GH positive. These findings indicate that hyperstimulated somatotropes contain increased stores of tachykinins and that these cells are a source of tachykinins in the anterior pituitary. Tachykinin stores in the anterior pituitary of transgenic mice were affected by thyroid hormones but seem to be insensitive to estrogens. The GHRH transgenic mice may be an interesting model to study the regulation of tachykinin stores in the anterior pituitary gland.

Effect of nutrient restriction on the somatotropes and substance P-immunoreactive cells in the pituitary of the female ovine fetus

“…Somatotrope hypertrophy in mice can be caused by GHRH [60], which also increases GH secretion and synthesis [43,[61][62][63][64]. Transgenic hGHRH mice, with functional GH receptors, have larger pituitary glands because of somatotrope hyperplasia and, to some extent, somatotrope hypertrophy [25,60,65,66]. The somatotrope hypertrophy in our study was transient as there was no difference between the groups by Day 135.…”

“…Indeed, it is noteworthy that effects induced by the fetal nutrient restriction may only be manifest later in life. Humans and mice secreting excess GHRH exhibit somatotrope hyperplasia and acromegaly [25,54,67,68]. This abnormal pituitary histology observed with excess GHRH secretion often leads to the development of pituitary tumors later in life [67,68].…”

“…Substance P has been colocalized with gonadotropes, lactotropes, thyrotropes, and somatotropes [69][70][71] and tachykinins have been found to influence the secretion of anterior pituitary hormones [25]. The pituitary content of substance P was increased 100-fold in GHRH over-expressing female transgenic mice and substance P was immunocytochemically detectable in both somatotropes and non-GH containing cells [25]. Thus, the elevated coexistence of substance P in somatotropes observed in the present study and the overall increase in the density of substance P-immunoreactive cells may be suggestive of elevated GHRH release in nutritionally challenged ovine fetuses.…”

“…Thus, our first objective was to determine the effects of nutrient restriction on the somatotropes of the pituitary gland. In addition, changes in substance P-immunoreactivity in the pituitary gland have been associated with elevated GHRH release [25]. Substance P is also known to affect GH secretion [26].…”

No effect of nutrient restriction from gestational days 28 to 78 on immunocytochemically detectable growth hormone-releasing hormone (GHRH) neurons and GHRH receptor colocalization in somatotropes of the ovine female fetus

“…Although substance P itself may affect the GH axis (Arisawa et al, 1989;Coiro et al, 1992;Mau et al, 1997), we hypothesized that our finding may reflect a perturbation of the GHRH system. This hypothesis was based on a study showing that transgenic mice over-expressing GHRH have increased levels of substance P in their pituitary glands (Debeljuk et al, 1999).…”