Growth Hormone‐Releasing Hormone (GHRH)‐GH‐Somatic Growth and Luteinizing Hormone (LH)RH‐LH‐Ovarian Axes in Adult Female Transgenic Mice Expressing Human GH Gene

Abstract

We have examined alterations in the hypothalamo-pituitary GH-somatic growth axis and the hypothalamo-pituitary LH-ovarian axis in a line of transgenic ICR mice expressing human GH (hGH) under the influence of the whey acid protein promoter. Transgenic female mice weighed twice as much as control females and were infertile. The size of the anterior pituitary (AP) was 1/3 that of the controls. In transgenic mice, acinar cells in the mammary and mandibular glands displayed hGH-immunoreactivity, and plasma hGH was detected by radioimmunoassay. In the medial basal hypothalamus (MBH) of transgenic females, the immunoreactive-GHRH level was decreased (P<0.01). There was a corresponding reduction in the number of GHRH-immunoreactive neurons in the arcuate nucleus (ARC) and in the immunostaining of GHRH nerve terminals in the median eminence. The level of somatostatin (SRIH) in the MBH was increased (P<0.05), and SRIH-immunoreactive neurons in the periventricular nucleus (PeV) were increased in size and number in transgenic mice. The MBH level of LHRH in transgenic animals was greater (P<0.01) than in controls, although there was no apparent difference in the number of LHRH-immunoreactive neurons or in LHRH level in the preoptic area. There are fewer SRIH- and LHRH-immunoreactive neurons in the ARC in transgenic mice. Cells in the AP for GH, PRL, and LH were fewer in transgenic mice. The ovary suffered disturbance of follicular development and of corpora lutea formation. These results demonstrate that chronic overproduction of hGH may profoundly affect the organization of the GHRH/SRIH-GH-somatic growth axis and the LHRH-LH-ovarian axis due to reduction of GHRH-, SRIH- and LHRH-neurons in the ARC and increase of SRIH-neurons in the PeV.

Centrally Applied Somatostatin Inhibits the Estrogen-Induced Luteinizing Hormone Surge via Hypothalamic Gonadotropin-Releasing Hormone Cell Activation in Female Rats1

“…Also, in male GHreceptor knockout mice, in which GH levels are consistently elevated, the LH response to a GnRH stimulus is attenuated [5,6]. In female transgenic mice overexpressing GH, the proestrus LH surge is decreased [6] and the distribution of GnRH-containing neurons in the hypothalamus is altered [7]. These data show that decreased reproductive function as a result of altered GH release is, at least partially, characterized by changes at the hypothalamic-pituitary level.…”

“…Overexpression of GH as well as GH deficiency causes dramatic changes in reproductive function (i.e., a reduced fertility in animals that overexpress GH [3][4][5] and complete infertility in GH-deficient animals [4,6]). At the level of the ovaries, GH overexpression results in only primary, secondary, and atretic follicles, and no corpora lutea [7], whereas GH-deficient animals are hypogonadal [6].…”

GH as a co-gonadotropin: the relevance of correlative changes in GH secretion and reproductive state

“…The quantity of -FSH mRNA and protein (Tang et al 1993, Bartke et al 1994) and the number of LH-immunoreactive cells (Sasaki et al 1997) are similarly reduced in GHtransgenic mice, as is the feedback control of LH release by gonadal steroids in pigs (Guthrie et al 1991) and rodents (Bartke et al 1996). This inhibition of gonadotropin production by pharmacological levels of GH is also associated with reproductive dysfunction, since male transgenic mice expressing the GH-V gene mount less often, ejaculate more slowly and have more frequent intromissions, impregnate fewer females and sire fewer offspring (Meliska & Bartke 1997).…”

Analysis of Gender Difference of Cardiac Risk Biomarkers Using hGH-Transgenic Mice

“…1-B. In addition, it was reported that the transgenic rats and mice carrying the same WAP/hGH transgene showed lower concentrations of endogenous GH owing to atrophy of GH secretion cells in the pituitary gland [15,21,29], as compared to normal animals. Therefore, it is postulated that the transgenic mice in the present study also displayed a lower level of GH although we did not measure the concentration of mouse GH.…”