Growth hormone and fertility in oMt1a-oGH transgenic mice

Abstract

Female mice carrying a regulatable growth hormone transgene (oMt1a-oGH) are subfertile when the transgene is actively expressed. This study was designed to characterize subfertility caused by increased concentrations of growth hormone. In particular, this study aimed to: (i) determine the effects of transgene activation and inactivation on mating, conception, maintenance of pregnancy, ovulation rate, litter characteristics and embryonic survival at day 17 of pregnancy, (ii) characterize oestrous cyclicity in transgenic versus wild-type female mice, and (iii) correlate corticosterone concentrations with transgene expression and reproductive performance. Transgenic and wild-type female mice were allocated randomly to one of four treatment groups at weaning: (i) transgenic female mice that always express the transgene, (ii) transgenic female mice that never express the transgene, (iii) transgenic female mice that express the transgene for up to 8 weeks of age and (iv) non-transgenic wild-type female mice receiving the transgene stimulus until 8 weeks of age. Activation followed by inactivation of the transgene resulted in an increased incidence of remating, resulting in an extended interval to establish pregnancy in comparison with all other treatment groups. Transgenic mice that always expressed the transgene and those that expressed the transgene for up to 8 weeks of age had lower pregnancy rates and higher ovulation rates compared with mice from other treatment groups. Both embryonic survival and the duration of the oestrous cycle did not differ among treatment groups. Active expression of the transgene resulted in an increase in the plasma concentration of corticosterone, which was associated with reduced fertility. These data indicate that the presence of a high growth hormone concentration impedes the establishment and maintenance of pregnancy. Increased plasma corticosterone concentrations may interfere with implantation as well as potentiate leptin resistance, which has been reported previously in studies with these mice.

Leptin modulates fertility under the influence of elevated growth hormone as modeled in oMt1a-oGH transgenic mice

“…This study confirms previous reports of GH-induced changes in body composition in oMt1a-oGH mice (Pomp et al 1992, Thomas et al 2001. The lean phenotype of the TG ON mice is the result of improved feed efficiency and increased lean tissue deposition (Pomp et al 1992).…”

“…High circulating growth hormone (GH) concentrations in females result in decreased reproductive performance in mice , Thomas et al 2001, humans (Jadresic et al 1982) and livestock (McGuffey et al 1991, Downer et al 1993, Oldenbroek et al 1993, Esteban et al 1994, Buskirk et al 1996, Chapula et al 1996. It is still unclear whether elevated GH suppresses reproductive function directly or through an intermediary pathway.…”

“…Arcuate NPY neurons contain glucocorticoid receptors (Cintra et al 1991), and the presence of a glucocorticoid response element (GRE) in the promoter region of several mammalian NPY genes (Moore et al 1985, Misaki et al 1992 indicates the potential for glucocorticoids to stimulate NPY expression. oMt1a-oGH transgenic mice actively expressing the transgene have elevated plasma corticosterone concentrations (Thomas et al 2001), suggesting that glucocorticoids may elevate NPY expression in these mice. Elevated NPY expression, then, could contribute to the reduced fertility observed in oMt1a-oGH mice.…”

“…Previous reproductive studies utilizing oMt1a-oGH mice have evaluated females mated at 8-12 weeks of age , Thomas et al 2001 when differences in body composition and leptin concentrations are just becoming pronounced between groups experiencing various elevated GH-exposure regimens . However, studies correlating reproductive function with body composition data, GH effects and leptin have not been done.…”

Reproductive Responses to Daily Injections with Porcine Somatotropin Before Mating in Gilts

“…Somatotropin (ST) or growth hormone (GH) is an important regulator of ovulation in a range of mammalian species. In transgenic mice and sheep constitutively expressing ST ovulation rate is increased but fertility decreased, which is due to decreased mating rates in mice, and increased fetal loss in sheep [8][9][10]. Conversely, resistance to ST reduces litter size in the last week of pregnancy by 35-55% in GH receptor/GH binding protein knockout mice, largely due to reduced ovulation rate [11,12].…”