Animal models for aberrations of gonadotropin action

Abstract

During the last two decades a large number of genetically modified mouse lines with altered gonadotropin action have been generated. These mouse lines fall into three categories: the lack-of-function mice, gain-of-function mice, and the mice generated by breeding the abovementioned lines with other disease model lines. The mouse strains lacking gonadotropin action have elucidated the necessity of the pituitary hormones in pubertal development and function of gonads, and revealed the processes from the original genetic defect to the pathological phenotype such as hypo- or hypergonadotropic hypogonadism. Conversely, the strains of the second group depict consequences of chronic gonadotropin action. The lines vary from those expressing constitutively active receptors and those secreting follicle-stimulating hormone (FSH) with slowly increasing amounts to those producing human choriogonadotropin (hCG), amount of which corresponds to 2000-fold luteinizing hormone (LH)/hCG biological activity. Accordingly, the phenotypes diverge from mild anomalies and enhanced fertility to disrupted gametogenesis, but eventually chronic, enhanced and non-pulsatile action of both FSH and LH leads to female and male infertility and/or hyper- and neoplasias in most of the gonadotropin gain-of-function mice. Elevated gonadotropin levels also alter the function of several extra-gonadal tissues either directly or indirectly via increased sex steroid production. These effects include promotion of tumorigenesis in tissues such as the pituitary, mammary and adrenal glands. Finally, the crossbreedings of the current mouse strains with other disease models are likely to uncover the contribution of gonadotropins in novel biological systems, as exemplified by the recent crossbreed of LHCG receptor deficient mice with Alzheimer disease mice.

Fig. 1

An example of ovaries affected by chronically elevated gonadotropin action. Micrographs of ovarian sections from wild-type (wt) mice (a, c), mice expressing constitutively active FSHR (Fshr ^D580H +) (b, d–e) and mice expressing hCGβ-subunit (UBC-hCGβ+) (f). Arrowheads indicate oocytes trapped inside lutenized follicles in the hyperstimulated Fshr ^D580H + ovary (b); arrows indicate multinuclear and foamy cell clusters in the ovaries of ageing Fshr ^D580H + mice (d, e). UBC-hCGβ+females have heavily luteinized ovaries (asterisk) by the age of 3 months (f). AF antral follicle; SF secondary follicle; H haemorrhage; CL corpus luteum; mo month. Scale bar 500 μm

Fig. 2

Representative light micrographs of testicular sections from homozygous Lurko (−/−) and wild type control (+/+) mice. Samples were taken from Lurko (−/−) at the ages of 2 months (a and b) and 12 months (c and d) and from control wild-type mice at 12 months (e and f). b, d, and f are views of a, c, and e at higher magnification. Arrows and arrowheads indicate round spermatids and elongated spermatids, respectively. mo month. The figure is a modification from the original figure presented in [78]