Fertility in luteinizing hormone receptor-knockout mice after wild-type ovary transplantation demonstrates redundancy of extragonadal luteinizing hormone action

Abstract

The luteinizing hormone receptor (LHR), mainly expressed in gonads, is essential for normal reproduction. However, numerous recent studies have also demonstrated LHR expression in multiple extragonadal reproductive and nonreproductive tissues. Although some effects of luteinizing hormone (LH) or its agonist, human chorionic gonadotropin, have been shown in extragonadal sites, their physiological significance remains open. In the present study, we have addressed the function of the extragonadal LHR using LHR-KO mice (LuRKO mice), in which the ovaries of prepubertal mice were orthotopically replaced with pieces of WT ovary using similarly transplanted WT mice as controls . Most ovarian transplants attained normal endocrine function in both groups of mice, as demonstrated by normal age at vaginal opening, estrous cycles, and sexual behavior. Both the LuRKO and WT mice repeatedly became pregnant (9/16 vs. 16/20 after first mating; difference not significant) and delivered similarly sized litters, which grew normally after birth, indicating normal lactation. In conclusion, fertility is restored in LuRKO mice by transplantation of WT ovarian tissue. This is achieved in the absence of extragonadal LHR expression, which indicates physiological redundancy for such receptor sites. IntroductionThe regulatory functions of the 2 gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), form the cornerstone of normal fertility. In addition to earlier studies on hypophysectomized animals, immunoneutralization of gonadotropins or gonadotropin-releasing hormone (GnRH), and treatment with GnRH analogs, more recent studies on targeted inactivation of the gonadotropin subunit and receptor genes have specifically demonstrated the need of proper function of LH, FSH, and their receptors for the maintenance of female reproduction (1-7).Quite unexpectedly, a number of studies have recently reported the presence of the common LH and human chorionic gonadotropin (hCG) receptor (LHR) in a variety of extragonadal tissues, including the uterus, oviduct, cervix, placenta, mammary gland, sperm, certain areas of the brain, and many others (8-11). Many of the findings were made on human tissues, but similar observations have been reported on a number of other mammalian species, including baboons, bovines, pigs, rats, and mice (9,(12)(13)(14)(15). On the basis of these observations, a shift in the old paradigm that gonadotropins only have gonadal actions has been proposed (8). A number of extragonadal actions for LH/hCG have been suggested, including effects on brain development and sexual behavior, regulation of

A novel compound heterozygous mutation of the luteinizing hormone receptor –implications for fertility

“…A more recent study however, showed that LuRKO mice recovered most of their fertility potential and achieved pregnancy after orthotopic ovarian tissue transplantation using wild type ovaries [40]. Our patient had a successful pregnancy after using donor eggs supporting the findings reported by Pakarainen et al [40] that functional extragonadal LHCGR may not be indispensable for pregnancy. Whether the murine model is different from the human model and whether progesterone replacement in humans can compensate for the defective uterine LHCGR is unknown.…”

“…Pregnancy was impaired in null mice following donor embryo transfer, even after estrogen and progesterone hormonal pretreatment and priming [39]. A more recent study however, showed that LuRKO mice recovered most of their fertility potential and achieved pregnancy after orthotopic ovarian tissue transplantation using wild type ovaries [40]. Our patient had a successful pregnancy after using donor eggs supporting the findings reported by Pakarainen et al [40] that functional extragonadal LHCGR may not be indispensable for pregnancy.…”

Extragonadal LH/hCG action—Not yet time to rewrite textbooks

“…In conclusion, poorly developed secondary sex characteristics and infertility are observed in both sexes. Further detail about the phenotype of this model are in our previous reports (Zhang et al, 2001a;Zhang et al, 2003;Zhang et al, 2004;Pakarainen et al, 2005c;Pakarainen et al, 2005b;Pakarainen et al, 2005a).…”

“…Due to the difficulties in discriminating between direct and indirect actions of LH/hCG and to clarify the real functional significance of the extragonadal LH/hCG-R in vivo, we carried out orthotopic ovarian transplantations in LuRKO mice (Pakarainen et al, 2005a). We replaced bilaterally the ovaries of LuRKO mice with pieces of WT ovaries by a method described previously (Lavebratt et al, 1998) .…”

“Been hit twice”: a novel bi-allelic heterozygous mutation in LHCGR

“…Although controversy exists on functional relevance of uterine LHCGRs with the existing Lhcgr mutant mouse models [30,31], the present results by Mitri et al establish that uterine LHCGRs are not indispensible for implantation and pregnancy maintenance in a single patient.…”