title: Testosterone replacement therapy induces spermatogenesis and partially restores fertility in luteinizing hormone receptor knockout mice.
abstract: Testosterone (T) is essential for spermatogenesis, fertility, and maintenance of the male phenotype. We analyzed in hypogonadal LH receptor knockout (LuRKO) male mice whether T treatment can restore their phenotype, spermatogenesis, and fertility. In LuRKO mice, spermatogenesis is arrested at round spermatids, adult-type Leydig cells are absent, T production is dramatically decreased, the animals are cryptorchid, and their accessory sex organs are atrophic. T replacement therapy from 21 d of life for 60 or 120 d in LuRKO mice induced a male phenotype macroscopically indistinguishable from that of wild-type littermates as well as full spermatogenesis and testicular descent. Thus, the absence of LH-dependent prepubertal androgen priming is not necessary for subsequent maturation of the male phenotype. Conspicuously, some abnormalities remained in epididymal histology after T treatment despite normal expression of several epididymis-specific genes in caput epididymis. The mice displayed normal mating behavior, although at lower frequency than wild-type controls. The spermatozoa were able to fertilize oocytes, but their impaired passage from epididymis to uterus was apparent. The mice remained subfertile, because only 9% of all breedings resulted in pregnancy, and only two of 13 mice (15%) were fertile. Moreover, inflammation in epididymides and prostate was found in many T-treated LuRKO mice, which probably impaired sperm transport and contributed to their high rate of subfertility. In conclusion, T replacement initiated prepubertally only partially restores the fertility of LuRKO mice, even though most features of the male phenotype recover. Full fertility may require higher and/or earlier postnatal T exposure or production of other Leydig cell factors lacking in this model.
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Finland.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pakarainen
authors.forename: Fu-Ping
authors.initials: FP
authors.lastname: Zhang
authors.forename: Sari
authors.initials: S
authors.lastname: Mäkelä
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
mesh_terms: D000728:Androgens / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D004822:Epididymis / Q000254:growth & development / Q000473:pathology / Q000502:physiology; D005837:Genitalia, Male / Q000254:growth & development / Q000473:pathology / Q000502:physiology; D020249:Hormone Replacement Therapy; D007248:Infertility, Male / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis; D011974:Receptors, LH / Q000235:genetics*; D013081:Sperm Motility; D013091:Spermatogenesis / Q000187:drug effects*; D013739:Testosterone / Q000097:blood / Q000494:pharmacology*
chemical_list: D000728:Androgens; D012333:RNA, Messenger; D011974:Receptors, LH; D013739:Testosterone