Testosterone replacement therapy induces spermatogenesis and partially restores fertility in luteinizing hormone receptor knockout mice.
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.
Pakarainen
Tomi
T
Department of Physiology, Institute of Biomedicine, University of Turku, Finland.
Zhang
Fu-Ping
FP
Mäkelä
Sari
S
Poutanen
Matti
M
Huhtaniemi
Ilpo
I
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*
D000728:Androgens; D012333:RNA, Messenger; D011974:Receptors, LH; D013739:Testosterone