Testosterone Supplementation Rescues Spermatogenesis and In Vitro Fertilizing Ability of Sperm in Kiss1 Knockout Mice
- 1 September 2020
- journal article
- research article
- Published by The Endocrine Society in Endocrinology
- Vol. 161 (9)
- https://doi.org/10.1210/endocr/bqaa092
Abstract
Restoration of spermatogenesis and fertility is a major issue to be solved in male mammals with hypogonadotropic hypogonadism. Kiss1 knockout (KO) male mice are postulated to be a suitable animal model to investigate if hormonal replacement rescues spermatogenesis in mammals with this severe reproductive hormone deficiency, because KO mice replicate the hypothalamic disorder causing hypogonadism. The present study investigated whether testosterone supplementation was able to restore spermatogenesis and in vitro fertilization ability in Kiss1 KO mice. To this end, spermatogenesis, in vitro fertilization ability of Kiss1 KO sperm, and preimplantation development of wild-type embryos inseminated with Kiss1 KO sperm, were examined. The newly generated Kiss1 KO male mice showed infertility with cryptorchidism. Subcutaneous testosterone supplementation for 6 weeks restored plasma and intratesticular testosterone levels, elicited testicular descent, and induced complete spermatogenesis from spermatocytes to elongated spermatids in the testis, resulting in an increase in epididymal sperm number in testosterone-supplemented Kiss1 KO male mice. Epididymal sperm derived from the testosterone-supplemented Kiss1 KO mice showed normal in vitro fertilization ability, and the fertilized eggs showed normal preimplantation development, while the males failed to impregnate females. These results suggest that the failure of spermatogenesis in Kiss1 KO mice is mainly due to a lack of testosterone production, and that Kiss1 KO sperm are capable of fertilizing eggs if the animals receive the appropriate testosterone supplementation without local kisspeptin signaling in the testis and epididymis. Thus, testosterone supplementation would restore spermatogenesis of male mammals showing hypogonadotropic hypogonadism with genetic inactivation of the KISS1/Kiss1 gene.Funding Information
- Japan Society for the Promotion of Science (18H03973, 19H03103, 14J10751, 19K16270)
- National Institute for Physiological Sciences
This publication has 41 references indexed in Scilit:
- Localization of Gonadotropin‐Releasing Hormone (GnRH), Gonadotropin‐Inhibitory Hormone (GnIH), Kisspeptin and GnRH Receptor and Their Possible Roles in Testicular Activities From Birth to Senescence in MiceJournal of Experimental Zoology – A (JEZ-A), 2012
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Characterization of the kisspeptin system in human spermatozoaInternational Journal of Andrology, 2011
- Androgen Receptor Roles in Spermatogenesis and Fertility: Lessons from Testicular Cell-Specific Androgen Receptor Knockout MiceEndocrine Reviews, 2009
- The Role of Kisspeptin–GPR54 Signaling in the Tonic Regulation and Surge Release of Gonadotropin-Releasing Hormone/Luteinizing HormoneJournal of Neuroscience, 2007
- Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 geneProceedings of the National Academy of Sciences of the United States of America, 2007
- Activation of Gonadotropin-Releasing Hormone Neurons by Kisspeptin as a Neuroendocrine Switch for the Onset of PubertyJournal of Neuroscience, 2005
- Testicular Phenotype in Luteinizing Hormone Receptor Knockout Animals and the Effect of Testosterone Replacement Therapy1Biology of Reproduction, 2004
- Kisspeptin Activation of Gonadotropin Releasing Hormone Neurons and Regulation of KiSS-1 mRNA in the Male RatNeuroendocrinology, 2004
- Follicle stimulating hormone is required for ovarian follicle maturation but not male fertilityNature Genetics, 1997