The role of alpha-Klotho protein in male and female reproduction. A systematic review

Objective

The aim of this systematic review is to provide the first comprehensive overview of the current knowledge regarding the role of the alpha-Klotho protein in male and female fertility, focusing on the testicle, spermatozoa, ovary, and oocyte.

Evidence Review

A comprehensive literature search was conducted up to March 2024 to determine the role of Klotho (KL, alpha-Klotho) in human reproductive tissues. The search terms included the following: “Klotho” AND “Sperm” OR “Testicle” OR “Oocyte” OR “Ovary” OR “Reproduction” OR “Fertility” OR “Infertility” OR “Gamete” OR “Gonad.” Following Cochrane methodology, the search covered MEDLINE, EMBASE, Cochrane Library, National Center for Biotechnology Information Gene, Tabula Sapiens, GTEx, Trip Database, Google Scholar, medRxiv, Open Grey, Central Register of Controlled Trials, and World Health Organization International Clinical Trials Registry, including all relevant studies up to March 2024 without language or publication status restrictions. The focus was on the role of alpha-Klotho in fertility, including studies involving animals and humans and basic experimental or observational designs. After removing duplicates, 2 investigators (N.S-.G., F.M.) independently screened titles and abstracts, with disagreements resolved by a third investigator (P.S.). The search identified a total of 258 articles, of which 18 were selected for the review. Final eligibility was determined by 4 investigators (N.S-.G., P.S., T.Q-.L., F.M.).

Results

The Klotho protein levels decrease with age. This decline influences male fertility by impacting spermatogenesis, sperm maturation, androgen production, and local homeostasis. In women, KL influences ovulatory function by inhibiting hypothalamic gonadotropin-releasing hormone secretion, regulating growth hormone secretion and oocyte quality, and controlling granulosa cells and follicular apoptosis. Overall, animal and human studies indicate that Klotho is an important factor in fertility, contributing to sperm quality and oocyte maturation and development. Additionally, the antioxidant properties of KL may help preserve the integrity of sperm cells and could serve as an effective antioxidant for the cryopreservation of ovarian tissue.

Conclusion

Further research is warranted to fully understand the mechanisms underlying the role of KL protein in human fertility, both as a potential biomarker and as a therapeutic target for infertility treatments and fertility preservation strategies. Advances in functional genetic variations studies will clarify the pathways linking genotype to phenotype in reproductive health.