Low KLOTHOM level related to aging is associated with diminished ovarian reserve

This case-control study, including 157 patients with diminished ovarian reserve (DOR) and 159 control women, found that diminished KLOTHO expression in both serum and granulosa cells was associated with DOR.

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VOLUME 114, ISSUE 6, P1250-1255


Xiaofei Xu, Ph.D., Yongxiu Hao, Ph.D., Qihang Zhong, Ph.D., Jing Hang, Ph.D., Yue Zhao, Ph.D., Jie Qiao, M.D., Ph.D.



To explore the relationship between KLOTHO expression and diminished ovarian reserve (DOR).


A case-control study.


Reproductive medicine center.


A total of 157 patients with DOR and 159 control women were recruited from the Centre of Reproductive Medicine, Peking University Third Hospital.



Main Outcome Measure(s)

The granulosa cells were isolated from follicular fluid after oocyte retrieval, and the KLOTHO level of granulosa cell was measured using a modified quantitative polymerase chain reaction technique. The serum KLOTHO level was measured by solid-phase sandwich enzyme-linked immunosorbent assay.


In both granulosa cells and serum derived from women with DOR, KLOTHO expressions were significantly lower compared with normal ovarian reserve controls. Moreover, KLOTHO expression diminished with advancing age.


Diminished KLOTHO expression was associated with DOR. Further longitudinal studies in a similar population accompanying disease progression and mechanism exploration are needed to substantiate the rules of KLOTHO in reproductive aging.

Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. 


α-Klotho and in vitro fertilization

We read with interest the article by Xu X et al on the relationship of Klotho expression to the diminished ovarian reserve in patients undergoing in vitro fertilization – embryo transfer (IVF-ET). They measured serum Klotho levels (ELISA) and Klotho expression in granulosa cells (RT- PCR) and demonstrated that:

  1. Diminished ovarian reserve was associated with age-related reduction of Klotho expression.
  2. The rate of oocytes with two pronuclei was significantly higher in women with higher Klotho expression compared with those of lower Klotho expression.
  3. The rate of fertilization, implantation and clinical pregnancy proved to be independent of Klotho expression (1).

In contrast to these observations Takemura and Okabe reported that in patients undergoing intracytoplasmic sperm injection (ICSI) the serum α-Klotho concentrations during preimplantation were positively related not only to the oocyte maturation but also to the rate of fertilization, implantation and clinical pregnancy. They concluded, therefore , that preimplantation serum α-Klotho might serve as a simple, reliable biomarker of IVF success (2).

In a recent study our group also attempted to explore the possible contribution of α-Klotho protein to the success of IVF-ET procedure. Serum and follicular fluid (FF) were obtained from 61 IVF patients at oocyte retrieval and the α-Klotho levels were measured simultaneously (ELISA). It was found that serum α-Klotho levels were markedly elevated as compared to those of healthy, non-pregnant women (742 ±271 vs 602±100 pg/ml, p<0.01) and were closely related to the their respective FF values (r = 0.63, p < 0.01) suggesting that FFα-Klotho mostly derived from circulating plasma, the local ovarian production might be limited. Moreover, FF but not serum α-Klotho correlated significantly with the number of mature oocytes (r = 0.25, p < 0.05) and viable embryos (r = 0.26, p < 0.05). No significant differences could be detected either in serum or in FF α-Klotho levels between IVF patients with or without clinical pregnancy (3).

These observations are consistent with the concept that α-Klotho protein is involved in creating appropriate endocrine milieu and it may confer protection to the maturing oocytes and early embryos due to its anti-inflammatory, antioxidant and anti-apoptotic properties. Therefore, it has the potential to predict IVF outcome.

  1. Bódis J MD, PhD, DSc professor of obstetrics and gynecology
  2. Sulyok E MD, PhD, DSc emeritus professor

Assisted Reproduction Unit, Department of Obstetrics and Gynecology, University of Pécs, Hungary


  1. Xu X, Hao Y, Zhung Q, Hang J, Zhao Y, Qiao J. Low KLOTHO level related to aging is associated with diminished ovarian reserve. Fertil Steril 2020; 114:1250-1255.
  2. Takemura T, Okabe M. Serum α-Klotho concentrations during preimplantation can predict aging or quality of human oocytes and clinical pregnancy rates. SpringerPlus 2016; 5:1-5.
  3. Bódis J, Sulyok E, Peti MA, Prémusz V, Kovács LG, Várnagy Á, Koppán M: Serum and follicular fluid α-Klotho protein levels in women undergoing in vitro fertilization (In preparation)