Skewed X-chromosome inactivation and shorter telomeres associate with idiopathic premature ovarian insufficiency

Fertil Steril. 2018 Aug;110(3):476-485.e1. doi: 10.1016/j.fertnstert.2018.04.017.


Objective: To analyze whether telomere length, X-chromosome inactivation (XCI), and androgen receptor (AR) GAG polymorphism are related to idiopathic premature ovarian insufficiency (POI).

Design: Case-control study.

Setting: University hospital.

Patient(s): A total of 121 women, including 46 nonsyndromic POI and 75 controls.

Intervention(s): None.

Main outcome measure(s): Age, weight, height, body mass index (BMI), systolic and diastolic arterial pressure, E2, androstenedione, T, and C-reactive protein were assessed. Telomere length was estimated by quantitative real-time polymerase chain reaction, XCI was measured using the Human Androgen Receptor and X-linked retinitis pigmentosa 2 (RP2) methylation assays. AR and FMR1 polymorphism was assessed by quantitative fluorescent polymerase chain reaction and sequencing.

Result(s): Premature ovarian insufficiency women had a higher mean age, weighed less, and exhibited lower C-reactive protein, E2, and androstenedione levels. The AR polymorphism did not differ between the groups. Four patients had premutation (55-200 CGG repeats), and none displayed a full mutation in the FMR1 gene. However, patients with POI showed shorter telomere length and higher frequency of skewed XCI. Extreme skewing (≥90%) was observed in 15% of women with POI, and shorter telomeres correlated with XCI skewing in both groups.

Conclusion(s): Skewed XCI and shortened telomere length were associated with idiopathic POI, despite no alterations in the AR and FMR1 genes. Additionally, there is a tendency for women with short telomeres to exhibit skewed XCI.

Keywords: Anovulation; DNA methylation; epigenetic mechanisms; genomic instability; trinucleotide repeats.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Humans
  • Primary Ovarian Insufficiency / diagnosis*
  • Primary Ovarian Insufficiency / genetics*
  • Prospective Studies
  • Receptors, Androgen / genetics
  • Telomere / genetics*
  • Telomere Shortening / genetics*
  • X Chromosome Inactivation / genetics*
  • Young Adult


  • FMR1 protein, human
  • Receptors, Androgen
  • Fragile X Mental Retardation Protein