Telomere Length Regulation and Reproduction: Current Concepts and Putative Threats To Ovarian Reserve

Introduction

Clinically, ovarian reserve describes a woman's reproductive potential with respect to the number and quality of ovarian follicles she possesses [1–5]. Fundamentally, it represents the number of primordial follicles within the ovaries at a given time point—a number that can only accurately be determined by microscopic investigation of the ovaries [6]. Declining ovarian reserve with age significantly affects fertility, ultimately resulting in reproductive senescence and the menopause [1–5]. In addition to the oocyte loss that occurs with age, a significant increase in meiotic errors occurs in oocytes as women reach their late 30s and 40s [7, 8]. This phenomenon contributes to risk of embryonic aneuploidy, miscarriage, and fetal aneuploidy syndromes [4, 7, 8]. Maternal age-related changes in oocyte quantity and quality present a significant challenge to natural fertility and place a limit on the efficacy of infertility treatments [7–10]. The complex molecular underpinnings of reproductive senescence are a matter of active investigation with many questions to still be elucidated.

Abstract

Ovarian aging is an inevitable process and is the basis of reproductive exhaustion in women. It is also the driving force behind the most dramatic endocrine transition in the female—the menopause. In addition to the oocyte loss that occurs with age, a significant increase in meiotic errors occurs in oocytes as women reach their late 30s and 40s, increasing the risk of embryonic aneuploidy and miscarriage. Despite the magnitude of the impact of ovarian senescence on multiple facets of women’s health, the complex determinants of ovarian aging have not been fully elucidated.

Telomeres consist of repetitive arrays of the nucleotide sequence (5'-TTAGGG-3')n that cap the ends of chromosomes providing stability to the genome. Because they shorten with successive rounds of DNA replication, they are regarded as markers of cell replicative history and senescence; telomere attrition has been postulated to play a role in aging and the development of age-related disease by mediating the onset of cellular senescence and imposing a limit on the proliferative life span of certain cell types. Mounting evidence also suggests that telomeres may represent a marker linking cellular aging, oocyte quality, and reproductive aging. Data supporting a theory of reproductive senescence that involves regulation of telomere homeostasis will be presented in this review. In addition, telomeres acting as targets of reactive oxygen species and other exogenous stresses may represent a putative link between environmental exposures and reproductive outcomes in women. Emerging evidence supporting this theory will also be discussed in the review.

Keywords

Infertility, occult ovarian insufficiency, diminished ovarian reserve, oxidative stress, telomere, telomerase