The association of female and male infertility with telomere length (Review)

Vasilopoulos E, Eleni Vasilopoulos, Fragkiadaki P, Persefoni Fragkiadaki, Charikleia Kalliora, Kalliora C, Domniki Fragou, Anca Oana Docea, Vakonaki E, Elena Vakonaki, Dimitris Tsoukalas, Daniela Călina, Daniela Calina, Buga AM, Ana Maria Bugă, Ana Maria Buga, George Georgiadis, George S. Georgiadis, Georgiadis G, Mamoulakis C, Charalampos Mamoulakis, Antonios Makrigiannakis, Antonis Makrigiannakis, Demetrios A Spandidos, Demetrios�� Spandidos, Aristidis Tsatsakis
International journal of molecular medicine · 2019 · vol. 44(2) , pp. 375–389 · doi:10.3892/ijmm.2019.4225 · PMID:31173155 · PMC6605974 · W2947352916
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

This review analyzed 45 studies and found that female infertility factors are mostly associated with shorter telomere length, while male infertility factors are consistently linked to shorter telomere length.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 · read from full text ⓘ

This systematic review evaluated the association between relative telomere length (TL) and factors of female and male infertility by searching PubMed for studies linking TL with infertility, screening 206 records down to 45 that met validity and relevance criteria. The authors found that most female infertility factors were associated with shorter TL, while endometriosis, premature ovarian failure, and clear cell carcinoma were associated with longer TL; polycystic ovary syndrome showed conflicting results across studies, leading to ambiguous conclusions, and male infertility factors were generally associated with shorter TL. A key limitation explicitly noted is that further epidemiological and original research is needed to clarify the varying TL associations. Relevance to endometriosis: the review explicitly includes endometriosis among female infertility factors and reports an association with longer telomere length, though the paper’s main focus is broadly summarizing TL–infertility associations across many infertility categories.

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Abstract

Telomere length (TL) has long been associated with aging, as telomeres serve as protective caps of chromosomes, and are thus deeply involved in the preservation of genome integrity and are vital to cellular functions. Traditionally, a strong link connects aging and infertility in both sexes, with an earlier onset in females. Over the past decade, telomeres have attracted increasing attention due to the role they play in fertility. In this review, we investigated the potential positive or negative association between relative TL and different factors of female and male infertility. A systematic search of the PubMed database was conducted. Out of the 206 studies identified, 45 were reviewed as they fulfilled the criteria of validity and relevance. Following an analysis and a comparison of the study outcomes, several clear trends were observed. The majority of female infertility factors were associated with a shorter TL, with the exception of endometriosis, premature ovarian failure and clear cell carcinoma that were associated with a longer TL and polycystic ovary syndrome (PCOS), which revealed conflicting results among several studies, leading to ambiguous conclusions. Male infertility factors were associated with a shorter TL. Although this review can provide an outline of general trends in the association of TL with infertility factors, further epidemiological and original research studies are required to focus on investigating the basis of these varying lengths of telomeres.
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Intro

The irreversible process of aging is marked by a decline in the body's physiological functions and adaptation ability. One of the systems impaired by this process is the reproductive system. According to recent publications, infertility affects an estimated 15% of couples globally ( 1 ). In 2016, almost 66,000 births in the United States were achieved from the assisted reproduction techniques application ( 2 ). According to the statistics of the Society for Assisted Reproductive Technology (SART), 241,570 cycles for egg retrieval, frozen embryo transfer and frozen egg thawing were performed ( 3 ). Despite common belief that infertility factors are usually associated with only the female sex, male factors have been found to be solely responsible for 20-30% of infertility cases and to contribute to 50% of the cases overall ( 4 ). The deleterious effects of reproductive aging affect both males and females; however, an earlier onset is observed among females, as a sharp decrease in fertility is reported after the age of 35 ( 5 ). The process of aging is strongly influenced by genetics, as well as environmental and lifestyle factors. Currently, the aging process is divided into two major components, biological and chronological age, which can differ for the same individual. Biological aging can be calculated by telomere length (TL) and DNA methylation levels ( 6 ). Telomeres are the end parts of linear chromosomes and consist of many tandem repeats of 5′-TTAGGG-3′. When cells divide, they are unable to replicate approximately 50 base pairs to the end of each chromosome. This leads to the progressive shortening with each round of cell division ( 7 ) ( Fig. 1 ), resulting in cell proliferation arrest and cell senescence. This mechanism is the leading cause of aging and age-related chronic diseases. In 2009, Blackburn, Greider and Szostak received the Nobel Prize for discovering the protective role of telomeres and the enzyme telomerase on chromosomes. These highly significant discoveries opened the way for researchers to further explore the role of telomere shortening in aging. By the construction of a biological age equation, the measuring of TL has come to be a calculating tool for the biological age of the body, including, but not limited to gonadal age ( 8 , 9 ) thus more accurately predicting the fertility status. Recently, a database was published named 'BIOTEL version 2.4', Telomere Length Database Project (TLDP), a semi-automated worksheet that calculates a wide range of TL statistics and it is a useful tool with applications in research on telomere biology, and in biological age estimation ( 10 ). Both genetic signature and external factors can decrease the gonadal pool and can thus subsequently increase male and female infertility, despite a favorable chronological age ( 11 ). Specifically, such external factors include human exposure to chemicals and pesticides used in agriculture and industry that act as endocrine disruptors (EDs) ( 11 - 15 ), dysregulating normal reproductive system functions ( 16 - 18 ), as well as drug abuse ( 19 ). It has been claimed that epigenetic factors, such as nutrition, exercise and tobacco can also affect the rate at which telomeres shorten and the risk of developing chronic diseases. Notably, nutrition supplements have been shown to benefit the length of short telomeres ( 20 ). A method of delaying the aging process has been proposed to be telomerase activation ( 21 ). Telomerase activation by natural molecules has been suggested to be potent in anti-aging and the treatment of related diseases. Telomerase activation can be achieved through natural molecules, synthetic molecules, and genetic manipulation and intervention. Recently, supplements and natural extracts were tested for their capacity to enhance telomerase activity (TA) in human peripheral blood mononuclear cells. It was demonstrated that formulations containing Astragalus extract activate telomerase to higher levels than the reported levels, indicating that the synergistic effects of nutrients and natural compounds can activate telomerase and can produce more potent formulations ( 22 ). One way in which telomerase can repair short or dysfunctional telomeres is by the addition of nucleotides at their ends, further stabilizing them. Indeed, TL and TA have been proposed as biomarkers of aging and studies have investigated their implications in other chronic diseases ( 23 , 24 ). In an effort to identify the causes of age-related infertility, researchers have managed to link the aging process to genomic and epigenomic alterations, DNA damage and oxidative stress ( 25 ). However, several human studies, which will be further reviewed below, have attempted to investigate the role of telomeres in infertility on a wider spectrum, by indicating the relative TL in individuals with varying types of infertility. The aim of this review was to elucidate the potential positive or negative association between relative TL and different factors of infertility, namely male factor, tubal factor, polycystic ovary syndrome (PCOS), ovarian reserve, endometriosis, anovulation, cancer related infertility and idiopathic infertility. The Medline [Ovid MEDLINE(R) In-Process & Other Non- Indexed Citations and Ovid MEDLINE(R) (1946 to February, 2018)] electronic database was searched to detect all publications focusing on the association of TL with human female and male infertility. The comprehensive literature was searched in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement ( 26 ), using the following literature search strategies: i) Telomeres OR TL AND fertility OR infertility; ii) Male Factor: telomere AND (idiopathic male infertility OR oligospermia OR azoospermia OR hypospermia OR teratospermia OR aspermia OR asthenozoospermia OR necrozoospermia OR leukospermia); iii) Tubal Factor: Telomere AND (hydrosalpinx OR fallopian tube OR tubal factor); iv) PCOS: Telomere AND PCOS; v) Ovarian Reserve: Telomere AND (ovary OR ovarian reserve); vi) Endometriosis: Telomere AND endometriosis; vii) Anovulation: Telomere AND (anovulation OR ovulation); viii) Unknown: Telomere AND (unexplained infertility OR idiopathic infertility). After excluding duplicates, titles and abstracts were screened for relevance, marked by a link between infertility cause and relative TL (longer or shorter). Two review authors (E. Vasilopoulos and C. Kalliora) independently scanned the title or the abstract content, or both, of every record retrieved to determine which studies should be assessed further and extracted all data. Citations in conference abstract form, review articles, animal studies, editorials, and non-English language articles were excluded. For each of these studies, it was determined whether a positive or negative association between the infertility factor they are focused on and TL is shown. This specific infertility factor was noted for each study, along with other important information (sex, relative TL and the method of measurement, population size, population age, population region, sample type and conclusion). The studies were further organized by infertility factor, allowing collective conclusions to be drawn. A total of 45 studies showing either a positive or negative association between male or female infertility and TL were included in the present review ( Fig. 2 ).

Other

In light of the increasing life expectancies of individuals worldwide, age-related diseases, such as infertility have progressively become a greater medical and social concern. The standard laboratory markers for age-related diseases or infertility have been insufficient. TL has long been a marker of cellular aging. The question posed is whether TL can be used to predict not only the biological, but also the reproductive age. Multiple studies have focused on elucidating this question and have demonstrated that infertility is in fact most often associated with shorter telomeres. Specifically, a trend associating female infertility factors, such as PCOS, DOR, ovarian insufficiency and tubal factor with shorter TLs was observed in oocyte granulosa cells, endometrial tissue and leukocytes. On the contrary, longer TLs were observed in endometrial biopsy, the eutopic endometrium, cyst and lymphocyte tissue in cases of endometriosis. As regards studies focusing on male infertility factors, including azoospermia, oligospermia, abnormal sperm motility and idiopathic male infertility, these demonstrated a shorter TL in either sperm or leukocyte samples obtained. Although this study was able to identify major trends in the association of several factors of infertility and TL, limitations apply due to the relatively low number of relevant studies for each infertility factor published to date. Additionally, TL in a number of established factors of infertility has not yet been studied. Specifically, no published literature on oligospermia, hypospermia, teratosperimia, aspermia, asthenozospermia, necrozospermia, leukospermia and hydrosalpinx was found. Although this serves as a limitation, it indicates a knowledge gap where further research could be undertaken. Regardless, TL is associated with a sufficient amount of infertility factors, thus not compromising the external validity of the review. As regards female infertility factors, ovarian HGSC, mature oocytes, low-quality embryos, multiform endometrial dysfunction, premature ovarian insufficiency, DOR, and nulliparity were all linked to a shorter TL. Conversely, all studies on endometriosis and TL agreed that TLs are longer. Additionally, one study noted that clear cell carcinoma stromal cells exhibit longer TL that other histological types. A noticeable disagreement is evident in studies exploring the TL of females with PCOS, as TL has been negatively and positively associated, and further correlated to both a shorter and longer TL in different studies. Thus, although for all other above-mentioned infertility factors a clear conclusion is drawn, for PCOS, the present evidence is inconclusive. Of the 21 studies reviewed focusing on male infertility factors, 1 study showed no association between TL in the sperm of older versus younger males, while 2 studies showed that older males had a longer relative TL and one study found STL not crucial for male fertility. Furthermore, the remaining studies were in agreement, indicating a shorter TL in infertile patients. With recent advances in reproductive technology, we need powerful predictive biomarkers that will improve the clinical strategy in individuals with infertility. TL can be a marker used to identify the reproductive capacity. Additionally, premature senescence can be avoided by the use of drugs preventing telomere shortening, thereby increasing the reproductive capacity of patients. However, many questions must first be answered before the efficient use of such methods in a clinical setting is possible. It is critical that further studies are conducted to understand the bases of TL associations with biological aging and reproductive capacity. The strength of this review is that, at least to the best of our knowledge, this is the first collection of the results from human epidemiological studies exploring the association of different factors of infertility and TL. Despite the present limitations, this review may be a useful aid, and the studies mentioned, may function as building blocks for further research needed to establish further associations and to determine how this knowledge can be used in medical applications.

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Condition tags

endometriosisinfertility

MeSH descriptors

Infertility, Female Infertility, Male Telomere Shortening Aging Female Humans Infertility, Female Infertility, Female Infertility, Female Infertility, Male Infertility, Male Infertility, Male Male Telomere Telomere

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