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Review

Contribution of Androgen Receptor CAG Repeat Polymorphism to Human Reproduction

by
Alessandro Ciarloni
,
Nicola delli Muti
*,
Nicola Ambo
,
Michele Perrone
,
Silvia Rossi
,
Sara Sacco
,
Gianmaria Salvio
and
Giancarlo Balercia
Department of Endocrinology, Polytechnic University of Marche, 60126 Ancona, Italy
*
Author to whom correspondence should be addressed.
DNA 2025, 5(1), 9; https://doi.org/10.3390/dna5010009
Submission received: 31 December 2024 / Revised: 4 February 2025 / Accepted: 6 February 2025 / Published: 8 February 2025
Browse Figures
Figure 1
<p>The <span class="html-italic">AR</span> gene is located on the X chromosome, at Xq11-12, and encodes for the androgen receptor (AR) protein. It consists of four domains: the N-terminal domain (NTD), the DNA-binding domain, the hinge domain, and the C-terminal ligand-binding domain. Testosterone, mainly through its active metabolite dihydrotestosterone (DHT), binds to the AR, and together they translocate to the nucleus of the cell, where they exert their transcriptional activity. Created in <a href="https://BioRender.com" target="_blank">https://BioRender.com</a>.</p> "> Figure 2
<p>Influence of CAG repeat polymorphism of androgen receptor (AR) on human reproduction. PCOS = polycystic ovary syndrome; RSA = recurrent spontaneous abortions. Created in <a href="https://BioRender.com" target="_blank">https://BioRender.com</a>.</p> "> Figure 3
<p>Influence of CAG repeat polymorphism of androgen receptor (<span class="html-italic">AR</span>) on transcriptional activity. Triplet number reduces transcriptional activity of <span class="html-italic">AR</span> by reducing its transactivation and hindering binding with transcriptional regulatory proteins. As a result, cells targeted by testosterone exhibit lower expressivity. Created in <a href="https://BioRender.com" target="_blank">https://BioRender.com</a>.</p> ">
Review Reports Versions Notes

Abstract

:
Background: Exon 1 of the gene encoding for the androgen receptor (AR) contains a polymorphic sequence of variably repeated CAG triplets ranging from 11 to 36. The number of triplets appears to inversely correlate with receptor transcriptional activity, conditioning the peripheral effects of testosterone. Methods: We conducted a narrative review to explore the current evidence regarding the relationship between the number of CAG repeats and the human reproductive system. Results: We found several articles that investigate the relationship between CAG polymorphism and the male reproductive system, suggesting a possible modulatory effect on spermatogenesis, sexual function, prostate cancer, and testicular cancer. Similarly, in women, evidence has emerged to support a possible relationship between CAG repeat number and breast cancer, polycystic ovary syndrome (PCOS), and recurrent spontaneous abortions (RSAs). Unfortunately, the data in the current literature are largely discordant, largely due to an important influence of ethnicity on the variability of the CAG polymorphism, and partly due to the quality of the available studies. Conclusions: In the current state of the art, the study of CAG polymorphism does not have a sufficient literature base to allow its use in common clinical practice. However, it represents an interesting research target and, in the future, as new evidence emerges, it could help to elucidate some pathogenetic aspects of human reproductive disorders.

1. Introduction

The androgen receptor (AR) protein consists of four structurally and functionally distinct domains: the N-terminal domain (NTD), the DNA-binding domain, the hinge domain, and the C-terminal ligand-binding domain [1]. Both testosterone and dihydrotestosterone (DHT) bind to AR, but the latter has the highest binding affinity [2]. The NTD, which has transactivation activity, is encoded by a single large exon (exon 1) of the AR gene, which is located on the X chromosome, at Xq11-12 [1]. Exon 1 of the AR gene contains a polyglutamine stretch coded by a highly polymorphic CAG trinucleotide repeat [3]. Furthermore, in the same region of the AR gene, another polymorphic tract characterized by an invariant stretch of six glycines (GGT/GGG), followed by variable GGC repeats, exists [4] (Figure 1).
The transcriptional activity of the AR gene inversely correlates with the number of CAG repeats, which usually varies from 11 to 36 [5], depending in part on ethnicity [6], with an average of 20–23 repeats [7]. Variations in the number of triplet repeats beyond these limits are associated with various pathological conditions, such as spinal and bulbar muscular atrophy (SBMA), or Kennedy syndrome, which is caused by CAG tracts beyond the normal range (>40 CAG repeats) that lead to loss of function of the AR. This results in abnormal sperm production, male infertility, and hypoandrogenism. In addition, the pathologic expiation of the CAG tract leads to aggregation of aberrant AR proteins that cause the characteristic neuromuscular toxicity [7,8]. Conversely, an association between shorter CAG repeats in the AR gene and hyperandrogenic states, such as hirsutism and ovarian hyperandrogenism potentially leading to fertility issues, has been hypothesized [7], although studies are inconclusive [9]. Considering the role of testosterone in male sexual health and gonadal germ cell development, and the presence of hormone-sensitive neoplasms in the human species, it is of interest to evaluate the role of AR’s CAG polymorphism length on male sexual dysfunction, spermatogenesis, and testicular, prostate, and breast neoplasms.
In the present review, we discuss the potential role of the CAG polymorphism of the AR gene in modulating its effects on human reproduction (Figure 2), aiming to unravel the most controversial aspects in the current literature.

2. CAG Repeat Polymorphism and Male Reproductive Health

2.1. Spermatogenesis

In vitro studies have shown that an elongation of the CAG repeat length may result in reduced AR transactivation, with consequent lower levels of receptor protein and mRNA that may compromise sperm production in men due to reduced androgen activity [10]. In addition, elongation of the CAG tract may significantly influence the receptor’s interactions with various transcription regulatory proteins. For example, variations in the AR can affect its binding capacity with steroid receptor coactivator 1 (SRC-1), thereby modulating the transcription efficiency of androgen-dependent genes. This reduction may compromise important physiological processes, such as spermatogenesis and the maintenance of secondary sexual characteristics [11] (Figure 3).
Notably, the CAG polymorphism may also interact with other genetic variants involved in spermatogenesis, influencing male fertility in a multifaceted manner. In the last decade, research has highlighted how (CAG)n and (GGC)n repeats in the AR gene correlate with altered hormonal profiles and compromised seminal parameters, particularly in idiopathic male infertility [12]. Longer (CAG)n repeats have been associated with reduced testosterone concentrations and sexual dysfunctions, suggesting that these genetic variants may directly affect metabolic pathways of spermatogenesis [13]. Moreover, environmental factors may interact with the CAG polymorphism, modulating its effects on spermatogenesis. For instance, endocrine disruptors could potentially alter AR functions through multiple intracellular targets. Various compounds might directly or indirectly change AR conformation, thereby affecting its preference for coactivators or corepressors, as well as its androgenic or anti-androgenic activities [14].
In vivo, many authors have focused on AR gene polymorphisms to explore their potential role in alterations of male fertility and spermatogenesis. In a study by Bogefors et al. [15], the authors investigated the effects of the CAG and GGN polymorphisms in the AR gene on sperm recovery in 130 men who underwent testicular germ cell cancer treatment. After 12 months, they found that men with 22–23 CAG repeats showed lower sperm counts than those with shorter or longer CAG lengths (8.4 × 106 mL−1 vs. 16 × 106 mL−1; 95% CI: 1.01–2.65; p = 0.04). According to the authors, this suggests that a higher number of repeats may interfere with receptor DNA-binding and the recruitment of transcriptional co-factors, leading to a less efficient AR variant. This hypothesis was confirmed in a recent study by Ashraf et al. [16], who observed that men with altered sperm parameters had significantly higher CAG repeat numbers (27 vs. 24, p < 0.001), and CAG length was significantly associated with lower sperm count and altered sperm motility when a cut-off of 26 CAG repeats was used. Similarly, von Eckardstein et al. [17] demonstrated an inverse correlation between number of CAG repeats and sperm concentration in men with normal semen parameters, but not in infertile men, suggesting that polymorphism in the AR gene could contribute to spermatogenesis in healthy men. However, longer CAG repeats have also been observed in men with idiopathic oligozoospermia, cryptorchidism, and Y chromosome long arm microdeletions [18]. However, these data were not confirmed in Iranian men, suggesting that ethnicity could influence this phenomenon [19]. This was in agreement with a recent study by Osadchuk et al. [20] that confirmed the association between longer CAG repeats and impaired semen quality, also reporting significant differences in CAG repeat numbers between ethnic cohorts of Caucasians and Asians in a large Russian population. These data are summarized in Table 1.
In conclusion, men with longer CAG repeats may show impaired semen quality. Therefore, CAG repeat polymorphism in the AR gene could be one of the elements to be included in the assessment of infertile males, but the variability brought about by ethnicity and the complex interactions with additional genetic and environmental factors still represent a major limitation for clinical practice.

2.2. Sexual Function

Following the discovery of the CAG polymorphism on exon 1 of the AR, many studies analyzed the correlation between the number of CAG repeats and male sexual function. As was previously mentioned, Kennedy syndrome is characterized by reduced virilization, providing direct evidence of the close correlation between AR activity and male sexual function [12,21]. Consequently, various studies have evaluated this aspect in relation to different areas of male sexuality.
Concerning erectile dysfunction (ED), only a few, and mostly cross-sectional, studies have been conducted, with conflicting results. Pastuszak et al. [22] found a negative association between the length of CAG repeats and erectile function, according to the International Index of Erectile Function (IIEF15), in 85 men. Liu et al. [9] confirmed these data, finding that in men older than 40 with total testosterone levels above 3.40 ng/mL, a CAG polymorphism length > 25 repeats was associated with worse sexual function scores according to the Androgen Deficiency in Aging Males (ADAM) questionnaire. Similar results were reported by Tirabassi et al. [23], who found that the IIEF15 scores of 85 patients inversely correlated with the number of CAG repeats. The results were valid only in eugonadal subjects, and the logistic regression confirmed their independence from other confounding factors. On the other hand, the GGC polymorphism of the AR gene seemed not to influence sexual function. Conversely, Andersen et al. [24] did not find a correlation between the length of the CAG polymorphism and erectile function when 79 ED patients were compared with 340 controls, but it must be considered that the study was a population-based survey conducted with a single question regarding ED. Concerning longitudinal data, two studies have evaluated the recovery of sexual function after the introduction of testosterone replacement therapy (TRT) in relation to the length of the CAG polymorphism of the AR gene, with both of them finding higher values on the IIEF questionnaire for those patients with a shorter length of the CAG polymorphism [25,26]. However, important limitations should be taken into account for one of these studies, such as the small sample size (15 patients), the peculiar nature of low testosterone levels (post-surgical hypogonadotropic hypogonadism), and the possible influence of other pituitary replacement therapies [26]. In a double-blind, randomized, placebo-controlled cross-over study, Francomano et al. [27] evaluated the effects of TRT with transdermal gel testosterone on acute endothelial response measured by peripheral arterial tonometry. Surprisingly, a direct correlation between the length of CAG repeats and the natural logarithm of the hyperemic response was found. However, the low number of patients evaluated (n = 10) did not allow for definitive conclusions regarding this association to be drawn.
Ryan et al. [28], in 2017, explored the possible relationship between CAG repeat polymorphism and hypothalamic–pituitary–gonadal (HPG) axis function by measuring total plasma testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in 722 young Filipino males. Since no significant (or only marginally significant) results emerged, the authors concluded that the AR gene CAG polymorphism is more likely to regulate androgenic activity in peripheral tissues, rather than affecting HPG axis function. In addition, there is also evidence regarding a correlation between the length of AR CAG repeats and glucometabolic parameters, especially in Asian males; in particular, longer CAG repeats seem correlated with metabolic syndrome [29,30], and may contribute to the development of functional hypogonadism [31]. These data suggest that CAG polymorphism could modulate hypogonadism symptomatology. In the same vein, Park et al. did not find significative differences in CAG polymorphism length when comparing men with late-onset hypogonadism (LOH) and without LOH, but longer CAG lengths were associated with higher values on the Aging Male Symptoms Scale (AMS), independently from the diagnosis of LOH [32]. In 2018, Kim et al. found that men with LOH had longer CAG repeat lengths compared with men without LOH (26.1 vs. 21.6, p < 0.001), and that longer CAG repeats were associated with higher LOH symptoms, measured by the AMS and lower IIEF5 scores [33]. Both studies evaluated more than 200 Korean men, and in both cases, the diagnosis of LOH was based on total testosterone levels < 3.5 ng/mL and AMS scores indicative of androgen deficiency. Notably, the lack of data on sex hormone binding globulin (SHBG) and free calculated testosterone levels can be considered a limitation of both studies [32,33]. Another study on 676 men in the Vietnam Era Twin Study of Aging (VETSA) found that a shorter length of the CAG polymorphism was associated with lower vitality, evaluated by the 36-item Short Form (SF-36), in men with low testosterone levels, but not in men with normal to high testosterone, suggesting that men with more sensitive ARs may be more likely to experience symptoms of testosterone deficiency [34]. However, it must be considered that testosterone levels were measured only using salivary testosterone, which is not the standard parameter used for the diagnosis of LOH [31]. In addition, low testosterone levels were arbitrarily defined as 1 standard deviation (DS) lower than the mean values of all patients. Interestingly, higher lengths of the CAG polymorphism seem to be associated with more severe clinical features in subjects affected by Klinefelter syndrome, in terms of testicular volume, hypogonadism, and pubertal development. A tendency towards inactivation of the over-numbered X-chromosome containing the gene for the AR with the lowest number of CAG repeats has also been suggested in these patients. However, not all studies have confirmed this hypothesis, which certainly needs further investigation [35].
Since androgens are directly involved in bone health, the relationship between length of CAG polymorphism and skeletal diseases has been explored. In 2010, Guadalupe-Grau et al. evaluated the length of CAG and GGN polymorphisms in 282 healthy men (mean age 28.6 years). The study showed conflicting results, with higher bone mineral density (BMD) values at the femoral neck in patients with combined short polymorphisms, and higher lumbar spine BMD in men with combined long polymorphism. In addition, no significative association between CAG or GGN length and regional BMD was observed [36]. On the other hand, a pilot study in 2011 evaluated the length of the CAG polymorphism in 454 Israeli soldiers that underwent radiological examination to rule out a stress fracture. In those with confirmed stress fractures, the length of the polymorphism was longer, and the risk of a stress fracture significantly decreased if the length of CAG repeats was < 16 [37]. Recently, Sasako et al. [38] assessed the length of the AR CAG and GGC triplets in a large population of 181,217 patients, in relation to various clinical, biochemical, and instrumental parameters. The whole-genome and/or whole-exome sequence data from the UK Biobank were used in the study. As the main findings, the authors reported a positive correlation between CAG and GGC repeat length, and total testosterone and estimated BMD. The correlation with testosterone levels can be explained by the resistance to the peripheral action of testosterone itself, whereas the association with the estimated BMD values was understated by the authors themselves, since the effect detected appeared too small to be clinically relevant. In addition, it should be noted that BMD was estimated at the heel by means of quantitative ultrasound, speed of sound, and broadband ultrasound attenuation, while a bone density measurement by dual-energy X-ray absorptiometry (DXA), which is the mainstay for the diagnosis of osteoporosis in men [39], was not performed.
In conclusion, many studies have evaluated the associations between AR polymorphism length and testosterone-related biochemical, clinical, and instrumental parameters (Table 2). However, some aspects remain unclear, and further studies are needed.

2.3. Testicular Cancer

Testicular cancer is the most common malignancy among young males in the world, and its incidence is increasing, especially among males in Western and Northen Europe [40]. Most of these tumors arise from primordial germ cells, and they are therefore referred to as testicular germ cell tumors (TGCTs) [41]. In 2001, Skakkebaek et al. [42] first hypothesized the association of TGCTs, poor semen quality, cryptorchidism, and hypospadias as the expression of a testicular dysgenesis syndrome (TDS) caused by the disturbance of gonadal development during fetal life. According to their hypothesis, environmental factors (including endocrine disrupters) and genetic defects may concur to determine Sertoli cell dysfunction and reduced Leydig cell function. This would lead to impaired germ cell differentiation and androgen insufficiency, with consequent reduced semen quality, undescended testicles, and hypospadias. Moreover, germ cells escaping from normal differentiation in utero may give rise to intratubular germ cell neoplasia (ITGCN) of the testis, which in turn can progress to TGCTs [43]. Since the number of CAG repeats in the AR gene seems to modulate androgen sensitivity [5] (Figure 3), AR polymorphisms may represent one of the genetic factors involved in TDS and TGCTs. In line with this hypothesis, recently, Moreno-Mendoza et al. [44] evaluated the relationship between the CAG repeat polymorphism and TGCTs in a Spanish population. Interestingly, they found a shorter anogenital distance (a surrogate biomarker of exposure to androgens during fetal life) in men with TGCTs compared with normozoospermic controls, but no differences in the number of CAG repeats emerged between cases and controls. Of note, the small sample size (10 TGCT patients and 20 controls) was a significant limitation of the study. Conversely, Grassetti et al. [45] investigated the influence of CAG repeats in a large population of TGCT patients (n = 302) who were compared with 322 controls. Although the mean number of CAG repeats was not different between the two groups, the authors reported a significantly higher proportion of males with ≥25 CAG repeats in TGCT patients than in controls (26.2% versus 18.6%, p = 0.027), and a 76% higher risk of TGCTs in men with >24 CAG repeats compared with men with 21–24 CAG repeats. In addition, the OR for the presence of stage II disease was 92% higher in patients with >24 CAG repeats compared with those with 21–24 CAG repeats.
Similarly, Giwercman et al. [46] compared 83 TGCT patients (divided in three diagnostic subgroups: seminomas, non-seminomas, and mixed) with 220 controls, finding no differences in mean CAG repeats between the two main groups. In addition, when CAG repeats were compared among subgroups, a higher proportion of men with a CAG length > 25 was found in pure non-seminoma subgroup (20%) and control subgroup (13%) compared with seminoma and mixed type subgroup (0%). In addition, the authors found the longest repeats in those patients with the most advanced disease at the time of diagnosis, with an OR of 4.1 for the presence of metastases for a CAG length > 21. Therefore, the authors concluded that CAG numbers exceeding 25 are more common in patients without any seminoma component. On the contrary, the risk of seminoma was reported to be increased with a shorter CAG repeat length by Davis-Dao et al. [47]. This is in line with the findings of the already-cited work by Grassetti et al. [45], who not only reported a higher risk of testicular cancer for a CAG length > 24, but also a 50% higher risk of TGCTs in men with <21 CAG repeats.
Taken together, these data suggest a possible, but unclear, relationship between AR gene polymorphism and TGCT susceptibility. Unfortunately, meta-analysis studies have led to mixed results. In 2016, Jiang et al. [48] first conducted a meta-analysis including seven studies (3255 TGCT cases and 2804 controls). Surprisingly, they found that AR polymorphisms with >25 CAG repeats acted, respectively, as a protective factor against testicular cancer (OR 0.54; CI 95% 0.41–0.70) in the high-latitude subgroups (including studies from Sweden, Denmark, and Norway), and as a risk factor for testicular cancer (OR 1.65; CI 95% 1.09–2.50) in the mid-latitude subgroups (including studies from Italy and USA). More recently, Qin et al. [49] found 11 articles that were included in their meta-analysis. According to their findings, a number of CAG repeats of > 24 was a significant risk factor for testicular cancer when compared with a number of CAG repeats of ≤ 24 (OR 1.587; CI 95% 1.145–2.199; p = 0.006) and of 21–24 (OR 1.772; CI 95% 1.255–2.502; p = 0.001). Of note, the authors also reported that no significant results were found when a different cut-off of 25 or 23 CAG repeats was adopted, making the authors question themselves regarding the meaningfulness of their findings and whether different cut-off lengths of CAG repeats could affect the results.
In conclusion, CAG length might represent one of the genetic factors modulating susceptibility to testicular cancer, but the effect varies greatly depending on the triplet cut-off used and the tumor histotype considered.

2.4. Prostate Cancer

Prostate cancer is the second most frequent cancer worldwide, and the leading cause of cancer death among men in a quarter of the world’s countries [50]. AR activation is involved in growth signaling of prostate cancer at any stage [51]. Furthermore, the relationship between endogenous testosterone levels and prostate cancer is still controversial, since studies report conflicting results suggesting negative, positive, or null association [52]. Interestingly, as testosterone levels increase, the risk of prostate cancer appears to increase, until a cut-off beyond which no further increase in cancer risk is observed. This has been partly explained by the so-called “saturation model”, according to which the AR gene, which stimulates prostate cell growth, has a maximum testosterone-binding capacity that is already reached for blood values of testosterone slightly above castration levels, so that further increases do not result in further stimulation of tumor growth [53].
In 2017, two meta-analyses on the association between AR gene polymorphisms and prostate cancer were conducted by two distinct research groups [54,55]. In both studies, 51 publications were included, and although there were some minor differences in the selection of studies that resulted in slightly different numbers of analyzed populations (14,803 cases and 18,888 controls for Weng et al. [54], and 11,891 cases and 15,351 controls for Qin et al. [55]), the main findings were quite similar. Indeed, Weng et al. reported that men with shorter CAG repeats (<22) showed a higher prostate cancer risk than those with longer CAG repeats (≥22): OR = 1.31, 95% CI 1.16 to 1.47 [54]. Similarly, Qin et al. reported a protective effect of long CAG repeats (≥22) versus short CAG repeats (<22): OR = 0.82, 95% CI: 0.70–0.97 [55]. The latter observation remained valid with a cut-off of 20 CAG repeats (OR = 0.27, 95% CI: 0.13–0.52), but not with 23 CAG repeats (OR = 0.88, 95% CI: 0.63–1.24) [55]. These results are in line with the previous meta-analysis by Sun and Lee [56], who observed an increased prostate cancer risk in men with shorter CAG repeats when a cut-off of 22 was adopted (OR = 1.21, 95% CI 1.10 to 1.34). Intriguingly, sub-analysis by ethnicity confirmed their results only in Asians (OR = 1.83, 95% CI 1.04 to 3.22) [56]. This has been observed in the more recent meta-analyses as well [54,55].
Notably, there is great variability in the number of CAG repeats and, potentially, in the resulting androgenic sensitivity, determined by ethnicity. In a large multiethnic study, an increasing number of CAG repeats was observed in Afro-Caribbean, Caucasian, Hispanic, and Thai groups [57]. Likewise, there is great variability in the incidence and mortality of prostate cancer around the world. Epidemiological studies have shown the highest incidence of prostate cancer in Caucasians from the US (107.8 per 100,000 and 185.4 per 100,000 among white and Black men, respectively), and the lowest incidence in Asians (with the lowest worldwide value recorded in China of 1.7 per 100,000); autopsy studies have confirmed twice the incidence of prostate cancer in Caucasian men compared with Asian men (83% in white men from the US versus 41% in Japanese men of 71–80 years of age). Mortality, in turn, is highest in Africans, intermediate in Caucasians, and lowest in Asians [58].
Fusion between the androgen-regulated promoter sequence of the TMPRSS2 gene (encoding for the transmembrane protease serine 2) and the erythroblast transformation-specific (ETS) transcription factor family member ERG (ETS-related gene) has been reported in about half of Caucasian patients with prostate cancer, and it has been hypothesized that this common fusion event represents one of the key factors in the early development of prostate cancer [59]. Yoo et al. [60] found that patients with shorter CAG repeats have an increased risk of ERG-positive prostate cancer, but not of ERG-negative cancer. This seems to be related to the fact that AR stimulation promotes gene proximity and increases the colocalization of TMPRSS2 and ERG genes, thus increasing the risk of a fusion event [61]. Consequently, increased transactivation of the AR gene observed in men with shorter CAG repeats could result in an increased likelihood of TMPRSS2:ERG fusion-positive prostate cancer [60]. Although fascinating, such data require confirmation with larger cohorts of patients, since the studies available to date are based on limited series, burdened by marked ethnic heterogeneity.

3. CAG Repeat Polymorphism and Female Reproductive Health

3.1. Breast Cancer

Brest cancer is a rare malignancy in men, but is the most prevalent cancer worldwide, and the leading cause of cancer deaths in women [62]. Breast cancer can be hormone-sensitive in both men and women, and androgens may play an indirect role in tumor development through aromatization and the consequent activation of estrogen receptors (ERs) on cancer cells [63]. Interestingly, the AR gene is also expressed by breast cancer cells, but its exact function remains unclear. Indeed, in the early stage of hormone-positive breast cancer, a high AR:ER ratio appears to direct cells toward apoptosis, and is a positive prognostic factor; conversely, in the advanced stage of hormone-positive breast cancer, high expression of AR genes is associated with reduced distant metastatic-free survival and worse prognosis [64]. This leads to the consequence that active breast cancer represents an absolute contraindication to testosterone replacement therapy in hypogonadal men [65], but at the same time, makes the AR gene a possible target for future hormone therapy in AR-positive breast cancers that are unresponsive to classical hormone therapies [64].
Given this assumption, the modulation of AR activity could play an important role in the risk of developing breast cancer and in its progression (Figure 1). In 2006, Cox et al. [66] conducted an extensive genetic evaluation of 95 advanced breast cancer cases, exploring the possible relationship between AR genetic variants and cancer risk, but no association with the number of CAG repeats was observed in Caucasian women. Similarly, a study involving 604 Australian and British women showed that the AR CAG repeat polymorphism did not affect cancer risk in BRCA1 and BRCA2 mutation carriers [67]. In a meta-analysis of 17 studies by Mao et al. [68], the overall analysis confirmed no association between the CAG polymorphism and breast cancer risk (OR 1.031, 95% confidence interval [CI] 0.855–1.245), but the subgroup analysis suggested a higher cancer risk in Caucasian women with ≥22 CAG repeats (OR 1.315, 95% CI 1.014–1.707).
On the other hand, a study by Lee at al. [69] suggested that the length of CAG repeats could be an important prognostic factor. The authors, indeed, observed that CAG length ≥ 23 was associated with much higher mortality (HR, 3.08; 95% CI, 1.42–6.67, p = 0.004) over a median follow-up period of 6.59 years. Intriguingly, Cogliati et al. observed lower overall survival in women with longer CAG repeats (X-weighted biallelic mean ≥ 20) and ER-negative breast cancer, but better survival in women with shorter CAG repeats and ER-positive breast cancer, suggesting that AR may both stimulate and inhibit cancer growth, depending on ER status [70].
In conclusion, the number of CAG repeats appears to play little role in breast cancer risk, but it is possible that the AR gene is part of a broad hormonal system in which numerous factors come into play, making it difficult to draw firm conclusions.

3.2. Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a complex disease, with clinical or biochemical hyperandrogenism representing one of the three diagnostic criteria, together with menstrual irregularities and micropolycistic appearance of the ovaries on ultrasound evaluation. For the diagnosis of PCOS, at least two out of three of these conditions (also known as the Rotterdam criteria) must be present [71]. Surprisingly, a discrepancy between clinical and biochemistry exists, and may result from variable sensitivity of the AR gene, which may depend on the length of the CAG repeat polymorphism (Figure 3). Studies comparing the length of the CAG repeat polymorphism in patients with or without a diagnosis of PCOS according to the Rotterdam criteria have yielded conflicting results [72,73,74]. To delve deeper into this association, some meta-analyses have been conducted. A first study conducted in 2012 by Wang et al. analyzed 17 case–control studies, without finding significant correlations between the length of the CAG polymorphism of the AR gene and the diagnosis of PCOS [75]. These results must be interpreted with consideration of the heterogeneity of the control groups, that were made of women with various characteristics, isolated or in combination: proven fertility, tubal infertility, normal ovarian ultrasound characteristics, normal menstrual cycles, and others. It is also important to consider that some studies used diagnostic criteria that are not included in the Rotterdam criteria, such as anovulation and LH/FSH ratio. Furthermore, the sample size of the individual studies analyzed was not adequate to guarantee sufficient statistical power to limit false negatives. A subsequent meta-analysis conducted in 2013 by Rajender et al. analyzed 17 case–control studies, and highlighted overlapping results [76]. However, it should be considered that the diagnostic criteria used and the control groups were not adequately described in terms of fertility, infertility, and ovarian ultrasound characteristics. Another meta-analysis was conducted in 2014 by Peng et al. [77], who included 10 case–control studies. The authors found shorter CAG repeats in women suffering from PCOS, but it should be considered that the control group consisted of women from infertile couples, due to tubal or male factors, undergoing in vitro fertilization, whereas a comparison with a healthy population was not carried out. It should also be considered that subgroup analysis showed high heterogeneity in the Western subgroup and low heterogeneity in the Eastern subgroup, suggesting that ethnicity could be a potential source of heterogeneity. Following the release of the latest international guidelines [71], a recent study by Yan et al. evaluated the correlation between polycystic ovarian morphology (PCOM) and the length of the androgen receptor CAG polymorphism. This study showed that a lower CAG repeat length in the androgen receptor was associated with an antral follicle count of > 20 and with PCOM [78]. These results have therefore rekindled the interest of researchers in the study of this association, which is certainly far from being fully understood in all of its facets.

3.3. Recurrent Spontaneous Abortion

Recurrent spontaneous abortion (RSA) is a condition that is often difficult to address in the female population. Following the finding in some scientific studies of higher blood levels of androgens in this population [79,80], some studies have tried to evaluate whether the length of the CAG polymorphism of the AR gene could also play a role in the pathogenesis of this condition. Two case–control studies conducted in China, in 2012 by Chuan et al. [81] and in 2022 by Sui et al. [82], respectively, have shown a greater risk of RSA in patients with a shorter AR CAG polymorphism. The first study included 149 women with RSA and 210 controls [81], whereas the second one included 131 women with RSA and 126 controls [82]. On the other hand, another case–control study conducted on Indian women in 2011 by Aruna et al. showed that longer repeats of the CAG polymorphism of the AR gene were associated with a greater risk of RSA. This study included 117 RSA cases and 224 controls; it also had an estimated statistical power of 90% [83]. The results of these studies suggest that the length of the CAG polymorphism of the AR gene may play a role in RSA, but this seems to depend on the ethnicity of the patients. The AR single-nucleotide polymorphism (SNP) G1733A (rs6152) was associated with a greater risk of RSA in Iranian [84], Greek [85], and Mexican women [86]. These data, on the one hand, strengthen the hypothesis that the AR gene plays a role in RSA, but on the other hand, they also underline, in this case, the importance of ethnicity. To study this association in more depth, further studies are certainly necessary that focus not only on the CAG polymorphism, but also on SNPs, and consider the importance of ethnicity.

4. Diagnosis and Management of CAG-Associated Pathologies

The diagnosis of reproductive disorders influenced by the AR gene, particularly those linked to CAG and GGN repeat polymorphisms, is primarily based on endocrine profile analysis, physical examinations, and imaging techniques. In clinical practice, male infertility and ED are diagnosed through hormonal assessments (T, LH, FSH), semen analysis, and genetic testing (such as Y-microdeletion), while PCOS is diagnosed using hormonal profiles and ultrasound imaging. However, these methods typically ignore genetic factors affecting AR activity [87,88,89]. Similarly, RSA diagnosis often focuses on pregnancy history and hormonal evaluations, with genetic analysis rarely considered [90]. Integrating CAG and GGN repeat polymorphisms into the diagnostic process could enhance these practices. Simple, cost-effective techniques such as PCR and DNA sequencing allow for the detection of repeat length variations that may affect receptor function. CAG repeat analysis could deepen our understanding of genetic predispositions, offering a more precise diagnostic approach in the future. For instance, the identification of altered CAG repeats can lead to the choice of proper treatment for male idiopathic infertility [91]. On the other hand, specific CAG/GGN profiles in PCOS could lead to more personalized hormonal therapies [76]. Genetic insights may also offer important implications for prostate and testicular cancer, since CAG repeat variations have been associated with increased risk [48]. In these cases, genetic testing could be integrated into risk assessments, enabling more customized treatments and preventive strategies. In RSA, genetic testing could identify women at higher risk, enabling more targeted interventions for improved pregnancy outcomes [81]. Moreover, understanding CAG/GGN polymorphisms could inform treatment strategies, such as adjusting TRT dosages for hypogonadal men [25]. In conclusion, while current diagnostic methods remain essential, the integration of genetic testing for CAG/GGN repeats holds great potential to improve both diagnosis and treatment, opening the way for more personalized management of androgen-related reproductive disorders, including prostate and testicular cancer.

5. Conclusions

The AR CAG polymorphism plays a key role in modulating the peripheral effects of testosterone, as demonstrated by in vitro evidence. The effects of androgens on reproductive health in men and women are numerous, and certainly, the CAG polymorphism plays a key role in their regulation. Unfortunately, the presence of numerous biological variables and profound variability determined by ethnicity makes it difficult to draw up recommendations that are useful for clinical practice. Therefore, although, at present, the assessment of the CAG polymorphism is not a useful parameter for defining a diagnostic-therapeutic pathway, its role in the pathogenesis of numerous reproductive health disorders makes it an interesting research target.

Author Contributions

Conceptualization, A.C., N.d.M. and G.S.; writing, review, and editing, all authors; supervision, G.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
ADAMAndrogen Deficiency in Aging Males
AMSAging Male Symptoms
ARAndrogen receptor
DHTDihydrotestosterone
EDErectile dysfunction
EREstrogen receptor
ERGETS-related gene
FSHFollicle-stimulating hormone
HPGHypothalamic–pituitary–gonadal
IIEFInternational Index of Erectile Function
ITGCNIntratubular germ cell neoplasia
LHLuteinizing hormone
LOHLate-onset hypogonadism
NTDN-terminal domain
SBMASpinal and bulbar muscular atrophy
SF-3636-item Short Form
RSARecurrent spontaneous abortion
TDSTesticular dysgenesis syndrome
TGCTTesticular germ cell tumor

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Figure 1. The AR gene is located on the X chromosome, at Xq11-12, and encodes for the androgen receptor (AR) protein. It consists of four domains: the N-terminal domain (NTD), the DNA-binding domain, the hinge domain, and the C-terminal ligand-binding domain. Testosterone, mainly through its active metabolite dihydrotestosterone (DHT), binds to the AR, and together they translocate to the nucleus of the cell, where they exert their transcriptional activity. Created in https://BioRender.com.
Figure 1. The AR gene is located on the X chromosome, at Xq11-12, and encodes for the androgen receptor (AR) protein. It consists of four domains: the N-terminal domain (NTD), the DNA-binding domain, the hinge domain, and the C-terminal ligand-binding domain. Testosterone, mainly through its active metabolite dihydrotestosterone (DHT), binds to the AR, and together they translocate to the nucleus of the cell, where they exert their transcriptional activity. Created in https://BioRender.com.
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Figure 2. Influence of CAG repeat polymorphism of androgen receptor (AR) on human reproduction. PCOS = polycystic ovary syndrome; RSA = recurrent spontaneous abortions. Created in https://BioRender.com.
Figure 2. Influence of CAG repeat polymorphism of androgen receptor (AR) on human reproduction. PCOS = polycystic ovary syndrome; RSA = recurrent spontaneous abortions. Created in https://BioRender.com.
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Figure 3. Influence of CAG repeat polymorphism of androgen receptor (AR) on transcriptional activity. Triplet number reduces transcriptional activity of AR by reducing its transactivation and hindering binding with transcriptional regulatory proteins. As a result, cells targeted by testosterone exhibit lower expressivity. Created in https://BioRender.com.
Figure 3. Influence of CAG repeat polymorphism of androgen receptor (AR) on transcriptional activity. Triplet number reduces transcriptional activity of AR by reducing its transactivation and hindering binding with transcriptional regulatory proteins. As a result, cells targeted by testosterone exhibit lower expressivity. Created in https://BioRender.com.
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Table 1. Influence of CAG repeat polymorphism on spermatogenesis.
Table 1. Influence of CAG repeat polymorphism on spermatogenesis.
ReferencesCountryPopulationMain Findings
[15]Sweden130 men who underwent testicular cancer treatmentLower sperm count 12 months after treatment in men with CAG length shorter than 22 or longer than 23
[16]Pakistan208 men with normal sperm parameters and 168 men with altered sperm parametersSignificantly longer CAG length in men with altered sperm parameters
[17]Germany131 men with normal sperm parameters (62 fathers and 69 volunteers)Inverse correlation between CAG length and sperm output in normal fertile population
[18]Italy110 men with idiopathic infertility, 19 men with previous history of cryptorchidism, 10 men with Y chromosome long arm microdeletions, and 61 fertile controlsLonger CAG repeats in men with idiopathic oligozoospermia, cryptorchidism, and Y chromosome long arm microdeletions
[19]Iran42 infertile men and 42 fertile controlsNo significant differences in CAG repeat length between fertile and infertile men
[20]Russia1324 young male volunteers of different ethnicitiesSignificantly longer CAG length in men with impaired semen quality; significantly different CAG length in men from different ethnic cohorts
Table 2. Influence of CAG repeat polymorphism on male sexual function.
Table 2. Influence of CAG repeat polymorphism on male sexual function.
ReferencesCountryPopulationMain Findings
[22]U.S.85 unselected menSignificant negative correlation between CAG repeat number and all domains of IIEF.
[9]Taiwan702 subjects who had attended a free health screening for men older than 40 yearsNo association between serum testosterone levels and CAG length. Higher risk of andropausal symptoms assessed by ADAM questionnaire in men with AR CAG repeats > 25 and normal testosterone levels.
[4]Italy85 men with sexual dysfunctionInverse correlation between CAG length and total IIEF score in whole sample. Higher number of CAG triplets associated with lower values for all IIEF sub-domains in eugonadal subjects.
[24]Brazil79 men with ED and 340 controlsNo association between CAG length and ED, gonadal steroids, and sleep parameters.
[25]Italy73 men with LOH, evaluated before and after TRTLower improvement of sexual function after TRT in men with longer CAG length.
[26]Italy15 men affected by post-surgical hypogonadotropic hypogonadism, evaluated before and after TRTGreater metabolic improvement after TRT in men with shorter CAG length.
[27]Italy10 men with hypogonadism undergoing a 4-day double-blind, randomized, placebo-controlled cross-over study with transdermal testosterone gelAdministration of testosterone gel caused acute vasodilatation and improved arterial stiffness that was directly correlated to CAG length.
[28]U.S.722 young Filipino malesNo relationship between CAG length and testosterone and LH level. Negative correlation between CAG length and FSH levels.
[29]U.K.100 South Asian adultsNo correlation between CAG repeat length and insulin resistance or β-cell function. Positive association of AR CAG with systolic and diastolic blood pressure, and negative association of AR CAG with total and low-density lipoprotein cholesterol.
[30] Kim, 2018Korea337 unselected menSignificantly longer CAG length in men with metabolic syndrome. CAG repeat length significantly associated with high-density lipoprotein, triglyceride, and glycated hemoglobin levels.
[32] Park, 2016Korea241 unselected menSignificantly longer CAG length in men with metabolic syndrome. CAG repeat length significantly associated with glycated hemoglobin levels. No differences in CAG length between eugonadal and LOH men.
[30]Korea229 eugonadal and 33 LOH menLonger CAG length in men with LOH. Significant correlation between CAG length and adropausal symptoms assessed by AMS. Age and CAG length independently associated with LOH based on multivariate analysis.
[34]U.S.676 unselected menHigher salivary testosterone levels in men with longer CAG length. Lower vitality assessed by SF-36 in men with shorter CAG length.
[36]Spain282 healthy menHigher BMD values at femoral neck in patients with combined short CAG and GGN polymorphisms, and higher lumbar spine BMD in men with combined long polymorphism. No significant association between CAG or GGN length and regional BMD.
[37]Isreal454 Israeli soldiers with symptoms compatible with stress fracturesHigher risk of fracture stress in men with shorter CAG length.
[38]Japan181,217 males from European-ancestry male participants in the UK BiobankCAG length positively associated with circulating testosterone levels and BMD, and negatively associated with male-pattern baldness.
ADAM = Androgen Deficiency in the Aging Male; AMS = Aging Males’ Symptom Scale; BMD = bone mineral density; ED = erectile dysfunction; FSH = follicle-stimulating hormone; IIEF = International Index of Erectile Function; LOH = late-onset hypogonadism; LH = luteinizing hormone; SF-36 = 36-item Short Form; TRT = testosterone replacement therapy.
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Ciarloni, A.; delli Muti, N.; Ambo, N.; Perrone, M.; Rossi, S.; Sacco, S.; Salvio, G.; Balercia, G. Contribution of Androgen Receptor CAG Repeat Polymorphism to Human Reproduction. DNA 2025, 5, 9. https://doi.org/10.3390/dna5010009

AMA Style

Ciarloni A, delli Muti N, Ambo N, Perrone M, Rossi S, Sacco S, Salvio G, Balercia G. Contribution of Androgen Receptor CAG Repeat Polymorphism to Human Reproduction. DNA. 2025; 5(1):9. https://doi.org/10.3390/dna5010009

Chicago/Turabian Style

Ciarloni, Alessandro, Nicola delli Muti, Nicola Ambo, Michele Perrone, Silvia Rossi, Sara Sacco, Gianmaria Salvio, and Giancarlo Balercia. 2025. "Contribution of Androgen Receptor CAG Repeat Polymorphism to Human Reproduction" DNA 5, no. 1: 9. https://doi.org/10.3390/dna5010009

APA Style

Ciarloni, A., delli Muti, N., Ambo, N., Perrone, M., Rossi, S., Sacco, S., Salvio, G., & Balercia, G. (2025). Contribution of Androgen Receptor CAG Repeat Polymorphism to Human Reproduction. DNA, 5(1), 9. https://doi.org/10.3390/dna5010009

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