Is fertility reduced in ovulatory women with polycystic ovary syndrome? An opinion paper

Abstract

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility; however, whether women with PCOS and spontaneous or drug-induced ovulatory cycles have the same reproductive potential as non-PCOS controls is a matter of debate. In the present opinion paper, the author takes the opportunity to summarize the collective evidence supporting the hypothesis of reduced fertility potential in women with PCOS, regardless of ovulatory status, and speculate that reduced reproductive potential may be caused by altered oocytes, embryo and endometrial competence, and infertility-related co-morbidities as well as an increased risk of pregnancy complications.

embryo, endometrium, implantation, infertility, miscarriage, oocyte, polycystic ovary syndrome, pregnancy complications, subfertility

Introduction

Polycystic ovary syndrome (PCOS) is a common multifaceted condition that is often associated with reproductive compromise (Dumesic et al., 2015) and, in particular, anovulatory infertility (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008; Legro et al., 2013). A wide range of effective interventions have been suggested for improving ovulation rates (Balen et al., 2016; Teede et al., 2018; Costello et al., 2019), even though the proportion of infertile patients with PCOS who undergo IVF is very high (Roos et al., 2011; Hart and Doherty, 2015; Rees et al., 2016; Mills et al., 2020). This discrepancy suggests other abnormalities that influence fertility among patients with PCOS, independent of ovulation. In addition, whether women with PCOS and normal ovulatory cycles, i.e. the ovulatory PCOS phenotype (Rotterdam ESHRE/ASRM-Sponsored PCOS consensus Workshop Group, 2004), have the same fertility of matched controls without PCOS is a matter of debate.

Based on these considerations, the author presents his opinion about the complex relationship between PCOS and fertility, regardless of ovulatory function, to address gaps in understanding and consider future research priorities.

Clinical data

Women with PCOS, when compared to matched controls without PCOS, seek infertility consultations and undergo ART more often, are older, and are more likely to be nulliparous at the time of delivery (Roos et al., 2011; Hart and Doherty, 2015; Rees et al., 2016; Mills et al., 2020). The probability of a first childbirth is ∼20% lower than matched controls without PCOS when considering total pregnancies and ∼40% lower considering only spontaneous pregnancies, with a time-to-first childbirth after spontaneous conception ∼2 years longer (Persson et al., 2019). Moreover, women with PCOS had the same number of children at the end of the reproductive span (Hudecova et al., 2009) and a similar prevalence for at least one child (Chen et al., 2020) when compared to matched controls without PCOS.

The overall analysis of available data suggests that women with PCOS have a reduced spontaneous fecundity rate, but the treatments and strategies employed are highly effective. This is true especially for IVF treatment (Heijnen et al., 2006; Sha et al., 2019) that influences significantly the reproductive outcomes of infertile patients with PCOS (Joham et al., 2014; West et al., 2014; Chen et al., 2020), especially for women of advanced maternal age (Kalra et al., 2013). In fact, even if the standardized fertility ratio is ∼20% lower in women with PCOS than in matched controls without PCOS, the fertility rates are restored at all ages after the diagnosis, suggesting that infertility in women with PCOS is treatable (Rees et al., 2016).

Pregnancy complications in PCOS

Women with PCOS are at increased risk of late pregnancy complications, including pregnancy-induced hypertension, pre-eclampsia, gestational diabetes mellitus, and preterm delivery (Palomba et al., 2015). Indeed, the increased risk of late pregnancy complications has been confirmed after controlling data for all potential confounders (Mills et al., 2020) and in IVF patients (Sha et al., 2019). An increased risk of early pregnancy complications, such as miscarriage, has been also demonstrated in women with PCOS when compared to matched controls without PCOS, independent of obesity (Bahri Khomami et al., 2019a, Bu et al., 2020), BMI, and karyotype (Luo et al., 2017). Neonates of women with PCOS are also at increased risk of admission to the neonatal intensive care unit and perinatal mortality (Palomba et al., 2015), even when that data are confounded by BMI and neonatal assistance (Bahri Khomami et al., 2019b). Finally, data on congenital malformations require large data sets to capture reliable findings (Sha et al., 2019; Mills et al., 2020; Schmidt et al., 2020).

The increased risk of pregnancy complications in women with PCOS is also supported by experimental findings that confirm impaired decidual trophoblast invasion and placentation (Kelley et al., 2019). These abnormalities are closely related to androgen levels, markers of insulin resistance, and an enhanced state of low-grade chronic inflammation, all of which are more frequent in specific PCOS phenotypes, such as full-blown PCOS and non-polycystic ovarian morphology (PCOM) phenotypes (Palomba et al., 2015; Kelley et al., 2019).

From a clinical perspective, other co-existing factors may increase the risk of pregnancy complications in women with PCOS. These risk factors are closely related to the syndrome and include obesity, hyperandrogenism, and insulin resistance/metabolic syndrome, and/or factors related to infertility, such as a lengthy time to achieve pregnancy, advanced maternal age, and the use of fertility drugs for ovarian stimulation and IVF (Palomba et al., 2016a, b).

PCOS-related cofactors

Women with PCOS are characterized by obesity, insulin resistance, glucose metabolism impairment, and metabolic syndrome (Dumesic et al., 2015). These abnormalities influence oocyte development and endometrial competence, as well as trophoblast invasion, placentation, and pregnancy outcome (Palomba et al., 2015, 2017, 2021), and act independently of PCOS in reducing reproductive performance. Obesity and glucose metabolism impairment are associated with an increased time to achieve pregnancy, impaired fecundability (Lim et al., 2019; Oostingh et al., 2019), and pregnancy complications (Farrar et al., 2016; Santos et al., 2019; Saravanan et al., 2020). An increased BMI is closely related to reproductive outcomes in both the general and IVF populations (Oostingh et al., 2019; Sermondade et al., 2019). Moreover, live-birth rates are even lower when obesity is associated with PCOS (Oostingh et al., 2019). Finally, metabolic syndrome is also associated with a longer time to achieve pregnancy and infertility in general populations that is independent of obesity (Grieger et al., 2019), and in patients with PCOS who undergo IVF (He et al., 2019).

Adjusting for confounders whenever possible is key to understanding the full range of PCOS-related factors that affect infertility. In contrast, evaluation of specific PCOS populations, such as lean, ovulatory, and/or non-hyperandrogenic women, may not provide comprehensive data of the syndrome or the clinical risk of infertility. Thus, from a clinical perspective, the relative risk reported in the literature is likely lower than that observed outside the clinical trial setting because PCOS is closely related to several conditions that are related to infertility.

Oocyte quality and competence in PCOS

Neuroendocrine, endocrine, and metabolic alterations influencing ovarian functions have also been reported in normo-ovulatory women with PCOS (Qiao and Feng, 2011; Dewailly et al., 2016; Palomba et al., 2017).

Genomic data demonstrate differences in global transcriptomic signatures in oocytes obtained from women with PCOS that are relevant to altered meiotic processes, intra-follicular oxidative stress, glucose and lipid metabolism regulation, and cross-talk between developing oocytes and surrounding somatic cells during folliculogenesis (Palomba et al., 2017). In women with PCOS, the increased oxidative stress induces an excessive production of reactive oxygen species that increase the incidence of meiotic abnormalities (Robker et al., 2011; Seidler and Moley, 2015) and final oocyte quality (Murri et al., 2013; Palomba et al., 2017). High follicular fluid levels of free fatty acids (Niu et al., 2014; Baddela et al., 2020) and several inflammatory markers closely related to low-grade chronic inflammation (Merhi, 2014) may also reduce oocyte competence in PCOS, thus causing lipotoxicity, endoplasmic reticulum stress, and changes in protein secretion, with an alteration of granulosa cell function and the expression and function of membrane receptors (Palomba et al., 2017).

Short and long non-coding RNAs, which are crucial in folliculogenesis, ovarian steroidogenesis, oocyte maturation, and embryo development, are aberrantly expressed in women with PCOS, suggesting abnormal post-transcriptional gene regulation via RNA silencing (Luo et al., 2021). In fact, several biomolecules with regulatory functions in oocyte development, including growth factors, cytokines, deaminases, metalloproteases, hormones, adipokines, and lipidases, are abnormally expressed in women with PCOS (Qiao and Feng, 2011; Ambekar et al., 2015).

Finally, glucose metabolism in in vitro-matured oocytes from women with PCOS is increased, when compared with in vitro-matured oocytes from matched controls with PCOS, thus indicating that oocyte metabolism from women with PCOS may be altered independent of the follicular environment (Harris et al., 2010).

Embryo quality and competence in PCOS

A significant temporal delay for pronuclei breakdown, first cleavage, and three-, four-, and seven-cell cleavages is observed using time-lapse analysis of embryos from women with PCOS and hyperandrogenism compared to healthy controls without PCOS (Wissing et al., 2014). Studies involving embryonic/fetal aneuploidy from gravidas with PCOS confirm reduced fertility in affected women, independent of ovulatory status. Indeed, the incidence of chromosomal aneuploidies, assessed using single nucleotide polymorphism array analysis, in miscarriages following successful IVF cycles is higher in women with PCOS than in matched controls without PCOS, even after multivariate analysis (Li et al., 2019).

Endometrial competence in PCOS

Several primary abnormalities, including abnormal expression of proteins involved in cell cycle regulation, cellular transport, and signaling, DNA repair, apoptotic processes, and mitochondrial metabolism, have been detected in the endometrium of women with PCOS (Palomba et al., 2021) independent of ovulation and/or normal menstrual cyclicity (Hulchiy et al., 2016; Paulson et al., 2017), suggesting that these primary abnormalities are not directly related to ovulatory function.

Aberrant expression of estrogen, progesterone, and androgen receptors and their co-regulators have been reported in the endometrium of women with PCOS (Palomba et al., 2021). The endometrium of women with PCOS exhibits progesterone resistance, a complex mechanism linked to the altered quantitative and qualitative expression of progesterone receptors (Paulson et al., 2017; Savaris et al., 2011). The reduced binding and activation of the progesterone receptor caused by reduced synthesis and/or altered expression of its less active isoforms (Mote et al., 2000; Young, 2018) results in impaired glucose metabolism and altered endometrial decidualization (Neff et al., 2020). The increased expression of androgen receptors in endometrial epithelial cells in women with PCOS (Slayden et al., 2001; Brenner et al., 2003; Slayden and Brenner 2003), the PCOS-related hypothalamic/pituitary dysfunction (Daniels and Berga, 1997; Pastor et al., 1998), and the increased systemic levels of estrogens (Hu et al., 2018) and of androgens (Young, 2018) may worsen the progesterone resistance in women with PCOS.

Abnormal regulation of enzymatic and metabolic pathways inducing an increased uptake and intracrine synthesis of molecules with enhanced and low estrogenic activity (Leon et al., 2008; Plaza et al., 2010), as well as androgens and free/active androgens (Maliqueo et al., 2007; Plaza-Parrochia et al., 2014, 2015, 2017), has been demonstrated in the endometrium from women with PCOS. Altered inflammatory (Matteo et al., 2010; Piltonen et al., 2013, 2015; Oróstica et al., 2016; Amjadi et al., 2018; Alkhuriji et al., 2020) and immune (Hu et al., 2020a; Liu et al., 2021) patterns have also been detected in the endometrium from women with PCOS, which are consistent with the local expression of a typical chronic low-grade inflammation state. Indeed, the increased endometrial inflammation and abnormal immune cells are closely related to the corresponding metabolic alterations of women with PCOS and may disrupt endometrial insulin sensitivity, which in turn contributes to local insulin resistance (Oróstica et al., 2020). Inflammation, hyperandrogenism, and insulin resistance may regulate several factors favoring angiogenesis in the endometrium of women with PCOS (Tal et al., 2015; Gong et al., 2019; Zhao et al., 2020).

The endometrium of women with PCOS is also the target of almost all clinical and biochemical/metabolic alterations known to be present in women with PCOS, and the primary alterations of the endometrium may enhance the tissue response (Palomba et al., 2021). In particular, hyperandrogenism, independent of ovulation and/or regular menstrual cycles (Margarit et al., 2010; Gonzalez et al., 2012; Freis et al., 2017), significantly influences endometrial function, thus enhancing the expression of sex hormone receptors (Su et al., 2012; Young, 2018) and co-activators (Simitsidellis et al., 2018), increasing oxidative stress (Hu et al., 2019; Zhang et al., 2019), activating ferroptosis (Zhang et al., 2020), and modulating the expression of several factors involved in the control of endometrial differentiation and receptivity (Daftary and Taylor, 2006; Hu et al., 2020b; Mokhtar et al., 2020). In women with PCOS, high testosterone levels affect insulin signaling, and glucose metabolism and transport at the endometrial level (Zhang and Liao, 2010; Rivero et al., 2012; Lee et al., 2020), thus inducing local insulin resistance and local hyperinsulinemia, which together potentiate the deleterious effects of hyperandrogenism on endometrial function (García et al., 2015; Oróstica et al., 2016; Rosas et al., 2016; Ujvari et al., 2020).

Discussion

Head-to-head data comparing the live-birth rates in patients with PCOS who ovulate spontaneously (ovulatory phenotype) or following ovulation induction versus healthy matched controls without PCOS are unavailable. Clinical trials and observational studies involving ovulatory agents in PCOS populations have reported overall fecundity rates, including reproductive outcomes in patients who receive fertility drugs and/or undergo ART, but do not selectively report the reproductive outcomes in women with PCOS who ovulate. Clinical findings showing a lack of differences in fecundity between women with and without PCOS may be linked to the efficacy of the fertility treatments in infertile patients with PCOS; however, women with PCOS receive more infertility consultations, undergo more treatments, and have a lower probability of a first childbirth in both total and spontaneous pregnancies, with a longer time to achieve the first childbirth. In this scenario and in consideration of the great amount of experimental and translational data indicating alterations in several reproductive pathways in women with PCOS, the opinion herein suggests considering women with PCOS, independent of ovulatory status, as patients with a reduced reproductive potential. Altered oocyte development and decreased endometrial competence, such as a potentially impaired endometrial-embryo cross-talk, are present in women with PCOS. Nearly all features related to PCOS also influence the reproductive potential independent of PCOS. Figure 1 summarizes the concepts of this opinion.

Figure 1

Infertility in women with polycystic ovary syndrome: a proof-of-concept. Notwithstanding the lack of robust evidence, almost all available experimental and translational data suggest that polycystic ovary syndrome (PCOS) and its co-morbidities are linked to altered oocyte and endometrial competence, and an impaired endometrial-embryo cross-talk, increasing the risk of infertility, and of early and late pregnancy complications through an abnormal trophoblast invasion and placentation.

The opinion herein supports four key points. First, the overall efficacy of the strategies employed and suggested by international guidelines over time (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008; Legro et al., 2013; Balen et al. 2016; Teede et al., 2018) for treating infertile women with PCOS is high. As detailed before, PCOS patients, particularly in the presence of PCOM, have a high ovarian reserve and reproductive performances better than matched controls without PCOS (Kalra et al., 2013), thus, confounding fecundity data. Second, we feel that it is essential to follow infertile patients with PCOS, keeping in mind that restoring ovulatory function is not the only objective in terms of fertility. Both general and specific non-medical interventions for improving fertility and reducing direct (owing to the high proportion of IVF) and indirect (owing to ovarian hyperstimulation syndrome and high-risk pregnancies) costs should be suggested and monitored (Teede et al., 2018; Costello et al., 2019). In particular, factors such as blood glucose, weight, blood pressure, smoking status, and sleep as well as mental, emotional, and sexual health should be optimized in women with PCOS through lifestyle modification programs (Teede et al., 2018; Costello et al., 2019). Third, it is important that women with PCOS are counseled about their fertility potential, the efficacy of the strategies for treating infertility (including IVF treatments), and the need to promote interventions to improve spontaneous/natural fertility prior to use of the more aggressive interventions in order to achieve more healthy pregnancies. Fourth, current opinion reveals a crucial scientific gap in the knowledge of ovulatory function in women with PCOS. In fact, more collaborative studies are needed and more resources should be allocated to better understand the mechanism underlying infertility problems independent of ovulation in women with PCOS (Al Wattar et al., 2020). Future research is also needed to inform international recommendations on how to improve fecundity with a high quality of evidence and to reduce dependence on medical and/or surgical interventions, including ART, with clinical and pharmaco-economic benefits. Broader treatment approaches beyond ovulation induction may be a key strategy with which to improve fertility potential and reduce pregnancy complications in the PCOS population.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Acknowledgments

The author acknowledges Mrs. Matilde Bongio for preparing Fig. 1.

Author’s role

S.P. conceived and designed the study, searched and interpreted the literature, drafted the article and approved its final version.

Funding

No specific funding was sought for the current study, and no roles were played by sponsors, as well as by institutional affiliation, in the research.

Conflict of interest

The author has no conflict of interest to declare.