https://orcid.org/0000-0002-0782-8578
Abstract
Fibroids are benign tumours of the myometrium and are the most common gynaecologic abnormality. Although most fibroids are asymptomatic, they can cause symptoms like heavy menstrual bleeding, pelvic pain, sexual dysfunction, pressure complaints, and infertility. The association between fibroids and infertility has been debated for decades. It is generally acknowledged that the closer the fibroid is to the uterine cavity and the endometrium lining, the more unfavourable effect it might have on fertility, reducing the odds for successful implantation and gestation. Based on the limited available literature, we propose and discuss seven hypotheses on the underlying mechanism by which fibroids may reduce fertility. (i) Fibroids can cause sexual dysfunction, as fibroids can cause dyspareunia, pelvic pain, and prolonged and heavy menstrual bleeding, which could interfere with sexual arousal and as a consequence the frequency of intercourse, resulting in a reduced probability of conception. (ii) Mechanical compression by fibroids on theinterstitial part of the fallopian tubes or deformation of uterine cavity could disturb oocyte and sperm transport. (iii) Fibroids can disturb peristalsis of the junctional zone in the myometrium, which could negatively influence oocyte and sperm transport as well as implantation. In addition, fibroids could induce a detrimental environment for implantation in other ways, by: (iv) changing the vagino-uterine microbiome; (v) disturbing the levels of inflammation and autophagy; (vi) inducing molecular changes in the endometrium; and (vii) inducing aberrant angiogenesis and altering the endometrial blood supply. After the discussion of these hypotheses, the implication of the influence of fibroids on early pregnancy loss is discussed. Surgical fibroid treatment is not tailored nor focussed on the pathophysiology of the fibroid; consequently it may be accompanied by recurrence of fibroids and risks of complications. Unravelling the pathogenic mechanisms about how fibroids influence fertility is essential to evolve classic surgical fibroid treatment. Instead of treatment of fibroid-related symptoms, the research should supports development of fibroid-targeted (pharmaceutical) treatment that is compatible with an active wish to become pregnant.
Introduction
Over the past decade, researchers have investigated factors that may influence women’s fertility. One of the possible causes of reduced fertility is uterine fibroids, also known as leiomyomas (Khaund and Lumsden, 2008). Fibroids are benign tumours of the myometrium, which develop in or around the uterus. The prevalence of fibroids ranges from 4.5% to 68.6%, partly depending on main risk factors such as ethnicity and age (Stewart etal., 2017). The incidence is significantly higher in women of African origin; these women may display fibroids at a younger age and may suffer from more severe symptoms (Baird etal., 2003). Oestrogen and progesterone stimulate the growth of uterine fibroids and, as a consequence, development usually starts after menarche. During the reproductive years fibroids are most progressive and usually regress after menopause (Moravek and Bulun, 2015). Studies indicate that at least 50–75% of fibroids are asymptomatic (Divakar, 2008; Stewart etal., 2016). However, if they become symptomatic, the most common symptoms are extensive blood loss during menstruation, pelvic pain, sexual dysfunction, and pressure complaints frequently leading to urological and/or gastrointestinal symptoms (Stewart etal., 2016; Bochenska etal., 2021). Fibroid-related symptoms are associated with the size, number, and locationof the fibroids. The location of fibroids are classified according to the International Federation of Gynecology and Obstetrics (FIGO) system (Munro etal., 2018). Generally, fibroids do not influence women’s fertility, however, in women with infertility, fibroids are more prevalent. Fibroids are diagnosed in approximately 5–10% of women with infertility, and are estimated to be solely responsible for infertility in 2–3% of patients (Khaund and Lumsden, 2008; Klatsky etal., 2008; Brady etal., 2013; Bosteels etal., 2018). Next to infertility, research has shown that fibroids are associated with early pregnancy loss (Benecke etal., 2005; Somigliana etal., 2007; Khaund and Lumsden, 2008; Klatsky etal., 2008; Pritts etal., 2009) and adverse obstetric outcomes like abdominalpain during pregnancy (because of excessive fibroidgrowth or fibroid necrosis), preterm labour, placenta abnormalities, intrauterine growth restriction, and increased rates of caesarean section and postpartum haemorrhage (Exacoustos and Rosati, 1993; Coronado etal., 2000; Benson etal., 2001; Sheiner etal., 2004; Ouyang etal., 2006; Qidwai etal., 2006; Cook etal., 2010). The extent of the impact on reproductive outcomes appears to largely depend on the location of the fibroid. For example, it is suggested that fibroids distorting the uterine cavity could mechanically alter implantation, where intramural fibroids have more impact on functionality of the myometrium, as both negatively influencing receptivity (Casini etal., 2006; Brady etal., 2013; Christopoulos etal., 2017; Behbehani etal., 2018). Up to now, the most intriguing questions are about how uterine fibroids influence fertility and pregnancy, and which underlying pathophysiological mechanisms have been studied sufficiently. Constructed on the available literature, we postulate seven hypotheses to clarify the association of uterine fibroids with infertility and unfavourable pregnancy outcomes. In addition, we determine the knowledge gaps as perspectives for future research. Figure 1 and Table 1 show an overview of the postulated hypotheses on the underlying mechanisms that may be responsible for the detrimental effect of fibroids on fertility.
An overview of the seven postulated hypotheses responsible for the detrimental effect of fibroids on fertility.
Seven postulated hypotheses on the underlying mechanisms that could be responsible for the detrimental effect of fibroids on fertility.
| Mechanism | Stage of fertility |
|---|---|
| 1. Pelvic pain, dyspareunia, and prolonged and heavy menstrual bleeding interfere with sexual arousal and, as a consequence, the frequency of intercourse | Sexual dysfunction |
| 2. Physical compression of the interstitial part of the fallopian tubes or deformation of uterine cavity | Disturbed oocyte and sperm transport |
| 3. Disturbed peristalsis of the junctional zone in the myometrium | |
| 4. Changes in vagino-uterine microbiome | Detrimental environment for implantation |
| 5. Disturbed levels of inflammation and autophagy | |
| 6. Molecular changes in the endometrium | |
| 7. Aberrant angiogenesis and altered endometrial blood supply |
| Mechanism | Stage of fertility |
|---|---|
| 1. Pelvic pain, dyspareunia, and prolonged and heavy menstrual bleeding interfere with sexual arousal and, as a consequence, the frequency of intercourse | Sexual dysfunction |
| 2. Physical compression of the interstitial part of the fallopian tubes or deformation of uterine cavity | Disturbed oocyte and sperm transport |
| 3. Disturbed peristalsis of the junctional zone in the myometrium | |
| 4. Changes in vagino-uterine microbiome | Detrimental environment for implantation |
| 5. Disturbed levels of inflammation and autophagy | |
| 6. Molecular changes in the endometrium | |
| 7. Aberrant angiogenesis and altered endometrial blood supply |
Seven postulated hypotheses on the underlying mechanisms that could be responsible for the detrimental effect of fibroids on fertility.
| Mechanism | Stage of fertility |
|---|---|
| 1. Pelvic pain, dyspareunia, and prolonged and heavy menstrual bleeding interfere with sexual arousal and, as a consequence, the frequency of intercourse | Sexual dysfunction |
| 2. Physical compression of the interstitial part of the fallopian tubes or deformation of uterine cavity | Disturbed oocyte and sperm transport |
| 3. Disturbed peristalsis of the junctional zone in the myometrium | |
| 4. Changes in vagino-uterine microbiome | Detrimental environment for implantation |
| 5. Disturbed levels of inflammation and autophagy | |
| 6. Molecular changes in the endometrium | |
| 7. Aberrant angiogenesis and altered endometrial blood supply |
| Mechanism | Stage of fertility |
|---|---|
| 1. Pelvic pain, dyspareunia, and prolonged and heavy menstrual bleeding interfere with sexual arousal and, as a consequence, the frequency of intercourse | Sexual dysfunction |
| 2. Physical compression of the interstitial part of the fallopian tubes or deformation of uterine cavity | Disturbed oocyte and sperm transport |
| 3. Disturbed peristalsis of the junctional zone in the myometrium | |
| 4. Changes in vagino-uterine microbiome | Detrimental environment for implantation |
| 5. Disturbed levels of inflammation and autophagy | |
| 6. Molecular changes in the endometrium | |
| 7. Aberrant angiogenesis and altered endometrial blood supply |
Sexual dysfunction
Hypothesis 1: pelvic pain and dyspareunia interfering with sexual intercourse
Sexual dysfunction in premenopausal women is a relatively common disorder with a prevalence of 30–50%, and fibroids may be associated with sexual dysfunction; however, prospective data exploring this association are limited and conflicting (Moshesh etal., 2014; Chang etal., 2019). Fibroids can cause pelvic pain and/or dysmenorrhea resulting in dyspareunia (Ferrero etal., 2006; Ertunc etal., 2009). Additionally, fibroids can cause heavy and/or prolonged menstrual bleeding; this combined with dyspareunia could interfere sexual arousal, and as a consequence negatively influence the frequency of intercourse, resulting in a reduced probability of pregnancy (Moshesh etal., 2014). Several studies have shown that the presence of fibroids had a significant association with deep dyspareunia and impaired sexual satisfaction compared to the absence of fibroids (Lippman etal., 2003; Ertunc etal., 2009; Moshesh etal., 2014). No association was found between fibroid size and pelvic floor problems, although fundal fibroids were more associated with dyspareunia (Moshesh etal., 2014; Bochenska etal., 2021). Treatment of fibroids, like myomectomy, may relieve pelvic pain during intercourse, thereby improving sexual function in these women (Ertunc etal., 2009; Don etal., 2022, 2023b; Dedden etal., 2023). However, Ferrero etal. (2006) did not find an association of fibroids with impaired sexual function, neither did they find an association between fibroid location and dyspareunia (Ferrero etal., 2006). In conclusion, sexual dysfunction in an infertile couple is a complex issue and, along with possible treatment of fibroids, it might be necessary to also address other medical or psychosocial problems (Berger etal., 2016).
Disturbed oocyte and sperm transport
Hypothesis 2: physical compression of the interstitial part of the fallopian tubes or deformation of uterine cavity
Fibroids can obstruct sperm cells from reaching the oocyte, obstructan embryo from reaching the uterine cavity and/or hinderimplantation, by compressing the endometrium through mechanical distortion of the endometrial cavity, the interstitial part of the fallopian tubes or the cervix (Oliveira etal., 2004; Horne and Critchley, 2007; Donnez and Dolmans, 2020). Extrinsic compression by large subserosal or intramural fibroids can cause gross anatomical distortion of the interstitial part of the fallopian tubes, resulting in tubal factor infertility, as this could hinder sperm or oocyte penetration, and consequently conception (Hart, 2016; Zepiridis etal., 2016). It is essential to differentiate between fibroids that distort the uterine cavity, submucosal fibroids FIGO type 0,1 and 2 and intramural fibroids FIGO type 2-5, and fibroid types that do not distort the uterine cavity, intramural fibroids FIGO type 3,4,5 and subserosal fibroids FIGO type 6,7 (Munro etal., 2018). The negative effect of fibroids distorting the uterine cavity on fertility have been widely documented, as women with cavity distorting fibroids are demonstrated to have significant lower implantation, clinical pregnancy and live birth rates, and significantly higher miscarriage rates (Pritts etal., 2009; Donnez and Dolmans, 2016). Myomectomy of submucosal fibroids appears to restore reproductive potential (Klatsky etal., 2008; Pritts etal., 2009; Bosteels etal., 2018). While there is still debate about whether myomectomy of intramural and subserosal fibroids can improve reproductive outcomes, if the myomectomy releases the mechanical compression caused by large fibroids, this could in theory improve oocyte and sperm transport, and thus fertility. Additionally, when patients simultaneously suffer from fibroid-related symptoms, myomectomy of submucosal, intramural, or subserosal fibroids would not delay the time to live birth despite the required recovery time after surgery and the risk of intrauterine adhesions (Don etal., 2022). On the other hand, if a fibroid is located close to the interstitial part of the fallopian tube, it may be challenging to restore its anatomy after myomectomy without disturbing the transport functions. Futures studies are needed to elucidate the benefit of myomectomy in these specific cases.
Disturbed oocyte and sperm transport, and detrimental environment for implantation
Hypothesis 3: disturbed peristalsis of the junctional zone in the myometrium
The third hypothesis states that fibroids possibly disturb the frequency, direction, amplitude, and coordination of junctional zone peristalsis resulting in inadequate oocyte and sperm transport. The contractility of the subendometrial layer or inner myometrium in a non-pregnant uterus moves in specific patterns and directions depending on the phase of the menstrual cycle, also known as junctional zone peristalsis (Harmsen etal., 2022). By junctional zone peristalsis, the journey of sperm through the genital tract to the fallopian tubes is enhanced during the late follicular phase until ovulation, and after ovulation, junctional zone peristalsis decreases dramatically to support implantation (Bulletti and de Ziegler, 2006; Fanchin and Ayoubi, 2009; Huang etal., 2022). Altered junctional zone peristalsis is considered to cause IVF failure, because alterations to the direction and/or frequency of the contractions could induce the evacuation of an embryo out of the uterine cavity (Bulletti and de Ziegler, 2006; Fanchin and Ayoubi, 2009). Additionally, the contraction amplitude is of influence, as it has been suggested that frequent contractions of low amplitude can favour implantation (Lyons etal., 1991). Fibroids are reported to negatively influence the frequency, direction, and coordination of junctional zone peristalsis, although their influence on the amplitude of contractions has not been explored (Nishino etal., 2005; Yoshino etal., 2010; Kido etal., 2014; Fornazari etal., 2019). The results about which specific changes of junctional zone peristalsis are caused by which type of fibroids seem conflicting. Nishino etal. (2005) found that only submucosal fibroids, not intramural or subserosal fibroids, cause interruption or even total loss of uterine peristalsis (Nishino etal., 2005), while, Kido etal. (2014) showed that in women with symptomatic fibroids, the presence and frequency of peristalsis and the cervix-to-fundus direction of contractions were significantly decreased, without relationship to the fibroid location or other fibroid characteristics (Kido etal., 2014). Yoshino etal. (2010) demonstrated that in women with intramural fibroids, both low- and high-frequency peristalsis are present, yet pregnancy is significantly more likely to occur in the low-frequency group (Yoshino etal., 2010). Furthermore, submucosal fibroids have a significantly thicker pseudocapsule, like a neurovascular bundle surrounding the fibroid, compared to both intramural and subserosal fibroids (Tinelli etal., 2018). Hypothetically, this pseudocapsule could play a role in infertility, since it has a recently discovered neuroendocrine function, possibly influencing junctional zone peristalsis (Tinelli etal., 2018). Nevertheless, research has shown that treatment of fibroids, such as uterine artery embolization, high-intensity focused ultrasound or myomectomy, can restore the presence, direction, frequency, and coordination of junctional zone peristalsis (Kido etal., 2011; Yoshino etal., 2012; Fornazari etal., 2019; Qu etal., 2019). Moreover, Yoshino etal. (2012) found that not only the frequency of junctional zone peristalsis was normalized after myomectomy, but the pregnancy rate also was increased (n = 15, pregnancy rate: 40%) (Yoshino etal., 2012). To conclude, fibroids can disturb junctional zone peristalsis, probably hampering the journey of sperm cells and oocytes through the genital tract or resulting in implantation failure. Myomectomy might restore junctional zone peristalsis, however, studies reporting on this are scare (Yoshino etal., 2012). While studies about obstetric outcomes after myomectomy of submucosal fibroids generally report a positive effect of the procedure (Klatsky etal., 2008; Pritts etal., 2009; Bosteels etal., 2018; Don etal., 2022), we still need to elucidate whether this effect is in part because of the normalization of junctional zone peristalsis.
Detrimental environment for fertilization and implantation
Hypothesis 4: changes in the vagino-uterine microbiome
Today it is known that human foetal development is far from a sterile event (Green etal., 2015; Chen etal., 2017). The fourth hypothesis relates to the influence of fibroids on the vagino-uterine microbiome, since fibroids may induce inflammation and changes in local nutrients, as well as heavy and prolonged menstrual bleeding, all of which influence the vagino-uterine microbiome. A microbiome was found not only in the vagina and endocervical canal, but also in the uterine cavity and fallopian tubes, and even the intrafollicular environment can have its own active microbiome (Franasiak and Scott, 2015). Recent reviews highlight the influence and relevance of the vagino-uterine microbiome to female fertility (Punzón-Jiménez and Labarta, 2021; Vitale etal., 2021). The cervicovaginal microbiota is dominated by Lactobacilli species and changes in this dominance may influence the reproductive potential (Huttenhower etal., 2012; Franasiak and Scott, 2017; Kroon etal., 2018). Studies investigating the endometrial microbiome show heterogeneous and conflicting results. Sola-Leyva etal. (2021) reported endometria with prevalent Clostridium and Staphylococcus (8–13%) and low Lactobacilli species (<1%) (Sola-Leyva etal., 2021), while other studies showed Lactobacillus-dominated endometrial samples (>90%) (Franasiak etal., 2016; Moreno etal., 2016). Moreover, Moreno etal. (2016) showed that for about one in five endometrial samples, the microbiota was significantly different from that identified in the corresponding vaginal sample (Moreno etal., 2016). In women with non-Lactobacillus-dominated microbiota in the endometrial fluid, a significant decrease in implantation, pregnancy, ongoing pregnancy, and live birth rates was found compared to women with a Lactobacillus-dominated microbiota (Moreno etal., 2016). Gynaecological diseases, like endometriosis, ovarian or endometrial cancer and polycystic ovary syndrome, have been shown to influence the microbiome in the female reproductive tract (Punzón-Jiménez and Labarta, 2021). Only two studies have investigated the microbiome in women with fibroids. Chen etal. (2017) found that in women with fibroids, Lactobacillus species were more often present in vaginal and cervical samples, while L. iners was more often present in the cervical canal, compared to women without fibroids (Chen etal., 2017). Winters etal. (2019) found different bacterial profiles in vagina and endometrium samples of patients with fibroids, and the endometrium samples were not dominated by Lactobacillus, but Acinetobacter, Pseudomonas, Comamonadaceae, and Cloacibacterium (Winters etal., 2019). Moreover, these authors questioned the observations in other studies of a dominant Lactobacillus presence in the upper reproductive tract, since these endometrium samples were generally collected transcervically, and Winters etal. (2019) collected their samples after hysterectomy. Unfortunately, the fibroid characteristics or associations with fibroid-related abnormal uterine bleeding were not reported. In addition, validation of the results is required in larger prospective cohort studies. It is important to note that the microbiome comprises more than a simple accumulation of bacteria and in many cases it is formed by complex 3-dimensional lattices, also described as the biofilm (Franasiak and Scott, 2015). The relationship between the reproductive tract and its biofilm might be more complex than only the mere absence, presence, or relative concentration of various species of bacteria (Benner etal., 2018; Punzón-Jiménez and Labarta, 2021). Additionally, the question remains, what a kind of healthy baseline microbial state of the uterus is and whether ‘correcting’ the microbiome or biofilm to a more baseline state will positively impact reproductive outcomes. In our opinion, this question needs to be answered first, and afterwards research needs to be done in patients with fibroids specifically to clarify what these conditions do to the vagino-uterine microbiome and whether treatment like myomectomy can restore a healthy and receptive vagino-uterine microbiome.
Hypothesis 5: disturbed levels of inflammation and autophagy
The fifth hypothesis is that fibroids could disturb levels of inflammation and autophagy, resulting in a detrimental environment for implantation. It is clear that the female reproductive tract has a symbiotic relationship with its microbiome, and the detection of these microbes by the immune system is followed by a complex dialogue involving its adaptive and innate components (Agostinis etal., 2019). The uterine immune system is very unique, due to its adaptation to hormonal stimuli during the menstrual cycle and its toleration of the semi-allogeneic foetus (Agostinis etal., 2019). Immune cells show a distinctive pattern of changes throughout the phases of the menstrual cycle, and during implantation and pregnancy. Located in the endometrium, CD68+ macrophages can induce pro-inflammatory cytokines, and these are suggested to have a significant role in fertility, since they support preparation of the endometrium during the window of implantation (Thiruchelvam etal., 2013). Macrophage numbers significantly increase during the secretory phase, especially at the site of implantation (Agostinis etal., 2019). Supporting the role of local inflammation in fibroid pathogenesis, it is reported that in patients with fibroids, CD68+ macrophages exist in abundance at the myometrial site of the fibroid, compared with that observed in distant autologous endometrium (Protic etal., 2016; AlAshqar etal., 2021). These macrophages produce various growth factors, including transforming growth factor β (TGF-β), which attracts even more macrophages (AlAshqar etal., 2021). In women without fibroids, natural killers (NK) cells are scarcely scattered in the stroma of the functional layer of the myometrium during the proliferative phase; only during ovulation does their number dramatically increase until a couple days before menstruation (Agostinis etal., 2019). Low levels of interleukin (IL)-11 are associated with decreased numbers of NK cells, and IL-11 is decreased during the window of implantation in patients with fibroids (Ikhena and Bulun, 2018). This reduction in IL-11 may therefore result in implantation failure in these women, however, further research is needed to assess this association. A summary of the above two processes is depicted in Fig. 2. Local endometrial inflammatory changes may contribute to the observed structural changes in patients with fibroids, like glandular atrophy, ulceration, and elongated glands, resulting in implantation failure, early pregnancy loss, and infertility (Mukhopadhaya etal., 2007; Somigliana etal., 2007; Zepiridis etal., 2016; Roșu etal., 2021). Whether or not a myomectomy procedure could subsequently re-establish the normal endometrial inflammatory state and allow the repair of the structural endometrial changes still needs to be clarified.
Two possible inflammatory routes how fibroids could negatively influence implantation and cause infertility. TGF-β, transforming growth factor β.
Autophagy comprises a collection of processes that facilitate cells to recycle and digest harmful or surplus contents in their cytoplasm, such as damaged organelles, proteins, macromolecules, or microorganisms (Parzych and Klionsky, 2014; Andaloussi etal., 2017). Recent evidence shows that basal autophagy is essential to maintain endometrial homeostasis and mediate the menstrual cycle and implantation (Popli etal., 2022). Additionally, invitro and invivo studies in mice have shown that autophagy is crucial to establish the process of decidualization, which is indispensable for successful implantation (Popli etal., 2022). Disturbed levels of autophagy can lead to endometrial pathologies like fibroids, in which decreased expression of ATG4D is shown to promote fibroid growth (Andaloussi etal., 2017; Popli etal., 2022). Additionally, high expression of fibroblast activation protein (FAP) is associated with fibroids. Uterine fibroblast proliferation is stimulated by oestrogen, as this induces expression of FAP and extracellular matrix components (fibronectin, laminin, collagen I), and secretion of growth factors (TGF-β and IGF-1) (Luo etal., 2014). Whether or not these alterations which are involved in fibroid development and growth, are simultaneously involved in impaired autophagy in the endometrium, leading to implantation failure, is yet to be elucidated. To conclude, more fundamental research is needed to verify whether fibroids alter autophagy in the endometrium and whether this contributes to fibroid related infertility.
Hypothesis 6: molecular changes in the endometrium
In our sixth hypothesis, we describe the influence of fibroids on different molecular pathways that could result in a detrimental environment for implantation, as illustrated in Fig. 3. Homeobox genes, specifically homeobox A10 (HOXA10) and homeobox A11 (HOXA11), are transcription factors in the endometrium which are important during implantation (Ikhena and Bulun, 2018; Roșu etal., 2021). In women with submucosal fibroids, HOXA10 and HOXA11 are significantly decreased in the endometrium, especially in the endometrium overlying the submucosal fibroid (Rackow and Taylor, 2010; Cakmak and Taylor, 2011). Also, in infertile women with intramural fibroids (without cavity distortion), a lower expression of both HOXA10 and the cell adhesion molecule E-cadherin was found during the window of implantation compared to that in fertile women without fibroids (Makker etal., 2017). Similarly, Unlu etal. (2016) found that in infertile women with intramural fibroids, there is reduced expression of HOXA10 and HOXA11, which significantly increases after myomectomy. Conversely, this effect was not seen in women with submucosal fibroids (Unlu etal., 2016). Bone morphogenetic protein type II (BMP2) regulates HOXA10 expression, and thus BMP2 increases endometrial receptivity (Ikhena and Bulun, 2018). However, fibroids produce high amounts of TGF-β3, which downregulates the BMP-receptor, resulting in impaired decidualization and implantation (Doherty and Taylor, 2015b). Decreased levels of glycodelin and IL-10 have also been described in uterine flushings of women with fibroids, and since these are also involved in the implantation process, the changes could alter this process (Donnez and Dolmans, 2020; Roșu etal., 2021). Additionally, as described above, IL-11 is involved in the regulation of trophoblast invasion and in the presence of fibroids, IL-11 levels are reduced (Donnez and Dolmans, 2020). Furthermore, in uterine flushings and in serum of women with fibroids, tumour necrosis factor (TNF)-α level was reported to be increased. As TNF-α is involved in preimplantation development of the embryo, immunological pregnancy loss and regulation of trophoblast invasion, changes in its expression could result in implantation failure and infertility (Roșu etal., 2021). These findings suggest that fibroids induce multiple changes in molecular pathways involved in implantation, however, further studies are required to outline all of the affected pathways in patients through which fibroids may cause implantation failure.
A summary of possible molecular routes how fibroids could negatively influence implantation and cause infertility. BMP2, bone morphogenetic protein type II; HOXA10/11, homeobox A10/11; IL-10/11, interleukin-10/11; TGF-β3/R, transforming growth factor β3/receptor; TNF-α, tumour necrosis factor-α.
Hypothesis 7: aberrant angiogenesis and impaired endometrial blood supply
A recent published review underlines how aberrant endometrial angiogenesis and disturbed vessel maturation caused by fibroids may result in both abnormal uterine bleeding and infertility (Don etal., 2023a; Middelkoop etal., 2023). As mentioned above, alterations in the BMP pathway can negatively influence endometrial decidual differentiation and may result in implantation failure (Sinclair etal., 2011; Doherty and Taylor, 2015a). BMP activates the downstream SMAD proteins and regulates the TGF-β superfamily, which are involved in several angiogenic activities like endothelial cell differentiation and vessel maturation (Sinclair etal., 2011; Richards etal., 2017). Two studies found decreased expression of BMP and its receptors in the endometrium of women with fibroids (Sinclair etal., 2011; Doherty and Taylor, 2015a). Another study showed that in patients with heavy menstrual bleeding, BMP7 was increased, although some patients without fibroids were included in this study (Richards etal., 2017). As BMP7 is part of the BMP family and also plays a role in endometrial differentiation, this could have an effect on embryo implantation as well as tissue integrity maintenance during the receptivity window (Middelkoop etal., 2023). Endometrial nitric oxide synthase (eNOS), the predominant isoform of nitric oxide in the human endometrium, is also an important angiogenic factor involved in vasodilatation and permeability of endothelial cells and it is induced by vascular endothelial growth factor (VEGF), a major initiator of angiogenesis (Griffioen and Molema, 2000; Wong etal., 2012). In infertile women with fibroids higher levels of eNOS were found compared to normal controls; while eNOS stimulates myometrial quiescence during pregnancy, overexpression can induce cellular apoptosis and/or impair endometrial and myometrial functions (Novin etal., 2018).
Fibroids, especially those close to the uterine cavity, can restrict endometrial blood flow (Donnez and Dolmans, 2020). Several studies have shown that good endometrial blood flow on the day of the embryo transfer during assisted reproductive treatment is associated with high rates of pregnancy, supporting the idea that alterations in endometrial blood flow can affect blastocyst implantation (Mercé etal., 2008; Kim etal., 2014). One study found that in women with fibroids and a lower uterine artery pulsatility index and resistance index, conception rates were significantly lower, suggesting that inadequate blood supply of the endometrium due to fibroids can impair implantation (Ng and Ho, 2002). These findings indicate that fibroids do alter angiogenic factors and blood flow in the endometrium, however, many of the factors have been studied only in single studies and more studies are needed to verify these outcomes. This is an essential first step before it is possible for future research to identify key targets for possible therapy or evaluate whether myomectomy can restore normal endometrial angiogenesis.
Increased risk of miscarriage
As discussed above, fibroids can negatively influence embryo implantation. Studies have shown that patients with fibroids can also experience a number of problems during pregnancy, including miscarriage or early pregnancy loss (Khaund and Lumsden, 2008; Klatsky etal., 2008). A number of studies have shown higher miscarriage rates in the first and second trimester in women with fibroids (Benson etal., 2001; Salvador etal., 2002; Klatsky etal., 2008; Majeed etal., 2011; Saravelos etal., 2011). The exact miscarriage rate in women with fibroids varies widely between these studies, and this could be due to heterogeneous inclusion criteria regarding fibroid characteristics, notably size, number, and location. Benson etal. (2001) even found a nearly 2-fold increase in miscarriage rate in women with fibroids, and additionally the miscarriage rate in women with multiple fibroids was significantly higher compared to women with a single fibroid (Benson etal., 2001). While Benson etal. (2001) did not find an effect of fibroid location, it is believed that submucosal fibroids in close proximity to the placenta are likely to be associated with first trimester blood loss and also miscarriage (Khaund and Lumsden, 2008). We believe this could be because submucosal fibroids seem to affect junctional zone peristalsis and molecular changes in the endometrium, as we postulated in our hypotheses. While multiple cohort studies about the miscarriage rate after IVF/ICSI in women with fibroids showed no significant difference to that of women without fibroids, a trend towards a higher miscarriage rate was notable (Vimercati etal., 2007; Klatsky etal., 2008; Bozdag etal., 2009). This could be due to the fact that these studies were underpowered; moreover one control group of women without fibroids but receiving IVF/ICSI was already at a higher risk of miscarriage compared to patients not receiving IVF/ICSI (Klatsky etal., 2008). Additionally, these studies only included patients with a single fibroid, while Gianaroli etal. (2005) found a significantly higher miscarriage rate in women with one or multiple fibroids after IVF compared to patients without fibroids, which underlines the effect of multiple fibroids (Benson etal., 2001; Gianaroli etal., 2005). Conversely, a recent meta-analysis of 1394 pregnant women with fibroids versus >20 000 pregnant women without fibroids, and excluding women with recurrent pregnancy loss or infertility care, found no association between fibroids and the risk of miscarriage (Coutinho etal., 2022). Therefore, the current data are conflicting and do not answer the question of whether there is or is no association between fibroids and miscarriage. Future studies examining this issue should therefore focus on a large cohort of the general obstetric population in which patients with and without fibroids are compared. Preferably, in such a study the fibroids should be differentiated according to their characteristics (size, number, location, and vascularization) and there should be correction for potential confounders.
Summary
Infertility in patients with fibroids may have various causes. We have postulated seven hypotheses demonstrating mechanisms by which fibroids could cause infertility. The first states that fibroids can cause pelvic pain, dyspareunia, and prolonged and heavy menstrual bleeding, which can disturb sexual arousal and frequency of intercourse, resulting in a reduced probability of conception. The second and third hypotheses state that fibroids could negatively influence oocyte and sperm transport by disturbing myometrial peristalsis of the junctional zone, and/or by mechanical compression on the interstitial part of the fallopian tubes or deformation of uterine cavity. Finally, fibroids could cause a detrimental environment for implantation in five different ways: again by disturbing myometrial peristalsis of the junctional zone, and additionally by altering the vagino-uterine microbiome, affecting the levels of inflammation and autophagy, stimulating molecular changes in the endometrium, and/or disturbing angiogenesis and the endometrial blood supply. Table 2 shows the future perspectives for the seven hypotheses, as we note the unanswered questions. It is essential to remember that not all fibroids cause symptoms, and the association of infertility and fibroids still needs more research to expose its specific relationship, especially keeping in mind that the effect of fibroids can be dependent on their location, number, vascularization, and molecular influence. We advocate for systematic myometrial assessment during ultrasounds, not only when patients present with gynaecologic complaints indicating fibroids, but also when presenting with infertility. Moreover, fibroid screening is not incorporated in routine ultrasonic checks during pregnancy and therefore is easily missed. To encourage further research about fibroids, it is essential to integrate systematic myometrial assessment, including standard registration of fibroid characteristics (number, size, FIGO location, and vascularization) before, during, and after pregnancy, particularly in case of miscarriages, malpresentation, or premature delivery. This could provide more insight into the disease prevalence and severity, and help in developing research investigating the effect of fibroids on fertility and reproductive outcomes.
Summary of questions for future research of the seven postulated hypotheses.
| Hypothesis | Future perspectives |
|---|---|
| 1. Sexual dysfunction | Could fibroid treatment like myomectomy reduce sexual dysfunction due dyspareunia and vaginal blood loss and subsequently improve frequency of conception focused intercourse? |
| 2. Physical compression | What is the effect of mild distortion by fibroids of the uterine cavity on fertility? |
| Does myomectomy of (large) intramural and/or subserosal fibroids improve reproductive outcomes? | |
| 3. Disturbed junctional zone peristalsis | Could fibroid treatment like myomectomy restore normal junctional zone peristalsis, and specifically, restore the frequency, direction, and coordination of peristalsis? |
| And, if normal junctional zone peristalsis is restored in patients with fibroids, does this improve reproductive outcomes? | |
| 4. Changes in vagino-uterine microbiome | What is the exact influence of fibroids on the vagino-uterine microbiome? |
| What is actually a healthy microbial state of the uterus? And does modulation of this microbiome improve reproductive outcomes? | |
| 5. Changes in inflammation and autophagy | What are all of the affected inflammatory pathways in the endometrium of patients with fibroids? An overview is missing. |
| Could fibroid treatment like myomectomy reduce the endometrial inflammatory state? And does this change improve reproductive outcomes? | |
| Do fibroids influence autophagy in the endometrium? And is this influence related to implantation failure? | |
| 6. Molecular changes | What are all the affected molecular pathways in the endometrium of patients with fibroids? An overview is missing. |
| Could fibroid treatment like myomectomy restore molecular pathways in the endometrium to normality? And does this correction improve reproductive outcomes? | |
| 7. Aberrant angiogenesis | Could it be verified whether the most important angiogenic factors, like VEGF, eNOS, and BMP are altered in patients with fibroids? |
| Can we influence angiogenesis in women with symptomatic fibroids and does this result in better reproductive outcomes? | |
| Could fibroid treatment like myomectomy restore normal endometrial angiogenesis? And does this correction improve reproductive outcomes? |
| Hypothesis | Future perspectives |
|---|---|
| 1. Sexual dysfunction | Could fibroid treatment like myomectomy reduce sexual dysfunction due dyspareunia and vaginal blood loss and subsequently improve frequency of conception focused intercourse? |
| 2. Physical compression | What is the effect of mild distortion by fibroids of the uterine cavity on fertility? |
| Does myomectomy of (large) intramural and/or subserosal fibroids improve reproductive outcomes? | |
| 3. Disturbed junctional zone peristalsis | Could fibroid treatment like myomectomy restore normal junctional zone peristalsis, and specifically, restore the frequency, direction, and coordination of peristalsis? |
| And, if normal junctional zone peristalsis is restored in patients with fibroids, does this improve reproductive outcomes? | |
| 4. Changes in vagino-uterine microbiome | What is the exact influence of fibroids on the vagino-uterine microbiome? |
| What is actually a healthy microbial state of the uterus? And does modulation of this microbiome improve reproductive outcomes? | |
| 5. Changes in inflammation and autophagy | What are all of the affected inflammatory pathways in the endometrium of patients with fibroids? An overview is missing. |
| Could fibroid treatment like myomectomy reduce the endometrial inflammatory state? And does this change improve reproductive outcomes? | |
| Do fibroids influence autophagy in the endometrium? And is this influence related to implantation failure? | |
| 6. Molecular changes | What are all the affected molecular pathways in the endometrium of patients with fibroids? An overview is missing. |
| Could fibroid treatment like myomectomy restore molecular pathways in the endometrium to normality? And does this correction improve reproductive outcomes? | |
| 7. Aberrant angiogenesis | Could it be verified whether the most important angiogenic factors, like VEGF, eNOS, and BMP are altered in patients with fibroids? |
| Can we influence angiogenesis in women with symptomatic fibroids and does this result in better reproductive outcomes? | |
| Could fibroid treatment like myomectomy restore normal endometrial angiogenesis? And does this correction improve reproductive outcomes? |
Summary of questions for future research of the seven postulated hypotheses.
| Hypothesis | Future perspectives |
|---|---|
| 1. Sexual dysfunction | Could fibroid treatment like myomectomy reduce sexual dysfunction due dyspareunia and vaginal blood loss and subsequently improve frequency of conception focused intercourse? |
| 2. Physical compression | What is the effect of mild distortion by fibroids of the uterine cavity on fertility? |
| Does myomectomy of (large) intramural and/or subserosal fibroids improve reproductive outcomes? | |
| 3. Disturbed junctional zone peristalsis | Could fibroid treatment like myomectomy restore normal junctional zone peristalsis, and specifically, restore the frequency, direction, and coordination of peristalsis? |
| And, if normal junctional zone peristalsis is restored in patients with fibroids, does this improve reproductive outcomes? | |
| 4. Changes in vagino-uterine microbiome | What is the exact influence of fibroids on the vagino-uterine microbiome? |
| What is actually a healthy microbial state of the uterus? And does modulation of this microbiome improve reproductive outcomes? | |
| 5. Changes in inflammation and autophagy | What are all of the affected inflammatory pathways in the endometrium of patients with fibroids? An overview is missing. |
| Could fibroid treatment like myomectomy reduce the endometrial inflammatory state? And does this change improve reproductive outcomes? | |
| Do fibroids influence autophagy in the endometrium? And is this influence related to implantation failure? | |
| 6. Molecular changes | What are all the affected molecular pathways in the endometrium of patients with fibroids? An overview is missing. |
| Could fibroid treatment like myomectomy restore molecular pathways in the endometrium to normality? And does this correction improve reproductive outcomes? | |
| 7. Aberrant angiogenesis | Could it be verified whether the most important angiogenic factors, like VEGF, eNOS, and BMP are altered in patients with fibroids? |
| Can we influence angiogenesis in women with symptomatic fibroids and does this result in better reproductive outcomes? | |
| Could fibroid treatment like myomectomy restore normal endometrial angiogenesis? And does this correction improve reproductive outcomes? |
| Hypothesis | Future perspectives |
|---|---|
| 1. Sexual dysfunction | Could fibroid treatment like myomectomy reduce sexual dysfunction due dyspareunia and vaginal blood loss and subsequently improve frequency of conception focused intercourse? |
| 2. Physical compression | What is the effect of mild distortion by fibroids of the uterine cavity on fertility? |
| Does myomectomy of (large) intramural and/or subserosal fibroids improve reproductive outcomes? | |
| 3. Disturbed junctional zone peristalsis | Could fibroid treatment like myomectomy restore normal junctional zone peristalsis, and specifically, restore the frequency, direction, and coordination of peristalsis? |
| And, if normal junctional zone peristalsis is restored in patients with fibroids, does this improve reproductive outcomes? | |
| 4. Changes in vagino-uterine microbiome | What is the exact influence of fibroids on the vagino-uterine microbiome? |
| What is actually a healthy microbial state of the uterus? And does modulation of this microbiome improve reproductive outcomes? | |
| 5. Changes in inflammation and autophagy | What are all of the affected inflammatory pathways in the endometrium of patients with fibroids? An overview is missing. |
| Could fibroid treatment like myomectomy reduce the endometrial inflammatory state? And does this change improve reproductive outcomes? | |
| Do fibroids influence autophagy in the endometrium? And is this influence related to implantation failure? | |
| 6. Molecular changes | What are all the affected molecular pathways in the endometrium of patients with fibroids? An overview is missing. |
| Could fibroid treatment like myomectomy restore molecular pathways in the endometrium to normality? And does this correction improve reproductive outcomes? | |
| 7. Aberrant angiogenesis | Could it be verified whether the most important angiogenic factors, like VEGF, eNOS, and BMP are altered in patients with fibroids? |
| Can we influence angiogenesis in women with symptomatic fibroids and does this result in better reproductive outcomes? | |
| Could fibroid treatment like myomectomy restore normal endometrial angiogenesis? And does this correction improve reproductive outcomes? |
Conclusion
Fibroids are the most common benign tumours and not all patients with fibroids suffer from infertility while not all infertile patients have fibroids. However, growing numbers of studies underline the possible negative effect of fibroids on fertility and reproductive outcomes. Insight in the underlying mechanisms provides options for the development of targeted therapy and to increase the effect of fibroid surgery due to improved patient selection of who will benefit from a fertility sparing myomectomy. Structural and routinely assessment of fibroids, sizes, localization, and vascularization in women who want to become pregnant and in women with infertility before possible surgery is needed to develop prediction models and to gain insight in the underlying mechanisms of fibroid related infertility.
Authors’ roles
All authors approve the publication of this version. They all participated in the conception and drafting of the manuscript, including the interpretation of data from the literature.
Funding
No external funding was either sought of obtained for this study.
Conflict of interest
The authors declare that they have no competing interests.
