Validity of the association between periodontitis and female infertility conditions: a concise review

in Reproduction

Correspondence should be addressed to V Machado; Email: vmachado@egasmoniz.edu.pt

Hormones and inflammatory mechanisms are implicated with female reproductive function, including follicle maturation, ovulation, embryo implantation, and pregnancy. Periodontitis is a chronic inflammatory disease due to a polymicrobial disruption of the homeostasis and may be considered as a potential risk factor that affect female fertility. The role of periodontitis is becoming meaningful, with significant associations with polycystic ovary syndrome, endometriosis and bacterial vaginosis. Further, periodontitis is linked with known risk factors towards female infertility, such as age, obesity, and chronic kidney disease. This review aims to summarize the available evidence on the association between periodontitis and female infertility-associated conditions, and to discuss warranting steps in future research.

Abstract

Hormones and inflammatory mechanisms are implicated with female reproductive function, including follicle maturation, ovulation, embryo implantation, and pregnancy. Periodontitis is a chronic inflammatory disease due to a polymicrobial disruption of the homeostasis and may be considered as a potential risk factor that affect female fertility. The role of periodontitis is becoming meaningful, with significant associations with polycystic ovary syndrome, endometriosis and bacterial vaginosis. Further, periodontitis is linked with known risk factors towards female infertility, such as age, obesity, and chronic kidney disease. This review aims to summarize the available evidence on the association between periodontitis and female infertility-associated conditions, and to discuss warranting steps in future research.

Introduction

According to the International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO), infertility is defined as a condition where the reproductive system is incapable to secure a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse (Adamson et al. 2018). Moreover, a healthy woman at the time of conception is more likely to have a successful pregnancy and to deliver a healthy child (Stephenson et al. 2018).

In 2010, 48.5 million couples worldwide were estimated to be infertile (Mascarenhas et al. 2012), yet nowadays, infertility is anticipated to be increasing, affecting more than 186 million people (8–12% of reproductive-aged couples), and fluctuates according to the level of development of the country. Furthermore, 14.3 and 25% of the couples are affected in the Western world and in developing countries, respectively (Vander Borght & Wyns 2018).

The consequences of infertility may hamper population growth (Vander Borght & Wyns 2018) and could negatively impact on the marital relationship (Onat & Beji 2012), sexual satisfaction (Ramezanzadeh et al. 2006) and psychosocial well-being (Cousineau & Domar 2007). Besides, couples can also experience anger, sadness, anxiety, depression, guilt, shame, a feeling of loss of control and incompleteness, dysfunction coping strategies, altered self-esteem, social isolation and increased marital distress (Cousineau & Domar 2007, Schmidt 2009, Omu & Omu 2010, Péloquin et al. 2013).

Infertility is a multi-factorial and multi-faceted clinical condition for both members of a couple and can be categorized as primary or secondary. In females, primary infertility represents a woman that has never been diagnosed with a clinical pregnancy and meets the infertility criteria. Secondary female infertility refers to the inability to become pregnant or to carry a baby to term after a previous successful pregnancy (Zegers-Hochschild et al. 2017). Aging is a key negative factor for women fertility (Hart 2016), though other risk factors comprising lifestyle and environmental factors have been gaining some relevance (Vander Borght & Wyns 2018).

Among the relevant factors for female infertility, oral health is key for maintaining and allowing vital quotidian functions. A recent review highlighted the urgent need to address oral diseases as a global health priority (Peres et al. 2019). In particular, oral diseases share common risk factors with several conditions and have recognized impactfulness, such as pain, reduced quality of life, family interference, loss of work productivity and required high costs for treatment (Peres et al. 2019). One of the most important group of oral conditions is periodontal disease which affect the periodontium.

The periodontium encompasses mineralized (alveolar bone proper and root cementum) and soft connective tissues (periodontal ligament and gingiva) (Mark Bartold & Van Dyke 2013). Periodontal health is defined as an absence or very significant reduction of clinical signs of periodontal inflammation (Lang & Bartold 2018). Periodontal disease initially presents as gingivitis, a reversible inflammation of the periodontium’s soft tissues, with gingival bleeding and swelling. If progresses, gingivitis might evolve to periodontitis (PD), which is a progressive destruction of the periodontium.

The pathogenesis of PD relies on a complex interdependent relationship between a dysbiotic biofilm and host response, and if untreated results in the loss of periodontal attachment (Meyle & Chapple 2015, Roberts & Darveau 2015, Tonetti et al. 2018). The symptoms start with reversible gum inflammation (Bartold & Van Dyke 2017, Murakami et al. 2018, Trombelli et al. 2018) to an exacerbated and uncontrolled inflammatory response from the innate and adaptive immune systems (Ebersole et al. 2013, 2017). Ahead, periodontal tissues are progressively destroyed in an irreversible fashion, causing tooth mobility and its loss (Darveau 2010, Tonetti et al. 2015, 2018, Kinane et al. 2017) (Fig. 1).

Figure 1
Figure 1

Periodontal health and immune response in periodontitis. Schematics of healthy gingiva (A) and periodontitis (B). The oral microbiome is a complex form ecosystems and contribute to maintain health when the the interaction between host and pathogen is in equilibrium in the gingival sulcus and periodontal pocket site. In this healthy environment, the host have a protective response by the immunity system and commensal bacteria. The first line of the defense is the sentinel cells involving macrophages, dendritic cells and mast cells, securing for evidence of pathogen invaders (A). However, when the biofilm-host balance is lost, causing a dysbiosis and immune overreaction of the host to microbial presences. This imbalance depends on the variance of patient’s genetic, immune and biofilm profiles, and results in a heightened inflammatory state with increased levels of cytokines that leads to the local resorption of alveolar bone by osteoclast. These inflammatory cytokines activate macrophages, neutrophils, and fibroblasts to generate reactive oxygen species (ROS), which ultimately results in tissue damage.

Citation: Reproduction 160, 3; 10.1530/REP-20-0176

The systemic repercussions caused by PD are now well established, and occur when bacteria and their products pass through the gingival epithelial barrier, and then spread into the bloodstream causing infectious and inflammatory responses (Chan et al. 2017, Albandar et al. 2018) (Fig. 1).

The main cause of PD, that is biofilm accumulation, results from negligent oral hygiene habits. Smoking habits are a key risk factor for periodontal disease (Jansson & Lavstedt 2002, Johannsen et al. 2014, Buduneli & Scott 2018), though due to the common inflammatory pathways, PD is strongly associated with other clinical conditions including diabetes mellitus (DM), metabolic syndrome, high blood pressure, rheumatoid arthritis, cardiovascular disease, stress, among others (Preshaw et al. 2012, D’Aiuto et al. 2013, Nibali et al. 2013, Tonetti & Van Dyke 2013, Jepsen et al. 2018, Polak & Shapira 2018, Botelho et al. 2020a, Hussain et al. 2020, Machado et al. 2020a,b). Also, PD has significant impact on the quality of life yet it can be recovered after periodontal treatment (Buset et al. 2016, Botelho et al. 2020b).

Very recently, two systematic reviews have comprehensively linked PD with male infertility and erectile dysfunction (Práger et al. 2017, Kellesarian et al. 2018a,b). PD was found highly prevalent among infertile men and severe PD was associated with higher deterioration of sperm quality (Zhu et al. 2010). Moreover, men with PD are at increased risk of developing erectile dysfunction, oligozoospermia and concomitant asthenozoospermia than periodontally healthy individuals (Kellesarian et al. 2017, 2018b, Práger et al. 2017). Drawing parallels with male infertility, the association between PD and female infertility-related conditions is important to discuss, and a comprehensive revision would be of great interest.

Notwithstanding, an important question that still remains is whether female fertility may influence the onset and progression of PD and if periodontal infection and consequent inflammatory burden may influence female infertility (Kassebaum et al. 2014). Thus, this review aims to summarize the available lines of evidence on the relation between PD and female infertility-associated conditions, as well the possible pathophysiological pathways.

Female infertility-related conditions and Periodontitis

PD produces a local (saliva and gingival crevicular fluid (GCF)) and systemic inflammatory response (Kjeldsen et al. 1993, Cekici et al. 2014, Barros et al. 2016, Stadler et al. 2016, Cardoso et al. 2018, Polak & Shapira 2018). This response triggers the production of cytokines, resulting in tissue destruction, immunological reactions and indirectly influences other systems (Garlet 2010, Gonzales 2015). Comprehensively, the association between the periodontal status and the female reproductive system seems difficult to follow. Notwithstanding, the secondary role of PD in other diseases might contribute to explain how it can compromise female fertility. PD has been linked to polycystic ovary syndrome (PCOS), endometriosis (EM), obesity, bacterial vaginosis (BV), chronic kidney disease (CKD), and age, which in turn are risk factors affecting the spontaneous probability of conception.

Polycystic ovary syndrome

PCOS is a genetically complex endocrine, reproductive and metabolic disorder, affecting 5–15% of women in reproductive age worldwide (Azziz 2016). It is characterized by hyperandrogenism with distorted gonadotropin secretory activity, hyperinsulinemia, hypothalamic-pituitary-ovarian (HPO) axis dysfunction, ovulatory and menstrual dysfunction, and the presence of polycystic ovaries (Hull 1987, Norman et al. 2007, Dumesic et al. 2015, McCartney and Marshall 2016, Lambertini et al. 2017, Macut et al. 2017, Greenwood & Huddleston 2019). Moreover, PCOS appears to be associated with increased metabolic syndrome (MetS), including type 2 DM and insulin resistance (Dunaif 1997, Macut et al. 2017, Greenwood & Huddleston 2019), dyslipidemia (Caserta et al. 2014, Mirza et al. 2014), cardiovascular disease (Osibogun et al. 2019), and nonalcoholic fatty liver disease (Paschou et al. 2020). Despite many theories, the etiology of this syndrome remains poorly understood.

Growing evidence supports a relationship between PCOS and chronic infections through the increase of oxidative stress (OS), inflammatory burden, adhesion molecules and leukocyte response (Pawelczak et al. 2014, Porwal et al. 2014, Dos Santos et al. 2015, Victor et al. 2016, Saglam et al. 2017a) (Fig. 2). Accordingly, the relationship between PCOS and PD was initially based on its common association with MetS (Dursun et al. 2011). In the latter, PCOS women had higher levels of periodontal inflammation and destruction than non-PCOS females, with marked hallmarks of OS and glycemic dysregulation on GCF (Dursun et al. 2011). Indeed, DM and OS are well-established risk factors towards PD (Preshaw et al. 2012, Chen et al. 2019) and might be significant mediating factors in the PCOS-PD way. Additionally, MetS may play a key role by inducing systemic inflammation and insulin resistance (Nibali et al. 2013).

Figure 2
Figure 2

Polycystic ovary syndrome (PCOS) pathophysiology and the role of periodontitis. In PCOS, luteinizing hormone (LH) is key for hyperandrogenemia, and gonadotropin-releasing hormone (GnRH) pulse generator is resistant to the negative feedback effects of progesterone. Therefore, high GnRH pulse frequencies favor the production of LH and limit the production of FSH, which promotes androgen production and interfere with normal follicular development. Still, PCOS is associated with insulin resistance, abnormal ovarian function and adrenal steroidogenesis, which contributes to hyperandrogenemia and female infertility. Further, PCOS women have higher serum levels of IL-6, TNF-α, C-reactive protein (CRP), and white blood cell count. The PCOS-PD association is proposed to be grounded with common systemic inflammation, oxidative stress (OS) and insulin resistance. Further, higher levels of sex steroid hormones in PCOS patients negatively impact periodontal health.

Citation: Reproduction 160, 3; 10.1530/REP-20-0176

Later, the cascade of proinflammatory events was proposed as a possible interplay between PD and PCOS (Özçaka et al. 2012, 2013, Akcall et al. 2015, Akcalı et al. 2017, Kellesarian et al. 2017, Tong et al. 2019). Both diseases appear to act in a synergistic manner to increase the expression of proinflammatory cytokines (Knebel et al. 2008, Özçaka et al. 2013), and the severity of PD might also be associated with the aggravation of PCOS (Porwal et al. 2014).

Comprehensively, the possible mechanism linking PD and PCOS is rooted in the chronic subclinical inflammation of both diseases (Escobar-Morreale et al. 2011, Tong et al. 2019). In other words, a chronic subclinical inflammatory status elevates the concentrations of proinflammatory markers (such as C-Reactive Protein (CRP), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-17, and matrix metalloproteinase-9) (Özçaka et al. 2012, 2013, Akcali et al. 2013, Cekici et al. 2014) and potentiates an oxidative stress environment (through local oxidant status-like myeloperoxidase and nitric oxide) (Dursun et al. 2011, Akcalı et al. 2017). Consequently, the subclinical inflammation due to PCOS may worsen periodontal destruction, and in the opposite way, subclinical inflammation due to PD through direct invasion of periodontal microbiota might underpin the pathogenesis of PCOS. Additionally, PD management has been implicated in insulin levels control as periodontal treatment alleviated high glycemic levels (D’Aiuto et al. 2018), and therefore, uncontrolled PD may indirectly impact on PCOS clinical status.

Still, PCOS is characterized by excessive levels of sex steroid hormones that have a negative impact on PD (Dursun et al. 2011, Porwal et al. 2014, Rahiminejad et al. 2015, Hameed & Ahmend 2017, Najah et al. 2017, Saglam et al. 2017, Işık et al. 2020) due to the presence of androgens, estrogen and progesterone receptors in the gingival tissues (Parkar et al. 1996, Gornstein et al. 1999, Kawahara & Shimazu 2003). It seems that estrogen and progesterone changes modify the gingival tissues, leading to a higher vascular permeability and decreased keratinization of the gingival epithelium (Parkar et al. 1996, Gornstein et al. 1999, Kawahara & Shimazu 2003).

Although several studies had shed light on the association between PCOS and PD, the relationship between PD and infertility in women with PCOS still remains to be fully elucidated (Kellesarian et al. 2017, Tong et al. 2019). Despite the lack of longer prospective studies, a recent investigation on women with both PCOS and PD has assessed the impact of PD treatment with standard Myo-inositol (MI) on systemic conditions (Deepti et al. 2017). The results of this randomised clinical trial showed that treating PD with MI reduced systemic inflammation and improved metabolic parameters in comparison to a therapy only with MI (Deepti et al. 2017). However, this study did not consider how much PCOS women were infertile at the baseline and, therefore, was not able to retrieve if resolving PD could have influenced the fertility rate.

Nevertheless, the influence of PCOS-PD link on female infertility is reasonable and might be grounded in (1) PCOS is associated with hyperandrogenism, hyperinsulinemia, and increased OS levels and which in turn have a negative impact on periodontal inflammation and destruction; (2) PD triggers proinflammatory and OS levels that dysregulate insulin resistance and negatively impact ovarian function.

Obesity

The adipose tissue is no longer seen as a simple stock of energy but a complex endocrine organ that produces many pro-inflammatory adipokines including hormones (such as adiponectin, leptin, and resistin) and pro-inflammatory cytokines (such as TNF-α, IL-6) (Kern et al. 2003). CRP serum levels are positively correlated with BMI and obesity (Maiorino et al. 2018, Pavela et al. 2018). Therefore, obesity is considered to be a chronic low-grade inflammatory state (Broughton & Moley 2017, Pavela et al. 2018, Sudhakar et al. 2018).

Obesity contributes to higher levels of insulin and consequently insulin resistance and appears to exacerbate the symptoms of PCOS (McCartney & Marshall 2016). Furthermore, obesity has a negative effect on female infertility by HPO axis (Broughton & Moley 2017, Slopien et al. 2019) and overproducing androgens (Rachoń & Teede 2010). These increased androgens are highly transformed in estrogen at the periphery due to excessive adipose tissue (Jungheim & Moley 2010). As a consequence, HPO axis is negatively feedbacked and affects gonadotropin secretion, resulting in menstrual irregularities, ovarian malfunction, and therefore, infertility states (Jungheim & Moley 2010, Rachoń & Teede 2010).

Similar to PCOS, obesity is also a risk factor for the onset and worsening of PD due to an excessive levels of sex steroid hormones and higher levels of systemic inflammation (Chaffee & Weston 2010, Keller et al. 2015, Broughton & Moley 2017, Martinez-Herrera et al. 2017, Khan et al. 2018). Obesity increases the risk for the colonization of red complex periodontal microorganisms, which in turn may further lead to the onset of periodontal inflammation (Suresh et al. 2017). A recent evidence-based study concluded that obese patients have 30% higher risk of having PD and patients with PD have an average difference of 2.74 kg/m2 on BMI mean than non-PD patients (Moura-Grec et al. 2014). Additionally, obese patients with PD have elevated TNF-α and IL-1B GCF levels compared to non-obese PD individuals and, therefore, a higher localized proinflammatory state (Akram et al. 2016) (Fig. 3).

Figure 3
Figure 3

Suggested hypothesis of periodontitis in obese patients may lead to ovarian dysfunction. Obesity and increased body mass index (BMI) in women stimulate multiple aspects of lipotoxicity, such as intracellular lipid accumulation, inflammatory responses, and oxidative stress (OS). Alter levels of adipokines, such as leptin, in the obese state can affect steroidogenesis and directly affect the developing embryo, and can alter the function of hypothalamic-pituitary-ovarian (HPO) axis. Further, obesity is related to higher circulating levels of insulin, which stimulus the ovarian production of androgen. These androgens are aromatized to estrogen at high rates in the periphery due to excess adipose tissue, leading to negative feedback on the HPO axis and affecting gonadotropin production. Furthermore, the excessive levels of sex steroid hormones are linked to PD, that in turn increases the periodontal inflammation and increases the OS. The sum of systemic inflammation induces inflammatory responses in other tissues including the ovary.

Citation: Reproduction 160, 3; 10.1530/REP-20-0176

An underlying common characteristic is the subclinical inflammation caused by obese states. As previously discussed in this review, a subclinical inflamed organism will contribute to worsen PD status (Suvan et al. 2011), and this might explain a possible mediation effect of PD on infertile conditions. Also, increased concentration of adipocytes may dysregulate immune responses (Falagas & Kompoti 2006) resulting in increased PD susceptibility and exaggerated host immune responses (Suvan et al. 2011).

However, the effect of obesity and PD simultaneously on female infertility is still yet to be fully clarified, and future studies should be performed to assess this possible association using multivariate logistic regression or even mediation analysis. Further, such association might be due to the increase of inflammatory cytokines and the inflammatory burden at the systemic level, which may hamper time to conception.

Endometriosis

EM is one of the most intriguing gynaecological diseases and remains a challenging condition to treat (Bullon & Navarro 2017). It is a chronic inflammatory and an oestrogen-dependent disorder (Giudice & Kao 2004, Burney & Giudice 2012, Hickey et al. 2014, Vercellini et al. 2014, Vallvé-Juanico et al. 2019), characterized by the presence of endometrial tissue outside the uterine cavity and mainly found attached to sites within the pelvic peritoneum (Giudice & Kao 2004, Greene et al. 2016). EM is estimated to affect 3–10% of women in the reproductive age group (Burney & Giudice 2012, Jiang et al. 2016) and also in 50–57% of infertile women (Kavoussi et al. 2009, Meuleman et al. 2009).

Infertility due to EM has been widely investigated and multiple pathways are on its cause, such as inflammatory processes, anatomical distortions, local endocrine alterations and OS (Van Langendonckt et al. 2002, Agarwal et al. 2005, 2012, Gupta et al. 2006, De Ziegler et al. 2010, Visioli & Hagen 2011, Scutiero et al. 2017, Li et al. 2019).

An association between EM and PD has been proposed via inflammatory and OS mechanisms, though only two cross-sectional studies could provide such information (Kavoussi et al. 2009, Thomas et al. 2018). In particular, women suffering from EM had a 57% higher risk of having diagnosed PD (Kavoussi et al. 2009). Also, moderate-to-severe PD was found to be higher among women with EM (Thomas et al. 2018).

Similarly to the PD-PCOS association, EM also promotes a subclinical inflammatory status, with the increase of cytokines and pro-inflammatory markers such as IL-1 beta, IL6, IL-8, TNF-α, that might complicate PD condition with higher periodontal tissue destruction (Kavoussi et al. 2009, Cekici et al. 2014). On the other hand, no studies have investigated whether PD might contribute towards the onset or progression of EM. Nevertheless, the rationale that PD might be a direct cause of intrauterine and chorionic tissues infection through bacterial spreading has been demonstrated (Gonçalves et al. 2002, Barak et al. 2007, Katz et al. 2009, Fardini et al. 2010, Hasegawa-Nakamura et al. 2011). Therefore, the hypothesis that PD might trigger a local immune reaction aside with the installed subclinical inflammatory state in EM is conceivable though it shall be investigated indeed.

Bacterial vaginosis

Vaginal microbiota usually changes throughout the menstrual cycle and it depends on vaginal hygiene, sexual activity, use of intimate products, hormonal contraception, and lubricant use (Gajer et al. 2012). Nevertheless, greater microbiota stability is associated with the estradiol peak at ovulation and progesterone rise in the midluteal phase (Gajer et al. 2012).

The dysbiosis of vaginal microbiota can result in BV. This condition is highly prevalent, affecting nearly 30% of women during the reproductive years (Allsworth & Peipert 2007) and it is described by a decrease in the commonly predominant Lactobacillus bacterial species, and an increase in anaerobic microbiome (Fredricks et al. 2005). Typically asymptomatic, the most common symptoms are discharge and odor (Klebanoff et al. 2006). Although not fully understand (Koumans et al. 2007), BV etiology is currently attributed to hormonal disturbances (Schwebke et al. 1996, Keane et al. 1997, Wilson et al. 2002). From the obstetric view, BV was associated with abortion (Ralph et al. 1999, van Oostrum et al. 2013, Isik et al. 2016, Carlsson et al. 2018, Haahr et al. 2019), implantation failure (Moreno et al. 2016), premature rupture of membranes and preterm birth (Yudin 2005). However, the link between BV and woman infertility is still not firmly established (van Oostrum et al. 2013, Haahr et al. 2019).

The female reproductive tract microbiota is not confined to the vaginal compartment but also in the uterus and endometrium (Swidsinski et al. 2013, Mitchell et al. 2015). Although endometrial microbiota has particular species and the bacterial load is significantly lower compared to vaginal area (Moreno et al. 2016, Bedaiwy 2019), vaginal microbiota appears to be an important source of ascending bacterial colonization (Swidsinski et al. 2013, Mitchell et al. 2015). BV was significantly related to tubal factor infertility among in vitro fertilization (IVF) patients (van Oostrum et al. 2013, Haahr et al. 2019). Despite these results highlighting the biological plausibility of bacterial ascending to the upper genital tract and cause subclinical infection and inflammation (Haahr et al. 2019), it is imperative to conduct more research before inferring a definitive causal relationship.

Some studies propose that the vaginal Lactobacillus genus produces lactic acid and short-chain fatty acids, and this homeostasis environment at pH ≤ 4.5 prevents the dysbiosis in healthy women (Skarin & Sylwan 1986, Yamamoto et al. 2009). The mechanism that occurs in the endometrium apparently does not have the same function because no correlation was found in the pH levels of endometrial fluid samples and endometrial microbiota (Moreno et al. 2016). Thus, it is important to assess how bacterial endometrial dysbiosis can trigger an inflammatory response, direct production of microbial metabolites and/or enzymes capable of inducing major cell pathways in the endometrial epithelium that affects the adhesion of the blastocyst to the epithelial endometrial wall (Dominguez et al. 2010, Cha et al. 2012).

While not equal, there are microbial similarities between the oral and vaginal environments in the presence of both PD and BV, respectively (Genco 1992, Cauci 2004). This relationship may show common pathophysiology mechanisms, for instance, deficient host response to infection (Genco 1992, Cauci 2004, Pretorius et al. 2007). Yet, PD and BV may be related through the similarity in the microbiota, in particular, Prevotella species and via Prevotella-mediated inflammation (Larsen 2017, Coyne et al. 2019). On the one hand, Prevotella stimulate the release of IL-1b, IL-6 and IL-23 by dendritic cells through Toll-like receptor 2 (TLR2), that mediates IL-17 production by T helper 17 (Th17) cells and in turn activate neutrophils (Larsen 2017). On the other hand, recently discovered peptide toxins secreted by Prevotella may play an important role, contributing to the widespread inflammation (Coyne et al. 2019). Consequently, Prevotella-mediated chronic inflammation leads to localized bone loss and tissue destruction in PD and endotoxemia via lipopolysaccharides. Local inflammation caused in both pathologies disseminates and may collapse systemic health (Larsen 2017).

Comprehensively, the hypotheses for contamination are the haematogenous spread or oral-genital direct transfer (Hill 1993, Edwards & Carne 1999, Harville et al. 2004); however, the relationship between these two pathologies remains poorly understood.

Hormonal dysregulation through chronic kidney disease

CKD is a general term for heterogeneous disorders affecting the kidney’s function and structures (Levey & Coresh 2012, Ricardo et al. 2015, Webster et al. 2017). The discrepancy in disease expression is connected to etiology, progression rate and severity (Levey & Coresh 2012). Nowadays, the definition of CKD is based on the presence of kidney damage or decreased kidney function for 3 months or more, irrespective of clinical diagnosis (National Kidney Foundation 2002, Vassalotti et al. 2007), and it has been found that CKD is developed through chronic inflammation in the renal tissues (Chopra & Sivaraman 2019). The burden of early stages of CKD is difficult to measure because CKD is found mostly before the onset of symptoms (Stevens & Levey 2009), and its 10–15% worldwide prevalence continues to rise, particularly among female patients (Dumanski & Ahmed 2019, Elhoseny et al. 2019).

Among its vital roles, kidney is responsible for sex hormones turnover and its dysfunction directly influences the HPO axis, resulting in progressive fertility loss (Finkelstein et al. 2007, Kuczera et al. 2015, Ahmed & Ramesh 2016, Palmer & Clegg 2017, Dumanski & Ahmed 2019). Regarding this loss of fertility secondary to CKD, luteinizing hormone (LH) and the follicle-stimulating hormone (FSH) increase but the levels of estrogen and progesterone dwindle, culminating in an abnormal hormonal cycle (Dumanski & Ahmed 2019). Furthermore, CKD female patients may also experience anovulation, reduced ovarian reserves, menstrual disorders, abnormal endometrium, reduced libido, and sexual dysfunction (Kuczera et al. 2015, Palmer & Clegg 2017, Dumanski & Ahmed 2019). As a consequence, the rates of spontaneous pregnancy in CKD patients decrease to 1–7%, rather than the physiological 65–94% (Hou 2007).

Remarkably, PD and CKD share a relationship based on bacterial spreading and cytokines dissemination from periodontal pockets through the bloodstream (Kshirsagar et al. 2007, Fisher et al. 2008, Chambrone et al. 2013, Ismail et al. 2015, Ricardo et al. 2015, Akram et al. 2016, Sharma et al. 2016, Almeida et al. 2017, Chopra & Sivaraman 2019, Deschamps-Lenhardt et al. 2019). Moreover, a recent systematic review concluded that patients with PD have a risk of 1.49–2.39 times higher to develop CKD, and this risk is directly related to the severity of periodontal destruction (Deschamps-Lenhardt et al. 2019). Notwithstanding, the PD treatment in CKD patients might partially recover kidney function through the reduction of the inflammatory state, in particular, improvement of glomerular filtration rate, creatinine levels, and endothelial function (Deschamps-Lenhardt et al. 2019).

Since CKD is one of the causes of female infertility, and PD is a well-established modifiable risk factor towards CKD, it is reasonable to consider that PD might worsen the women infertility secondary to CKD. Thus, it is important to consider periodontal screening in the multidisciplinary management of infertile women due to CKD, and future studies should investigate this possible association.

Age

Age is undoubtedly related to female fertility (Eijkemans et al. 2014), and the age at last birth (ALB) curve shows a gradual increase to 35 and 40 years old, and after that a rapidly increase in fertility woman’s loss (Leridon 1977, Spira 1988, Wood 1989, Eijkemans et al. 2014). In addition to the latter, age is also a risk factor for onset and development of PD (van der Velden 1984, Rajendran et al. 2013, Ebersole et al. 2016). We find relevant to emphasize that the age peak of PD onset is placed at 38 years old (Kassebaum et al. 2014) (ranging 25–45 years of age) which may overlap the time interval of the major likelihood of conception. Further, women using hormonal contraceptives have higher association with PD (Tilakaratne et al. 2000, Mullally et al. 2007, Prachi et al. 2019). Therefore, the risk timeline for PD onset matches the timeline for pregnancy, and this factor should not be forgotten.

Assisted reproductive technologies

Many couples continue to be diagnosed with idiopathic infertility or receive descriptive diagnoses that do not provide a cause for their defect (Cousineau and Domar 2007, Ray et al. 2012, Djurovic et al. 2018), and therefore hampering their infertility problem (Matzuk & Lamb 2008). Besides, whether the etiology is known or not, the advances in ART have overcome this problem, though ART is used to make it possible to conceive and is not a cure to the causes of infertility (Qin et al. 2017). However, females believe that fertility can be manipulated through ART (Te Velde et al. 2010), and many women believe erroneously that infertility care can address the fertility decline associated with age (Maheshwari et al. 2008).

ART range from a simple oral administration of drugs to stimulate ovulation, to more invasive techniques such as intrauterine insemination to install a processed sample of sperm into the uterine cavity directly, and IVF (Qin et al. 2017, Sullivan-Pyke et al. 2017)

Nowadays, 65 countries reported the use of ART during 2011, and Europe had the highest number of participants (41.6%), followed by Asia (33.9%) and North America (16%) (Adamson et al. 2018). Besides, evidence confirms that pregnancies resulting from IVF and/or intrauterine insemination have worse adverse perinatal outcomes than spontaneous conceptions, after controlling for patient factors (Hansen & Bower 2014). These outcomes include an risk of low birth weight, preterm birth, stillbirth, perinatal mortality, admission to a neonatal intensive care unit, antepartum haemorrhage, hypertensive disorders during pregnancy, gestational DM (Helmerhorst et al. 2004, Chung et al. 2006, McDonald et al. 2010, Pandey et al. 2012, Pinborg et al. 2013, Davies et al. 2017), and also congenital anomalies, imprinting disorders (Vermeiden & Bernardus 2013), autism spectrum disorders (Lehti et al. 2013) and neurodevelopmental disorders (Strömberg et al. 2002).

Despite the lower number of available literature, the stimulated ovulation via a hormonal overload in ART might turn women more prone to gingival inflammation (Haytaç et al. 2004, Vasudevan et al. 2013, Lalasa et al. 2014, Pavlatou 2014, Smadi 2017), warranting constant periodontal monitoring. Notwithstanding, PD may act as a modifiable risk factor limiting conception (Hart et al. 2012, Nwhator et al. 2014, Paju et al. 2017), and periodontal therapy on women prior to conception reduces significantly adverse birth outcomes (Jiang et al. 2013). Since PD is common among adults (Albandar & Rams 2002, Dye 2012, Petersen & Ogawa 2012) and there is a possible link between PD and pregnancy outcome (Wu et al. 2015, Abariga & Whitcomb 2016, Puertas et al. 2017) in a world where the infertility rates are high, highlighting its relation with infertility treatments becomes very relevant.

Overall, it should be noted that ART is not harmless (Zhu et al. 2006, Wisborg et al. 2010, Zollner & Dietl 2013, Morency et al. 2016, Iwashima et al. 2017). Therefore, it is crucial to investigate the real implication of PD in female infertility. Besides, if proven a negative impact of PD in women seeking ART, then periodontal consultations might be of importance for prenatal care, possibly increasing fertility success and avoiding complex and invasive treatment such as ART.

Conclusions

This comprehensive review has brought to light gaining evidence that links female infertility-related conditions as a modifiable risk factor towards PD. Further research is needed to clarify this causal relationship as well the mechanisms underlined. The current evidence does not support a role for PD in on female infertility-related conditions.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author contribution statement

V M, J B conceived and planned the review article. J L, M P, J B and V M have performed the review of the literature. J L, M P, J B, L P, J J M and V M drafted, provide critical feedback and helped shape the research and manuscript. J L and M P are equally first authors.

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