Infertility and inflammation: The potential connection to periodontal disease

"The consequences of periodontal disease on
systemic diseases has been documented extensively.
However, one area that is lacking research relates
to the effect that the disease has on successful
conception in infertile couples."

By Emily Brockette

Abstract: Periodontal disease is a chronic infection that has been linked to various systemic diseases such as cardiovascular problems and diabetes. Through the circulation of periodontal pathogens or their metabolic products, the infection is able to cause a wide spread inflammatory response in the body. The disease has been linked to adverse pregnancy outcomes like low birth weight and premature birth.

Periodontal disease has also been proposed to have a negative effect on a couples’ ability to conceive. According to the World Health Organization, roughly 8% to 10% of people are affected by infertility.¹ Of those, 8% to 10%, about half are related to male infertility.² Depending on the source of the couple’s infertility, there are various treatment options available, such as hormone therapy or in vitro fertilization (IVF). The purpose of this paper was to explore the literature and review the research about how periodontal disease can have an adverse effect on the fertility of both men and women.

Detrimental effects of periodontal disease

Within the last couple of decades, it has well been established that periodontal disease not only affects the oral cavity, it can also have detrimental effects on other systems in the body. Through well conducted studies, the chronic inflammatory disease has been shown to affect the cardiovascular and respiratory systems, as well as diabetes, and adverse pregnancy outcomes, such as premature births and low birth weight.³

In addition, it has been proposed that periodontal disease is linked to infertility and subfertility. Infertility has been defined as, “the inability of a couple to achieve conception after a year or more of regular, unprotected intercourse or the incapacity to carry a pregnancy to a live birth.”¹ While subfertility is used to describe any form of reduced fertility in couples.⁴ It is estimated by the World Health Organization that 8% to 10% of couples experience trouble with conception worldwide. A number of studies suggest a correlation between periodontal disease, “time to conception (TTC),” and infertility in both men and women. It is important to remember that, while these studies show such correlations, there is still work to be done to confirm and understand the mechanisms of how periodontal disease can affect conception.

Some of the pathogens seen in periodontal disease have been shown to circulate the entire body, negatively affecting other organs like the heart.⁴ The disease can also cause an increased number of inflammatory markers to circulate in the blood leading to systemic inflammation.⁵ It is hypothesized that periodontal disease affects the reproductive system similar to the way it affects the rest of the body.

Furthermore, an increase in inflammatory markers can interfere with conception in two ways: “a) preventing ovulation; b) preventing implementation of the embryo or not sustaining its implementation.”⁶ Another way periodontal pathogens can negatively affect conception is by the metabolic waste products produced by the bacteria, which can circulate through the body and are able to cross the placenta to affect the fetus. This fetal toxicity can result in preterm birth, low birth rates, and possibly prolong infertility.⁷

Much like periodontal disease, infertility is a multifactorial condition that is affected by a number of different variables such as: endometriosis, ovulation dysfunctions, cervical mucous disorders, fallopian tube conditions in woman, and sperm or testicular conditions in men.⁸ In many cases, it can be difficult for couples to identify the cause of their infertility. In the case of periodontal disease, the infection could be treated to increase their chances at conception. Haytac et al. (2004) suggests that the periodontal status of an individual can have an effect on the success of infertility treatments because it can lead to “bacteremia, endotoxemia, increased plasma levels of biologically active cytokines, and increase immunity to HSP [heat shock proteins], all of which have been suggested to be associated with reproductive failure” (p. 808).

Identifying bacteria associated with infertility

Numerous bacteria are associated with periodontal disease including: Porphyromonas ginigvalis, Tannerela forsynthia, Prevotella intermedia, Aggregatibacter actinimucentemcomitans, and Treponema denticola. These five are gram-negative bacteria that emerge as the biofilm develops and plaque accumulates.

A study performed by Paju et al. (2017), found that P. gingivalis had a role in TTC and could possibly be a marker for the association between periodontal disease and infertility. They found that “the detection of P. gingivalis in saliva and elevated concentrations of salivary antibodies against this periodontal species significantly increases the risk for unsuccessful conception among young women” (Paju et al., 2017, p. 4). They also found that women had an increased risk of not becoming pregnant if they had a high number of IgA antibodies against P. gingivalis as well as signs of periodontal disease. This was one of the first studies to demonstrate the association between a specific periodontal pathogen with conception.

As part of the Smile study, Hart et al.⁹ performed an observational assessment on the women that were treated for periodontal disease. This report was one of the first to show that periodontal disease was a modifiable risk factor that could be altered by patient and clinician intervention to help improve the chances of successful conception. These women were asked questions about their TTC and whether fertility treatments were needed to facilitate conception.

Hart et al. found that the average TTC was extended by two months in women who had periodontal disease. They were also able to confirm other negative associations affecting TTC such as age, smoking, and obesity. It was shown that periodontal disease has the same extended TTC and obesity.

From their observations, they proposed two hypotheses as to why periodontal disease is related to TTC. In the first, they theorized that non-Caucasian women are immunologically different than Caucasian women, which can make them more susceptible to periodontal disease and its systemic effects. They discussed the various single nucleotide polymorphisms (SNPs) like IL-1, IL-6, TNF-alpha, and others that have been shown in studies to have an association with periodontal disease. The frequency of these SNPs has been shown to differ between ethnicities—thus, leading the authors to believe that ethnic differences in the SNPs could contribute to an increase TTC in non-Caucasian women.

The second hypothesis focused on how the inflammatory response of the host plays a role in conception. Studies have shown that individuals with a hyper-responsive immune system have an increased likelihood of periodontal disease. This hyper-responsive immune system has also been linked to infertility and other reproductive problems.⁹

Infertility treatment options

Couples experiencing infertility have different treatment options including hormone therapy and assisted reproductive therapy (ART) including in vitro fertilization. These treatments depend on what is causing the couple’s infertility. If the woman is having trouble with ovulation, hormone therapies are utilized to stimulate the release of an egg. The most common drugs for this treatment is clomiphene citrate (CC), human menopausal gonadotropin (HMG), and follicle stimulating hormone (FSH).

Generally, a woman will use CC for six menstrual cycles before adding additional hormone protocols, such as FSH or HMG, or the couple will explore other treatment options, such as IVF.¹ It has been shown that the use of these drugs increases the serum levels of female sex hormones like estrogen and progesterone. It has been well noted that increased levels of these hormones have been linked to various periodontal pathologies due to the estrogen and progesterone receptors in the gingiva.¹

In a study performed by Haytac et al., they measured periodontal changes in women who were undergoing fertility treatment for ovulation induction (2004). They observed that women who had been taking the medications for more than three menstrual cycles had increased levels of gingival inflammation and bleeding compared to those not on the drug therapy. They found that the increased levels of estrogen and progesterone may have acted as a growth factor that promoted the growth of periodontal pathogens in the biofilm.¹

In another study, it was found that the increase in estrogen and progesterone had an effect on the growth of P. intermedia.¹⁰ These findings show that these bacteria are able to utilize the steroid hormone as a growth factor and proliferate in the diseased periodontium. It was also found that the high levels of the sex hormones could “alter the host defense mechanisms in the gingiva and depress neutrophil chemotaxis and phagocytosis.”¹ Because these drug therapies can result in gingival inflammation, there could also be a resulting increase in the inflammatory markers in the body. As seen from previous studies, the increase of the inflammatory markers could lead to an increase in TTC as well as interfere with conception.¹

Another treatment method for infertility is through in vitro fertilization or IVF. This procedure utilizes ovulation induction medications in order to manipulate the time of ovulation to ensure the successful retrieval of an oocyte to be used for the treatment.¹¹ Once the mature oocytes are collected, they are then fertilized by sperm in the lab. The embryo is then implanted into the uterus. A complete cycle of IVF takes about two weeks. Depending on a number of factors, like age and reproductive history, IVF can be a successful alternative for fertility.¹²

In a study by Pavlatou and Tsami et al, they observed various women who were undergoing IVF treatments for infertility. They found that the medications, similar to those in the Haytac et al. (2004), were causing inflammation to the gingiva and increasing gingival bleeding. They also found a negative correlation between the number of retrieved follicles before IVF and the number of transferred embryos after IVF. From this study, one can conclude that the hormone medications before IVF can affect the maternal periodontium, and it can have an effect on the outcome of IVF.¹¹

Male infertility

In society, much of the burden of infertility is placed on the woman, but men also can contribute to a lack of conception. According to Kellersarian et al. (2016), it is estimated that “48.5 million couples worldwide are unable to conceive, and at least 40% to 50% of the cases are associated with male factor infertility” (p. 1). Based off this statistic, it would be unfair and inaccurate for the burden of infertility to be solely placed on the woman.

Much like periodontal disease, male factor infertility (MFI) is considered to be multifactorial with many possible risk factors. Some of the risk factors identified for MFI are: “bacteriospermia, elevated reactive oxygen species levels, urogenital infections, immunological and endocrine diseases, environmental factors, and genetic disorders.”²

As seen in studies of women, similar inflammatory response markers have been observed in relation to their effects on male infertility. It was found that bacteriospermia may be initiated by an oral cavity infection that was spread by the blood. It was shown that the presence of IL-6 in the seminal fluid may be associated with infertility.³ Periodontal disease has been shown to have a positive association with reduced sperm quality. It can cause an increase in the concentration of the bacteria in the ejaculate, a condition which is believed to lower the fertility of the male.²

Kellesarian et al. (2016) systematically reviewed studies to determine whether there was a plausible association between oral disease and MFI. In each of the seven studies, a positive correlation was shown between male infertility and various dental infections, like caries, chronic periodontitis, and necrotic pulp. One study reviewed by Bustos-Obregron et al. (1983) indicated that, once the necessary restorative procedures we completed, participants showed improvement in sperm motility. Other studies revealed that sperm parameters, such as morphology, motility, and density, were improved after comprehensive dental treatment. These studies found that “33% of the patient’s female partners were able to conceive though in vitro fertilization after the men received dental treatment.”²

These findings were significant because researchers were able to establish the link between oral disease and infertility in men. It is unclear as to how they are associated. Kellsarian et al. (2016) proposed two mechanisms to explain this phenomenon. The first being that the chronic periodontitis can cause an increased bacterial load resulting in bacteriospermia which could lead to reduced sperm motility. The second proposed mechanism implies that the inflammatory cytokines associated with chronic periodontitis cause “a chronic systemic inflammation inducing sperm apoptosis and lower sperm count.”²

Furthermore, a 2010 study, the link between poor oral health in men was found to be associated with sperm count.¹³ They found that oligospermia (low sperm count) and azoopermia (a lack of sperm in the ejaculate) were often present in men with poor oral hygiene. They theorized that TNF-alpha caused testicular dysfunction which lead to sperm apoptosis. They also proposed that a “more plausible link might lie in the similarity between oral microflora and microbials in sperimograms.”¹³ Overall, further research needs to be conducted in order to confirm the correlation between periodontal disease and MFI as well as to establish how they are related.

Dental considerations

While infertility is not a condition that a dental hygienist can directly improve, there are ways for the dental team to help patients who are going through infertility treatments. In order to treat and help patients, it is important for the dental team to understand how fertility treatments can affect the oral structures.

In all of the literature, the authors promote meticulous oral hygiene for both men and women during fertility treatments as well as during pregnancies. They also recommend having a dental exam before starting any fertility treatment to resolve any possible oral diseases like chronic periodontitis or caries. It was found by Hart et al. (2012) that patients who were treated by non-surgical periodontal therapy (NSPT) displayed higher numbers of TNF-alpha, C-reactive protein, and IL-6 post treatment. This fluctuation in inflammatory cytokines could prevent conception, so it is recommended for these patients to wait a few weeks after periodontal therapy before beginning any fertility treatments.⁹

In women, hormone therapies can lead to gingival inflammation, and if plaque levels are not kept under control, the host response can exaggerate any gingivitis or periodontitis, which could lessen the success of the treatments.¹⁰ This circumstance is also true for pregnant women. The influx of estrogen and other sex hormones during pregnancy will cause the same gingival response, so visits during pregnancy will require identical treatment by the clinician and meticulous home care by the patient.

For men, studies have shown that improved oral hygiene is positively correlated with sperm count and motility.² Even if the link between periodontal disease and infertility is not correlated, maintaining a healthy periodontium is an important factor for an individual’s overall wellbeing.

The consequences of periodontal disease on systemic diseases has been documented extensively. However, one area that is lacking research relates to the effect that the disease has on successful conception in infertile couples. Research must done to understand how these conditions are related to each other. Overall, the research currently available has established a possible correlation between periodontal disease and infertility in both men and women, but further research must be done to solidify these findings.

Emily Brockette graduated from Collin College in May 2018 and obtained her dental hygiene license shortly after the publication of this article.

References

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