If you suffer from infertility and have undergone a diagnostic workup, you may already know that your infertility is a sign that something else is wrong, a symptom of an underlying issue or disease. One possible culprit could be chronic endometritis (CE), a persistent inflammation of the endometrium, leading to ongoing, low-grade infection. (CE is not to be confused with endometriosis, the condition where the endometrial lining grows outside the uterus.)
Research suggests that roughly 10% of women have chronic endometritis (CE), and it is known to impact a woman’s ability to achieve and sustain a pregnancy [1]. More specifically, CE may play a role in recurrent implantation failure as manifested by recurrent miscarriages.
Here, we’ll explore how the endometrium functions during a healthy pregnancy, what chronic endometritis is and how it’s diagnosed, and how chronic endometritis may impact fertility. We’ll also discuss how antibiotic treatment can help treat CE–and possible CE-related infertility as well.
The endometrium’s role in sustaining a healthy pregnancy
Maintaining a healthy female reproductive system requires a delicate balance between the immune system and the microorganisms that call it home. One of the most common sites for a break-down in that equilibrium is the endometrium—the tissue lining the uterus.
The endometrium plays a key role in the menstrual cycle, during which it thickens in preparation for the possible implantation of an embryo. Thousands of immune cells in endometrial tissue [2] perform two important implantation-related functions: First, the cells are primed to recognize foreign intruders and fight off harmful pathogens; second, those same cells also promote immune tolerance, allowing the womb to accept the genetically-separate, free-floating blastocyst (newly fertilized egg) which will develop into the embryo and placenta [3].
When the delicate balance between embryo and endometrium is disrupted, establishing and sustaining a pregnancy becomes difficult. CE, usually caused by a microbial infection, can trigger an immune response in the endometrium that reduces the tissue’s receptivity to the blastocyst, making successful implantation impossible.
What are the symptoms of chronic endometritis (CE)?
For some women, CE can cause symptoms such as abnormal uterine bleeding, pelvic pain, and abnormal discharge (leukorrhea). For others, the condition is asymptomatic [4]. Of course, abnormal bleeding and pelvic pain can be symptoms of other reproductive and menstrual disorders, so the nonspecific nature of CE symptoms, along with the potential lack of symptoms, can make the condition difficult to diagnose. Many asymptomatic women only learn they have CE when a doctor conducts a deep dive into their infertility or recurrent pregnancy loss.
Many of the causes of CE can be from STI’s, most commonly Chlamydia or Gonorrhea. CE may also occur after a miscarriage, a dilation & curettage procedure (D&C), or prolonged labor followed by a C-section.
How is CE diagnosed?
Pelvic Exam
To diagnose CE, doctors are likely to start with a detailed medical history, followed by a pelvic exam, in which they’ll check your abdomen, uterus, and cervix for tenderness or abnormal discharge. They might then look at any irregular discharge under a microscope or take a sample from the cervix to test for harmful bacteria.
Endometrial Biopsy
Endometrial biopsy, in which a small tissue sample is taken from the endometrium, is the current “gold standard” for CE diagnosis [5]. This method allows pathologists to detect the presence of plasma cells, white blood cells that secrete antibodies in response to antigens. The presence of plasma cells may be one sign of a microbial infection within the endometrium, as their presence indicates that the body is mounting an immune response. These plasma cells can be detected in the majority of women with CE.
A more extensive sampling may be obtained through a minor outpatient procedure that accompanies a hysteroscopy, i.e. a dilation and curettage (D&C) procedure.
Hysteroscopy
Some recent research suggests that hysteroscopy may actually be a better method for diagnosing CE [6]. The minimally invasive procedure, which involves using a narrow telescope to examine the inside of the uterus, has been shown to detect CE more often than endometrial cultures [7].
CE’s impact on fertility
Recent research indicates that CE does have the potential to adversely affect fertility [8].
Whether CE directly causes or simply correlates with embryo implantation failure remains controversial [9], but CE seems to significantly reduce endometrial receptivity to the embryo in several ways [10]. In patients with CE, the endometrium is colonized by harmful bacteria that induce an inflammatory immune response, creating a hostile environment for an embryo. CE also affects the production of small proteins called cytokines that are important in cell signaling and the inflammatory process. Inappropriate cytokine signaling can compromise placenta quality, resulting in abnormal implantation or abnormal placenta formation.
In theory, all these CE-related effects could negatively impact fertility, as they make it difficult for the endometrium to accept an embryo and promote its healthy growth.
Can treating CE improve fertility?
Once diagnosed, CE is relatively simple to treat with oral antibiotics. US-based providers often utilize doxycycline, while international providers are significantly more likely to prefer metronidazole/ciprofloxacin or broad-spectrum antibiotics and antifungals.
More research is needed, but antibiotic treatment appears promising: one study reported that fully 70% of CE cases diagnosed through endometrial biopsy were cured through antibiotic treatment [11], and another study reported that antibiotic treatment was successful for 96% of CE patients experiencing repeated implantation failure [12].
In fact, fertility and pregnancy outcomes consistently improve for CE patients after antibiotic treatment. One study reported that the pregnancy rate of CE patients whose diagnostic findings normalized after treatment was 74.8%, as opposed to 24.4% for those who were not cured [13]. In another study, the live birth rate per pregnancy in women with a history of recurrent miscarriage jumped from 7% before antibiotics to 56% after [14]!
Do you think you might have CE? Here’s how to get help
CE is not uncommon, especially in women experiencing infertility. In fact, the prevalence of this condition has been found to be 2.8-56.8% in infertile women, 14-67.5% in women with recurrent implantation failure, and 9.3-67.6% in women with recurrent miscarriage [15]! Though the enormous ranges in these percentages demonstrate how much we still don’t know about CE and its relationship to fertility, recent studies have shed light on the ways it may affect the implantation process, and how to successfully treat it.
Charting your cycle using a fertility awareness method (FAM) can help alert you to several of the nonspecific symptoms associated with CE, such as abnormal uterine bleeding and discharge. If you’ve experienced infertility, recurrent implantation failure, or miscarriage, it may be time for a conversation with your doctor about options for investigating your endometrial health; your fertility charts can give you a concrete place to start.
References:
[1] [8] and [10] Park HJ, Kim YS, Yoon TK, Lee WS. Chronic endometritis and infertility. Clin Exp Reprod Med. 2016;43(4):185-192. doi:10.5653/cerm.2016.43.4.185 [2] Jin LP, Fan DX, Zhang T, Guo PF, Li DJ. The costimulatory signal upregulation is associated with Th1 bias at the maternal-fetal interface in human miscarriage. Am J Reprod Immunol. 2011 Oct;66(4):270-8. doi: 10.1111/j.1600-0897.2011.00997.x. Epub 2011 Apr 11. PMID: 21481059. [3] Kitazawa J, Kimura F, Nakamura A, Morimune A, Takahashi A, Takashima A, Amano T, Tsuji S, Kaku S, Kasahara K, Murakami T. Endometrial Immunity for Embryo Implantation and Pregnancy Establishment. Tohoku J Exp Med. 2020 Jan;250(1):49-60. doi: 10.1620/tjem.250.49. PMID: 31996497. [4] and [5] Margulies SL, Flores V, Parkash V, Pal L. Chronic endometritis: A prevalent yet poorly understood entity. Int J Gynaecol Obstet. 2021 Oct 4. doi: 10.1002/ijgo.13962. Epub ahead of print. PMID: 34605024. [6] Cicinelli E, De Ziegler D, Nicoletti R, Colafiglio G, Saliani N, Resta L, Rizzi D, De Vito D. Chronic endometritis: correlation among hysteroscopic, histologic, and bacteriologic findings in a prospective trial with 2190 consecutive office hysteroscopies. Fertil Steril. 2008 Mar;89(3):677-84. doi: 10.1016/j.fertnstert.2007.03.074. Epub 2007 May 25. PMID: 17531993. [7] Cicinelli E, Matteo M, Tinelli R, Lepera A, Alfonso R, Indraccolo U, Marrocchella S, Greco P, Resta L. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod. 2015 Feb;30(2):323-30. doi: 10.1093/humrep/deu292. Epub 2014 Nov 10. PMID: 25385744. [9] Xu Y, Mei J, Diao L, Li Y, Ding L. Chronic endometritis and reproductive failure: Role of syndecan-1. Am J Reprod Immunol. 2020 Sep;84(3):e13255. doi: 10.1111/aji.13255. Epub 2020 Jun 26. PMID: 32329146. [11] Johnston-MacAnanny EB, Hartnett J, Engmann LL, Nulsen JC, Sanders MM, Benadiva CA. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril. 2010 Feb;93(2):437-41. doi: 10.1016/j.fertnstert.2008.12.131. Epub 2009 Feb 12. PMID: 19217098. [12] Kitaya K, Tada Y, Taguchi S, Funabiki M, Hayashi T, Nakamura Y. Local mononuclear cell infiltrates in infertile patients with endometrial macropolyps versus micropolyps. Hum Reprod. 2012 Dec;27(12):3474-80. doi: 10.1093/humrep/des323. Epub 2012 Sep 5. PMID: 22951914. [13] Cicinelli E, Matteo M, Tinelli R, Pinto V, Marinaccio M, Indraccolo U, De Ziegler D, Resta L. Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment. Reprod Sci. 2014 May;21(5):640-7. doi: 10.1177/1933719113508817. Epub 2013 Oct 31. PMID: 24177713; PMCID: PMC3984485. [14] McQueen DB, Bernardi LA, Stephenson MD. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise. Fertil Steril. 2014 Apr;101(4):1026-30. doi: 10.1016/j.fertnstert.2013.12.031. Epub 2014 Jan 23. PMID: 24462055. [15] Xu Y, Mei J, Diao L, Li Y, Ding L. Chronic endometritis and reproductive failure: Role of syndecan-1. Am J Reprod Immunol. 2020 Sep;84(3):e13255. doi: 10.1111/aji.13255. Epub 2020 Jun 26. PMID: 32329146.
