The endometrium is essential for the implantation and maintenance of pregnancy. Since inflammation of the endometrium contributes to implantation failure, miscarriage, and preterm birth, the endometrium has various defense mechanisms against inflammation. In the endometrium, innate immunity resulting from natural antimicrobial components functions as well as defense through immunocompetent cells (King et al., 2003).

Lactoferrin (Lf) is a glycoprotein responsible for the innate immunity of the endometrium and is expressed in the human endometrial glandular epithelium (Masson et al., 1968). Lf is contained within mammalian exocrine secretions, such as breast milk, tears, saliva, bile, pancreatic juice, semen, and cervical mucus, as well as in the secondary granules of neutrophils (Levy, 2004; Vogel, 2012). Lf exerts various effects, such as iron binding ability and antimicrobial, anti-inflammatory, and antitumor activity. It has also been reported that Lf induces cell proliferation of endometrial stromal cells (ESCs) in human endometrium (Yanaihara et al., 2000). Lf expression is estrogen-responsive, and in endometrial carcinoma and hyperplasia, Lf is overexpressed in endometrial glandular epithelial cells (KELVER et al., 1996, TENG et al., 2002, WALMER et al., 1995), but any other effects are unknown.

Chronic endometritis (CE) is a disease characterized by continuous and subtle inflammation of the endometrium. CE is usually asymptomatic, but sometimes it presents only with non-specific symptoms, such as abnormal uterine bleeding, pelvic pain, dyspareunia, and leucorrhea (Rotterdam, 1978; Yörükoğlu and Kuyucouğlu, 1998). CE is pathologically diagnosed by plasma cell infiltration in the endometrial stromal region, where they are not typically present except just before and during menstruation (Crum et al., 1983). Plasma cell expression suggests the presence of continuous immune response to some component of the endometrium (Kimura et al., 2019).

CE has been suggested to be involved in infertility and implantation failure (Johnston-MacAnanny et al., 2010; Smith et al., 2010; Hirata et al., 2021). We have previously reported that CE decreases term birth and live birth rates per pregnancy and increases miscarriage rates (Morimune et al., 2021). Antibiotics, such as doxycycline, ofloxacin, and metronidazole, currently comprise the most common treatments for CE, as administration of antibiotics to women with CE improves both clinical and pathological findings (McQueen et al., 2014; Kitaya et al., 2017). However, in some cases, CE is not cured even after several administrations of antibiotics. Moreover, some patients do not want to take antibiotics because their frequent use can lead to disruption of microbial flora in the body, including in the intestines. The development of a method to regulate inflammation in the endometrium of patients with CE without the use of antibiotics is expected. Therefore, in this study, we investigated whether Lf exerts an anti-inflammatory effect on the human endometrium.