lactoferrin and Endometritis

We prospectively investigated if oral enteric coating lactoferrin supplementation improves the reproductive outcomes in infertile women with a history of repeated implantation failure (RIF) and non-Lactobacillus-dominant (Lactobacillus rate < 90%) microbiota (NLDM) in vaginal secretions (VS)/endometrial fluid (EF).. Paired VS/EF samples were obtained from RIF women and control infertile women (non-RIF group) for microbiome analysis. Chronic endometritis (CE) was diagnosed histopathologically and hysteroscopically. In a pilot study, oral enteric coating lactoferrin (700 mg/day, at least 28 consecutive days) was administered to eligible patients with NLDM in VS/EF. Their reproductive outcomes in the subsequent vitrified-warmed embryo transfer cycles were followed up.. While CE was more prevalent (OR 2.41, 95% CI 1.02-5.63, p = 0.042) in the RIF group (29.1%, n = 117) than in the non-RIF group (14.5%, n = 55), The NLDM rate was similar between the two groups (44.4 vs 52.7%). Lactoferrin supplementation improved NLDM in 43.2% of RIF women (n = 37). Within the RIF group, the live birth rate in the subsequent cycles was higher (OR 10.67, 95% CI 1.03 - 110.0, p = 0.046) in women with improved microbiota (57.1%, n = 14) than in those with unimproved microbiota (11.1%, n = 9).. Unlike CE, NLDM was not unique to RIF but was common in infertile women. Although the therapeutic effect of the oral lactoferrin supplementation on NLDM was limited in a pilot study, the reproductive outcomes were better in RIF women who overcame NLDM than in those who failed. Randomized controlled trials are required to confirm the results. TRIAL REGISTRATION NUMBER AND DATE FOR PROSPECTIVELY REGISTERED TRIALS: UMIN-CTR 000036990, June 7, 2019.

Topics: Dietary Supplements; Dysbiosis; Embryo Implantation; Endometritis; Endometrium; Female; Humans; Infertility, Female; Lactoferrin; Live Birth; Pilot Projects; Pregnancy

Chronic endometritis (CE) is a type of chronic inflammation in the endometrium that is associated with infertility, which is primarily due to implantation failure. Antibiotics are the most common treatment for CE. However, some patients with CE are resistant to antibiotic treatment, while others refuse this treatment. Therefore, we focused on lactoferrin (Lf), which exhibits antimicrobial and anti-inflammatory properties, and studied its effect on inflammation in endometrial stromal cells (ESCs) from patients with CE. Endometrial tissue was collected from patients with CE, and ESCs were isolated and cultured. When ESCs were cultured with bovine lactoferrin (bLf: 1 mg/mL), the mRNA expression of TNF-α (p < 0.05) and IL-1β (p < 0.01) was significantly decreased compared with that in cells cultured without bLf. The level of TNF-α protein in the culture medium was significantly decreased (p < 0.01), while that of IL-1β was also decreased, but not significantly (p < 0.10), when 1 mg/mL of bLf was added to the culture medium. When more inflammation was induced artificially by adding 0.1 ng/mL of TNF-αto ESCs, the addition of bLf (1 mg/mL) to ESCs decreased IL-6 and IL-1β mRNA expression to levels similar to those in ESCs without TNF-α treatment. Furthermore, it was revealed that the actions of bLf are mediated by the AKT and MAPK intracellular signaling pathways, which are mechanisms by which the increase in TNF-α-induced cytokine expression is suppressed in ESCs. bLf suppresses the expression of inflammatory cytokines in human ESCs and may be a new therapeutic candidate for CE.

Topics: Anti-Bacterial Agents; Chronic Disease; Cytokines; Endometritis; Female; Humans; Inflammation; Lactoferrin; RNA, Messenger; Stromal Cells; Tumor Necrosis Factor-alpha

Topics: Animals; Anti-Inflammatory Agents; Body Temperature; Breeding; Cytokines; Endometritis; Female; Gene Expression Regulation; Heart Rate; Horse Diseases; Horses; Humans; Insemination, Artificial; Lactoferrin; Recombinant Proteins; Respiration

In the horse, breeding induces a transient endometrial inflammation. A subset of mares are unable to resolve this inflammation, and they are considered susceptible to persistent mating-induced endometritis PMIE Select seminal plasma proteins cysteine-rich secretory protein-3 (CRISP-3) and lactoferrin have been shown to affect the innate immune response to sperm in vitro. The objective of this study was to determine whether the addition of CRISP-3 and lactoferrin at the time of insemination had an effect on the mRNA expression of endometrial cytokines in susceptible mares after breeding. Six mares classified as susceptible to PMIE were inseminated during four consecutive oestrous cycles with treatments in randomized order of: 1 mg/ml CRISP-3, 150 μg/ml lactoferrin, seminal plasma (positive control) or lactated Ringer's solution (LRS; negative control) to a total volume of 10 ml combined with 1 × 10

Topics: Animals; Breeding; Cytokines; Endometritis; Endometrium; Estrous Cycle; Female; Horse Diseases; Horses; Insemination, Artificial; Lactoferrin; Male; Random Allocation; RNA, Messenger; Semen; Seminal Plasma Proteins

Lactoferrin (LF) is one of the most abundant proteins found in milk, and it has been reported to have anti-inflammatory properties. However, the anti-inflammatory effects of LF on lipopolysaccharide (LPS)-induced endometritis and the underlying molecular mechanisms remain to be elucidated. In this study, we evaluated the effects of LF on LPS-induced endometritis in mice. The endometritis model was established by the perfusion of mice with LPS. LF was administered by intraperitoneal injection 1h before and 12h after LPS induction. Our results demonstrated that LF significantly attenuated the histopathological changes in the uterus, reduced the activity of myeloperoxidase (MPO) and the levels of nitric oxide (NO), and inhibited the activation of NF-κB and the expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in a dose-dependent manner. The results suggest that LF has an anti-inflammatory effect on LPS-induced endometritis in mice. Therefore, LF may be a potential therapeutic agent for the treatment of endometritis.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Endometritis; Endotoxins; Female; Injections, Intraperitoneal; Interleukin-1beta; Lactoferrin; Mice, Inbred Strains; NF-kappa B; Signal Transduction; Tumor Necrosis Factor-alpha

Lactoferrin (LF) is an estrogen-regulated glycoprotein with well-described antibacterial and immunomodulatory properties. The present study is the first report on LF expression in horse endometrial specimens. Mares chosen for the study were either resistant or susceptible for persisting mating-induced endometritis (PMIE) during the natural ovulatory cycle and in early pregnancy. Our investigations included immunostaining for LF protein and CD18, a leukocyte marker, as neutrophils are a possible source for LF in the endometrium. Quantification of LF mRNA was performed by use of real-time RT-PCR. This study demonstrated that LF protein in equine endometrium was expressed in glandular and luminal epithelium and in neutrophils. Similar to other mammalian species, the level of endometrial LF transcription in the mare was modulated according to the stage of the estrus cycle and was 5500-fold higher during estrus compared with diestrus and early pregnancy. The endometria from mares susceptible for PMIE and delayed uterine clearance exhibited an increased LF transcription during all stages of the estrus cycle that reached statistical significance in proestrus. In the endometria of mares susceptible for PMIE the upregulated LF mRNA expression was not associated with a higher number of CD18 positive leukocytes but correlated with the number of uterine glands. Enhanced LF transcription within the endometrial epithelium might therefore be a response to recurrent persisting inflammation following insemination in mares with delayed uterine clearance.

Topics: Animals; Biopsy; CD18 Antigens; Endometritis; Estrous Cycle; Female; Horse Diseases; Horses; Immunohistochemistry; Lactoferrin; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric