Trafficking of circulating pro-NK cells to the decidualizing uterus: regulatory mechanisms in the mouse and human

Natural Killer (NK) lymphocytes, strongly expressing CD56, become abundant in the human uterus three to five days after the mid-menstrual cycle surge in pituitary-derived luteinizing hormone (LH). The primary functions of LH are to initiate final oocyte maturation/ovulation and to contribute to decidualization of the uterine stroma. Decidualization is the transformation of estrogen-primed uterine stromal fibroblasts into large hormone-producing cells under the influence of progesterone (P4). Decidual CD56bright (dNK) cells are a distinct, transient, tissue-specific NK cell subset that undergoes proliferation, terminal differentiation, and then death prior to menses. If pregnancy occurs, dNK cells increase during first trimester, then decline and are virtually absent in late pregnancy. In mouse models, pregnancy-associated uterine NK (uNK) cells appear coincident with onset of decidualization during embryonic implantation. Murine uNK cells traffic from the circulation to the antimesometrial side of the uterus and migrate to the mesometrial side of each implantation site. Here they proliferate and are implicated in regulation of midgestation structural changes to major arteries supplying the placenta, before dying in late gestation. Emerging data indicate that interactions between lymphocytes and endothelial cells within the uterine microenvironment are mediated by classical molecules associated with lymphocyte trafficking in immune surveillance and in response to inflammation. Here, we review factors influencing NK cell trafficking to decidualizing murine and human uteri and the differentiation and functions of these cells within the uterus.     

Decline in number of elevated blood CD3(+) CD56(+) NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy

PROBLEM: Patients with elevated blood natural killer (NK) cells may be offered intravenous immunoglobulin (IVIG) treatment, but there is controversy about the utility of blood NK cell testing. Human CD56(+) NK cells include several subpopulations that include the putatively cytotoxic CD56(+) CD16(+) subset. In mouse models of pregnant failure, NKT cells appear to be important. However, a mouse model may only be pertinent to a subset of patients, as recurrent pregnancy failure is a heterogenous group. METHOD OF STUDY: An ethics-approved observational study was done to observe the effect of treatment on total blood lymphoid cells, and subsets of CD56(+) blood lymphocytes including CD56(+) CD3(+) NKT cells determined by flow cytometry, and to correlate with pregnancy outcome. Fifteen fertile women with a history of successful pregnancy and thirty-one women suffering from repeated implantation failure or recurrent spontaneous abortion provided serial blood samples during one menstrual cycle or prior to and during treatment. IVIG was administered to the latter group with or without heparin/aspirin. RESULTS: Eight of thirty infertile women presented with high numbers of CD56(+) CD3(+) NKT cells, which declined after treatment with IVIG. The elevated NKT cell group with or without concomitant autoimmunity achieved a significantly higher successful pregnancy rate over the course of the study, as compared to women with average numbers of NKT cells and no evidence of autoimmunity (P = 0.018). Elevated NKT levels alone was an independent predictor of success on treatment (P = 0.003). CONCLUSION: Elevated NKT cells in recurrent pregnancy loss or implantation failure can be ameliorated with IVIG treatment, and result in successful pregnancy. Assay of NKT cell numbers may identify patients who are more likely to benefit from IVIG therapy and merits further examination in randomized phase II studies.     

Trafficking of Circulating Pro-NK Cells to the Decidualizing Uterus: Regulatory Mechanisms in the Mouse and Human

Natural Killer (NK) lymphocytes, strongly expressing CD56, become abundant in the human uterus three to five days after the mid-menstrual cycle surge in pituitary-derived luteinizing hormone (LH). The primary functions of LH are to initiate final oocyte maturation/ovulation and to contribute to decidualization of the uterine stroma. Decidualization is the transformation of estrogen-primed uterine stromal fibroblasts into large hormone-producing cells under the influence of progesterone (P₄). Decidual CD56^bright (dNK) cells are a distinct, transient, tissue-specific NK cell subset that undergoes proliferation, terminal differentiation, and then death prior to menses. If pregnancy occurs, dNK cells increase during first trimester, then decline and are virtually absent in late pregnancy. In mouse models, pregnancy-associated uterine NK (uNK) cells appear coincident with onset of decidualization during embryonic implantation. Murine uNK cells traffic from the circulation to the anti-mesometrial side of the uterus and migrate to the mesometrial side of each implantation site. Here they proliferate and are implicated in regulation of mid-gestation structural changes to major arteries supplying the placenta, before dying in late gestation. Emerging data indicate that interactions between lymphocytes and endothelial cells within the uterine microenvironment are mediated by classical molecules associated with lymphocyte trafficking in immune surveillance and in response to inflammation. Here, we review factors influencing NK cell trafficking to decidualizing murine and human uteri and the differentiation and functions of these cells within the uterus.     

Prognostic value of the measurement of uterine natural killer cells in the endometrium of women with recurrent miscarriage

BACKGROUND: Studies in mice suggest that CD56 + uterine natural killer (uNK) cells play an important role in implantation. Studies in humans have described an increase in the number of uNK cells in the non-pregnant mid-secretory endometrium of women with unexplained recurrent miscarriage (RM). However, the predictive value of uNK cell number in the maintenance of pregnancy is controversial. METHODS: A blind retrospective study was undertaken. The percentage of stromal cells positive for CD56 was identified by immunocytochemistry in endometrial biopsies from 10 normal control women and 87 women with unexplained RM, of whom 51 became pregnant following biopsy. Biopsies were obtained on days LH + 7 to LH + 9. RESULTS: As in previous studies, the number of uNK cells in the 87 women with RM (mean 11.2% range 1.1-41.4%) was significantly higher (P = 0.013) than in the control women (mean 6.2% range 2.2-13.9%). No significance difference in uNK numbers was observed between 19 women who miscarried (mean 9.6% range 1.7-25.0%) and 32 women who had a live birth (mean 13.3% range 1.1-41.4%) in a subsequent pregnancy. CONCLUSIONS: In this study numbers of uNK cells in the peri-implantation endometrium of women with unexplained recurrent miscarriage did not predict subsequent pregnancy outcome.     

Natural killer cell-triggered vascular transformation: maternal care before birth?

Natural killer (NK) cells are found in lymphoid and non-lymphoid organs. In addition to important roles in immune surveillance, some NK cells contribute to angiogenesis and circulatory regulation. The uterus of early pregnancy is a non-lymphoid organ enriched in NK cells that are specifically recruited to placental attachment sites. In species with invasive hemochorial placentation, these uterine natural killer (uNK) cells, via secretion of cytokines, chemokines, mucins, enzymes and angiogenic growth factors, contribute to the physiological change of mesometrial endometrium into the unique stromal environment called decidua basalis. In humans, uNK cells have the phenotype CD56^brightCD16^dim and they appear in great abundance in the late secretory phase of the menstrual cycle and early pregnancy. Gene expression studies indicate that CD56^brightCD16^dim uterine and circulating cells are functionally distinct. In humans but not mice or other species with post-implantation decidualization, uNK cells may contribute to blastocyst implantation and are of interest as therapeutic targets in female infertility. Histological and genetic studies in mice first identified triggering of the process of gestation spiral arterial modification as a major uNK cell function, achieved via interferon (IFN)-γ secretion. During spiral arterial modification, branches from the uterine artery that traverse the endometrium/decidua transiently lose their muscular coat and ability to vasoconstrict. The expression of vascular markers changes from arterial to venous as these vessels dilate and become low-resistance, high-volume channels. Full understanding of the vascular interactions of human uNK cells is difficult to obtain because endometrial time-course studies are not possible in pregnant women. Here we briefly review key information concerning uNK cell functions from studies in rodents, summarize highlights concerning human uNK cells and describe our preliminary studies on development of a humanized, pregnant mouse model for in vivo investigations of human uNK cell functions.     

Hormonal stimulation for IVF treatment positively affects the CD56bright/CD56dim NK cell ratio of the endometrium during the window of implantation

The effects of hormone stimulation for IVF treatment on endometrial receptivity remain controversial. Since CD56(bright) natural killer (NK) cells in the endometrium positively contribute to implantation and decidualization whereas CD56(dim) NK cells are negatively associated with reproduction, shifts in the balance between those cells will affect receptivity. Therefore, we compared the leukocyte composition in the endometrium of IVF women (n=20) with non-pregnant women (n=18) in a natural cycle, as a parameter for endometrial quality. Biopsies were obtained 7 days after ovulation. Histological dating of the endometrium showed no increased endometrial advancement after IVF treatment as compared to the control group. Flow cytometric analysis of leukocyte subsets showed that hormonal stimulation positively affected the CD56(bright)/CD56(dim) ratio in the endometrium by a relative decrease in the cytotoxic CD56(dim)CD16(+) NK cell numbers. The relative number of T-cells remained unaffected, while the number of non-T and non-NK cells (i.e. B-cells and macrophages) was higher in the IVF group. These effects were restricted to the endometrium and not observed in peripheral blood. Within the CD56(bright) population we could identify a distinct subset of NK cells (CD56(superbright)) that was unique for the endometrium. We conclude that hormonal stimulation for IVF treatment positively affects the CD56(bright)/CD56(dim) ratio of the endometrium during the window of implantation and does not affect endometrial advancement.     

Co-stimulation of human decidual natural killer cells by interleukin-2 and stromal cells

At the late secretory phase of the menstrual cycle and in early pregnancy, the uterine mucosa is infiltrated by large numbers of natural killer (NK) cells with a distinctive phenotype (CD56bright CD16- CD3-) and large granular lymphocyte (LGL) morphology. Circulating CD56bright NK cells generally proliferate in the presence of interleukin-2 (IL-2), but it is clear that cofactors besides IL-2 are required for optimal response. In the bone marrow, this co-stimulating signal is provided by stromal cells. In the present study we observe that uterine CD56+ cells from early pregnancy decidua similarly proliferate vigorously when cultured with decidual stromal cells and a suboptimal dose of IL-2. This response is dependent on cell-cell contact, as no proliferation of decidual NK cells was observed when they were separated from stromal cells by a permeable cyclopore membrane. In addition, we have studied the expression of Bcl-2 by decidual CD56+ cells. Our results show that the microenvironment of the uterus is likely to have a significant influence on the proliferation and survival of uterine CD56+ cells.     

On the frequency of intercourse around ovulation: evidence for biological influences

BACKGROUND: Intercourse in mammals is often coordinated with ovulation, for example through fluctuations in libido or by the acceleration of ovulation with intercourse. Such coordination has not been established in humans. We explored this possibility by examining patterns of sexual intercourse in relation to ovulation. METHODS: Sixty-eight sexually active North Carolina women with either an intrauterine device or tubal ligation provided data for up to three menstrual cycles. These women collected daily urine specimens and kept daily diaries of intercourse and menstrual bleeding. Major estrogen and progesterone metabolites excreted in urine were used to identify the day of ovulation. The fertile days of the cycle were defined as the 6 consecutive days ending with ovulation. Women contributed a total of 171 ovulatory cycles. Menstrual bleeding days were excluded from analysis. RESULTS: The frequency of intercourse rose during the follicular phase, peaking at ovulation and declining abruptly thereafter. The 6 consecutive days with most frequent intercourse corresponded with the 6 fertile days of the menstrual cycle. Intercourse was 24% more frequent during the 6 fertile days than during the remaining non-bleeding days (P < 0.001). CONCLUSIONS: There apparently are biological factors that promote intercourse during a woman's 6 fertile days.     

Immunoregulatory factors in multiple sclerosis patients during and after pregnancy: relevance of natural killer cells

Multiple sclerosis (MS) ameliorates typically during pregnancy but after the delivery the relapse rate often increases. Our study was conducted to understand the immunoregulatory mechanisms accompanying this phenomenon. MS patients were followed-up prospectively during pregnancy and 6 months postpartum, with immunological characterization of the peripheral blood. Groups of age- and parity-matched healthy pregnant women, and age- and sex-matched non-pregnant women and non-pregnant MS patients were studied as controls. In our patient cohort, the annualized relapse rate was 1.0 +/- 1.0 relapses/woman/year (mean +/- standard deviation) during the year before pregnancy, but dropped to 0.2 +/- 0.9 during the third trimester (P = 0.02). After the delivery the relapse rate increased again to 1.4 +/- 1.9 (1-3 months postpartum versus third trimester P = 0.003). While percentages of peripheral blood CD3, CD4, CD8 and CD19 immune cell subsets were unchanged over the observation period, reduced disease activity during the last trimester was associated with a significant increase in the percentage of circulating CD56(bright) natural killer (NK) cells. Simultaneously, the proportion of circulating CD56(dim) NK cells was clearly reduced. No alteration was noted in CD4+ CD25(high) forkhead box P3+ regulatory T cells. Production of interferon-gamma by peripheral blood lymphocytes was down-regulated significantly during pregnancy in comparison to the postpartum period, resulting in an increased T helper type 2 (Th2) : Th1 ratio during pregnancy. In conclusion, pregnant state in MS patients is characterized by an increase in the percentage of CD56(bright) NK cells and by enhanced Th2 type cytokine secretion. Our findings suggest a potential role for CD56(bright) regulatory NK cells in the control of autoimmune inflammation during pregnancy in MS.     

Uterine natural killer cells: a specialized differentiation regulated by ovarian hormones

Summary:  In adult females of many species, a transient population of natural killer (NK) cells appears in cycles within the uterine endometrium (lining). Appearance of these lymphocytes coincides with specific phases of the ovarian hormone cycle and/or early pregnancy. Studies in rodents, women, and pigs dominate the literature and suggest the uterine (u)NK cells are an activated subset sharing many but not all features with circulating or lymphoid organ-residing NK cells. During successful murine pregnancy, uNK cells appear to regulate initiation of structural changes in the feed arterial systems that support maternal endometrial tissue at sites of implantation and subsequent placental development. These changes, which reverse after pregnancy, create a higher volume arterial bed with flaccid vessels unresponsive to vasoactive compounds. These unique pregnancy-associated arterial changes elevate the volume of low-pressure, nutrient-rich, maternal arterial blood available to conceptuses. Regulation of the differentiation, activation, and functions of uNK cells is only partially known, and there is lively debate regarding whether and how uNK cells participate in infertility or spontaneous abortion. This review highlights the biology of uNK cells during successful pregnancy.     

Uterine natural killer (uNK) cells and their missions during pregnancy: A review

Natural killer (NK) cells are lymphocytes of the innate immune system. The aim of this review is to describe the properties and roles of NK cells in the human uterus during pregnancy. Uterine natural killer cells (uNK) constitute a major lymphocyte population during early gestation in the uterus. The uterine natural killer cells are recognized owing to their CD56^bright, CD16⁻, CD3⁻ phenotype. Their number increases in the first trimester with a subsequent decline as pregnancy progresses. They have been shown to be closely associated with cells of the extravillous trophoblast (EVT) and spiral arteries. They play important roles in remodeling of the spiral arteries, control of trophoblast invasion and in the development of the placenta. Some studies have shown the number and repertoire of receptors of uNK differ between women with healthy pregnancies and those with pathologic pregnancies, such as pre-eclampsia or intrauterine growth retardation. During pregnancy, the cytotoxic characteristics of the uterine killer cells are not directed towards the fetus, and scientists continue to question and explore this phenomenon with increasing evidence that these cells may perform differing beneficial roles during pregnancy. Contrary to their previously suspected “hostile” characteristics, the uterine killer cells are considered to be “friendly” and appear to be essential and very important regulators of successful implantation and pregnancy.     

Interleukin 2 receptor gamma chain (gamma(c)) knockout mice show less regularity in estrous cycle but achieve normal pregnancy without fetal compromise

PROBLEM: Implication of cytokines in pregnancy suggested but remains to be established. We studied the effect of cytokines on reproductive functions such as ovulation and pregnancy, with mutant mice lacking interleukin 2 receptor gamma (IL-2Rgamma), the so-called common gamma chain (gamma(c)), which is shared among receptors for multiple cytokines such as IL-2, IL-4, IL-7, IL-9 and IL-15. METHOD OF STUDY: Regularities of estrous cycles were observed by vaginal smear. Ovaries stimulated with postmenopausal serum gonadotropin (PMSG) were examined for the ovarian capacities. The uteri at 13 days of gestation were used for histological analysis of the maternal-fetal interface. RESULTS: The estrous cycles in gamma(c) knockout (gamma(c) KO) mice were irregular compared with wild-type mice, although, the mutants could become pregnant. No uterine natural killer (uNK) cell was found in the uterus at 13 days of pregnancy, and poor decidual formation and thickness of blood vessel walls were observed. Apparent differences were not seen in the numbers and weight of the fetuses between wild type and mutant animals, and fetuses were not compromised throughout pregnancy. CONCLUSIONS: The gamma(c) KO mice showed irregular estrous cycle but they could carry out normal pregnancy despite lacking uNK and cytokines actions of IL-2, 4, 7, 9 and 15.     

CD3- leukocytes present in the human uterus during early placentation: phenotypic and morphologic characterization of the CD56++ population.

In this study, the CD3- LGL/NK cells present in the pregnant human uterus have been characterized. Phenotypic and morphologic analyses of decidual LGL revealed many similarities to the minor CD56bright+, CD16- subset in peripheral blood, but there were some important differences. The relative surface density of CD56+ is greatly increased on decidual LGL to 22x that found on the majority of CD56+ peripheral blood NK cells. The CD56bright+ cells in decidua show LGL morphology, whereas in peripheral blood, they are mainly agranular. Proliferation of CD56+ cells occurs predominantly during the nonpregnant secretory (luteal) phase, indicating these CD56+ uterine LGL do not migrate as terminally differentiated cells. The appearance of CD56+ cells was examined at the ultrastructural level using immunoelectron microscopy. Cells with phenotypic characteristics of decidual LGL occur in a higher percentage (1.11%) in the peripheral blood of women of reproductive age than in men (0.66%). On the basis of these results, it is proposed that the CD56bright+ uterine leukocytes represent a distinctive, hormonally regulated subset possibly adapted to control human placentation.     

Establishment of Long‐Term Model throughout Regular Menstrual Cycles in Immunodeficient Mice

Citation Kikuchi‐Arai M, Murakami T, Utsunomiya H, Akahira J, Suzuki‐Kakisaka H, Terada Y, Tachibana M, Hayasaka S, Ugajin T, Yaegashi N. Establishment of long‐term model throughout regular menstrual cycles in immunodeficient mice. Am J Reprod Immunol 2010 Problem The number of uterus natural killer (NK) cells change through the menstrual cycle, but the origin of uterus NK cell was not unclear. Our aims are to study whether we can reproduce repetition of menstrual cycle and to reveal the origin of uterus NK cells. Method of study Endometrial samples were obtained from fertile women, and the tissues were transplanted into ovariectomized non‐obese diabetic (NOD)/severe combined immunodeficiency (SCID)/γCnull (NOG) mice. Mice were treated with sex hormones which were in accord with human menstrual cycle. Results The replants showed similar histological changes as in eutopic endometrium repeatedly. CD56‐positive, CD16‐negative NK cells increased significantly during the treatment with estradiol and progesterone combination. Conclusion Histological assessment demonstrated that this model of NOG mice repeatedly exhibited regular menstrual cycles, and this model mimicked not ‘ectopic endometrium’, but ‘eutopic endometrium’ in humans. Change in number of NK cells suggested that NK cell might be derived from the endometrium.     

An increase in the absolute count of CD56dimCD16+CD69+ NK cells in the peripheral blood is associated with a poorer IVF treatment and pregnancy outcome

BACKGROUND: Our aim was to evaluate the effect of the absolute count of the activation marker (CD69), IgG Fc receptor (CD16) and inhibitor marker (CD94) expression on peripheral blood natural killer (NK) cells on implantation and miscarriage rates after IVF treatment. METHODS: Prospective observational study of 138 randomly selected women who underwent IVF treatment from December 2002 to September 2003. NK cells were identified as CD56(+) (dim + bright) and CD3(-) by flow cytometry. The absolute counts of the CD69(+), CD16(+) and CD94(+)expressing NK cells were recorded and their relation to IVF treatment outcome and miscarriage rate was analysed. RESULTS: The mean (+/-SD) absolute count of the CD56(dim)CD16(+)CD69(+) NK cells for women who had a successful ongoing pregnancy was 0.61 x 10(6)/l (+/-0.31). For those women who failed to achieve a pregnancy, the mean value of the absolute count of CD56(dim)CD16(+)D69(+) NK cells was significantly (P=0.003) higher at 1.66 x 10(6)/l (+/-0.52). The absolute count of CD56(dim)CD16(+)CD94(+) and CD56(dim)CD16(+) NK cells did not show any statistically significant differences between those women with successful and failed IVF treatment. Receiver operating characteristic (ROC) curve analysis was performed to select a CD69 threshold for further statistical analysis. The implantation rate (IR) was significantly lower (13.1%) and miscarriage rate (MR) was significantly higher (66.7%) for women with an absolute CD56(dim)CD16(+)CD69(+) NK cell count of >1.0 x 10(6)/l compared to women with count below this value (IR 28.2% and MR 16.7%). Further analysis of the absolute count of CD56(bright)CD69(+) and CD56(bright)CD94(+) NK cells did not show any significant difference between those women with successful and failed IVF treatment. CONCLUSIONS: An increase in the absolute count of activated NK cells (CD56(dim)CD16(+)CD69(+)) in the peripheral blood is associated with a reduced rate of embryo implantation in IVF treatment. Furthermore, women with high CD56(dim)CD16(+)CD69(+) peripheral blood NK cell absolute count, who are able to achieve pregnancy, have a significantly higher miscarriage rate.     

Elevated Peripheral Blood Natural Killer Cells Are Effectively Downregulated by Immunoglobulin G Infusion in Women With Recurrent Spontaneous Abortions

PROBLEM: We investigated the hypothesis that elevated peripheral blood natural killer cells (NK) are decreased by immunoglobulin G infusion (IVIg) therapy in women with recurrent spontaneous abortions (RSA) and elevated NK cells. METHODS: Seventy-three women with RSA and elevated NK cells received IVIg therapy (400 mg/Kg/day for 3 days ever 4 wks) and anticoagulation treatment. Peripheral blood immunophenotype assay by flow cytometry was done prospectively prior to and 7 days after first IVIg therapy, every 2 wks until 20 wks gestation and then monthly. Controls were 95 women with RSA and normal NK cells who received anticoagulation treatment. RESULTS: (1) 86.3% of women with elevated NK cells who received the IVIg and anticoagulation therapy had a successful pregnancy outcome; (2) Peripheral blood CD56+ NK cells and CD56+/16+ NK cells were significantly suppressed 7 days post IVIg infusion (P < 0.0005); (3) Pre-IVIg infusion levels of other lymphocyte subsets were not different as compared with those of 7 days post-IVIg therapy; (4) Women who delivered a liveborn infant with IVIg therapy demonstrated downregulation of peripheral blood NK cells (CD56+, CD56+/16+) during early pregnancy when compared to women who miscarried the index pregnancy (P < 0.05); (5) Women with normal NK cells who miscarried while on anticoagulation therapy demonstrated significantly elevated CD56+ NK cells during early pregnancy as compared with that of women who delivered a liveborn infant (P < 0.05); (6) CD19+ B cells were significantly downregulated during pregnancy in women with anticoagulation and IVIg therapy when compared to women with anticoagulation therapy (P < 0.05). CONCLUSION: Downregulation of NK cells in women with RSA is associated with a favorable pregnancy outcome. Peripheral blood NK cells (CD56+, CD56+/16+) are effectively suppressed after IVIg therapy. Women with RSA and high NK cells benefit from IVIg therapy and experience suppression of CD56+ and CD56+/16+ NK cells.     

Right-sided ovulation favours pregnancy more than left-sided ovulation

The aim of this study was to evaluate whether frequency of ovulation and fertility potential of oocytes from the two ovaries differed in regularly menstruating women (1057 cycles of 856 fertile women and 1033 cycles of 258 infertile women). For both fertile and infertile women ovulation from the right ovary occurred more often than from the left ovary (55 versus 45%; P: < 0.005). In infertile women follicular phase length was similar for right- and left-sided ovulation. However, infertile women treated with intrauterine insemination (IUI) or in-vitro fertilization (IVF) showed a pregnancy rate in connection with right-sided ovulation (13%) which was higher than that of left-sided (9%). The ratio of pregnancies deriving from the right ovary per total number of pregnancies was similar in infertile and fertile women (64.6%, 73/113 and 63.4%, 361/569 respectively). The ratio of pregnancies from right-sided ovulation (approximately 64%) per total number of pregnancies was higher than that of right-sided ovulation (approximately 55%) during non-pregnant cycles (P: < 0.0001). The implantation rate in right-sided ovulation seemed to be higher than in left-sided one, since IVF data showed a lower frequency (P: = 0.03) of pre-embryo formation from right-sided ovulation than left-sided. Mid-luteal serum oestradiol and testosterone were higher (P: < 0.05) in right-sided ovulation than left-sided. Taken together, in both fertile and infertile women the fertility potential of oocytes from the right ovary surpasses that of the left ovary.     

Implications of uterine NK cells and regulatory T cells in the endometrium of infertile women

A range of studies have shown that the complex process of implantation and an establishment of a pregnancy also involves immune factors. Disturbances in these underlying immune mechanisms might lead to implantation and pregnancy failure and may be involved in the pathogenesis of unexplained infertility. Several studies have reported that imbalances in uterine NK (uNK) cell abundance are associated with infertility; however, controversies exist. An increased amount of CD56⁺ uNK cells along with a decrease in CD16⁺ uNK cells have been associated with normal fertility in some studies. Very few studies of FoxP3⁺ regulatory T cells (Tregs) in the pre-implantation endometrium have been performed. Results are sparse and controversial, studies reporting both increased and decreased numbers of Tregs, respectively, in women suffering from infertility. In conclusion, studies imply that uNK cells, Tregs and HLA-G carry pivotal roles regarding the establishment of a healthy pregnancy, and that abnormal immune mechanisms involving these parameters may be associated with infertility. However, more research in early phases of the reproductive cycle, such as investigating the conditions in the endometrium before implantation, is needed to further clarify the underlying mechanisms.