At coitus, human sperm are deposited into the anterior vagina, where, to avoid vaginal acid and immune responses, they quickly contact cervical mucus and enter the cervix. Cervical mucus filters out sperm with poor morphology and motility and as such only a minority of ejaculated sperm actually enter the cervix. In the uterus, muscular contractions may enhance passage of sperm through the uterine cavity. A few thousand sperm swim through the uterotubal junctions to reach the Fallopian tubes (uterine tubes, oviducts) where sperm are stored in a reservoir, or at least maintained in a fertile state, by interacting with endosalpingeal (oviductal) epithelium. As the time of ovulation approaches, sperm become capacitated and hyperactivated, which enables them to proceed towards the tubal ampulla. Sperm may be guided to the oocyte by a combination of thermotaxis and chemotaxis. Motility hyperactivation assists sperm in penetrating mucus in the tubes and the cumulus oophorus and zona pellucida of the oocyte, so that they may finally fuse with the oocyte plasma membrane. Knowledge of the biology of sperm transport can inspire improvements in artificial insemination, IVF, the diagnosis of infertility and the development of contraceptives.

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Sperm transport in the female reproductive tract

Premature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heterogeneous disorder with a multicausal pathogenesis involving chromosomal, genetic, enzymatic, infectious, and iatrogenic causes. There remains, however, a group of POF patients without a known etiology, the so-called "idiopathic" form. An autoimmune etiology is hypothesized for the POF cases with a concomitant Addison's disease and/or oophoritis. It is concluded in this review that POF in association with adrenal autoimmunity and/or Addison's disease (2-10% of the idiopathic POF patients) is indeed an autoimmune disease. The following evidence warrants this view: 1) The presence of autoantibodies to steroid-producing cells in these patients; 2) The characterization of shared autoantigens between adrenal and ovarian steroid-producing cells; 3) The histological picture of the ovaries of such cases (lymphoplasmacellular infiltrate around steroid-producing cells); 4) The existence of various autoimmune animal models for this syndrome, which underlines the autoimmune nature of the disease. There is some circumstantial evidence for an autoimmune pathogenesis in idiopathic POF patients in the absence of adrenal autoimmunity or Addison's disease. Arguments in support of this are: 1) The presence of cellular immune abnormalities in this POF patient group reminiscent of endocrine autoimmune diseases such as IDDM, Graves' disease, and Addison's disease; 2) The more than normal association with IDDM and myasthenia gravis. Data on the presence of various ovarian autoantibodies and anti-receptor antibodies in these patients are, however, inconclusive and need further evaluation. A strong argument against an autoimmune pathogenesis of POF in these patients is the nearly absent histological confirmation (the presence of an oophoritis) in these cases (< 3%). However, in animal models using ZP immunization, similar follicular depletion and fibrosis (as in the POF women) can be detected. Accepting the concept that POF is a heterogenous disorder in which some of the idiopathic forms are based on an abnormal self-recognition by the immune system will lead to new approaches in the treatment of infertility of these patients. There are already a few reports on a successful ovulation-inducing treatment of selected POF patients (those with other autoimmune phenomena) with immunomodulating therapies, such as high dosages of corticosteroids (288-292).

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Premature ovarian failure and ovarian autoimmunity.

Ho H-N, Wu M-Y, Yang Y-S. Peritoneal cellular immunity and endometriosis. AJRI 1997; 38:400-412 © Munksgaard, Copenhagen PROBLEM: An immunologic basis has long been considered to be very important in the pathogenesis of endometriosis. Interactions of the peritoneal cells, which comprise macrophages, B cells, T cells, natural killer (NK) cells, and retrograde endometrial cells, are critical, but remain controversial, for exploring the pathogenesis of endometriosis. METHOD OF STUDY: Accumulated data from the literature were reviewed, and our data were analyzed. RESULTS: The data show that peritoneal macrophages are activated by the recurrent reflux of menstrual shedding. Humoral and local endometrial autoantibodies are detected in patients with endometriosis, but B cells are not quantitatively increased. There is decreased NK cell activity in the peritoneal cavity and peripheral blood, and this decreased activity may be related to the failure to clear out the ectopic endometrial tissue. Peritoneal T cells are predominant by Thl inflammatory cells, and these cells are impaired because of a decrease in activation (especially HLA-DR + CD4 + CD3 + population) and in the production of interleukin-2. Inflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor-α are elevated in the peritoneal fluid of women with endometriosis. CONCLUSIONS: The peritoneal NK and T lymphocytes are suppressed in women with endometriosis, but whether these immunologic deviations are the cause or the result of endometriosis is still unclear. Further studies are required to determine what role immunologic factors play in the pathophysiology of endometriosis.

Peritoneal Cellular Immunity and Endometriosis

Human reproductive failure may be a consequence of aberrant expression of immunological factors during pregnancy. Although the relative importance of immunological factors in human reproduction remains controversial, substantial evidence suggests that human leukocyte antigens (HLA), antisperm antibodies, integrins, the leukaemia inhibitory factor (LIF), cytokines, antiphospholipid antibodies, endometrial adhesion factors, mucins (MUC1) and uterine natural killer cells contribute to reproductive failure. In contrast, fewer data support the roles of anti-trophoblast antibodies, anti-endometrial antibodies, T-cells, peripheral natural killer cells, anti-HLA antibodies, blocking antibodies and suppressor cells in reproductive failure. Although immunological factors involved in reproductive failure have been studied traditionally using assays for antibodies and/or antigens, detailed research on these factors demonstrates conflicting results in humans. Maternal and fetal immunology is also difficult to investigate in humans. For these reasons, molecular assays may serve as a valuable alternative to investigate how the immune system affects reproductive outcome. In Part I of this review, immunological factors involved in human reproductive failure are summarized and critically evaluated. Immunogenetic and interacting factors in human reproductive failure will be summarized and evaluated in Part II.

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Human reproductive failure I: Immunological factors

Cytokines released by various cell subsets in the male urogenital tract are capable of markedly influencing sperm function and fertility. We determined the cytokine content in the seminal plasma of patients with unexplained infertility and correlated the results with urogenital infections and sperm parameters. Routine sperm parameters, bacterial culture of seminal plasma and blood follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were obtained from 14 infertile males and 8 healthy control subjects. Interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF alpha) levels in the seminal plasma were measured by enzyme-linked immunosorbent assay (ELISA). IL-1 beta, IL-6, and TNF alpha levels in the seminal plasma were negatively correlated with the number of progressively motile sperm, but there was no correlation with total sperm counts, viability, pH, morphological alterations, type of abnormality, and hormone parameters. Cytokine levels were significantly elevated in seminal plasma exhibiting bacterial or mycoplasmal infections of the urogenital tract. Urogenital infections lead to an release of inflammatory cytokines, most probably by immunocompetent cells of the lymphocyte/macrophage origin. Cytokines such as IL-1, IL-6, and/or TNF alpha might influence sperm motility via direct or indirect effects, resulting in reduced mucosa penetration properties. Therefore, our data suggest that cytokines may be involved in reduced male fertility.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.1939-4640.1996.tb01765.x

Cytokine levels in the seminal plasma of infertile males

Anti-sperm antibodies, detected by agglutination, immobilization, microcytotoxicity and immunobead-binding assays.

Endometrial antigens involved in the autoimmunity of endometriosis.

Sera from three fertile men and four infertile men without sperm antibodies, 17 infertile men with sperm antibodies in serum and seminal plasma (S.P.), and 25 infertile men with sperm antibodies in S.P. were tested by Western Blot analysis against sperm membrane extracts and S.P. from fertile nonautoimmune men and infertile autoimmune men. Sera from fertile men reacted against common antigens with molecular weights (MW) of 28, 38, 48, 60, and 68 kD present on sperm from autoimmune and nonautoimmune men and special antigen of MW 76 kD on the sperm of fertile men. Sera from 15 of 17 (88%) autoimmune infertile men with sperm antibodies in serum and S.P. detected special antigens with MW of 58 kD (sera reactivity in 47% of these men), 43kD (in 29%), 30 kD (in 24%), 35 kD (in 18%), 52 kD (in 12%), 41 kD (in 6%), and 71 kD (in 6%) on the sperm of autoimmune men in addition to the common antigens. Sera from 15 of 25 (60%) men with sperm antibodies in their S.P. showed reactivity to special antigens with MW 52 kD (in 20%), 35 kD (in 16%), 41 kD (in 16%), 58 kD (in 8%), 70/71 kD (in 8%), 30 kD (in 8%), and 56 kD (in 4%). Sera from 18 of 42 (43%) infertile men with sperm antibodies also detected special antigens of MW 26, 46, and 76 kD present only in fertile men's sperm. Sera from only 15 of 42 (36%) autoimmune infertile men reacted against special antigens with MW 17, 20, 23, 30, 43, and 58 kD in the seminal plasma of autoimmune infertile men. Cross-absorption studies using sera from autoimmune infertile men further supported the presence of unique antigens on their sperm. It is proposed that the special antigens present on the sperm from infertile autoimmune men may be responsible for the enhanced humoral and cell-mediated immune responses observed in these men.

Special antigens on sperm from autoimmune infertile men.

The effect of cytotoxic sperm antibodies and native complement in the serum and secretions from 40 fertile and 93 infertile couples on in vitro sperm survival and motion characteristics was studied. Sperm survival in vitro was unaffected by sera from fertile and infertile subjects without cytotoxic sperm antibodies and from infertile men with antibodies to control but not to autologous sperm. Sperm survival was reduced (P less than .001) by sera from infertile men with antibodies to autologous sperm or to antologous and control sperm and from women with cytotoxic antibodies to sperm from both. Sera from fertile couples without sperm antibodies enhanced sperm swimming speed and motility index (P less than .0001). Sera from infertile women with or without cytotoxic sperm antibodies did not affect sperm motility. Sperm survival and motility were reduced by seminal plasma from infertile men with cytotoxic antibodies to autologous and/or control sperm. Seminal plasma from fertile men enhanced sperm survival. Cervical mucus from infertile women with antibodies to autoimmune husbands' sperm or to husbands' and control sperm inhibited sperm motion, whereas cervical mucus from infertile women without sperm antibodies and women with antibodies to control sperm failed to have any effect. It is concluded that cytotoxic sperm antibodies developed through exposure to sperm antigens in autoimmune infertile men decrease in vitro sperm survival and/or motility.

Studies on sperm survival and motility in the presence of cytotoxic sperm antibodies.

Semen samples from 55 fertile nonautoimmune and 44 infertile sperm autoimmune men were evaluated by computerized sperm cell motion analysis. Sperm counts (mean ± SEM, 59.6 ± 10.3 ± 106 per ml), motility (39.0 + 4.6%), mean swimming speed (μm/sec, 26.5 ± 0.9), mean linearity (straight line distance of the cell track divided by the actual track length and multiplied by 10, 6.5 + 0.2), and motility index (% motility ± mean speed, 10.7 ± 1.4) in 23 men with significant titers of cytotoxic sperm antibodies in their serum and seminal plasma were less (p<0.0001) than those in the fertile controls. However, these parameters were comparable in 18 men with sperm antibodies in their seminal plasma but not in their serum, and the control group. Infertile men with serum cytotoxic sperm antibodies had more sperm cells swimming at 11–30 μm/sec, and fewer moving at 31 μm or higher; this was in contrast to results obtained from fertile men (p < 0.05). The percentages of sperm cells moving at 21–30 μm/sec were increased, while those moving at 51–60 μm/sec were decreased in men with seminal plasma sperm antibodies, versus controls. Spermatozoa with low linearities (≤6) were higher (p<0.05) in men with serum and seminal plasma cytotoxic sperm antibodies than in the fertile group. The numbers of sperm cells moving at a linearity of ten, on the other hand, were lower in the infertile men with sperm antibodies in the serum and seminal plasma (21.8 ± 2.7 versus 36.4 ± 1.3; p< 0.00001) or seminal plasma only (28.0 ± 1.5; p< 0.0001). We suggest that the spermatozoa of men with cytotoxic sperm antibodies in their serum and seminal plasma have poorer sperm motion characteristics than those of fertile men.

H.O. Williamson

Papers

Anti-sperm antibodies, detected by agglutination, immobilization, microcytotoxicity and immunobead-binding assays.

Endometrial antigens involved in the autoimmunity of endometriosis.

Special antigens on sperm from autoimmune infertile men.

Studies on sperm survival and motility in the presence of cytotoxic sperm antibodies.

Motion characteristics of spermatozoa from men with cytotoxic sperm antibodies.