Human Reproduction Update 1998, Vol. 4, No. 2 pp.

169–176

E

European Society for Human Reproduction and Embryology

Autoantibodies in infertility: current opinion
Norbert Gleicher
The Center for Human Reproduction, The Foundation for Reproductive Medicine, Inc. and the Department of Obstetrics and Gynecology, University of Illinois at Chicago

TABLE OF CONTENTS Historical notes The autoantigens and autoantibodies Neuroimmunology Clinical utility and conclusions References 169 169 174 174 175

central nervous system (CNS) level will have considerable impact on infertility. This review will therefore report on autoimmune abnormalities at CNS and gonadal levels and on non-organ-specific abnormalities systemically. It will also separate female from male findings since they are usually distinct, though both can often be found in a single couple presenting with an infertility problem. The autoantigens and autoantibodies
In the female Premature ovarian failure

Historical notes The concept of autoimmune-related infertility has remained controversial. Traditionally, abnormal autoimmune function has been implicated as a contributing factor to female as well as male infertility. In the female, abnormal autoimmunity primarily relates to autoantibody activity against ovarian tissue components, whereas in the male, abnormal autoimmunity, believed to be clinically relevant, is mostly directed against the spermatozoon itself. Historically, abnormal autoimmune function has been seen as a rather organ-specific process in both female and male infertility, with either ovarian or testicular antigens as the primary targets. In recent years it has, however, also been recognized that additional, and possibly less organ-specific, processes of autoimmune nature may play a role. For example, female infertility patients have demonstrated a significantly higher incidence of nonorgan-specific autoantibody abnormalities. The incidence of such autoantibody abnormalities appears to be positively correlated to increasing intractability of infertility (Gleicher et al., 1993). On the other hand, there is doubt as to whether such non-organ-specific autoantibodies themselves cause disease or only serve as epiphenomena for a still undefined immunological defect which causes infertility (Gleicher, 1994). Lastly, the newly evolving field of neuroimmunology needs to be considered here. Since reproductive function is under neuroendocrine control, autoimmune processes that affect the hypothalamic–pituitary–gonadal axis at the
Address for correspondence: 750 North Orleans Street, Chicago, IL 60610, USA

The most clearly defined condition of autoimmuneassociated infertility is premature ovarian failure, defined as the cessation of menses due to failing ovaries before the age of 40 years and consequently increased peripheral gonadotrophin levels (Blumenfeld et al., 1993). Its incidence is poorly defined but it has been estimated to occur in 2–10% of women with amenorrhoea and in 1–3% of females in the general population, with autoimmune abnormalities being detectable in up to 66% of cases (Cohen and Speroff 1991). This observation formed the basis for the current understanding that a large percentage of premature ovarian failure cases are due to an autoimmune aetiology. Premature ovarian failure has thus been associated with rheumatoid arthritis, myasthenia gravis, candida endocrinopathy, pseudoparathyroidism, Addison’s disease and, especially, thyroid disorders (Cohen and Speroff, 1991). Antithyroid antibodies can be found in approximately one-third of premature ovarian failure patients, based on rather dated studies (Coulam, 1982). One can therefore assume that with current assay techniques, which have significantly greater sensitivity, an even greater percentage of premature ovarian failure patients would be positive for antithyroid antibodies. Premature ovarian failure can also be part of the multiple autoimmune endocrine deficiency syndrome. It is therefore not surprising that Addison’s disease can be

zona pellucida and/or steroid-producing cells within the ovary. mice in this model also developed gastritis with accompanying antibodies. caused autoimmune oophoritis and gastritis with corresponding serum autoantibodies in the recipient in 73% of animals. however. however. neonatal thymocytes. Attempts to identify target autoantigens may therefore be futile and investigations may have to focus on disease stages that precede premature ovarian failure. or phenotypically mature adult thymocytes. 1991) Moreover. By the time a woman is diagnosed. This observation suggests that the T-cell response. Especially the validity of an alleged association with generic antibodies to zona pellucida seems questionable. (1989) who reported antibody activity against the unoccupied luteinizing hormone (LH)/human chorionic gonadotrophin (HCG) receptor as well as the hormone–receptor complex of the bovine corpus luteum. is rare and therefore cannot be seen as the universal precursor. (1988) reported in their mouse model that oophoritis was characterized by the presence of circulating antibodies to ooplasm.. Blumenfeld et al. The investigation of autoantibodies may be severely hampered by the fact that premature ovarian failure represents an end-stage of disease. at least in its clinical manifestation. Detection methods..Gleicher diagnosed in up to 20% of premature ovarian failure patients (Cohen and Speroff. Von Weissenbruch et al. rather than the autoantibody response. 1983).170 N. Autoimmune oophoritis has quite clearly been established as a precursor lesion to premature ovarian failure (Biscotti et al. Unfortunately. More interesting observations suggest that the observed antiovarian activity may be geared at gonadotrophin receptors (Chiauzzi et al. the authors did not investigate women with premature ovarian failure. also the target antigen for the autoimmune attack on her ovary. Tang and Farman. In resistant ovary syndrome. (1991) suggested that an immunoglobulin (Ig)G fraction can block ovarian granulosa cell growth in vitro and thus potentially in vivo contribute to the occurrence of resistant ovary syndrome. oophoritis can be transferred to young mouse recipients and the disease can be prevented by reconstitution with normal adult spleen cells. Circulating antibodies in ovarian tissue have been widely reported (Cohen and Speroff. from the same research group. transferred from normal BALB/c mice to syngeneic athymic nu/nu (or SCID) mice. thymectomy has been shown to induce an autoimmune oophoritis (Miyake et al. 1982. though they are highly resistant to stimulation by gonadotrophins (Blumenfeld et al. the ovary still contains follicles. Smith et al. ZP3 is the sperm-binding site of the zona pellucida. adoptive transfer of CD4+ T-cells in this mouse model caused oophoritis without an antibody response to the zona. 1991). 1988. (1993) reported an astonishing 40% conception rate in premature ovarian failure patients treated with routine ovulation induction and non-specific immunosuppression with corticosteroids.. They suggested that their treatment rescued follicles in immunologically induced resistant ovary syndrome patients on the way to premature ovarian failure. they were unable to substantiate the claim of others that suppressor cells are normally specific for ovarian antigen. These . The peptide induced T-cell as well as antibody responses. However. Since we were unable to demonstrate autoimmune differences between women with and without resistance to stimulation in a well-defined infertility population (Gleicher et al. In mouse models. 1994). (1991) speculated that an endogenous ovarian antigen may be required to activate effector T-cells. presumably. Kenneth Tung’s group (Smith et al.. Rhim et al. This was also suggested by Moncayo et al. and transfer of oophoritis can be abrogated by an antibody to CD4 (but not a CD8 antibody). Specific autoantigens which elicit abnormal autoimmune responses within the ovary have so far not been identified in the human. only relatively little is known on the precursor stages to autoimmune-induced premature ovarian failure. Unfortunately. Miyake et al. Whether antibody activity to gonadotrophin receptorrelated epitopes is present in women with resistant ovary syndrome is at best questionable. may have primacy in this model. Interestingly.. Unfortunately. Smith et al.. this condition. The effector cells are CD4+. 1992) also demonstrated the connection between oophoritis and gastric autoimmune disease (gastritis) by showing that neonatal splenocytes. we doubt the concept of resistant ovary syndrome as a precursor stage to premature ovarian failure. a fact further suggested by the finding that peptides of as little as eight amino acids (Asn-Ser-Ser-Ser-Ser-Glu-Phe-Glu) caused oophoritis but not an antibody response. Such antiovarian activity was especially prevalent in infertile women and in women with polyendocrinopathy. were also able to induce ovarian autoimmunity with a 15 amino acid ZP3 peptide (Cys-Ser-Asn-Ser-Ser-Ser-Ser-Glu-PheGln-Ile-His-Gly-Pro-Arg).. also vary widely. CD4+ neonatal spleen cells and CD4+CD8– adult thymocytes were required for the induction of autoimmune disease. 1993). she has by definition exhausted her follicular supply and. Some authors have suggested that the so-called resistant ovary syndrome represents such a precursor stage. 1989). The alleged association of premature ovarian failure with a variety of non-specific antiovarian antibodies therefore needs to be viewed with some caution. 1991). (1992).

Whether these abnormalities of immune function are causally related to infertility has not yet been determined... Since in-vitro fertilization (IVF) generally represents the final treatment option. Fisch et al. unpublished observations). Moreover. Unexplained infertility and endometriosis Unexplained infertility and endometriosis.. The incidence of such immunological abnormalities increases in infertile women in direct correlation to the intractability of their condition. at least on a theoretical basis. a recent study of women with rheumatoid arthritis does exactly that (Lee Nelson et al. 1993). A similar observation has been reported in IVF patients (Dmowski et al. antibody and cellular abnormalities can be seen in both conditions locally within the peritoneum as well as systemically (Gleicher et al. were initially implicated amongst non-organ-specific antibodies. 1988). as well as autoantibody abnormalities have been widely reported in women afflicted by premature ovarian failure (Cohen and Speroff. due to the similarity of the ZP3 protein in mouse and human (67% homology) a similar process may be involved in human premature ovarian failure. 1993).. . This is. A multitude of immunological studies strongly suggest that a broadly based activation of the immune system is responsible for both of these clinical conditions. Coulam and Stern (1991) concluded that all of the immunological findings described above and the increased prevalence of HLA DR3 in women with premature ovarian failure strongly support a cytokine-mediated autoimmune aetiology for at least some cases. 1994). For this purpose the reader is referred to another review (Gleicher et al. Histological findings compatible with oophoritis. antibodies to phosphatidylserine have been most often mentioned (Rote et al. and especially antibodies to cardiolipin. (1990) suggested that the induction of class II major histocompatibility complex antigen expression in human granulosa cells by interferon-γ may contribute to the process of premature ovarian failure.. antiphospholipid antibodies. classically associated with a significant level of autoantibody abnormalities. may not be the best target for an immune response and that some cell membrane-based phospholipids may. thus at this point abnormal (auto)immune function may be (causally) associated with decreased fecundity in females. In a recent study we demonstrated that infertile women also exhibit a high incidence of other immunological abnormalities. 1989.. As noted before. 1991). such as monoclonal and polyclonal gammopathies. at least in part. generally considered distinct clinical entities. is characterized by autoantibody abnormalities. 1995). are of exceedingly poor quality. both patient groups also demonstrate (similar to premature ovarian failure patients) a remarkably broad spectrum of T-cell abnormalities. IgA deficiency and abnormalities in IgG subclasses (N. 1989. be better candidates as epitopes that initiate an antibody response.. Considerable evidence suggests that the presence of certain non-organ.. especially in naturally occurring non-organ-specific autoantibody groupings. 1990). Gleicher et al. changes in total T-cell counts. Amongst those.. We have therefore raised the question whether endometriosis does not represent a classical autoimmune disease (Gleicher et al. Since then. Lastly. 1987.. Our understanding differs from that of many of our colleagues working in this area. As also previously described in conjunction with premature ovarian failure. An initial association was made with the presence of lupus anticoagulant.Antibodies in infertility 171 investigations also suggested that. 1987). in fact. Nelson et al. and recurrent pregnancy loss was the first clinical condition to be associated with abnormal autoimmune function. Concomitantly.Gleicher et al.and organ-specific autoantibodies is predictive of an increased miscarriage risk. Therefore a considerable percentage of women with intractable infertility demonstrate an abnormal immunological profile which. this immunological profile is characterized by autoantibody abnormalities. 1991.. one could expect the highest incidence of immunological abnormalities amongst IVF patients. Birkenfeld et al. Older studies. 1990). as a primarily intracellular epitope. 1991. 1993). as reported by us and confirmed by a variety of other investigators (El Roeiy et al. 1994. which was later expanded to phospholipid antibodies. Pregnancy loss Immunological pregnancy loss also represents a form of infertility. in our opinion represent a continuum of disease. some authors have argued that cardiolipin. It would exceed the framework of this review to explain in detail all the scientific data in support of our statement. while traditional textbooks do not associate classical autoimmune diseases with infertility. usually associated with classical autoimmune diseases. and especially anticardiolipin antibody (Gleicher et al. the case... We have been able to demonstrate that a reduction in abnormal autoantibody levels in women with endometriosis appears to improve fecundity (El Roeiy et al. which failed to demonstrate such an association. Hill and Anderson... Confino et al. Hill et al.

in a recent review. moreover. We demonstrated that women who present for infertility treatment demonstrate the same increased incidence of monoclonal and polyclonal gammopathies.Gleicher A number of published studies have exclusively investigated anticardiolipin responses in patients who repeatedly abort or are at risk of doing so. similar to most other autoimmune conditions. are familial and may be linked to the presence of certain HLA loci. (1996). which therefore requires a much more broadly based immunological evaluation.. selective IgA deficiency and IgG subclass abnormalities as patients with classical autoimmune diseases (N. A few researchers. namely antiphosphatidylserine. On the one hand Shoenfeld’s group has been able to develop an animal model for cardiolipin antibody-induced pregnancy loss (and. Yet those same investigators pursue exactly such a course of action in autoimmune-associated reproductive failure.. However. their paper represented a wide-ranging survey of the various theories of immunological pregnancy loss rather than a focused description of a possible pathophysiology. What triggers the expression of such a genetic predisposition and its manifestation as reproductive failure is undetermined. rather than autoimmune-caused pregnancy loss.. He suggests that the frequent occurrence of autoantibodies in women with recurrent pregnancy loss is due to a Th1 response against the trophoblast. Considering an apparent increase in this phenomenon. have argued that the arbitrary selection of one or two antiphospholipid specificities simply does not make sense. demonstrate an elevated level of natural killer (NK) cell activity (Aoki et al.. 1993). In contrast. represents a likelihood of a T-cell defect. remain without an opinion about the mechanism by which autoantibodies contribute to pregnancy loss. may manifest itself in abnormal autoantibody production in addition to many other epiphenomena. such as endometriosis. 1993). even those investigators who have argued against cardiolipin as the ‘ideal’ epitope for investigation. Since some of the previously noted infertility-associated conditions. neither clinically nor from a conceptual immunological viewpoint.. Our opinion represents that of a minority insofar as we have reached the conclusion that a direct autoantibody-mediated process is probably not the cause of repeated pregnancy loss (Gleicher. these non-specific findings suggest that autoantibodies serve as an epiphenomenon rather than as a direct pathogen (Aoki et al. 1995a).172 N.. we were able to demonstrate that habitually aborting women. Once again.. a contributing genetic factor is likely (Gleicher et al. Moreover. it is very difficult to understand. incidentally. how such vastly different autoantibody specificities such as non-organ-specific antiphospholipid antibodies and organ-specific antithyroid antibodies. characteristic of an overall activation of the immune function (Gleicher. However. Lim et al. can be responsible for basically the same processes that lead to pregnancy loss (Gleicher et al. have usually only concentrated on one additional antiphospholipid. 1994). and ourselves. although a co-factor-dependent single assay was superior to a co-factor-independent single assay. 1992). at least on a theoretical basis. We thus currently postulate that autoimmune-associated reproductive failure in the female. 1989. 1993). 1992). as is also postulated in classical autoimmune diseases. Such an approach could be equated to attempts to diagnose systemic lupus erythematosus (SLE) simply through one single antibody test (Gleicher et al. a broadly based panel of co-factor-independent assays is at least as sensitive in detecting the immunological abnormality associated with reproductive failure. We have demonstrated that. 1995b). Pratt et al. whether in conjunction with infertility or repeated pregnancy loss. Most rheumatologists would argue that such an approach to SLE would be clinically naive and immunologically unsound since SLE.. even prior to their miscarriage. an observation that potentially suggests a direct antibody effect (Bakimer et al. The reader may have noticed that this review only refers to autoimmuneassociated pregnancy loss. This view is based on many conflicting observations that have been reported in the literature. infertility). 1994). also suggested that the clinical activity of antiphospholipid antibodies was largely restricted to those specificities that were only detectable with a co-factor (β2-glycoprotein I)-dependent assay system (Matsuura et al. does not represent a monoclonal event. . both independent risk markers for pregnancy loss. On the other hand. we have advocated for many years the concept of autoimmune-associated pregnancy loss as a polyclonal event.Gleicher et al. unpublished observations). Christiansen (1996) in a recent review came to similar conclusions.. All of these observations point towards an immunological defect at the T-cell level which. An all-encompassing hypothesis might conclude that the presence of autoantibody abnormalities represents only an epiphenomenon. it would be tempting to speculate that an infectious agent may be the culprit. 1993). Such a generalized activation of the immune system is not uncommon in patients with classical autoimmune diseases and has been repeatedly described in women with immunologically associated infertility as well as pregnancy loss (Gleicher et al.. Recent data. the nature of which has so far not been determined.

The clinical significance of antisperm antibodies has. infectious or unknown insults. as with autoimmune oophoritis. Even though autoimmune orchitis is clearly a cause of male infertility. Antibody activity to spermatozoa has been demonstrated in males and in females. Autoimmunity to sperm antigens is therefore avoided through the prevention of their exposure to immunoreactive cell populations. However. sperm–egg interaction and. the majority of orchitis cases have no known aetiology and. appears to be mediated by IgG and IgM antisperm antibodies (Bronson and Fusi. sperm capacitation and acrosome reaction. However. Autoimmune orchitis has been comprehensively reviewed by Mahi-Brown (1994). Spermatozoa must undergo capacitation and acrosome reaction before being able to fuse with the zona pellucida of the oocyte in the first step of the fertilization process. is a T-cell-mediated condition regulated by immunological factors under genetic control. As with oophoritis. 1994). Since this review addresses only autoantibodies. Orchitis not infrequently follows viral infection. responses. demonstrating considerable infiltrates by monocytes. with an infectious agent. in contrast. since spermatogenesis is not initiated until puberty. autoimmune processes can also affect the gonads and in this case cause orchitis. This is at least partially due to the fact that the true incidence of the condition in men is not known (Mahi-Brown. 1994). with mumps representing the most frequent and best investigated association. as in the female. Histological examination of affected testes reveal immunoglobulin deposits which correlate in density to the severity of the disease. not dissimilar to the proposed cross-reactivity between thyroid and ovarian antigens in females. since orchitis is (similar to oophoritis) usually only diagnosed in advanced stages. As comprehensively reviewed by Bronson and Fusi (1994). Considerable data from both human and animal experiences suggest that antisperm antibodies can affect fertility in a variety of ways. 1994). Both IgA and IgG antibody isotypes appear capable of this inhibition. further discussion of antisperm immunity will concentrate on the male. little is also known about the aetiology and pathophysiology of this condition in humans. These antibodies may represent a response to severe tissue injury rather than be a cause of disease. Complementmediated sperm immobilization. It has been suggested that some antisperm antibodies can induce a premature acrosome reaction. 1991. Skakkebaek. 1994). It has been suggested that molecular mimicry. Since in men the antigen causing the initial insult is usually unknown. lastly. To what extent antisperm antibodies cause infertility has remained controversial. when self-tolerance develops. In females it obviously does not represent an autoimmune event. Sperm antibodies Antisperm antibodies represent an autoimmune response against a variety of tissue-specific sperm antigens which are not present during embryonic life. 1995. Mechanisms that can affect the fertility potential of a male include a effect on sperm transport. carrying shared epitopes with testicular tissues. remained controversial in both genders. 1994). There appears to be a consensus that antisperm activity in males has to reach higher titres than in the female to be considered clinically significant. no significant progress in our understanding of the condition in the human seems likely unless the disease-inducing antigens can be identified (Mahi-Brown. in analogy to female oophoritis. in contrast to animals. possibly non-specific. 1991). thus shortening the life . 1994). Orchitis can also be focal in nature. A cross-reactivity between salivary gland and testicular antigens has been suggested (Mahi-Brown. 1994). Coulam and Stern. a possible systemic effect under which the presence of antisperm antibodies is only reflective of a general immune activation and thus represents only one amongst many. could be a contributing factor. at least in animal models.Antibodies in infertility 173 In the male Autoimmune reproductive failure in the male is even more controversial. The classically defined autoimmune aetiology of male reproductive failure is the presence of antibodies to spermatozoa. With regard to sperm transport. vasectomy in men does not lead to orchitis (Mahi-Brown. Such an event can take place as a consequence of a variety of traumatic. it is often overlooked. Not even the presence of antibodies to testicular components in the circulation is informative. resulting in a high degree of antithyroid antibodies in women with premature ovarian failure (Cohen and Speroff. Various animal models and limited human experience have led to the current opinion that this condition. antisperm autoimmunity will be generated if the blood–testis barrier between Sertoli cells is breached. thus resembling animal models actively immunized with testis homogenates (Mahi-Brown. even in authoritative reviews (Howard. CD4+ positive T-cells appear to play a crucial role in inducing and suppressing the disease. However. however. investigations have suggested that the spermatozoon’s capability to pass through the cervical mucus is affected if spermatozoa are coated by sperm antibodies.

More importantly. 1993). suggests that hyperprolactinaemia may affect fecundity not only by affecting ovulation and implantation through hormonal but also through immunological processes. Its effect on immune function in general and on Autoimmunity to gonadotrophins has been suggested by a number of authors. In the human model the data have remained controversial. This issue has also repeatedly entered the literature in reference to the exogenous administration of gonadotrophic drugs. Autoimmunity to gonadal hormones was suggested ~15 years ago when some authors reported the induction of anti-oestrogenic autoantibodies after oral contraceptive use. The interested reader is therefore referred to the recent review by Reichlin (1993). Gonadal hormones do. exert considerable effects on the immune system and can greatly affect autoimmune conditions. have been shown to block the acrosome reaction and thus prevent fertilization.174 N. which represents standard therapy for most infertility couples (Jones and Toner. Hyperprolactinaemia in the female can directly affect ovulation and probably also implantation. 1997). Convincing evidence that such autoantibodies do exist is lacking. Polyclonal autoimmune activation may also result in production of sperm antibodies. This hypothesis obviously requires a scientific confirmation. Gonadotrophins Prolactin. though the whole concept has remained controversial. semen quality can be affected. other antisperm antibodies. The high incidence of hyperprolactinaemia in women with infertility problems.. hypophysectomy equally suppresses the production of antibodies. This increasing resistance to stimulation by gonadotrophins has been attributed to the development of autoantibodies to gonadotrophins. which mimics the presence of significant autoimmune abnormalities in this population (Gleicher 1993). 1992). Without being able to address all those interactions in detail within the framework presented here. many have demonstrated exactly the opposite. As previously noted in this review. Bromocriptine. The presence of such antibodies has never been confirmed. is a hormone of major importance for reproductive processes of both female and male. While some authors have suggested that fertilization is impaired in the presence of antisperm antibodies. 1994). increasing dosages of medication may be required. however. In contrast. produced by lactotrope cells within the anterior pituitary.. Reichlin (1993) exhaustively reviewed the topic. Human data are primarily derived from clinical IVF experiences which cannot always be equated with in-vivo conditions. especially in various animal models. This observation has led to the conclusion that some antisperm antibodies and at least some classical non-organ-specific autoantibodies can inhibit the fertilization process in identical fashion (Gleicher et al. Observational studies in treated patients have suggested that with increasing numbers of stimulation cycles. Prolactin enhances antibody production and.. Sperm–egg interaction has in recent years been quite well investigated. Saling et al. 1985). Treatment with bromocriptine also ameliorates experimental autoimmune encephalitis (Riskind et al. exerts a similar effect on antibodies as does a hypophysectomy. Hyperprolactinaemia autoimmune function in particular has been reviewed (Rabin. immune and endocrine systems are seen as an intertwined web of signals and responses. we were also able to demonstrate that mouse antisperm antibodies which were able to inhibit fertilization. the following will be a brief summary of the most salient points. . A recent symposium on microcontraception also failed to report on the occurrence of any significant autoimmune responses with newer generations of contraceptives (Anank Kumar. while either prolactin or the administration of growth hormone appears able to induce antibody production. Hyperprolactinaemia represents an extremely common finding in women but is seen much less frequently in males with infertility problems. as expected. We were able to demonstrate this indirectly by showing that individuals with significant sperm antibody levels concomitantly demonstrated a significant degree of non-organ-specific autoantibody abnormalities. In the male. Nowhere is this more apparent than in the fields of neuroendocrinology and neuroimmunology. Neuroimmunology Increasingly.Gleicher span of available spermatozoa for fertilization. It would exceed the framework of this review to describe those any further. gonadal failure in the female could be caused by antigonadotrophic activity by autoantibodies. which effectively suppresses prolactin production. 1993. mediated by often identical messengers of information. however. were completely cross-reactive with some nonorgan-specific autoantibodies. In various animal models sperm antibodies have been able to prevent sperm binding to zona pellucida-based receptors.

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(1982) Inhibition of follicle-stimulating hormone receptor binding by circulating immunoglobulins. J. 54. Confino. E.H. Med. Steril.. and inter-assay variability between laboratories can be considerable (Peaceman et al. 74. 84. Am. 1993). H. Am.). 158. Steril. Welch. A. A. Reprod. J.Antibodies in infertility 175 Clinical utility and conclusions Autoantibodies that have been associated with infertility are often non-specific to the disease state. Ikeda. J. N.. if specific. 89. 162. N.M. 168. J. Fertil. A.. 1145–1149. Obstet. (1994) Autoimmune orchitis. Pratt. 534–540. N. Chiauzzi.B.J. 55. N.. J. 115–140. 747–748. 54. et al.. Obstet.. and Fleisher. Faris.. Surv. V. F. Christiansen. Invest. The clinical utilization of autoantibodies for diagnostic purposes is currently very limited and restricted to a number of research centres.. Benz. (1991) Premature ovarian failure: Update. J..... (1989) Cystic ovarian enlargement resulting from autoimmune oophoritis.M. 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