Autoantibodies in infertility current opinion by mikeholy

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									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                                                              central nervous system (CNS) level will have considerable
                                                                               impact on infertility.
Historical notes                                                  169            This review will therefore report on autoimmune
The autoantigens and autoantibodies                               169          abnormalities at CNS and gonadal levels and on
Neuroimmunology                                                   174          non-organ-specific abnormalities systemically. It will also
Clinical utility and conclusions                                  174          separate female from male findings since they are usually
References                                                        175          distinct, though both can often be found in a single couple
                                                                               presenting with an infertility problem.

Historical notes                                                               The autoantigens and autoantibodies
                                                                               In the female
The concept of autoimmune-related infertility has
remained controversial. Traditionally, abnormal auto-                          Premature ovarian failure
immune function has been implicated as a contributing                          The most clearly defined condition of autoimmune-
factor to female as well as male infertility. In the female,                   associated infertility is premature ovarian failure, defined
abnormal autoimmunity primarily relates to autoantibody                        as the cessation of menses due to failing ovaries before the
activity against ovarian tissue components, whereas in the                     age of 40 years and consequently increased peripheral
male, abnormal autoimmunity, believed to be clinically                         gonadotrophin levels (Blumenfeld et al., 1993). Its
relevant, is mostly directed against the spermatozoon itself.                  incidence is poorly defined but it has been estimated to
   Historically, abnormal autoimmune function has been                         occur in 2–10% of women with amenorrhoea and in 1–3%
seen as a rather organ-specific process in both female and                     of females in the general population, with autoimmune
male infertility, with either ovarian or testicular antigens as                abnormalities being detectable in up to 66% of cases
the primary targets. In recent years it has, however, also                     (Cohen and Speroff 1991). This observation formed the
been recognized that additional, and possibly less                             basis for the current understanding that a large percentage
organ-specific, processes of autoimmune nature may play                        of premature ovarian failure cases are due to an
a role. For example, female infertility patients have                          autoimmune aetiology. Premature ovarian failure has thus
demonstrated a significantly higher incidence of non-                          been associated with rheumatoid arthritis, myasthenia
organ-specific autoantibody abnormalities. The incidence                       gravis, candida endocrinopathy, pseudoparathyroidism,
of such autoantibody abnormalities appears to be                               Addison’s disease and, especially, thyroid disorders
positively correlated to increasing intractability of                          (Cohen and Speroff, 1991). Antithyroid antibodies can be
infertility (Gleicher et al., 1993). On the other hand, there is               found in approximately one-third of premature ovarian
doubt as to whether such non-organ-specific autoanti-                          failure patients, based on rather dated studies (Coulam,
bodies themselves cause disease or only serve as                               1982). One can therefore assume that with current assay
epiphenomena for a still undefined immunological defect                        techniques, which have significantly greater sensitivity, an
which causes infertility (Gleicher, 1994).                                     even greater percentage of premature ovarian failure
   Lastly, the newly evolving field of neuroimmunology                         patients would be positive for antithyroid antibodies.
needs to be considered here. Since reproductive function is                    Premature ovarian failure can also be part of the multiple
under neuroendocrine control, autoimmune processes that                        autoimmune endocrine deficiency syndrome. It is
affect the hypothalamic–pituitary–gonadal axis at the                          therefore not surprising that Addison’s disease can be
Address for correspondence: 750 North Orleans Street, Chicago, IL 60610, USA
170   N.Gleicher

diagnosed in up to 20% of premature ovarian failure             astonishing 40% conception rate in premature ovarian
patients (Cohen and Speroff, 1991).                             failure patients treated with routine ovulation induction
   Specific autoantigens which elicit abnormal                  and non-specific immunosuppression with corticosteroids.
autoimmune responses within the ovary have so far not           They suggested that their treatment rescued follicles in
been identified in the human. Circulating antibodies in         immunologically induced resistant ovary syndrome
ovarian tissue have been widely reported (Cohen and             patients on the way to premature ovarian failure.
Speroff, 1991). Detection methods, however, also vary              Autoimmune oophoritis has quite clearly been
widely. The alleged association of premature ovarian            established as a precursor lesion to premature ovarian
failure with a variety of non-specific antiovarian antibodies   failure (Biscotti et al., 1989). Unfortunately, this condition,
therefore needs to be viewed with some caution. Especially      at least in its clinical manifestation, is rare and therefore
the validity of an alleged association with generic anti-       cannot be seen as the universal precursor. In mouse models,
bodies to zona pellucida seems questionable. More               thymectomy has been shown to induce an autoimmune
interesting observations suggest that the observed anti-        oophoritis (Miyake et al., 1988; Smith et al., 1991)
ovarian activity may be geared at gonadotrophin receptors       Moreover, oophoritis can be transferred to young mouse
(Chiauzzi et al., 1982; Tang and Farman, 1983). This was        recipients and the disease can be prevented by
also suggested by Moncayo et al. (1989) who reported            reconstitution with normal adult spleen cells. The effector
antibody activity against the unoccupied luteinizing            cells are CD4+, and transfer of oophoritis can be abrogated
hormone (LH)/human chorionic gonadotrophin (HCG)                by an antibody to CD4 (but not a CD8 antibody). Smith et
receptor as well as the hormone–receptor complex of the         al. (1991) speculated that an endogenous ovarian antigen
bovine corpus luteum. Such antiovarian activity was             may be required to activate effector T-cells; however, they
especially prevalent in infertile women and in women with       were unable to substantiate the claim of others that
polyendocrinopathy. Unfortunately, the authors did not          suppressor cells are normally specific for ovarian antigen.
investigate women with premature ovarian failure.               Miyake et al. (1988) reported in their mouse model that
   The investigation of autoantibodies may be severely          oophoritis was characterized by the presence of circulating
hampered by the fact that premature ovarian failure             antibodies to ooplasm, zona pellucida and/or
represents an end-stage of disease. By the time a woman is      steroid-producing cells within the ovary. Interestingly,
diagnosed, she has by definition exhausted her follicular       mice in this model also developed gastritis with
supply and, presumably, also the target antigen for the         accompanying antibodies. Kenneth Tung’s group (Smith
autoimmune attack on her ovary. Attempts to identify            et al., 1992) also demonstrated the connection between
target autoantigens may therefore be futile and                 oophoritis and gastric autoimmune disease (gastritis) by
investigations may have to focus on disease stages that         showing that neonatal splenocytes, neonatal thymocytes,
precede premature ovarian failure.                              or phenotypically mature adult thymocytes, transferred
   Unfortunately, only relatively little is known on the        from normal BALB/c mice to syngeneic athymic nu/nu (or
precursor stages to autoimmune-induced premature                SCID) mice, caused autoimmune oophoritis and gastritis
ovarian failure. Some authors have suggested that the           with corresponding serum autoantibodies in the recipient
so-called resistant ovary syndrome represents such a            in 73% of animals. CD4+ neonatal spleen cells and
precursor stage. In resistant ovary syndrome, the ovary still   CD4+CD8– adult thymocytes were required for the
contains follicles, though they are highly resistant to         induction of autoimmune disease.
stimulation by gonadotrophins (Blumenfeld et al., 1993).           Rhim et al. (1992), from the same research group, were
Whether antibody activity to gonadotrophin receptor-            also able to induce ovarian autoimmunity with a 15 amino
related epitopes is present in women with resistant ovary       acid ZP3 peptide (Cys-Ser-Asn-Ser-Ser-Ser-Ser-Glu-Phe-
syndrome is at best questionable. Since we were unable to       Gln-Ile-His-Gly-Pro-Arg). ZP3 is the sperm-binding site
demonstrate autoimmune differences between women                of the zona pellucida. The peptide induced T-cell as well as
with and without resistance to stimulation in a well-defined    antibody responses. However, adoptive transfer of CD4+
infertility population (Gleicher et al., 1994), we doubt the    T-cells in this mouse model caused oophoritis without an
concept of resistant ovary syndrome as a precursor stage to     antibody response to the zona. This observation suggests
premature ovarian failure. Von Weissenbruch et al. (1991)       that the T-cell response, rather than the autoantibody
suggested that an immunoglobulin (Ig)G fraction can             response, may have primacy in this model, a fact further
block ovarian granulosa cell growth in vitro and thus           suggested by the finding that peptides of as little as eight
potentially in vivo contribute to the occurrence of resistant   amino acids (Asn-Ser-Ser-Ser-Ser-Glu-Phe-Glu) caused
ovary syndrome. Blumenfeld et al. (1993) reported an            oophoritis but not an antibody response. These
                                                                                               Antibodies in infertility   171

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

   A number of published studies have exclusively                   sensitive in detecting the immunological abnormality
investigated anticardiolipin responses in patients who              associated with reproductive failure. Once again, these
repeatedly abort or are at risk of doing so. However, even          non-specific findings suggest that autoantibodies serve as
those investigators who have argued against cardiolipin as          an epiphenomenon rather than as a direct pathogen (Aoki et
the ‘ideal’ epitope for investigation, have usually only            al., 1995a).
concentrated on one additional antiphospholipid, namely                Christiansen (1996) in a recent review came to similar
antiphosphatidylserine. A few researchers, and ourselves,           conclusions. He suggests that the frequent occurrence of
have argued that the arbitrary selection of one or two              autoantibodies in women with recurrent pregnancy loss is
antiphospholipid specificities simply does not make sense,          due to a Th1 response against the trophoblast. Lim et al.
neither clinically nor from a conceptual immunological              (1996), in a recent review, remain without an opinion about
viewpoint. Such an approach could be equated to attempts            the mechanism by which autoantibodies contribute to
to diagnose systemic lupus erythematosus (SLE) simply               pregnancy loss. However, their paper represented a
through one single antibody test (Gleicher et al., 1993).           wide-ranging survey of the various theories of immuno-
   Most rheumatologists would argue that such an                    logical pregnancy loss rather than a focused description of
approach to SLE would be clinically naive and immuno-               a possible pathophysiology.
logically unsound since SLE, similar to most other                     An all-encompassing hypothesis might conclude that the
autoimmune conditions, does not represent a monoclonal              presence of autoantibody abnormalities represents only an
event. Yet those same investigators pursue exactly such a           epiphenomenon, characteristic of an overall activation of
course of action in autoimmune-associated reproductive              the immune function (Gleicher, 1994). Such a generalized
failure.                                                            activation of the immune system is not uncommon in
   In contrast, we have advocated for many years the                patients with classical autoimmune diseases and has been
concept of autoimmune-associated pregnancy loss as a
                                                                    repeatedly described in women with immunologically
polyclonal event, which therefore requires a much more
                                                                    associated infertility as well as pregnancy loss (Gleicher et
broadly based immunological evaluation. The reader may
                                                                    al., 1993). We demonstrated that women who present for
have noticed that this review only refers to autoimmune-
                                                                    infertility treatment demonstrate the same increased
associated pregnancy loss, rather than autoimmune-caused
                                                                    incidence of monoclonal and polyclonal gammopathies,
pregnancy loss. Our opinion represents that of a minority
                                                                    selective IgA deficiency and IgG subclass abnormalities as
insofar as we have reached the conclusion that a direct
                                                                    patients with classical autoimmune diseases (N.Gleicher et
autoantibody-mediated process is probably not the cause of
                                                                    al., unpublished observations). Moreover, we were able to
repeated pregnancy loss (Gleicher, 1994). This view is
based on many conflicting observations that have been               demonstrate that habitually aborting women, even prior to
reported in the literature. On the one hand Shoenfeld’s             their miscarriage, demonstrate an elevated level of natural
group has been able to develop an animal model for                  killer (NK) cell activity (Aoki et al., 1995b). All of these
cardiolipin antibody-induced pregnancy loss (and,                   observations point towards an immunological defect at the
incidentally, infertility), an observation that potentially         T-cell level which, as is also postulated in classical
suggests a direct antibody effect (Bakimer et al., 1992). On        autoimmune diseases, may manifest itself in abnormal
the other hand, it is very difficult to understand, at least on a   autoantibody production in addition to many other
theoretical basis, how such vastly different autoantibody           epiphenomena.
specificities such as non-organ-specific antiphospholipid              We thus currently postulate that autoimmune-associated
antibodies and organ-specific antithyroid antibodies, both          reproductive failure in the female, whether in conjunction
independent risk markers for pregnancy loss, can be                 with infertility or repeated pregnancy loss, represents a
responsible for basically the same processes that lead to           likelihood of a T-cell defect, the nature of which has so far
pregnancy loss (Gleicher et al., 1989; Pratt et al., 1993).         not been determined. Since some of the previously noted
   Recent data, moreover, also suggested that the clinical          infertility-associated conditions, such as endometriosis,
activity of antiphospholipid antibodies was largely                 are familial and may be linked to the presence of certain
restricted to those specificities that were only detectable         HLA loci, a contributing genetic factor is likely (Gleicher
with a co-factor (β2-glycoprotein I)-dependent assay                et al., 1993). What triggers the expression of such a genetic
system (Matsuura et al., 1992). We have demonstrated that,          predisposition and its manifestation as reproductive failure
although a co-factor-dependent single assay was superior            is undetermined. Considering an apparent increase in this
to a co-factor-independent single assay, a broadly based            phenomenon, it would be tempting to speculate that an
panel of co-factor-independent assays is at least as                infectious agent may be the culprit.
                                                                                                  Antibodies in infertility    173

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

span of available spermatozoa for fertilization. In contrast,   autoimmune function in particular has been reviewed
other antisperm antibodies, especially in various animal        (Rabin, 1994). Prolactin enhances antibody production
models, have been shown to block the acrosome reaction          and, as expected, hypophysectomy equally suppresses the
and thus prevent fertilization.                                 production of antibodies. Bromocriptine, which effectively
  Sperm–egg interaction has in recent years been quite          suppresses prolactin production, exerts a similar effect on
well investigated. In various animal models sperm               antibodies as does a hypophysectomy, while either
antibodies have been able to prevent sperm binding to zona      prolactin or the administration of growth hormone appears
pellucida-based receptors. In the human model the data          able to induce antibody production. Treatment with
have remained controversial. While some authors have            bromocriptine also ameliorates experimental autoimmune
suggested that fertilization is impaired in the presence of     encephalitis (Riskind et al., 1992).
antisperm antibodies, many have demonstrated exactly the           The high incidence of hyperprolactinaemia in women
opposite. Human data are primarily derived from clinical        with infertility problems, which mimics the presence of
IVF experiences which cannot always be equated with             significant autoimmune abnormalities in this population
in-vivo conditions.                                             (Gleicher 1993), suggests that hyperprolactinaemia may
  Polyclonal autoimmune activation may also result in           affect fecundity not only by affecting ovulation and
production of sperm antibodies. We were able to                 implantation through hormonal but also through
demonstrate this indirectly by showing that individuals         immunological processes. This hypothesis obviously
with significant sperm antibody levels concomitantly            requires a scientific confirmation.
demonstrated a significant degree of non-organ-specific
autoantibody abnormalities. More importantly, however,
we were also able to demonstrate that mouse antisperm           Gonadotrophins
antibodies which were able to inhibit fertilization, were
                                                                Autoimmunity to gonadotrophins has been suggested by a
completely cross-reactive with some nonorgan-specific
                                                                number of authors, though the whole concept has remained
autoantibodies. This observation has led to the conclusion
                                                                controversial. As previously noted in this review, gonadal
that some antisperm antibodies and at least some classical
                                                                failure in the female could be caused by antigonadotrophic
non-organ-specific autoantibodies can inhibit the
                                                                activity by autoantibodies. This issue has also repeatedly
fertilization process in identical fashion (Gleicher et al.,
                                                                entered the literature in reference to the exogenous
1993; Saling et al., 1985).
                                                                administration of gonadotrophic drugs, which represents
                                                                standard therapy for most infertility couples (Jones and
Neuroimmunology                                                 Toner, 1993). Observational studies in treated patients have
                                                                suggested that with increasing numbers of stimulation
Increasingly, immune and endocrine systems are seen as an       cycles, increasing dosages of medication may be required.
intertwined web of signals and responses, mediated by           This increasing resistance to stimulation by
often identical messengers of information. Nowhere is this      gonadotrophins has been attributed to the development of
more apparent than in the fields of neuroendocrinology and      autoantibodies to gonadotrophins. Convincing evidence
neuroimmunology. Reichlin (1993) exhaustively reviewed          that such autoantibodies do exist is lacking.
the topic. Without being able to address all those inter-          Autoimmunity to gonadal hormones was suggested ~15
actions in detail within the framework presented here, the      years ago when some authors reported the induction of
following will be a brief summary of the most salient           anti-oestrogenic autoantibodies after oral contraceptive
points.                                                         use. The presence of such antibodies has never been
                                                                confirmed.
Hyperprolactinaemia                                                A recent symposium on microcontraception also failed
Prolactin, produced by lactotrope cells within the anterior     to report on the occurrence of any significant autoimmune
pituitary, is a hormone of major importance for                 responses with newer generations of contraceptives
reproductive processes of both female and male.                 (Anank Kumar, 1997).
Hyperprolactinaemia in the female can directly affect              Gonadal hormones do, however, exert considerable
ovulation and probably also implantation. In the male,          effects on the immune system and can greatly affect
semen quality can be affected. Hyperprolactinaemia              autoimmune conditions. It would exceed the framework of
represents an extremely common finding in women but is          this review to describe those any further. The interested
seen much less frequently in males with infertility             reader is therefore referred to the recent review by Reichlin
problems. Its effect on immune function in general and on       (1993).
                                                                                                                    Antibodies in infertility         175

Clinical utility and conclusions                                               Dmowski, W.P., Rana, N., Michalowska, J. et al. (1995) The effect of
                                                                                    endometriosis, its stage and activity, and of autoantibodies on in vitro
Autoantibodies that have been associated with infertility                           ferilization and embryo transfer success rates. Fertil. Steril., 63,
                                                                                    555–562.
are often non-specific to the disease state, and, if specific,                 El Roeiy, A., Gleicher, N., Friberg, J. et al. (1987) Correlation between
are often unidentified and are never produced in response                           peripheral blood and follicular fluid autoantibodies and impact on in
                                                                                    vitro fertilization. Obstet. Gynecol., 70, 163–170.
to a presently known antigen. The clinical utilization of                      El Roeiy, A., Dmowski, P.P., Gleicher, N. et al. (1988) Danazol but not
autoantibodies for diagnostic purposes is currently very                            gonadotropin-releasing hormone agonists suppresses autoantibodies
limited and restricted to a number of research centres. This                        in endometriosis. Fertil. Steril., 50, 864–871.
                                                                               Fisch, B., Rikover, Y., Shohat, L. et al. (1991) The relationship between in
should be considered when clinical decisions are made                               vitro fertilization and naturally occurring antibodies: evidence for
based on antibody data reviewed here or reported                                    increased production of antiphospholipid antibodies. Fertil. Steril.,
elsewhere in the literature. Furthermore, antibody assay                            56, 718–724.
                                                                               Gleicher, N. (1994) Autoantibodies and pregnancy loss. Lancet, 343,
systems are often laboratory-produced, and inter-assay                              747–748.
variability between laboratories can be considerable                           Gleicher, N., El Roeiy, A., Confino, E. and Friberg, J. (1987) Is
(Peaceman et al., 1992). It is therefore important to be                            endometriosis an autoimmune disease? Obstet. Gynecol., 70,
                                                                                    115–122.
familiar with the individual techniques utilized by                            Gleicher, N., El Roeiy, A., Confino, E. and Friberg, J. (1989) Reproductive
laboratories that supply autoantibody results to clinical                           failure because of autoantibodies: Unexplained infertility and
practitioners and it is crucial to choose reputable                                 pregnancy wastage. Am. J. Obstet. Gynecol., 160, 1376–1385.
                                                                               Gleicher, N., Pratt, D. and Dudkiewicz, A. (1993) What do we really know
laboratories. A very detailed critical review on this topic                         about autoantibody abnormalities and reproductive failure. A critical
has been published (Gleicher, 1993).                                                review. Autoimmunity, 16, 115–140.
                                                                               Gleicher, N., Liu, H.C., Dudkiewicz, A. et al. (1994) Autoantibody
                                                                                    profiles and immunoglobulin levels as predictors of in vitro
                                                                                    fertilization success. Am. J. Obstet. Gynecol., 170, 1145–1149.
References                                                                     Hill, J.A. and Andersen, D.J. (1989) Lymphocyte activity in the presence
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