Autoimmune infertility

1
Autoimmune infertility

• Professor
• Hassan El Maghraby

2
Autoimmunity primer

• Major determinants of autoimmune endocrine
  disease are
  
• T lymphocytes
• Autoantibodies produced by B lymphocytes

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Autoimmunity primer

• These 2 arms of the immune system differ
  fundamentally in their recognition of target
  antigens
  
• Autoantibodies react with intact molecules
  molecules that determine the shape of the
  autoantigen
  
• T cells recognize peptide fragments of
  autoantigens, only when they are presented to the
  surface of another cell by histocompatibility
  molecules HLAs in addition T cell activation
  requires other molecules

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Natural history of autoimmune disorders

• Can be divided into series of stages beginning
  with
  
• Genetic susceptibility, followed by
• Triggering of autoimmunity drugs, infection,
  idiopathicetc
  
• Active autoimmunity preceding clinical
  manifestations finally
  
• Overt disease

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Evaluation of autoimmune status

• Evaluation of autoimmune status by
• Antiphospholipid antibody panel,
• Antinuclear antibody panel,
• Total immunoglobulin levels (IgG, IgM, IgA),
• Thyroid antibodies (antiglobulin and
  antimicrosomal),
  
• Antiovarian antibodies, and
• Antiadrenal antibodies

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Disorders

• Endometriosis
• PMOF
• Antiphospholipid antibodies
• Female fertility preservation in autoimmune
  diseases
  
• Anti FSH antibodies
• Autoimmune polyendocrine syndrome type II

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Endometriosis

• Endometriosis lesions are characterized by the
  presence of
  
• Abundant plasma cells, many of which produce IgM,
  and
  
• macrophages that produce a member of the TNF
  superfamily implicated in other autoimmune
  diseases.
  
• B lymphocyte stimulator (BLyS) protein was found
  elevated in the serum of endometriosis patients.
  
  
• These observations suggest a model for the
  pathology of endometriosis where BLyS-responsive
  plasma cells interact with retrograde menstrual
  tissues to give rise to endometriosis lesions.

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COH suppresses autoantibodies

• Endometriosis and polycystic ovary syndrome were
  associated with a higher number of common serum
  autoantibodies compared with the tubal factor
  infertility .
• There was an overall decrease in the number of
  detectable autoantibodies after COH
  
• CONCLUSION COH may have a suppressive effect on
  the humoral immunity by the time of embryo
  transfer but more conclusive studies are needed.
  Am J Reprod Immunol. 2006 Nov-Dec56(5-6)364-70

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• 1 Fertil Steril. 2008 Apr 1 Epub ahead of
  print
  
• A pilot study of premature ovarian senescence
  II. Different genotype and phenotype for genetic
  and autoimmune etiologies.
  
• Gleicher N, Weghofer A, Barad DH.
• 2 J Am Acad Dermatol. 2008 Feb58(2)353-5.
• Autoimmune progesterone dermatitis associated
  with infertility treatment.
  
• Jenkins J, Geng A, Robinson-Bostom L.
• This is reported in 46 of our patients on one
  medication
  
• The infertility women with POF had high rate of
  abnormal karyotype (11/65, 16.92) and lower
  severe autoimmune disorders rate (2/138,1.45).
  
• Neuro Endocrinol Lett. 2007 Oct28(5)580-4
• Zhang P, Shi Y, Gao X, Wang S, Wang J, Chen ZJ.
• Abnormal autoimmune function represent a distinct
  etiology for premature ovarian senescence in
  infertile patients. It was reported in 55 of
  patients in one study
• Gleicher N, Weghofer A, Barad DH
• Fertil Steril. 2008 Apr 1 Epub ahead of print

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Definition of PMOF

• Premature ovarian failure occurs in approximately
  
  
• 11000 women before 30 years,
• 1250 by 35 years and
• 1100 by the age of 40.
• Premature ovarian failure is defined by
• Gonadal failure and
• High serum (FSH) levels
• The known causes of premature ovarian failure
  include
  
• chromosomal defects,
• autoimmune diseases,
• exposure to radiation or chemotherapy,
• surgical procedures, and
• certain drugs.
• Frequently, however, these cases are considered
  to be idiopathic

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PMOF

• Premature ovarian failure may be due to
  inflammatory autoimmunity targeted to zona
  pellucida proteins or inhibin-alpha).
  
• Moreover, the ovarian autoimmunity may be
  mediated by
  
• T cells (e.g., those targeting zona pellucida
  proteins) or
  
• B cells/antibodies (e.g., those targeting
  inhibin-alpha).
  
• Thus premature ovarian failure may be due to
  several distinctly different autoimmune mechanisms

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Antiphospholipid syndrome

• The antiphospholipid syndrome, an autoimmune
  disease with various clinical alterations
  
• miscarriage,
• hypertensive disorders,
• Preterm delivery,
• vascular thrombosis,
• intrauterine retard growth,
• death intrauterine,
• abruption placentae).
• There are major and minor clinical criteria and
  precise indications that guide the physician to
  its recognition.
  
• Antibodies related with the syndrome are
• anticardiolipin and
• lupus anticoagulant, but
• other phospholipids seem to be implicated on this
  pathology

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Prognosis

• The best therapy for reproductive future which
  has less undesirable effects, is with
  
• heparin and
• Acetylsalicylic acid administration
• prednisone (steroids) is used in cases of active
  illness.
  
• The current knowledge about this disease makes
  possible that a pregnancy at term can be achieved
  with the least as possible number of complications

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Female fertility preservation in autoimmune
diseases possibilities and practices

• Female fertility preservation in autoimmune
  diseases is a difficult question
  
• In autoimmune diseases, alkylating agents are
  also used and it is now established that 20 g as
  a cumulative dose of cyclophosphamide is
  associated with premature ovarian failure in 50
  of 20-year-old patients.
• Several strategies are discussed and offered to
  these patients to prevent the ovarian failure
  
• GnRH agonist treatment,
• In vitro fertilization and Embryos
  cryopreservation,
  
• Oocytes cryopreservation and
• Ovarian cortex cryopreservation.

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Anti FSH antibodies

• Anti-FSH Abs increase in infertile women with
  dysregulation of immune reactions and repeatedly
  performed IVF.
  
• Am J Reprod Immunol. 2007 Mar57(3)193-200

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Pituitary-ovarian axis

• Autoimmune targeted disruption of the
  pituitary-ovarian axis causes premature ovarian
  failure.
  
• J Immunol. 2006 Aug 1177(3)1988-96.

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• In infertility, the antibodies with significantly
  higher levels than controls were
  antiphospholipid OR, 5.11 and anti-prothrombin
  antibodies, OR, 5.15 .
• In RPL, anti-saccharomycetes cerevisiae
  antibodies (ASCA , anti-prothrombin and aPL were
  more prevalent than in controls, OR 3.9 CI,
  1.5-10.6, 5.4 CI, 2.4-12.5 and
• 4.8CI, 1.2-22.2 for each antibody,
  respectively.
  

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Two distinct autoimmune polyendocrine syndromes
APS

• APS-I is a rare disorder with autosomal recessive
  inheritance caused by defects in the autoimmune
  regulator gene on chromosome 21
  
• APS-II, has association with genes of HLA region
  on the short arm of chromosome 6 in addition to
  other genetic loci

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APS-II

• APS-II is defined by occurrence of 2 or more of
  the following
  
• Addisons disease primary adrenal
  insufficiency
  
• Graves disease autoimmune thyroiditis
• Type I diabetes mellitus
• Primary hypogonadism
• Myasthenia gravis

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APS-II

• Vitiligo,
• Alopecia,
• Serositis, and
• Pernicious anemia
• also occur with increased frequency in
  individuals with this syndrome and their family
  members

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Organ specific autoantibodies

• Most of the endocrine autoantigens are hormones
  insulin, FSH or enzymes associated with
  different endocrine functions hydroxylases..

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POEMS syndrome

• P plasma cell abnormality polyneuropathy
• O organomegaly
• E endocrinopathy
• M protein
• Skin lesions
• Primary gonadal failure is present in 70 of
  patients, diabetes in 50

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Therapy

• Immunosuppressive
• Corticosteroids
• Specific replacement

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Conclusions

• The presence of family history and other
  disorders in addition to infertility should raise
  suspicion of autoimmunity
  
• Other endocrine systems should be investigated
  particularly, pancreas, adrenal, and thyroid
  
• Preservation of fertility should be a prime
  concern
  
• Medications should not do harm more than the
  disease itself !!!!
  
• A multidisciplinary approach is fundamental