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This article was published in the March 2011 NDNR Journal
Infertility is a reproductive disease which has an enormous impact on
the quality of life for millions of patients. It affects 1 in 5 of all
couples, and most patients undergo extensive diagnostic and treatment
interventions on their journey to create a family. Infertility has a
myriad of causes including endocrine disorders, gynecological disease,
infectious disease, circulatory disease and aging and cellular health.
Autoimmune disorders are also implicated in reproductive disorders and
may especially play a role in unexplained cases of infertility.
It is known that autoimmune diseases such as diabetes, autoimmune
thyroiditis and systemic lupus erythematosis are linked to decreased
fertility. Other causes of infertility such as premature ovarian
insufficiency, endometriosis and polycystic ovarian syndrome include
autoimmune components. In many unexplained cases of infertility,
inflammatory processes may be involved or antibodies may be directed
against hormones, clotting factors, or reproductive tissues such as the
ovaries or testes. The research into autoimmune infertility is just in
its beginning, but as naturopathic physicians there are valuable tests
and treatments we can provide to our patients who present either with
known autoimmune disorders and difficulty conceiving, or with the ever
enigmatic diagnosis of "unexplained infertility”.
The biological factors involved in autoimmune infertility are
various. These include a multitude of cellular and inflammatory changes.
Some of the most common factors are discussed below.
Endometriosis has many autoimmune components including elevated
levels of cytokines, and T- and B-cell abnormalities. Peripheral
monocytes are more active, and peritoneal macrophages are present in
higher numbers with higher activity levels. This causes increased
inflammatory cytokine release.
There are alterations in B-cell activity and an increased incidence
of autoantibodies in women with endometriosis. Like classical autoimmune
diseases, endometriosis has been associated with polyclonal B-cell
activation, immunological abnormalities in T- and B-cell functions,
increased apoptosis, tissue damage, multiorgan involvement, familial
occurrence, possible genetic basis, involvement of environmental
cofactors, and association with other autoimmune diseases. TNF-a, levels
are elevated in the peritoneal fluid of patients with endometriosis. In
women with endometriosis, TH2 mediated immunity humoral responses are
A 2001 study found that 50% of endometriosis patients had
autoantibodies to candida enolase. The same study found increased levels
of these antibodies in patients with a list of other autoimmune
Autoimmune thyroid disease and infertility.
Thyroid diseases involving antithyroid antibodies have been
correlated to infertility and increased pregnancy loss. Autoimmune
thyroid disease, even in the absence of hypothyroidism has been
associated with infertility and reduced response to fertility treatment.
It has also been associated with gluten related autoimmunity.
Autoimmune thyroid disease can lead to hypo or hyperthyroidism which can
impact fertility and cause miscarriage.
Other Autoimmune Diseases and Fertility
Antinuclear antibodies (ANAs ) which have been associated with
infertility can be present in conditions such as SLE, Sjogren’s
syndrome, Raynaud’s syndrome, and can also be detected in women with a
history of exposure to chemicals such as bisphenol-A.
Addison’s disease is associated with anti-ovarian antibodies which
can reduce ovulatory function and cause premature ovarian failure in
Patients with celiac disease may have multiple nutritional
deficiencies that can lead to infertility. Celiac disease has been
linked to recurrent miscarriage, pregnancy complication and infertility.
A 2010 study found that between 5-10% of women with a history of
stillbirth, recurrent miscarriage, intrauterine growth restriction, and
infertility were seropositive for transglutaminase IgA compared to 1% of
the control group. Latent celiac disease may be a major cause of
In approximately 20% of women with premature ovarian
insufficiency(POI), autoimmune factors can be found. POI can be linked
to autoimmune thyroid disease, Addison’s disease, or SLE or may have
unknown etiology. Women may have antibodies against the ovarian tissues,
or reproductive hormones such as FSH.
Antisperm antibodies are another cause of infertility. These can be
present in either male or female patients. They are commonly found in
males after vasectomy procedures, and their presence can make vasectomy
difficult to reverse. Antisperm antibodies affect the ability of the
sperm to penetrate the egg or reduce motility by attaching to the tail
of the sperm . They have also been associated with antiphospholipid
antibodies. Antisperm antibodies are generally produced by CD19+/5+ B
cells and are associated with elevated natural killer cells and anti-dna
Autoimmune blood clotting disorders
Disorders with increased antiphospholipid antibodies( APAs) including
anti-cardiolipin antibodies cause a hypercoagulatory state in the blood
and can be associated with reproductive failure and recurrent
miscarriage. These antibodies can be found in systemic diseases such as
SLE, or on their own.
Immunological Considerations for Patients with Reproductive Challenges
A condition of TH1 cytokine dominance can be associated with the
inability to conceive or maintain a pregnancy. In women with high
TH1/TH2 ratios there is an increased incidence of pregnancy loss and
infertility however for different autoimmune conditions the predominant
immune pathway may differ.
Natural killer(NK) cells
Elevated peripheral NK cells are associated with many systemic
autoimmune diseases but can also be found in women with unexplained
infertility conditions. NK cells produce TH1 cytokines including
TNF-alpha and Interferon gamma. These cytokines are normally involved in
cellular toxicity directed at cancerous cells and viruses . If
increased in early pregnancy, the presence of NK cells and their
cytokines can disrupt the growth and development of the embryo.
TNF-alpha works as a signal to other immune cells which then migrate to
the uterus to attack the non-self invader which has been immunologically
detected. A 1999 study found that in women who had repeated
miscarriage, there was markedly increased NK cell cytotoxicity
associated with a rise in CD56+CD16+ and a drop in CD56+ cells. Another
special type of NK cell called uterine NK (uNK) cells have a protective
immunosuppressive effect locally in the endometrium. Dysfunction of
these cells has been associated with pregnancy loss
Homocysteine and Folate Metabolism
folate deficiency and hyperhomocysteinemia are known to be risk factors
for infertility and pregnancy complications. Errors in these pathways
caused by genetic mutations have been associated with autoimmune
diseases Patients with a mutation of the MTHFR gene have difficulty
reducing 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-
methyltetrahydrofolate is used to convert homocysteine to methionine by
the enzyme methionine synthase. A 2010 study on a group of 71 Swedish
and Finnish female patients with unexplained infertility found a higher
incidence of folate metabolism polymorphisms compared to women in the
general population. Folate receptor blocking autoantibodies have also
been related to subfertility
Folate metabolism disorders can can lead to reduced cell division,
inflammatory cytokine production, altered nitric oxide metabolism,
increased oxidative stress, abnormal methylation reactions and
thrombosis. This causes problems with folliculogenesis and implanting or
maintaining a healthy pregnancy. In males, defects in this pathway can
Diagnostic testing in the naturopathic clinic
In addition to general and endocrine panels for infertility, consider
testing for homocysteine, CRP, ESR, ANA panels, APA panels, PTT,
Partial PTT, DHEA-S, TSH, Antithyroglobulin, Antithyroid peroxidase,
HBA1C, CBC, diurnal cortisol, assessments for candida, and gluten
Clinically, I have found that optimal homocysteine levels should be
8mmol/L or below in patients with autoimmune infertility factors.
TH1 to TH2 ratios can be a very helpful tool for designing treatment
plans. NK assays and testing for genetic variants of MTHFR are also
These vary depending on results found and can include low dose
aspirin, anti-coagulants, corticosteroids, IVIG, Lymphocyte immunization
therapy (LIT) and TNF-alpha blockers. These are often combined with IVF
or other assisted reproductive technologies.
Treatments in the naturopathic clinic
Some of the following treatment options may be considered after a thorough assessment determines specific autoimmune factors.
- To reduce TH1 dominant inflammatory responses in patients who
require it, maritime pine extract (100mg bid), resveratrol ,(100mg bid) ,
and green tea EGCG (300mg catechins bid), . Maritime pine, and
resveratrol also inhibit platelet aggregation and thrombosis,,. The
antioxidant effects of these substances are also beneficial.
- Proline rich polypeptides such as those found in bovine colostrum
may favour a shift towards TH1 and downregulate overactive TH2
- High quality omega 3 fish oil. 2 – 3g of EPA and DHA daily to aid
with inflammatory and thrombotic disorders . A 2007 study on mice found
that a ratio of 23:14 EPA to DHA decreased tnf alpha in 8 hours. EPA
also regulates autoimmune markers in endometriosis
- L-5-methyltetrahydrofolate 5mg daily, vitamin B12 1000mcg qd and
vitamin B6 75mg qd to improve homocysteine and folate metabolism. Screen
for history of cancer before using high dose folate. Trimethylglycine
1000mg qd may also be used to lower homocysteine levels in selected
- N-Acetyl Cysteine 600mg bid. Reduces inflammatory cytokines.
Improves autoimmune thyroid disease NAC also enhances semen parameters
and the oxidative status and quality of the endometrium . NAC also
protects the integrity of ovaries subjected to physical and oxidative
damage, and aids liver detoxifcation pathways.
- For patients with thyroid antibodies, l-selenomethionine 200mcg
daily,,,. If hypothyroid, use of bio-identical hormone therapy may be
indicated to prevent miscarriage. Trace minerals for thyroid function
are also be beneficial.
- Thyroid protomorphogen may be useful for patients with antithyroid
antibodies to act as a decoy. Increase dosage slowly to 1 tablet tid.
- Elimination of gluten should be implemented as required for patients with positive serology.
- Probiotics 20 billion CFUs daily. Rotate strains monthly to modulate immunity and repair gut lining. Treat candida if present.
- Support liver detoxification pathways.
- Bio-identical progesterone is a potent immunosuppressive agent
capable of blocking both cytokine release and action . May be used in
the luteal phase of the cycle to support early pregnancy.
- DHEA – can be useful in premature ovarian insufficiency and to
improve pregnancy rate and reduce miscarriage in advanced maternal age.
It has also been found to be beneficial in the treatment of autoimmune
disease,, and to reduce NK cell activity. DHEA should only be used after
serum DHEA-S and androgen evaluation. Dose adjusted according to
patient need but is often 25mg tid or less.
- Addressing stress is very important in all patients suffering from
the effects of reproductive challenges. Autoimmune diseases are
aggravated by stress as it can increase humoral immunity and shift
TH1:TH2 ratios. Adrenal therapies, sufficient sleep, yoga, meditation,
movement therapy, and prayer can all positively effect patients in this
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