Dr. Fiona D. McCulloch, BSc, CEFP, ND
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[i]. 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[ii]. TNF-α, levels are elevated in the peritoneal fluid of patients with endometriosis. In women with endometriosis, TH2 mediated immunity humoral responses are commonly elevated[iii].
A 2001 study[iv] 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 conditions.
Autoimmune Thyroid Disease and Infertility
Thyroid diseases involving antithyroid antibodies have been correlated to infertility and increased pregnancy loss[v]. Autoimmune thyroid disease, even in the absence of hypothyroidism has been associated with infertility and reduced response to fertility treatment[vi]. It has also been associated with gluten related autoimmunity[vii]. 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[viii] 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 severe cases.
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[ix]. Latent celiac disease may be a major cause of unexplained infertility.
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 antibodies.
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[x]. 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 [xi] 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[xii]. 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[xiii]
Homocysteine and Folate Metabolism
Both folate deficiency and hyperhomocysteinemia are known to be risk factors for infertility and pregnancy complications[xiv]. Errors in these pathways caused by genetic mutations have been associated with autoimmune diseases[xv][xvi][xvii] 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[xviii]. Folate receptor blocking autoantibodies have also been related to subfertility[xix]
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 impair spermatogenesis[xx].
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 sensitivity testing.
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 available.
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[xxi] (100mg bid), resveratrol [xxii],[xxiii](100mg bid) , and green tea EGCG (300mg catechins bid)[xxiv],[xxv] . Maritime pine, and resveratrol also inhibit platelet aggregation and thrombosis[xxvi],[xxvii],[xxviii]. The antioxidant effects of these substances are also beneficial.
- High quality omega 3 fish oil. 2 – 3g of EPA and DHA qd to aid with inflammatory[xxix] and thrombotic[xxx] disorders[xxxi] . A 2007 study on mice found that a ratio of 23:14 EPA :DHA decreased tnf alpha in 8 hours[xxxii]. EPA also regulates autoimmune markers in endometriosis[xxxiii]
- L-5-methyltetrahydrofolate 1 to 5 mg daily depending on patient needs, 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 patients.
- N-Acetyl Cysteine 600mg bid. Reduces inflammatory cytokines[xxxiv]. Improves autoimmune thyroid disease[xxxv] NAC also enhances semen parameters[xxxvi] and the oxidative status and quality of the endometrium[xxxvii] . NAC also protects the integrity of ovaries subjected to physical and oxidative damage[xxxviii],[xxxix] and aids liver detoxifcation pathways.
- For patients with thyroid antibodies, l-selenomethionine 200mcg daily[xl],[xli],[xlii],[xliii]. 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[xliv]. 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 [xlv]. May be used in the luteal phase of the cycle to support early pregnancy.
- DHEA – can be useful in premature ovarian insufficiency[xlvi] and to improve pregnancy rate and reduce miscarriage in advanced maternal age[xlvii]. It has also been found to be beneficial in the treatment of autoimmune disease[xlviii],[xlix], and to reduce NK cell activity[l]. 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[li]. Adrenal therapies, sufficient sleep, yoga, meditation, movement therapy, and prayer can all positively effect patients in this journey.
Dr. Fiona McCulloch, BSc, ND, CEFP is a licensed Naturopathic Doctor. She has been in practice for over 10 years and is co-founder of White Lotus Naturopathic Clinic in Toronto, Canada. She holds a Bachelor of Science (Biological Science) degree from the University of Guelph, and earned her doctorate in Naturopathic Medicine from the Canadian College of Naturopathic Medicine.
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