Autoimmune Infertility in Women: Part 2
FIONA MCCULLOCH, BSC, ND
This is a follow-up article to “Autoimmune Infertility,” in the March, 2011, Autoimmune & Allergy Medicine issue of NDNR.1 This article will detail new developments since that time, as well as address underlying causes of the immunological disruption of fertility.
Women with autoimmunity experience greater rates of infertility than average.2 Although long-underestimated, the immune system plays a significant role in both normal and abnormal reproduction. Autoimmunity has been well-investigated for its role in recurrent pregnancy loss and implantation failure.3,4 In recent years, immunologic endocrinology, ie, the interaction between immune system and hormones, has also become a topic of interest.
Immunology and Infertility
The immune system must be in a specific state for fertility and pregnancy to occur. Firstly, pregnancy is a type 2 T-helper cell (TH2)-dominant state. Patients who remain TH1-dominant have an increased incidence of pregnancy loss and miscarriage.5 T regulatory cells (Tregs) also play an important role in fertility, as demonstrated by the fact that patients who have a higher level of serum Tregs have better fertility outcomes.6 Low levels of Tregs have also been implicated in infertility related to endometriosis,7 unexplained infertility,8 and miscarriage.9 Low T regulatory cells are also found in a wide variety of autoimmune disorders.10 Other cellular and molecular factors that affect fertility, such as natural killer cells and antiphospholipid antibodies, were covered in the first part of this series.
Autoimmune Endocrinology: The Interplay Between the Immune System and Hormones
Immunologic processes can not only directly affect implantation and fertility, but can also indirectly affect fertility through interference with the endocrine system. There is a good deal of “crosstalk” between the hormonal system and the immune system. Reproductive processes depend on the interactions between cytokines and lymphokines, and hormones.11 When the female immune system is functionally altered, as in autoimmune disease, the endocrine system can become affected and fertility can be compromised. It is important to consider that autoimmune antibodies can develop subclinically many years before an actual symptomatic autoimmune disease is diagnosed, and during such time, they may affect fertility.12
It is quite clear that the immune system and endocrine system are connected. For example, thyroid autoimmunity can result in hypothyroidism. This, in turn, can cause hyperprolactinemia, which then may suppress ovulation. Thyroid antibodies have also been associated with endocrine disorders such as polycystic ovarian syndrome13 and premature ovarian insufficiency.14 As another example of the link between the immune system on the endocrine system, systemic lupus erythematosus (SLE), celiac disease, endometriosis,15 and type 1 diabetes have all been associated with hyperprolactinemia.16 Interestingly, extra-pituitary immune sites can secrete prolactin, and this too has been associated with autoimmune disease.16 There is also evidence that there may be a silent form of autoimmune hypophysitis (pituitary inflammation) that can cause mild degrees of hormonal deficiencies.16,17 Such glandular autoimmunity may also involve the adrenals, ovaries, and even pancreas,18 all of which may have effects on reproduction.
The ovary itself has been described is an immunological hotspot.19 Immune dysfunction can adversely affect female fertility by prematurely diminishing ovarian reserve and increasing the speed of oocyte loss.19 Autoimmunity may also specifically impact androgen levels. It is well known that premature ovarian insufficiency (POI), a condition that affects 10% of all women, is associated with low levels of androgens.20 In women, the adrenal glands produce 50% of all of the androgens, and 100% of the DHEA. Androgens are crucial for the early growing follicle maturation stages; when androgen levels are low, the follicles are held back from development.
An immune-derived androgen-producing factor may exist which acts on the adrenal glands and which may be functionally altered in patients with POI.21 A recent study found that in women with normal fertility, those with autoimmune activation tended to have higher levels of testosterone than controls,21 suggesting that a functional autoimmune androgen-producing factor (APF) may regulate the production of androgens in women with normal functional ovarian reserve. It was also found that women with POI had lower levels of testosterone than control women and lacked this immune activation, suggesting that this autoimmune regulatory function was altered.
In polycystic ovary syndrome (PCOS), the most common reproductive disorder in women, this immunologic component may be important. Autoimmune overproduction of this APF may be involved in the etiology of some androgenic phenotypes of PCOS.21 These findings suggests the need for more research on a possible ovarian-adrenal autoimmune system which could be involved in both POI and PCOS. It is important to note that functional autoantibodies can be either suppressive or enhancing.
Women with PCOS also tend to have an increased incidence of autoimmune disorders, especially Hashimoto’s thyroiditis.22 Polymorphisms related to increased concentrations of inflammatory mediators, interleukin-1 (IL-1) and IL-6, are also more prevalent in PCOS, and CRP and IL-18 levels tend to be increased.23 It is difficult to determine however, if adjusting for obesity might remove these associations.
Diffuse Immunological Activity and Effects on Reproduction
Women with recurrent miscarriages and unexplained infertility often have a diffusely activated immune system. This can include thyroid autoimmunity, TH2 dominance, and elevated antibodies such as ANA, anticardiolipin, and others.1 As a variety of autoimmune diseases are associated with infertility, such as type 1 diabetes, Hashimoto’s and Grave’s thyroiditis, Addison’s disease, autoimmune thyroiditis, multiple sclerosis, and rheumatoid arthritis, it appears that a diffusely activated immune state may disrupt reproduction through some of the mechanisms previously detailed.
The Role of the Gut in Autoimmune Infertility
The intestine contains the largest amount of lymphoid tissue in the entire body. The gut-associated lymphoid tissue (GALT) underlying the intestinal epithelial cells is populated mostly by B and T cells in various stages of development. Many environmental components such as foods, microbes, and environmental toxins pass through the intestine; as such, the body must maintain a strong defense at the mucosal boundary. The tight junctions between the intestinal epithelial cells ideally create an impermeable barrier to the contents of the intestinal lumen.
These tight junctions in the intestinal lining keep antigens such as microbes and food particles from being “seen” by the immune system. Zonulin, discovered through the work of Alessio Fasano24 is the only known protein involved in the regulation of the tight junctions. If excessive zonulin is released, causing tight junctions to become “leaky,” the contents of the bowel are exposed directly to the GALT immune cells. In genetically susceptible individuals, this causes a miscommunication between the innate and adaptive immune systems, which can perpetuate autoimmunity25 and disrupt the natural immune processes required for reproduction.
Let’s take a step back and talk about the different causes of autoimmunity according to current theory:
1. Molecular mimicry26: This is the concept that autoimmune diseases can develop when an immune cell reacts to an antigen which is similar to “self.” As a result, the immune system goes on to attack its own tissues. An example of this is the association between Proteus infection and rheumatoid arthritis.27
2. Tissue damage: This occurs when, for example, a virus or a heavy metal enters the body and damages a tissue. The immune system then attacks the damaged tissue, in the process creating autoimmunity. This has been called the “bystander effect.”28
3. Malfunction during the development of the immune cells: During development, T cells normally develop tolerance to “self.” If development is disrupted, tolerance can also be affected. In addition, if the development of the T regulatory cells is specifically altered, the normal suppressive effects of these cells on autoimmunity can be lost. Examples of triggers that can disrupt the T cell development include environmental toxins, pathogens, and free radical damage.29
It is thought that a genetic susceptibility to autoimmunity must be present for any one of the above triggers to create the pathology.
Association of Autoimmune Pathology with Leaky Gut
These traditional theories of autoimmunity imply that a condition once started, is self-moderated. The role of intestinal permeability suggests that a condition can perhaps be reversed by preventing the interplay of genetics and environment. A permeable intestinal barrier allows microbes, toxins, and food substances direct access to the GALT, triggering immune response and/or disrupting immune cell development.30 An association between autoimmune diseases such as type 1 diabetes and elevated levels of zonulin implies that leaky gut can play a significant role in the process.
When it comes to fertility, the gut, and endocrine autoimmunity, we can also consider the action of the toll-like receptors, which are significantly expressed in the immune-rich GALT beneath the intestinal lining. Toll-like receptors have been proposed as a possible link between the immune, hormonal and metabolic systems.31 As part of the innate immune system, these receptors control responses to invading microbes. If the GALT is exposed to intestinal microbes, these receptors can become activated and produce immediate inflammation that can disrupt the endocrine system. This inflammatory response has been demonstrated in cells of the hypothalamus, pituitary, thyroid, and pancreas.31
So, if we look at autoimmune infertility as a process of widespread inflammation that may be disrupting reproductive endocrinology or the process of implantation, it makes sense to address it at both the level of the trigger of the process, and also at the level of the immunological parameters that influence the functional effect of the autoimmunity on fertility.
Treatments and Testing
Much of the testing for autoimmune infertility was covered in Part 1 of this article. Microbial stool analysis is helpful for patients with autoimmunity, to identify pathogenic organisms such as bacteria or yeast. If an organism is identified, an herbal compound determined by sensitivities can be used to kill the pathogen.
Autoimmune Diet
I often recommend a variation on the autoimmune Paleo diet for patients during the phase of treating their fertility concerns, to heal the gut lining and reduce inflammatory responses within the GALT. Grains (particularly gluten/gliadin, which is known to increase the expression of zonulin,32 dairy, soy, and legumes are eliminated. Other potential allergens and irritants, such as egg whites, nuts, and nightshades, are eliminated and then tested through reintroduction. Nutrient-dense foods are encouraged. Homemade fermented foods are recommended, such as sauerkraut or kombucha.
Probiotics
Reinoculation with probiotics is necessary. Strain selection is important. Anti-inflammatory strains include Bifidobacterium infantis,33 Lactobacillus rhamnosus,34 Lactobacillus casei.35 Some strains have been shown to trigger Hashimoto’s thyroiditis antibodies,36 in which case a disrupted gut barrier could be of concern. In addition, gut-healing nutraceuticals may be used, including L-glutamine, N-acetylglucosamine (NAG), mucilaginous herbs, and so on.
Updates on Supplements
A variety of supplements were discussed in Part 1 of this article; as such, it is important to detail new points based on recent findings since that time.
1. Vitamin D may improve the integrity of the tight junctions, benefit patients with thyroid autoimmunity, and enhance T regulatory cell function.37,38.39 A dose of 5000 IU per day is recommended.
2. Glutathione is required for T regulatory cell function. As oral glutathione is poorly correlated with increased intracellular glutathione, N-acetylcysteine, biologically-active whey, or S-acetylglutathione may be used to reduce the impact of autoimmunity.40
3. Dietary polyphenols: Epigallocatechin gallate (EGCG),41 grapeseed extract,42 and pinebark extract43 can be used to influence TH1:TH2 ratios to promote healthy reproduction. EGCG can protect the lymphocytes while in development, and reduce the triggering of autoimmunity.44
4. 5-MTHF: T regulatory cells express a high concentration of folic acid receptors on their cell surfaces. Folic acid is a survival factor for T regs.45
5. Omega-3 fish oil enhances the development of Fox P3 Tregs in vivo.46
6. If prolactin is elevated, consider Vitex agnus castus.
7. In patients with POI, androgen therapy such as DHEA or Tribulus terrestris may be beneficial.
8. Strain-specific probiotic supplementation, as outlined above, may be helpful.
Case Study
A 34-year-old woman with unexplained infertility arrived at the clinic with a history of trying to conceive for 3 years. Lisa had experienced 3 chemical pregnancies during that time (positive beta hCG but pregnancy not confirmed by ultrasound), and had attempted medicated intrauterine insemination (IUI) cycles with both clomiphene and letrozole. Two of the chemical pregnancies were conceived naturally and 1 with IUI. Lisa experienced frequent gastrointestinal bloating and was fairly constipated. She would occasionally experience achy joints, Raynaud’s syndrome, difficulty sleeping, and poor energy. Her temperature was quite good in the luteal phase, rising to 37 ºC.
Her cycles were occasionally irregular, ranging from 28-35 days, but tended to be 29 days. Her androgen panel was normal and she showed no androgenic signs clinically. Her FSH and anti-Mullerian hormone (AMH) were normal, and her ultrasound was unremarkable. Upon ordering her blood work, she was positive for anti-thyroid peroxidase antibodies, at 554 kIU/L, and she was homozygous for the MTHFR C677T mutation.
Lisa’s TSH was at 1.5 mIU/L, and her Free T3 and Free T4 were at the upper ends of the range. She also had elevated levels of total serum IgG (1876 mg/dL), and ANA (1:160, speckled), and her hs-CRP was borderline at 1.0 mg/L. Family history revealed that her mother had psoriatic arthritis and her brother also had psoriasis.
A comprehensive digestive stool analysis was ordered. It was revealed that Lisa was positive for 2 opportunistic bacterial strains which were sensitive to berberine, and she had a deficiency of Lactobacilli.
Lisa was initiated on a diet free of grains, dairy, eggs, corn, and soy, and high in vegetables, protein, fatty fish, and olive oil. A berberine compound was prescribed for a period of 4 weeks, along with anti-inflammatory probiotic strains and digestive enzymes, which were continued throughout treatment. This was followed by the gut-healing nutrients, L-glutamine and NAG. Our patient experienced a resolution of her GI symptoms during this time, and an increase in energy.
She was then initiated on EGCG (200 mg TID); pine bark (200 mg TID); MTHF (2 mg); selenium (200 mcg QD); and EPA (1300 mg)/DHA (800mg) QD. N-acetylglutathione was provided at a dosage of 1200 mg per day, and vitamin D at 5000 IU per day.
After 5 months on this protocol, she became pregnant. Her thyroid function was monitored throughout pregnancy to ensure that it remained below 2.5 mIU/mL which it did, despite rising toward the top of this range. Nine months later she delivered a beautiful baby girl.
Autoimmune processes can have a profound effect on healthy reproduction, an aspect of fertility care which has long been underestimated. A healthy immune system can not only promote implantation and prevent miscarriage, but it is also a key component to the dynamic interactions within the hormonal system in the body.
Fiona McCulloch, BSc, ND has been in naturopathic practice since 2001, after graduating from the Canadian College of Naturopathic Medicine and the University of Guelph (Biological Science). She is the founder of White Lotus Integrative Medicine in Toronto. She has published numerous articles on the topics of evidence-based medicine for infertility and women’s health concerns. Fiona is also currently working on her first book, PCOS: Fertility Restored, which will review evidence-based natural approaches to PCOS, new information on PCOS phenotypes, and strategies for treating PCOS differentiated by phenotype. Her book is set to be published in 2014.
References
1. McCulloch F. Autoimmune Infertility. NDNR; 2011;7(3). NDNR Web site. https://ndnr.com/e-version/mar11/mar11.pdf.html.
2. Cervera R, Balasch J. Bidirectional effects on autoimmunity and reproduction. Hum Reprod Update. 2008;14(4):359-366.
3. Kumar A, Meena M, Begum N, et al. Latent celiac disease in reproductive performance of women. Fertil Steril. 2011;95(3):922-927.
4. Yamada H, Atsumi T, Kato EH, et al. Prevalence of diverse antiphospholipid antibodies in women with recurrent spontaneous abortion. Fertil Steril. 2003;80(5):1276-1278.
5. Jin LP, Fan DX, Zhang T, et al. The costimulatory signal upregulation is associated with Th1 bias at the maternal-fetal interface in human miscarriage. Am J Reprod Immunol. 2011;66(4):270-278.
6. Zhou J, Wang Z, Zhao X, et al. An increase of Treg cells in the peripheral blood is associated with a better in vitro fertilization treatment outcome. Am J Reprod Immunol. 2012;68(2):100-106.
7. Chen S, Zhang J, Huang C, et al. Expression of the T regulatory cell transcription factor FoxP3 in peri-implantation phase endometrium in infertile women with endometriosis. Reprod Biol Endocrinol. 2012;10:34.
8. Jasper MJ, Tremellen KP, Robertson SA. Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue. Mol Hum Reprod. 2006;12(5):301-308.
9. Winger EE, Reed JL. Low circulating CD4(+) CD25(+) Foxp3(+) T regulatory cell levels predict miscarriage risk in newly pregnant women with a history of failure. Am J Reprod Immunol. 2011;66(4):320-328.
10. Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology. 2006 Mar;117(3):289-300.
11. Sen A, Kushnir VA, Barad DH, Gleicher N. Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol. 2014;10(1):37-50.
12. Carp HJ, Selmi C, Shoenfeld Y. The autoimmune bases of infertility and pregnancy loss. J Autoimmun. 2012;38(2-3):J266-J274.
13. Kachuei M, Jafari F, Kachuei A, Keshteli AH. Prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. Arch Gynecol Obstet. 2012;285(3):853-856.
14. Luborsky J, Llanes B, Davies S, et al. Ovarian autoimmunity: greater frequency of autoantibodies in premature menopause and unexplained infertility than in the general population. Clin Immunol. 1999;90(3):368-374.
15. Gómez R, Abad A, Delgado F, et al. Effects of hyperprolactinemia treatment with the dopamine agonist quinagolide on endometriotic lesions in patients with endometriosis-associated hyperprolactinemia. Fertil Steril. 2011;95(3):882-888.
16. De Bellis A, Bizzarro A, Pivonello R, et al. Prolactin and autoimmunity. Pituitary. 2005;8(1):25-30.
17. de Graaff LC, De Bellis A, Bellastella A, Hokken-Koelega AC. Antipituitary antibodies in Dutch patients with idiopathic hypopituitarism. Horm Res. 2009;71(1):22-27.
18. Codner E, Merino PM, Tena-Sempere M. Female reproduction and type 1 diabetes: from mechanisms to clinical findings. Hum Reprod Update. 2012;18(5):568-585.
19. Albertini DF. Searching for answers to the riddle of ovarian aging. J Assist Reprod Genet. 2012;29(7):577-578.
20. Janse F, Tanahatoe SJ, Eijkemans MJ, Fauser BC. Testosterone concentrations, using different assays, in different types of ovarian insufficiency: a systematic review and meta-analysis. Hum Reprod Update. 2012;18(4):405-419.
21. Gleicher N, Weghofer A, Kushnir VA, et al. Is androgen production in association with immune system activation potential evidence for existence of a functional adrenal/ovarian autoimmune system in women? Reprod Biol Endocrinol. 2013;11:58.
22. Ott J, Aust S, Kurz C, et al. Elevated antithyroid peroxidase antibodies indicating Hashimoto’s thyroiditis are associated with the treatment response in infertile women with polycystic ovary syndrome. Fertil Steril. 2010;94(7):2895-2897.
23. Deligeoroglou E, Vrachnis N, Athanasopoulos N, et al. Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecol Endocrinol. 2012;28(12):974-978.
24. Fasano A. Intestinal zonulin: open sesame! Gut. 2001;49(2):159-162.
25. Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012;42(1):71-78.
26. Christen U, von Herrath MG. Induction, acceleration or prevention of autoimmunity by molecular mimicry. Mol Immunol. 2004;40(14-15):1113-1120.
27. Ebringer A, Rahid T. Rheumatoid arthritis is an autoimmune disease triggered by Proteus urinary tract infection. Clin Dev Immunol. 2006;13(1):41-48.
28. Haring JS, Pewe LL, Perlman S. Bystander CD8 T cell-mediated demyelination after viral infection of the central nervous system. J Immunol. 2002;169(3):1550-1555.
29. Jorissen A, Plum LM, Rink L, Haase H. Impact of lead and mercuric ions on the interleukin-2-dependent proliferation and survival of T cells. Arch Toxicol. 2013;87(2):249-258.
30. Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol. 2005;2(9):416-422.
31. Kanczkowski W, Ziegler CG, Zacharowski K, Bornstein SR. Toll-like receptors in endocrine disease and diabetes. Neuroimmunomodulation. 2008;15(1):54-60.
32. Drago S, El Asmar L, Di Pierro M, et al. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006;41(4):408-419.
33. Groeger D, O’Mahony L, Murphy EF, et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. 2013;4(4):325-339.
34. Wallace TD, Bradley S, Buckley ND, Green-Johnson JM. Interactions of lactic acid bacteria with human intestinal epithelial cells: effects on cytokine production. J Food Prot. 2003;66(3):466-472.
35. Schiffer C, Lalanne AI, Cassard L, et al. A strain of Lactobacillus casei inhibits the effector phase of immune inflammation. J Immunol. 2011;187(5):2646-2655.
36. Kiseleva EP, Mikhailopulo KI, Sviridov OV, et al. The role of components of Bifidobacterium and Lactobacillus in pathogenesis and serologic diagnosis of autoimmune thyroid diseases. Benef Microbes. 2011;2(2):139-154.
37. Kong J, Zhang Z, Musch MW, et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G208-G216.
38. Tamer G, Arik S, Tamer I, Coksert D. Relative vitamin D insufficiency in Hashimoto’s thyroiditis. Thyroid. 2011;21(8):891-896.
39. Prietl B, Pilz S, Wolf M, et al. Vitamin D supplementation and regulatory T cells in apparently healthy subjects: vitamin D treatment for autoimmune diseases? Isr Med Assoc J. 2010;12(3):136-139.
40. Dröge W, Breitkreutz R. Glutathione and immune function. Proc Nutr Soc. 2000;59(4):595-600.
41. Byun JK, Yoon BY, Jhun JY, et al. Epigallocatechin-3-gallate ameliorates both obesity and autoinflammatory arthritis aggravated by obesity by altering the balance among CD4(+) T-cell subsets. Immunol Lett. 2014;157(1-2):51-59.
42. Ahmad SF, Zoheir KM, Abdel-Hamied HE, et al. Grape seed proanthocyanidin extract has potent anti-arthritic effects on collagen-induced arthritis by modifying the T cell balance. Int Immunopharmacol. 2013;17(1):79-87.
43. Cho KJ et al. Inhibition mechanisms of bioflavonoids extracted from the bark of Pinus maritime on the expression of pro inflammatory cytokines. Ann NY Acad Sci. 2001;928:141-156.
44. Wu D, Wang J, Pae M, Meydani SN. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases. Mol Aspects Med. 2012;33(1):107-118.
45. Kunisawa J, Hashimoto E, Ishikawa I, Kiyono H. A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo. PLoS One. 2012;7(2):e32094.
46. Han SC, Kang GJ, Ko YJ, et al. Fermented fish oil suppresses T helper 1/2 cell response in a mouse model of atopic dermatitis via generation of CD4+CD25+Foxp3+ T cells. BMC Immunol. 2012;13:44.
