Celiac Disease and the Risk of Infertility

Pablo Olivera, Juan Lasa

International Journal of Celiac Disease

Celiac Disease and the Risk of Infertility

Pablo Olivera1, Juan Lasa1,

1Gastroenterology Section, Internal Medicine Department, CEMIC, Buenos Aires, Argentina

Abstract

Celiac Disease is a chronic inflammatory disease, caused by an abnormal immune response triggered by intestinal exposure to dietary gluten, the protein fraction of wheat, rye and barley, in genetically susceptible individuals. Among atypical presentations of Celiac Disease, reproductive disorders and adverse pregnancy outcomes have been reported. Infertility is defined as the impossibility of conceiving after 12 months of unprotected intercourse. It can be related to both male and female factors, with the latter subdivided into ovarian, tubal, endometrial or unexplained causes. Celiac Disease has been related to infertility, but the evidence is inconclusive. In this review, we discuss the effect of Celiac Disease in both male and female fertility, as well as the possible mechanisms that may be involved.

Cite this article:

  • Pablo Olivera, Juan Lasa. Celiac Disease and the Risk of Infertility. International Journal of Celiac Disease. Vol. 3, No. 3, 2015, pp 84-86. http://pubs.sciepub.com/ijcd/3/3/9
  • Olivera, Pablo, and Juan Lasa. "Celiac Disease and the Risk of Infertility." International Journal of Celiac Disease 3.3 (2015): 84-86.
  • Olivera, P. , & Lasa, J. (2015). Celiac Disease and the Risk of Infertility. International Journal of Celiac Disease, 3(3), 84-86.
  • Olivera, Pablo, and Juan Lasa. "Celiac Disease and the Risk of Infertility." International Journal of Celiac Disease 3, no. 3 (2015): 84-86.

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1. Introduction

Celiac disease (CD) is a chronic inflammatory disease, caused by an abnormal immune response triggered by intestinal exposure to dietary gluten, the protein fraction of wheat, rye and barley, in genetically susceptible individuals. This genetic susceptibility to develop CD has been attributed to the presence of HLA DQ2 and DQ8 haplotypes, which are necessary but not sufficient for the development of the disease, since HLA DQ2 is carried by approximately a third of the general population [1, 2].

CD is a systemic disease, which can have different forms of presentation, with a wide clinical range. Typical symptoms are malabsorption-related and include chronic diarrhea, weight loss, abdominal bloating or iron-deficiency anemia, which in classic forms of CD usually lead to the diagnosis during childhood. However, CD can also present with several non-gastrointestinal symptoms and it may not be easily recognized until adulthood. As a systemic disease, CD may affect many organs; hence, it may present as dermatitis herpetiformis, aphthous stomatitis, osteopenia, hypertransaminasemia, dental enamel defects and various neurological complications such as depression or ataxia [3]. Malignant complications such as enteropathy-associated T-cell lymphoma and adenocarcinoma of the jejunum are infrequent.

An association with autoimmune disorders is often seen in CD, and include type 1 diabetes, autoimmune thyroiditis, Sjögren’s syndrome, systemic lupus erythematosus, autoimmune hepatitis, primary biliary cirrhosis, IgA deficiency, Addison’s disease, atopy, systemic and cutaneous vasculitis, psoriasis, and polymyositis [4].

Among atypical presentations of CD, both female and male infertility problems and adverse pregnancy outcomes have been described [1, 2]. Infertility is defined as the impossibility of conceiving after 12 months of unprotected intercourse [5]. It can be related to both male and female factors, with the latter subdivided into ovarian, tubal, endometrial or unexplained causes. It is a relatively frequent condition, affecting approximately 8% to 12% of couples [6].

CD has been related to infertility, but the evidence is inconclusive. In this review, we discuss the effect of CD in both male and female fertility, as well as the possible mechanisms that may be involved.

2. Female Infertility in Celiac Disease

In the last four decades, there has been a growing number of reports describing a association between fertility problems and CD. In 1970, Morris et al. reported three celiac patients with infertility, who were able to give birth after dietary gluten restriction [1], establishing the possible relationship between these two entities, and the potential beneficial role of gluten free diet (GFD). On the contrary, Jackson et al described a cohort of women suffering from infertility that were tested for CD by means of serology [7]. The authors compared the prevalence of positive findings to the background rate in the general US population: they found that their cohort had a lower prevalence. Another inconclusive finding was reported by Choi et al, who studied women attending to an infertility clinic [8]. They failed to find a higher prevalence of CD than the one reported in the general US population. It is worth mentioning however that these two studies lacked an adequate design for this purpose.

Several case-control studies have been published, and they share common features [9, 10, 11]. Firstly, they include patients with a diagnosis of unexplained infertility, which means that potential ovarian, tubarian and endometrial causes were already ruled out. Most of them used antigliadin, antitransglutaminase or antiendomysium antibodies to screen the patients enrolled in their studies, and biopsy was reserved for those patients with positive serology. Interestingly, most of them fail to find a statistically significant increased prevalence of CD in women with unexplained infertility – a finding that becomes significant when pooled analysis is performed [12].

More recently, in a large Swedish population-based cohort study, Zugna et al. included 11495 women with CD and 51109 controls, and found a similar fertility rate of both groups, but the fertility of celiac women was decreased in the 2 years preceding CD diagnosis [13].

In a case-control study, Sher et al. observed that celiac patients had a significant smaller mean number of children compared with controls before diagnosis of CD, but after diagnosis and GFD, the number of children were similar in both groups [14].

These data strongly indicate that impaired fertility is more common in patients with active CD when a GFD is unlikely to have been initiated, and show the benefit of gluten restriction in these patients. On the other hand, based on the results of case-control studies, unexplained infertility may have a significantly higher risk for CD, so it may be reasonable to exclude CD in women with this condition, after excluding other potential diagnoses.

2.1. Possible Pathogenic Mechanisms

The exact mechanisms underlying infertility in CD are still not clear, but several hypotheses have been described. Probably, the malabsorption in these patients, and the subsequent nutrient deficiency has a role in the pathogenesis. However, infertility cannot be explained solely by malabsorption and other mechanisms such as autoimmunity may have a role.

The villous atrophy seen in CD, generally leads to malabsorption and may produce deficiencies in micronutrients such as zinc, selenium or folic acid [15-20][15]. Both zinc and selenium deficiencies cause impaired synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently cause abnormal ovarian axis function, spontaneous abortions, secondary amenorrhea, and pre-eclampsia [21, 22]. Folic acid deficiency has also been implicated in the pathogenesis of infertility in CD. Folic acid has an important role in nucleic acid metabolism, and therefore has an impact in rapidly proliferating tissues like the embryo.

Nevertheless, in different series, celiac infertile women with total or subtotal villous atrophy failed to show signs of nutritional deficits [23, 24, 25]. For example, in the series published by Collin et al., celiac patients showed neither severe malnutrition nor signs of trace element deficiency; only two had iron deficiency [23].

Consequently, current evidence does not support nutritional deficiencies and malabsorption as the main pathological mechanism of infertility in CD. In recent years, other possible mechanisms to explain its pathogenesis have been investigated, such as autoimmune mechanisms.

Anti-tissue transglutaminase antibodies (anti-tTG), appear to be not only a diagnostic marker in celiac patients on gluten-containing diet, but also have been implicated in the pathogenesis of many CD manifestations [26, 27, 28], including fertility and pregnancy complications. The enzyme transglutaminase can be found in many organs, and may have a role in interactions of cells with the surrounding extracellular matrix [29], in processes of cell adhesion, migration and spreading. It has been demonstrated that this enzyme is present in endometrial cells and also in stromal and trophoblast placental cells [30]. Therefore, circulating anti-tTG may bind to placental and endometrial cell surfaces, preventing implantation. It has been demonstrated that anti-tTG class IgA can bind directly to the syncytial surface of the placenta, inhibiting tTG activity and compromising placental function [31]. Also Di Simone et al. showed that anti-tTG class IgG bind in vitro to human trophoblast, and cause decreased invasiveness, decreased activity of cellular matrix metalloprotease and cellular apoptosis [32]. The same group demonstrated an additional mechanism mediated by anti-tTG: they showed that these antibodies have a detrimental effect on human endometrial angiogenesis [33]. These observations provide an immune-mediated mechanism for infertility and adverse pregnancy outcomes seen in active CD.

3. Male Infertility in Celiac Disease

Compared with the number of studies evaluating female infertility in CD, evidence regarding celiac male partners fertility is relatively scarce. Although the existence of reports dating back to the 1950’s stating a possible association between CD and male infertility [34], recent studies have failed to show an increased prevalence of CD in this population. In a relatively large Dutch case-control study, Hogen Esch et al. described no differences in terms of CD prevalence between infertile male and the general population [11]. In a Swedish population-based cohort study, Zugna et al. compared fertility in 7121 men with biopsy-proven CD with 31677 controls. They found that there were no differences in the cumulative number of children during fertile years between men with CD and controls, and there were no difference in fertility before and after the diagnosis of CD [35].

4. Conclusions

There is increasing evidence to support a possible association between CD and infertility. This complication may not be exclusively due to a deficiency in micronutrients absorption, and an autoimmune mechanism may contribute to its development. Women presenting with infertility without a clear cause should be screened for CD. Although more evidence is needed, there seems to be a benefitial role of GFD in terms of fertility, judging from the results of large cohort studies.

References

[1]  Morris JS, Adjukiewicz AB, Read AE. Coeliac infertility: an indication for dietary gluten restriction? Lancet 1970; 1(7640): 213-214.
In article      View Article
 
[2]  Wilson C, Eade OE, Elstein M, Wright R. Subclinical coeliac disease and infertility. Br Med J 1976;2(6029): 215-216.
In article      View Article  PubMed
 
[3]  Reilly NR, Fasano A, Green PHR. Presentation of celiac disease. Gastrointest Endosc Clin N Am 2012;22(4):613-621.
In article      View Article  PubMed
 
[4]  Di Sabatino A, Corazza GR. Coeliac disease. Lancet 2009; 373(9673): 1480-1493.
In article      View Article
 
[5]  Balen AH, Rutherford AJ. Management of infertility. BMJ 2007;335(7620):608-611.
In article      View Article  PubMed
 
[6]  Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 2007;22(6):1506-1512.
In article      View Article  PubMed
 
[7]  Jackson JE, Rosen M, Mc Lean T, Moro J, Croughan M, Cedars MI. Prevalence of celiac disease in a cohort of women with unexplained infertility. Fertil Steril 2008; 89(4): 1002-1004.
In article      View Article  PubMed
 
[8]  Choi JM, Lebwohl B, Wang J, Lee SK, Murray JA, Sauer MV, Green PH. Increased prevalence of celiac diseasein patients with unexplained infertility in the United States: a prospective study. J Reprod Med 2011; 56(5): 199-203.
In article      PubMed
 
[9]  Tiboni GM, de Vita MG, Faricelli R, Giampietro F, Liberati M. Serological testing for celiac diseasein women undergoingassisted reproduction techniques. Hum Reprod 2006; 21: 376-379.
In article      View Article  PubMed
 
[10]  Kumar A, Meena M, Begum N, Kumar N, Gupta RK, Agarwal S, Prasad S, Batra S. Latent celiac disease in reproductive perfomance of women. Fertil Steril 2011; 95: 922-927.
In article      View Article  PubMed
 
[11]  Hogen Esch CE, Van Rijssen MJL, Roos A, Koning F, Dekker FW, Mearin ML, Helmerhorst FM, Schweizer JJ. Screening for unrecognized coeliac disease in subfertile couples. Scand J Gastroenterol 2011; 46: 1423-1428.
In article      View Article  PubMed
 
[12]  Lasa JS, Zubiaurre I, Soifer LO. Risk of infertility in patients with celiac disease: a meta-analysis of observational studies. Arq Gastroenterol 2014;51(2):144-150
In article      View Article  PubMed
 
[13]  Zugna D, Richiardi L, Akre O, Stephansson O, Ludvigsson JF. A nationwide population-based study to determine whether coeliac disease is associated with infertility. Gut 2010; 59(11):1471-1475.
In article      View Article  PubMed
 
[14]  Sher KS, Mayberry JF. Female fertility, obstetric and gynaecological history in coeliac disease. A case control study. Digestion 1994;55(4):243-246.
In article      View Article  PubMed
 
[15]  Jameson S. Zinc deficiency in malabsorption states: a cause of infertility? Acta Med Scan Suppl 1976;593:38-49.
In article      View Article
 
[16]  Cortigiani L, Nutini P, Caiulo VA, Ughi C, Ceccarelli M. Selenium in celiac disease. Minerva Pediatr 1989;41(11):539-542.
In article      PubMed
 
[17]  Yuce A, Demir H, Temizel INS, Kocak N. Serum carnitine and selenium levels in children with celiac disease. Indian J Gastroenterol 2004;23(3):87-88.
In article      PubMed
 
[18]  Haapalahti M, Kulmala P, Karttunen TJ et al. Nutritional status in adolescents and young adults with screen-detected celiac disease. J Pediatr Gastroenterol Nutr 2005;40(5):566-570.
In article      View Article  PubMed
 
[19]  Singhal N, Alam S, Sherwani R, Musarrat J. Serum zinc levels in celiac disease. Indian Pediatr 2008;45(4):319-321.
In article      PubMed
 
[20]  Hogberg L, Danielsson L, Jarleman S, Sundqvist T, Stenhammar L. Serum zinc in small children with coeliac disease. Acta Paediatr 2009;98(2):343-345.
In article      View Article  PubMed
 
[21]  Bedwal RS, Bahuguna A. Zinc, copper and selenium in reproduction. Experientia 1994;50(7):626-640.
In article      View Article
 
[22]  Rostami K, Steegers EA, Wong WY, Braat DD, Steegers-Theunissen RP. Coeliac disease and reproductive disorders: a neglected association. Eur J Obstet Gynecol Reprod Biol 2001; 96(2): 146-149.
In article      View Article
 
[23]  Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P. Inferility and coeliac disease. Gut 1996;39(3): 382-384.
In article      View Article  PubMed
 
[24]  Meloni GF, Dessole S, Vargiu N, Tomasi PA, Musumeci S. The prevalence of coeliac disease in infertility. Hum Reprod 1999; 14(11): 2759-2761.
In article      View Article  PubMed
 
[25]  Shamaly H, Mahameed A, Sharony A, Shamir R. Infertility and celiac disease: do we need more than one serological marker? Acta Obstet Gynecol Scand 2004;83(12):1184-1188.
In article      View Article  PubMed
 
[26]  Caputo I, Barone MV, Lepretti M, et al. Celiac anti-tissue transglutaminase antibodies interfere with the uptake of alpha gliadin peptide 31-43 but not of peptide 57-68 by epithelial cells. Biochem Biophys Acta 2010;1802(9):717-727.
In article      View Article
 
[27]  Cervio E, Volta U, Verri M, et al. Sera of patients with celiac disease and neurological disorders evoke a mithocondrial-dependent apoptosis in vitro. Gastroenterology 2007; 133(1): 195-206.
In article      View Article  PubMed
 
[28]  Caputo I, Barone MV, Martuciello S, Lepretti M Esposito C. Tissue transglutaminase in celiac disease: role of autoantibodies. Amino Acids 2009;36(4):693-699.
In article      View Article  PubMed
 
[29]  Zemskov EA, Janiak A, Hang J, Waghray A, Belkin AM. The role of tissue transglutaminase in cell-matrix interactions. Front Biosci 2006;11:1057-1076.
In article      View Article  PubMed
 
[30]  Robinson NJ, Glazier JD, Greenwood SL, Baker PN, Aplin JD. Tissue transglutaminase expression and activity in placenta. Placenta 2006;27(2-3):148-157.
In article      View Article  PubMed
 
[31]  Anjum N, Baker PN, Robinson NJ, Aplin JD. Maternal celiac disease autoantibodies bind directly to syncitiotrophoblast and inhibit placental tissue transglutaminase activity. Reprod Biol Endocrinol 2009;7:16.
In article      View Article  PubMed
 
[32]  Di Simone N, Silano M, Castellani R et al. Anti-tissue transglutaminase antibodies from celiac patients are responsible for trophoblast damage via apoptosis in vitro. Am J Gastroenterol 2010;105(10):2254-2261.
In article      View Article  PubMed
 
[33]  Di Simone N, De Spirito M, Di Nicuolo F et al. Potential new mechanisms of placental damage in celiac disease: anti-transglutaminase antibodies impair human endometrial angiogenesis. Biol Reprod 2013;89(4):88-98.
In article      View Article  PubMed
 
[34]  Cooke WT, Peeney ALP, Hawkins CF. Symptoms, signs and diagnostic features of idiopathic statorrhoea. Q J Med 1953;22(85):59-78.
In article      PubMed
 
[35]  . Zugna D, Richiardi L, Akre O, Stephansson O, Ludvigsson JF. Celiac disease is not a risk factor for infertility in men. Fertil Steril 2011;95(5):1703-1709.
In article      View Article  PubMed
 
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