Expression of thyroid antigens in the female reproductive system

Selma Aissiou, Nadjia Boucekkine, Eoghan M. Cunnane, Nasrin G. Gashti, Amina Oumeziane, Naima Kaci

Abstract

Thyroid autoimmunity (TAI) has been linked to fertility disorders and pregnancy complications, even in euthyroid women. However, the exact pathophysiological mechanism underlying this association is not fully understood. This study seeks to investigate the expression of thyroid antigens within the human female reproductive system, potentially identifying targets for thyroid antibodies. Human biopsies of endometrium and follicular granulosa cells were collected and thyroperoxidase (TPO) and thyroglobulin (TG) expression was evaluated in these tissues by immunohistochemistry. Results showed, for the first time, the expression of TG protein and confirmed the presence of thyroid TPO in human endometrium and granulosa cells. Results suggest that TPO antibodies (TPOAbs) and TG antibodies (TGAbs) could interact with TPO and TG expressed in the reproductive system in patients with positive thyroid antibodies, thereby disrupting the function of TPO and TG and generating an inflammatory response, leading to fertility disorders and pregnancy complications.

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References

Mazzilli R, Medenica S, Di Tommaso AM, Fabozzi G,

Zamponi V, Cimadomo D, Rienzi L, Ubaldi FM,

Watanabe M, Faggiano A, La Vignera S and Defeudis

G. The role of thyroid function in female and male

infertility: a narrative review. J Endocrinol Invest.

;46(1):15–26.

https://doi.org/10.1007/s40618

-01883-7

Ren B and Zhu Y. A new perspective on thyroid hormones:

crosstalk with reproductive hormones in females. Int

J

Mol

Sci.

;23(5):2708.

https://doi.org/10.3390/ijms23052708.

; PMCID: PMC8911152.

PMID:

Juneo FS, Ocarino NM and Serakides R. Thyroid hormones

and

female

reproduction.

;99(5):907–21.

Biol

Reprod.

https://doi.org/10.1093/biolre/ioy115.

Vissenberg R, Manders VD, Mastenbroek S, Fliers E, Afink

GB, Ris-Stalpers C, Goddijn M and Bisschop PH.

Pathophysiological aspects of thyroid hormone

disorders/thyroid peroxidase autoantibodies and

reproduction. Hum Reprod Update. 2015 May

Jun;21(3):378-87. doi: 10.1093/humupd/dmv004.

PMID: 25634660.

McGrogan A, Seaman HE, Wright JW and De Vries CS. The

incidence of autoimmune thyroid disease: a

systematic review of the literature. Clin Endocrinol

(Oxf). 2008;69(5):687-696. doi: 10.1111/j.1365

2008.03338.x.

Bogusławska J, Godlewska M, Gajda E and Piekiełko

Witkowska A. Cellular and molecular basis of thyroid

autoimmunity. Eur Thyroid J. 2022;11(1):e210024.

doi: 10.1530/ETJ-21-0024.

Conrad N, Misra S, Verbakel JY, Verbeke G, Molenberghs

G, Taylor PN, Mason J, Sattar N, McMurray J,

McInnes IB, Khunti K and Cambridge G. Incidence,

prevalence, and co-occurrence of autoimmune

disorders over time and by age, sex, and

socioeconomic status: a population-based cohort

study of 22 million individuals in the UK. Lancet

(London, England). 2023;401(10391):1878–1890.

https://doi.org/10.1016/S0140-6736(23)00457-9

Hu X, Chen Y, Shen Y, Tian R, Sheng Y and Que H. Global

prevalence and epidemiological trends of Hashimoto's

thyroiditis in adults: A systematic review and meta

analysis. Front Public Health. 2022;10:1020709. doi:

3389/fpubh.2022.1020709. ISSN: 2296-2565.

Carvalho GA, Perez CL and Ward LS. The clinical use of

thyroid function tests. Arq Bras Endocrinol Metabol.

;57(3):193-204.

Wémeau J-L. Les Maladies de la thyroïde. 2nd ed. Paris:

Elsevier Masson, 2022. 352 p. ISBN 9782294775833.

Twig G, Shina A, Amital H and Shoenfeld Y. Pathogenesis

of infertility and recurrent pregnancy loss in thyroid

autoimmunity. J Autoimmun. 2012;38(2-3):J275-81.

Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J and

Coomarasamy A. Association between thyroid

autoantibodies and miscarriage and preterm birth:

meta-analysis of evidence. BMJ. 2011 May 9;342:d2616. doi: 10.1136/bmj.d2616. PMID:

; PMCID: PMC3089879.

Van Den Boogaard E, Vissenberg R, L and JA, Van Wely

M, Van Der Post JA, Goddijn M and Bisschop PH.

Significance of (sub)clinical thyroid dysfunction and

thyroid autoimmunity before conception and in early

pregnancy: a systematic review. Hum Reprod Update.

;17:605–619.

Unuane D, Velkeniers B, Anckaert E, Schiettecatte J,

Tournaye H, Haentjens P and Poppe K. Thyroglobulin

autoantibodies:

is

there

any added value

in the detection of thyroid autoimmunity in women

consulting for fertility treatment? Thyroid. 2013

Aug;23(8):1022-8.

doi:

1089/thy.2012.0562.

PMID: 23405888; PMCID: PMC3752510.

Bucci I, Giuliani C, Di Dalmazi G, Formoso G and

Napolitano G. Thyroid autoimmunity in female

infertility and assisted reproductive technology

outcome. Front Endocrinol. 2022;13:768363.

https://doi.org/10.3389/fendo.2022.768363.

Tańska K, Gietka-Czernel M, Glinicki P and Kozakowski J.

Thyroid autoimmunity and its negative impact on

female fertility and maternal pregnancy outcomes.

Front

Endocrinol.

;13:1049665.

https://doi.org/10.3389/fendo.2022.1049665

Wang X, Ding X, Xiao X, Xiong F and Fang R. An

exploration on the influence of positive simple thyroid

peroxidase antibody on female infertility. Exp Ther

Med. 2018;16(4):3077-3081.

Bahreiny SS, Ahangarpour A, Amraei M, Mansouri Z,

Pirsadeghi A, Kazemzadeh R, Javidan M, Karamali N,

Bastani M-N and Dabbagh MR. Autoimmune thyroid

disorders and polycystic ovary syndrome: Tracing

links through systematic review and meta-analysis. J

Reprod Immunol. 2024;163:104215. ISSN 0165

https://doi.org/10.1016/j.jri.2024.104215.

Korevaar TIM, Mínguez-Alarcón L, Messerlian C, de

Poortere RA, Williams PL, Broeren MA, Hauser R

and Souter IC. Association of Thyroid Function and

Autoimmunity with Ovarian Reserve in Women

Seeking

Infertility

Care.

Thyroid.

Oct;28(10):1349-1358. doi: 10.1089/thy.2017.0582.

Epub 2018 Aug 14. PMID: 29943679; PMCID:

PMC6157366.

Chen CW, Huang YL, Tzeng CR, Huang RL and Chen CH.

Idiopathic low ovarian reserve is associated with more

frequent positive thyroid peroxidase antibodies.

Thyroid. 2017;27(9):1194–200.

Busnelli A, Beltratti C, Cirillo F, Bulfoni A, Lania A and

Levi-Setti PE. Impact of Thyroid Autoimmunity on

Assisted Reproductive Technology Outcomes and

Ovarian Reserve Markers: An Updated Systematic

Review and Meta-Analysis. Thyroid. 2022

Sep;32(9):1010-1028. doi: 10.1089/thy.2021.0656.

Epub 2022 Aug 29. PMID: 35819278.

Zhang J, Song Z, Yuan H and Cai ZH. The effects of

metabolic indicators and immune biomarkers on

pregnancy outcomes in women with recurrent

spontaneous abortion: a retrospective study. Front

Endocrinol (Lausanne). 2024;14:1297902. Published

Jan 17. doi:10.3389/fendo.2023.1297902

Liu M, Wang D, Zhu L, Yin J, Ji X, Zhong Y, Gao Y, Zhang

J, Liu Y, Zhang R and Chen H. Association of thyroid

peroxidase antibodies with the rate of first-trimester

miscarriage in euthyroid women with unexplained

recurrent spontaneous abortion. Front Endocrinol.

;13:966565.

https://doi.org/10.3389/fendo.2022.966565

Venables A, Wong W, Way M and Homer HA. Thyroid

autoimmunity and IVF/ICSI outcomes in euthyroid

women: a systematic review and meta-analysis.

Reprod Biol Endocrinol. 2020;18(1):120.

Leiva P, Schwarze JE, Vasquez P, Ortega C, Villa S, Crosby

J, Balmaceda J and Pommer R. There is no association

between the presence of anti-thyroid antibodies and

increased reproductive loss in pregnant women after

ART: a systematic review and meta-analysis. JBRA

Assist Reprod. 2017;21(4):361–365.

Rao M, Zeng Z, Zhang Q, Su C, Yang Z, Zhao S and Tang

L. Thyroid autoimmunity is not associated with

embryo quality or pregnancy outcomes in euthyroid

women undergoing assisted reproductive technology

in

China. Thyroid. 2023;33(3):380-388. doi:

1089/thy.2022.0184.

Kim NY, Cho HJ, Kim HY, Yang KM, Ahn HK, Thornton

S, Park JC, Beaman K, Gilman-Sachs A and Kwak

Kim J. Thyroid autoimmunity and the outcomes of

assisted reproductive technology: a meta-analysis.

Hum Reprod Update. 2022;28(3):277-292.

Lu H, Huang Y, Xin H, Hao C, Cui Y. The expression of

cytokines IFN-γ, IL-4, IL-17A, and TGF-β1 in

peripheral blood and follicular fluid of patients testing

positive for anti-thyroid autoantibodies and its

influence on in vitro fertilization and embryo transfer

pregnancy

outcomes.

;34(11):933–939.

Gynecol

Endocrinol.

Zhu Q, Xu QH, Xie T, Wang LL, Liu H, Muyayalo KP,

Huang XB, Zhao SJ, Liao AH. Recent insights into the

impact of immune dysfunction on reproduction in

autoimmune

thyroiditis.

Clin

Immunol.

;224:108663.Monteleone P, Faviana P and Artini

PG. Thyroid peroxidase identified in human granulosa

cells: another piece to the thyroid-ovary puzzle?

Gynecol Endocrinol. 2017;33(7):574-576.

Rahnama R, Mahmoudi AR, Kazemnejad S, Salehi M,

Ghahiri A, Soltanghoraee H, Vafaei S, Rezaei A and

Zarnani AH. Thyroid peroxidase in human

endometrium and placenta: a potential target for anti

TPO antibodies. Clin Exp Med. 2021;21(1):79-88.

Lee YL, Ng HP, Lau KS, Liu WM, O WS, Yeung WS and

Kung AW. Increased fetal abortion rate in

autoimmune thyroid disease is related to circulating

TPO autoantibodies in an autoimmune thyroiditis

animal model. Fertil Steril. 2009 May;91(5

Suppl):2104-9.

doi:

1016/j.fertnstert.2008.07.1704. Epub 2008 Sep 6.

PMID: 18774556.

Seror J, Amand G, Guibourdenche J, Ceccaldi PF and Luton

D. Anti-TPO Antibodies Diffusion through the

Placental Barrier during Pregnancy. PLoS ONE.

;9(1):e84647.

https://doi.org/10.1371/journal.pone.0084647.

Aghajanova L, Lindeberg M, Carlsson IB, Stavreus-Evers

A, Zhang P, Scott JE, Hovatta O and Skjöldebrand

Sparre L. Receptors for thyroid-stimulating hormone

and thyroid hormones in human ovarian tissue.

Reprod Biomed Online. 2009 Mar;18(3):337-47. doi:

1016/s1472-6483(10)60091-0. PMID: 19298732.

Matalon ST, Blank M, Levy Y, Carp HJ, Arad A, Burek L,

Grunebaum E, Sherer Y, Ornoy A, Refetoff S, Weiss

RE, Rose NR and Shoenfeld Y. The pathogenic role

of antithyroglobulin antibody on pregnancy: evidence

from an active immunization model in mice. Hum

Reprod. 2003;18(5):1094–9.

Monteleone P, Parrini D, Faviana P, Carletti E, Casarosa E,

Uccelli A, Cela V, Genazzani AR and Artini PG.

Female infertility related to thyroid autoimmunity: the

ovarian follicle hypothesis. Am J Reprod Immunol.

Aug;66(2):108-14. doi: 10.1111/j.1600

2010.00961.x. Epub 2011 Jan 18. PMID:

Buck T, Hack CT, Berg D, Berg U, Kunz L and Mayerhofer

A. The NADPH oxidase 4 is a major source of

hydrogen peroxide in human granulosa-lutein and

granulosa tumor cells. Sci Rep. 2019;9(1):3585.

Godlewska M and Banga PJ. Thyroid peroxidase as a dual

active

site

enzyme: focus on biosynthesis,

hormonogenesis

and

thyroid

disorders

of

autoimmunity and cancer. Biochimie. 2019;160:34

Brown EDL, Obeng-Gyasi B, Hall JE and Shekhar S. The

thyroid hormone axis and female reproduction. Int J

Mol Sci. 2023;24(12):9815.

Colella M, Cuomo D, Giacco A, Mallardo M, De Felice M

and Ambrosino C. Thyroid hormones and functional

ovarian reserve: systemic vs. peripheral dysfunctions.

J Clin Med. 2020;9(6):1679.

Poppe K, Bisschop P, Fugazzola L, Minziori G, Unuane D

and Weghofer A. 2021 European Thyroid Association

Guideline on Thyroid Disorders prior to and during

Assisted Reproduction. Eur Thyroid J. 2021

Feb;9(6):281-295. doi: 10.1159/000512790. Epub

Jan 21. Erratum in: Eur Thyroid J. 2021

Jun;10(3):268.

PMID:

PMC7923920.

;

PMCID:

Medenica S, Garalejic E, Arsic B, Medjo B, Bojovic Jovic

D, Abazovic D, Vukovic R and Zarkovic M. Follicular

fluid thyroid autoantibodies, thyrotropin, free

thyroxine levels and assisted reproductive technology

outcome. PLoS One. 2018 Oct 29;13(10):e0206652.

doi:

1371/journal.pone.0206652.

; PMCID: PMC6205652.

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