Female reproductive function after radioiodine therapy for differentiated thyroid carcinoma

Differentiated thyroid carcinoma (DTC) is the most common endocrine cancer, accounting for 90–95% of thyroid malignancy and predominant in the female population of all age groups. Surgery is the standard primary treatment for patients with DTC, followed by radioactive iodine therapy (RAIT) when indicated. After the main treatment, patients receive thyroid hormone therapy in a variety of regimens, either as a replacement therapy or as a therapy intended to suppress secretion of thyroid-stimulating hormone (TSH).

The impact of RAIT on the health of individuals with DTC has been studied for years. The accumulation of ¹³¹I in organs and tissues, as well as some organs’ direct involvement in the metabolism of ¹³¹I-containing substances and its excretion, can lead to secondary complications. Reproductive health in the context of RAIT has also been a popular research topic because DTC is frequently found in young individuals.

We may identify a direction for future study in this field and the requirement for adjustments in patient management thanks to the data summarized in this review on the effect of RAIT for DTC on female reproductive health.

1. Global Cancer Observatory. International Agency for Research on Cancer. Thyroid – Russian Federation. Available from: Cancer Today (iarc.fr). 2020

2. Pstrąg N, Ziemnicka K, Bluyssen H, Wesoły J. Thyroid cancers of follicular origin in a genomic light: in-depth overview of common and unique molecular marker candidates. Mol Cancer. 2018;17(1):116. doi: https://doi.org/10.1186/s12943-018-0866-1

3. Arrangoiz R, Cordera F, Caba D, Moreno E, Luque-de-Leon E, Muñoz, M. Thyroid Cancer. International Journal of Otolaryngology and Head & Neck Surgery. 2019;8:217-270. doi: https://doi.org/10.4236/ijohns.2019.86024

4. Beltsevich DG, Vanushko VE, Rumiantsev PO, et al. 2017 Russian clinical practice guidelines for differentiated thyroid cancer diagnosis and treatment. Endocrine Surgery. 2017;11(1):6-27. (In Russ.)] doi: https://doi.org/10.14341/serg201716-27

5. Tuttle RM, et al. Controversies, consensus, and collaboration in the use of 131I therapy in diferentiated thyroid cancer: A joint statement from the American thyroid association, the European association of nuclear medicine, the society of nuclear medicine and molecular imaging, and the European thyroid association. Tyroid. 2019;29(4):461–470. doi: https://doi.org/10.1089/thy.2018.0597

6. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133. doi: https://doi.org/10.1089/thy.2015.0020

7. Bel’tsevich DG, Mudunov AM, Vanushko VE, Rumiantsev PO, Mel’nichenko GA, et al. Differentiated thyroid cancer. Journal of Modern Oncology. 2020;22(4):30-44] doi: https://doi.org/10.26442/18151434.2020.4.200507

8. Pacini F, Fuhrer D, Elisei R, et al. 2022 ETA Consensus Statement: What are the indications for post-surgical radioiodine therapy in differentiated thyroid cancer? Eur Thyroid J. 2022;11(1):e210046 doi: https://doi.org/10.1530/ETJ-21-0046

9. Luster M, Clarke SE, Dietlein M, et al. Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2008;35(10):1941-1959. doi: https://doi.org/10.1007/s00259-008-0883-1

10. Reinberg MV, Slashchuk KYu, Trukhin AA, Avramova KI, Sheremeta MS. Preparation for radioiodine therapy in patients with differentiated thyroid cancer: a modern perspective (a review). Digital Diagnostics. 2023;4(4):543–568.] doi: https://doi.org/10.17816/DD532728

11. Lee SL. Complications of radioactive iodine treatment of thyroid carcinoma. J Natl Compr Canc Netw. 2010;8(11):1277-1287. doi: https://doi.org/10.6004/jnccn.2010.0094

12. Clement SC, Peeters RP, Ronckers CM, et al. Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma - a systematic review. Cancer Treat Rev. 2015;41(10):925-934. doi: https://doi.org/10.1016/j.ctrv.2015.09.001

13. Pashnehsaz M, Takavar A, Izadyar S, et al. Gastrointestinal Side Effects of the Radioiodine Therapy for the Patients with Differentiated Thyroid Carcinoma Two Days after Prescription. World J Nucl Med. 2016;15(3):173-178. doi: https://doi.org/10.4103/1450-1147.174703

14. Lu L, Shan F, Li W, Lu H. Short-Term Side Effects after Radioiodine Treatment in Patients with Differentiated Thyroid Cancer. Biomed Res Int. 2016;2016:4376720. doi: https://doi.org/10.1155/2016/4376720

15. Ahn B-C. Physiologic and False Positive Pathologic Uptakes on Radioiodine Whole Body Scan. In: 12 Chapters on Nuclear Medicine. InTech; 2011. doi: https://doi.org/10.5772/25514

16. Riachy R, Ghazal N, Haidar MB, Elamine A, Nasrallah MP. Early Sialadenitis After Radioactive Iodine Therapy for Differentiated Thyroid Cancer: Prevalence and Predictors. Int J Endocrinol. 2020;2020:8649794. doi: https://doi.org/10.1155/2020/8649794

17. Lee Y, Chung CH, Lin LF, et al. Radioactive Iodine Treatment for Thyroid Cancer Patients Increases the Risk of LongTerm Gastrointestinal Disorders: A Nationwide PopulationBased Cohort Analysis. Cancers (Basel). 2022;14(10):2505. doi: https://doi.org/10.3390/cancers14102505

18. Sparano C, Moog S, Hadoux J, et al. Strategies for Radioiodine Treatment: What’s New. Cancers (Basel). 2022;14(15):3800. doi: https://doi.org/10.3390/cancers14153800

19. Le Roux MK, Graillon N, Guyot L, et al. Salivary side effects after radioiodine treatment for differentiated papillary thyroid carcinoma: Long-term study. Head Neck. 2020;42(11):3133-3140. doi: https://doi.org/10.1002/hed.26359

20. Adramerinas M, Andreadis D, Vahtsevanos K, Poulopoulos A, Pazaitou-Panayiotou K. Sialadenitis as a complication of radioiodine therapy in patients with thyroid cancer: where do we stand? Hormones (Athens). 2021;20(4):669-678. doi: https://doi.org/10.1007/s42000-021-00304-3

21. Upadhyaya A, Meng Z, Wang P, Zhang G, Jia Q, et al. Effects of first radioiodine ablation on functions of salivary glands in patients with differentiated thyroid cancer. Medicine (Baltimore). 2017;96(25):e7164. doi: https://doi.org/10.1097/MD.0000000000007164

22. Horvath E, Skoknic V, Majlis S, et al. Radioiodine-Induced Salivary Gland Damage Detected by Ultrasonography in Patients Treated for Papillary Thyroid Cancer: Radioactive Iodine Activity and Risk. Thyroid. 2020;30(11):1646-1655. doi: https://doi.org/10.1089/thy.2019.0563

23. Demir AN, Kara Z, Sulu C, et al. The effect of radioiodine therapy on blood cell count in patients with differentiated thyroid cancer [published online ahead of print, 2023 Aug 21]. Hormones (Athens). 2023;10.1007/s42000-023-00479-x. doi: https://doi.org/10.1007/s42000-023-00479-x

24. Sönmez B, Bektaş Ö, Erkut N, Sönmez M. Assessment of Long-Term Hematologic Effects in Differentiated Thyroid Cancer Patients Treated with Radioactive Iodine. Turk J Haematol. 2021;38(4):306-313. doi: https://doi.org/10.4274/tjh.galenos.2021.2021.0092

25. Andresen NS, Buatti JM, Tewfik HH, Pagedar NA, Anderson CM, Watkins JM. Radioiodine Ablation following Thyroidectomy for Differentiated Thyroid Cancer: Literature Review of Utility, Dose, and Toxicity. Eur Thyroid J. 2017;6(4):187-196. doi: https://doi.org/10.1159/000468927

26. TRUNNELL JB, MARINELLI LD. The treatment of metastatic thyroid cancer with radioactive iodine; credits and debits. J Clin Endocrinol Metab. 1949;9(11). doi: https://doi.org/10.1210/jcem-9-11-1138

27. DOBYNS BM, MALOOF F. The study and treatment of 119 cases of carcinoma of the thyroid with radioactive iodine. J Clin Endocrinol Metab. 1951;11(11):1323-1360. doi: https://doi.org/10.1210/jcem-11-11-1323

28. Raymond JP, Izembart M, Marliac V, et al. Temporary ovarian failure in thyroid cancer patients after thyroid remnant ablation with radioactive iodine. J Clin Endocrinol Metab. 1989;69(1):186-190. doi: https://doi.org/10.1210/jcem-69-1-186

29. Izembart M, Chavaudra J, Aubert B, Vallée G. Retrospective evaluation of the dose received by the ovary after radioactive iodine therapy for thyroid cancer. Eur J Nucl Med. 1992;19(4):243-247. doi: https://doi.org/10.1007/BF00175136

30. Haynie TP, Vassilopoulou-Sellin R. How safe for the patient is iodine-131 therapy for differentiated thyroid carcinoma? J Nucl Med. 1995;36(1):27-28

31. Sarkar SD, Beierwaltes WH, Gill SP, Cowley BJ. Subsequent fertility and birth histories of children and adolescents treated with 131I for thyroid cancer. J Nucl Med. 1976;17(6):460-464

32. Edmonds CJ, Smith T. The long-term hazards of the treatment of thyroid cancer with radioiodine. Br J Radiol. 1986;59(697):45-51. doi: https://doi.org/10.1259/0007-1285-59-697-45

33. Smith MB, Xue H, Takahashi H, Cangir A, Andrassy RJ. Iodine 131 thyroid ablation in female children and adolescents: long-term risk of infertility and birth defects. Ann Surg Oncol. 1994;1(2):128-131. doi: https://doi.org/10.1007/BF02303556

34. Dottorini ME, Lomuscio G, Mazzucchelli L, Vignati A, Colombo L. Assessment of female fertility and carcinogenesis after iodine-131 therapy for differentiated thyroid carcinoma. J Nucl Med. 1995;36(1):21-27.34

35. Ceccarelli C, Bencivelli W, Morciano D, Pinchera A, Pacini F. 131I therapy for differentiated thyroid cancer leads to an earlier onset of menopause: results of a retrospective study. J Clin Endocrinol Metab. 2001;86(8):3512-3515. doi: https://doi.org/10.1210/jcem.86.8.7719

36. Souza Rosário PW, Fagundes TA, Fagundes AV, et al. Radioiodine therapy and age at menopause in patients with thyroid cancer [1]. Clin Endocrinol (Oxf ). 2006. doi: https://doi.org/10.1111/j.1365-2265.2005.02413.x

37. Manuel García-Quirós Muñoz J, Martín Hernández T, Torres Cuadro A, Cambil Molina T, Castro Montaño J, Sendón Pérez A. Edad de menopausia en pacientes tratadas con I131 por cáncer diferenciado de tiroides [Age of menopause in patients with differentiated thyroid cancer treated with radioiodine]. Endocrinol Nutr. 2010;57(3):105-109. doi: https://doi.org/10.1016/j.endonu.2010.01.014

38. Vini L, Hyer S, Al-Saadi A, Pratt B, Harmer C. Prognosis for fertility and ovarian function after treatment with radioiodine for thyroid cancer. Postgrad Med J. 2002. doi: https://doi.org/10.1136/pmj.78.916.92

39. Souza Rosário PW, Alvarenga Fagundes T, Villas-Boas Fagundes AS, et al. Ovarian function after radioiodine therapy in patients with thyroid cancer. Exp Clin Endocrinol Diabetes. 2005;113(6):331-333. doi: https://doi.org/10.1055/s-2005-837666

40. Sioka C, Kouraklis G, Zafirakis A, Manetou A, Dimakopoulos N. Menstrual cycle disorders after therapy with iodine-131. Fertil Steril. 2006;86(3):625-628. doi: https://doi.org/10.1016/j.fertnstert.2006.02.081

41. Esfahani AF, Eftekhari M, Zenooz N, Saghari M. Gonadal function in patients with differentiated thyroid cancer treated with (131)I. Hell J Nucl Med. 2004;7(1):52-55

42. Acıbucu F, Acıbucu DO, Akkar ÖB, Dokmetas HS. Evaluation of Ovarian Reserve with AMH Level in Patients with WellDifferentiated Thyroid Cancer Receiving Radioactive Iodine Ablation Treatment. Exp Clin Endocrinol Diabetes. 2016;124(10):593-596. doi: https://doi.org/10.1055/s-0042-115639

43. Adamska A, Tomczuk-Bobik P, Popławska-Kita AB, et al. Assessment of different markers of ovarian reserve in women with papillary thyroid cancer treated with radioactive iodine. Endocr Connect. 2021;10(10):1283-1290. doi: https://doi.org/10.1530/EC-21-0187

44. Nathalie Josso, MD, PhD an oral history conducted in 2011 by Michael Chappelle, The Endocrine Society, The Clark Sawin Library, Chevy Chase, Maryland, 2011.

45. Moolhuijsen LME, Visser JA. Anti-Müllerian Hormone and Ovarian Reserve: Update on Assessing Ovarian Function. J Clin Endocrinol Metab. 2020;105(11):3361-3373. doi: https://doi.org/10.1210/clinem/dgaa513

46. Dewailly D, Laven J. AMH as the primary marker for fertility. Eur J Endocrinol. 2019;181(6):D45-D51. doi: https://doi.org/10.1530/EJE-19-0373

47. Strauss JF. Yen and Jaffe’s Reproductive Endocrinology (Eighth Edition). Elsevier Masson; 2019. P

48. Yaish I, Azem F, Gutfeld O, et al. A Single Radioactive Iodine Treatment Has a Deleterious Effect on Ovarian Reserve in Women with Thyroid Cancer: Results of a Prospective Pilot Study. Thyroid. 2018;28(4):522-527. doi: https://doi.org/10.1089/thy.2017.0442

49. Evranos B, Faki S, Polat SB, Bestepe N, Ersoy R, Cakir B. Effects of Radioactive Iodine Therapy on Ovarian Reserve: A Prospective Pilot Study. Thyroid. 2018;28(12):1702-1707. doi: https://doi.org/10.1089/thy.2018.0129

50. van Velsen EFS, Visser WE, van den Berg SAA, et al. Longitudinal Analysis of the Effect of Radioiodine Therapy on Ovarian Reserve in Females with Differentiated Thyroid Cancer. Thyroid. 2020;30(4):580-587. doi: https://doi.org/10.1089/thy.2019.0504

51. Navarro P, Rocher S, Miró-Martínez P, Oltra-Crespo S. Radioactive iodine and female fertility. Sci Rep. 2022;12(1):3704. doi: https://doi.org/10.1038/s41598-022-07592-8

52. Hosseini A, Lavasani Z. The effect of radioactive iodine therapy on anti-Müllerian hormone changes in women with thyroid cancer at reproductive age: a prospective study. Middle East Fertil Soc J. 2023;28(1):24. doi: https://doi.org/10.1186/s43043-023-00147-5

53. van Velsen EFS, Massolt ET, Heersema H, et al. Longitudinal analysis of quality of life in patients treated for differentiated thyroid cancer. Eur J Endocrinol. 2019;181(6):671-679. doi: https://doi.org/10.1530/EJE-19-0550

54. Wu JX, Young S, Ro K, et al. Reproductive outcomes and nononcologic complications after radioactive iodine ablation for well-differentiated thyroid cancer. Thyroid. 2015;25(1):133-138. doi: https://doi.org/10.1089/thy.2014.0343

55. Sawka AM, Lakra DC, Lea J, et al. A systematic review examining the effects of therapeutic radioactive iodine on ovarian function and future pregnancy in female thyroid cancer survivors. Clin Endocrinol (Oxf ). 2008;69(3):479-490. doi: https://doi.org/10.1111/j.1365-2265.2008.03222.x

56. Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev. 2010;31:702–755

57. Seifer DB, Baker VL, Leader B. Age-specific serum anti-Mu¨llerian hormone values for 17,120 women presenting to fertility centers within the United States. Fertil Steril. 2011;95:747–750

58. Khan HL, Bhatti S, Suhail S, et al. Antral follicle count (AFC) and serum anti-Müllerian hormone (AMH) are the predictors of natural fecundability have similar trends irrespective of fertility status and menstrual characteristics among fertile and infertile women below the age of 40 years. Reprod Biol Endocrinol. 2019;17(1):20. doi: https://doi.org/10.1186/s12958-019-0464-0

59. Giusti M, Mittica M, Comite P, Campana C, Gay S, Mussap M. Anti-Müllerian hormone in pre-menopausal females after ablative radioiodine treatment for differentiated thyroid cancer. Endocrine. 2018;60(3):516-523. doi: https://doi.org/10.1007/s12020-017-1510-3

60. Pacini F, Ladenson PW, Schlumberger M, et al. Radioiodine Ablation of Thyroid Remnants after Preparation with Recombinant Human Thyrotropin in Differentiated Thyroid Carcinoma: Results of an International, Randomized, Controlled Study. J Clin Endocrinol Metab. 2006;91(3):926-932. doi: https://doi.org/10.1210/jc.2005-1651

61. Iakovou I, Goulis DG, Tsinaslanidou Z, Giannoula E, Katsikaki G, Konstantinidis I. Effect of recombinant human thyroidstimulating hormone or levothyroxine withdrawal on salivary gland dysfunction after radioactive iodine administration for thyroid remnant ablation. Head Neck. 2016;38 Suppl 1:E227-E230. doi: https://doi.org/10.1002/hed.23974

62. Rosario PW, Calsolari MR. Salivary and lacrimal gland dysfunction after remnant ablation with radioactive iodine in patients with differentiated thyroid carcinoma prepared with recombinant human thyrotropin. Thyroid. 2013;23(5):617-619. doi: https://doi.org/10.1089/thy.2012.0050

63. Sunavala-Dossabhoy G, Petti S. Effect of recombinant human thyroid stimulating hormone on long-term salivary gland dysfunction in thyroid cancer patients treated with radioactive iodine. A systematic review. Oral Oncol. 2023;136:106280. doi: https://doi.org/10.1016/j.oraloncology.2022.106280

64. Trukhin AA, Yartsev VD, Sheremeta MS, Yudakov DV, Korchagina MO, Salimkhanov RKh, Grishkov SV. Nasolacrimal Duct Obstruction Secondary to Radioactive Iodine-131 Therapy for Differentiated Thyroid Cancer. Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. Regulatory Research and Medicine Evaluation. 2022;12(4):415-424. (In Russ.)] doi: https://doi.org/10.30895/1991-2919-2022-12-4-415-424