Changes in ovarian function and ovarian reserve after combined treatment for differentiated thyroid cancer

BACKGROUND: The paradigm of combined treatment for differentiated thyroid cancer has been in use since the mid-20th century. This approach involves thyroidectomy, followed by radioactive iodine therapy, and after patients may be prescribed suppressive therapy. Combined treatment improves outcomes, particularly in cases of high risk of recurrence. However, it can also lead to a range of secondary complications, including those affecting the reproductive system.

AIM: Assessment and comparative analysis of ovarian function and ovarian reserve (OR) using anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2) and estrone (E1) in the early follicular phase in women of reproductive age who received combined treatment for DTC, and in healthy women of the same age.

MATERIALS AND METHODS. In a single-center, comparative cross-sectional study, clinical and morphological, anamnestic and laboratory parameters were analyzed in patients who underwent thyroidectomy and one course of radioiodine therapy for DTC, and in healthy women.

RESULTS: The study enrolled 90 women aged 18 to 40 years: 67 women with DTC with a median age of 31 years [26; 36] who underwent combined treatment, and 30 healthy women with a median age of 30 years [28; 35]. The frequency of menstrual cycle disorders over the past year was 33% in women with DPT and 13% in healthy women.

When comparing the results of hormonal examination, it was revealed that the levels of FSH, LH, PRL, E1 and E2 did not differ significantly between the groups. The level of AMH was the only parameter that significantly differed in patients with DTC receiving combined treatment and in healthy women — 2.49 ng/ml [1.1; 3.3] and 3.6 ng/ml [2.62; 4.18], respectively (P < 0.004). In 18 (27%) patients with DTC, the level of AMH was < 1.2 ng/ml, in the group of healthy women low level of AMH was found only in one case. Only patient's age at the time of RAIT and age at the time of examination on the background of thyroid stimulating hormone suppression were associated with diminished ovarian reserve, using the Juden index, the cut-off points of 31 years and 33 years were determined, respectively.

CONCLUSION. The level of AMH in patients with DTC who undergo combined treatment is significantly lower compared to healthy women of the same age. Only patient's age at the time of RAIT and age at the time of examination on the background of thyroid stimulating hormone suppression were associated with diminished ovarian reserve.

1. Злокачественные новообразования в России в 2022 году (заболеваемость и смертность) / под ред. А.Д. Каприна [и др.] − М.: МНИОИ им. П.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2023. – илл

2. Francis G, Waguespack S, Bauer A, et al. American Thyroid Association Guidelines Task Force Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid. 2015;25(7):716-59. doi: https://doi.org/10.1089/thy.2014.0460

3. James DL, Ryan ÉJ, Davey MG, Quinn AJ, Heath DP, et al. Radioiodine Remnant Ablation for Differentiated Thyroid Cancer: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Surg. 2021;147(6):544-552. doi: https://doi.org/10.1001/jamaoto.2021.0288

4. Schott M, Schott-Ohly P, Krieg S, et al. The Prognostic Impact of Radioiodine Therapy in Patients with Papillary Thyroid Cancer. Horm Metab Res. 2024;56(11):770-778. doi: https://doi.org/10.1055/a-2423-4849

5. 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

6. 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

7. 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

8. Anagnostis P, Florou P, Bosdou JK, et al. Decline in anti-Müllerian hormone concentrations following radioactive iodine treatment in women with differentiated thyroid cancer: A systematic review and meta-analysis. Maturitas. 2021;148:40-45. doi: https://doi.org/10.1016/j.maturitas.2021.04.002

9. Piek MW, Postma EL, van Leeuwaarde R, et al. The Effect of Radioactive Iodine Therapy on Ovarian Function and Fertility in Female Thyroid Cancer Patients: A Systematic Review and Meta-Analysis. Thyroid. 2021;31(4):658-668. doi: https://doi.org/10.1089/thy.2020.0356

10. Бельцевич Д.Г., Мудунов А.М., Ванушко В.Э., и др. Дифференцированный рак щитовидной железы // Современная онкология. — 2020. — Т. 22. — №4. — C. 30-44. doi: https://doi.org/10.26442/18151434.2020.4.200507

11. Tuttle RM, Ahuja S, Avram AM, et al. Controversies, Consensus, and Collaboration in the Use of 131I Therapy in Differentiated 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. Thyroid. 2019;29(4):461-470. doi: https://doi.org/10.1089/thy.2018.0597

12. Адамян Л.В., Андреева Е.Н., Артымук Н.В., и др. Федеральные клинические рекомендации Российской ассоциации акушеровгинекологов «Аномальные маточные кровотечения», 2021.

13. Адамян Л.В., Андреева Е.Н., Артымук Н.В., и др. Федеральные клинические рекомендации Российской ассоциации акушеровгинекологов «Аменорея и олигоменорея», 2021

14. Корсак В.С., Долгушина Н.В., Корнеева И.Е. и др. Федеральные клинические рекомендации Российской ассоциации акушеровгинекологов и ООО "Российская ассоциация репродукции человека" «Женское бесплодие», 2021.

15. Humaidan P, Alviggi C, Fischer R, Esteves SC. The novel POSEIDON stratification of ‘Low prognosis patients in Assisted Reproductive Technology' and its proposed marker of successful outcome. F1000Res. 2016;5:2911. doi: https://doi.org/10.12688/f1000research.10382.1

16. Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev. 2010; 31:702–755 doi: https://doi.org/10.1210/er.2009-0041

17. Mazzilli R, Medenica S, Di Tommaso AM, et al. The role of thyroid function in female and male infertility: a narrative review. J Endocrinol Invest. 2023;46(1):15-26. doi: https://doi.org/10.1007/s40618-022-01883-7

18. Güngör Semiz G, Hekimsoy Z. Menstrual Cycle Characteristics in Women With and Without Thyroid Disease. Cureus. 2024;16(6):e62724. doi: https://doi.org/10.7759/cureus.62724

19. P HH, G S, K P, Penumalla S, Kandimalla R. Hypothyroidism and Its Impact on Menstrual Irregularities in Reproductive-Age Women: A Comprehensive Analysis at a Tertiary Care Center. Cureus. 2024;16(6):e63158. doi: https://doi.org/10.7759/cureus.63158

20. Huang N, Zeng L, Yan J, Chi H, Qiao J. Impact of thyroid cancer treatment on assisted reproductive technology outcomes in women with infertility. J Assist Reprod Genet. 2021;38(8):2121-2128. doi: https://doi.org/10.1007/s10815-021-02204-2

21. Корчагина М.О., Андреева Е.Н., Шеремета М.С., Мельниченко Г.А. Репродуктивная функция женщин после радиойодтерапии дифференцированного рака щитовидной железы. // Проблемы Эндокринологии. — 2025. — Т.71. — №1. — С.72-82. doi: https://doi.org/10.14341/probl13407

22. 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

23. Rosario PW, Fagundes TA, Fagundes AV, Barraso AL, Rezende LL, et al. Radioiodine therapy and age at menopause in patients with thyroid cancer. Clin Endocrinol (Oxf ). 2006;64(2):225-6. doi: https://doi.org/10.1111/j.1365-2265.2005.02413.x

24. 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

25. Acıbucu F, Acıbucu DO, Akkar ÖB, Dokmetas HS. Evaluation of Ovarian Reserve with AMH Level in Patients with Well-Differentiated 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

26. 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

27. Berjeb KK, Debbabi L, Braham M, et al. Evaluation of ovarian reserve before and after chemotherapy. J Gynecol Obstet Hum Reprod. 2021;50(5):102035. doi: https://doi.org/10.1016/j.jogoh.2020.102035

28. 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

29. Iwase A, Hasegawa Y, Tsukui Y, et al. Anti-Müllerian hormone beyond an ovarian reserve marker: the relationship with the physiology and pathology in the life-long follicle development. Front Endocrinol (Lausanne). 2023;14:1273966. doi: https://doi.org/10.3389/fendo.2023.1273966

30. Ion A, Brossaud J, Corcuff JB, Lauro C, Georges A. Comparison of automated methods for the determination of antimüllerian hormone in women. Ann Biol Clin (Paris). 2025;83(2):227-230. doi: https://doi.org/10.1684/abc.2025.1967

31. Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Mullerian hormone in women [published correction appears in Hum Reprod Update. 2014 Sep-Oct;20(5):804]. Hum Reprod Update. 2014;20(3):370-385. doi: https://doi.org/10.1093/humupd/dmt062

32. La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014;20(1):124-140. doi: https://doi.org/10.1093/humupd/dmt037

33. 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

34. 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

35. Hale GE, Zhao X, Hughes CL, Burger HG, Robertson DM, Fraser IS. Endocrine features of menstrual cycles in middle and late reproductive age and the menopausal transition classified according to the Staging of Reproductive Aging Workshop (STRAW) staging system. J Clin Endocrinol Metab. 2007;92(8):3060-3067. doi: https://doi.org/10.1210/jc.2007-0066

36. Ulrich ND, Marsh EE. Ovarian Reserve Testing: A Review of the Options, Their Applications, and Their Limitations. Clin Obstet Gynecol. 2019;62(2):228-237. doi: https://doi.org/10.1097/GRF.0000000000000445

37. 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

38. Трухин А.А., Ярцев В.Д., Шеремета М.С., Юдаков Д.В., Корчагина М.О., Салимханов Р.Х., Гришков С.В. Вторичная облитерация слезоотводящих путей при проведении радиойодтерапии 131I дифференцированного рака щитовидной железы. Ведомости Научного центра экспертизы средств медицинского применения. // Регуляторные исследования и экспертиза лекарственных средств. — 2022. — Т.12. — №4. — 415-424. doi: https://doi.org/10.30895/1991-2919-2022-12-4-415-424

39. Iijima, S. . Effects of fetal involvement of inadvertent radioactive iodine therapy for the treatment of thyroid diseases during an unsuspected pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2021;259:53–59. doi: https://doi.org/10.1016/j.ejogrb.2021.02.003

40. Kim HO, Lee K, Lee SM, Seo GH. Association Between Pregnancy Outcomes and Radioactive Iodine Treatment After Thyroidectomy Among Women With Thyroid Cancer. JAMA Intern Med. 2020;180(1):54-61. doi: https://doi.org/10.1001/jamainternmed.2019.4644

41. Moon S, Yi KH, Park YJ. Risk of Adverse Pregnancy Outcomes in Young Women with Thyroid Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel). 2022;14(10):2382. doi: https://doi.org/10.3390/cancers14102382

42. Shan R, Li X, Tao M, et al. Pregnancy and the disease recurrence of patients previously treated for differentiated thyroid cancer: A systematic review and meta analysis. Chin Med J (Engl). 2024;137(5):547-555. doi: https://doi.org/10.1097/CM9.0000000000003008

43. Li X, Xiao WC, Mei F, et al. The Association of Pregnancy with Disease Progression in Patients Previously Treated for Differentiated Thyroid Cancer: A Propensity Score-Matched Retrospective Cohort Study. J Womens Health (Larchmt). 2023;32(11):1174-1181. doi: https://doi.org/10.1089/jwh.2023.0172