Effects of radioiodine therapy on fertility indicators among men with differentiated thyroid cancer: A cohort study

Abstract Background Following thyroidectomy, radioiodine therapy is the standard management of differentiated thyroid cancer. The effects of such treatment on testicular function remained a concern for cases and clinicians. Objective We aimed to observe changes in fertility indicators in men treated with ablation. Materials and Methods In this prospective cohort study, 18 men with differentiated thyroid cancer from June to December 2020 underwent thyroidectomy plus radioiodine therapy. Participants were grouped based on iodine dose (8 men with 30 mCi vs. 10 men with ≥ 150 mCi). Baseline values (V B ) of the follicular stimulating hormone, luteinizing hormone, testosterone, and sperm analyses were measured 3 wk before iodine ablation and repeated 3 (V 3 ) and 12 (V 12 ) months later. They were analyzed once as a whole and once based on their groups via ANOVA and Friedman's tests where appropriate. Results The mean age of participants was 35.61 ± 9.74 yr. Follicular stimulating hormone levels showed a significant trend among all participants (V B : 12.51 ± 1.72, V 3 : 13.54 ± 1.41, and V 12 : 13.10 ± 1.67 IU/mL; p < 0.001). Luteinizing hormone showed a similar pattern (V B : 4.98 ± 1.27, V 3 : 5.65 ± 1.29, and V 12 : 5.21 ± 0.95 IU/mL; p < 0.001). Testosterone levels did not differ significantly from baseline. Sperm count decreased at the first checkpoint and returned to normal after 12 months (V B : 38.22 ± 19.40, V 3 : 32.05 ± 17.96, and V 12 : 36.66 ± 18.81 million/mL; p < 0.001). Sperm motility and morphology did not change significantly. Conclusion Our research showed that even less than 5 GBq irradiation could induce a transient testicular dysfunction in the first 3 months of therapy, but it was mostly reversible after 12 months.


Introduction
Thyroid cancer is the most common endocrine malignancy. In 2021, it accounted for 2.3% of all new cancer diagnoses (1,2). The American Cancer Society estimated that 43,800 new cases would be diagnosed with thyroid cancer in 2022 (1). Differentiated thyroid cancer (DTC), namely follicular and papillary thyroid cancers, account for more than 90% of thyroid cancers. The standard management of DTC is surgical tumor removal followed by radioactive iodine (RAI) ablation (3).
Iodine-131 (I-131) can harm the radiation-sensitive tissues, which are mostly composed of labile cells (cells that are continuously divided). Although multiple studies have focused on the effects of radiation on the female reproductive system, male fertility-related complications have not been considered widely (4)(5)(6). While women have their oocyte bank at birth in a quiescent status, spermatogonia undergo continuous meiosis and are more vulnerable to radiation.
The β and γ radiations from RAI therapy can cause testicular damage (4). Spermatogonia are amongst the most radiation-sensitive cells.
The instant injury to the testes arises from direct radiation from I-131 in the blood and its accumulation in the bladder. Pelvic irradiation in the presence of pelvic metastases also directly affects spermatogonia. The released derivatives of irradiated thyroid or cancer cells, thyroglobulins, and thyroxine into the blood cause delayed harmful effects on spermatognia (3). The estimated absorptive dose of testis after RAI is 27-54 mGy/ giga-becquerel (GBq) (7,8). DNA alterations are expected following irradiation. A case report showed that following a single dose of 150 millicuries (mCi)/5.56 GBq I-131 therapy, the DNA fragmentation index returned to normal values after 3.25 months following RAI (3).
Thus, RAI ablation can affect sperm quality, and previous studies showed hormonal changes after such treatment modality (7,9).
Thyroid cancer tends to affect individuals at a younger age compared to other adult malignancies. The median age at diagnosis was 51 yr, while 36.1% of cases occur at < 44 yr (2); thus, a delicate evaluation of testes function is important for men with DTC, especially for those candidates for high-dose RAI cases or who suffer pelvic metastases. Several studies have also recommended sperm banking before iodine therapy, which is still controversial (3,10).
We aimed to observe the effects of iodine therapy on semen parameters and the hormonal status of men with DTC. were done after thyroidectomy and before levothyroxine cessation, 3 wk before iodine therapy ( Figure 1). Participants' sperm count, motility, and morphology were evaluated based on the 2010 World Health Organization criteria.

Study design and participants
We also interviewed participants for any history of sexual dysfunction, previous infertility, or related treatments. All men underwent a baseline urologic examination to assess confounding factors, like the development or progression of varicocele during the study.

Ethical considerations
The

Statistical analysis
We used the SPSS 24.0 software (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp.) to analyze the results with a p-value < 0.05 as the significance cut off. The included cases were analyzed once as a whole and once in groups.
We used the Shapiro-Wilk test for normality assessment. Repeated measures ANOVA was used to analyze quantitative values with normal distribution. We also used Friedman's test to analyze variables lacking normal distribution.

Results
Out  namely, the effects of iodine therapy were more significant in the 3-month follow-up for LH and FSH; however, its impact on morphology was more prominent at the 12-month followup.

Discussion
Our study aimed to evaluate the effects of iodine therapy on spermogram parameters in men with DTC. After 3 months, a significant increase in FSH and LH levels was detected at the first checkpoint, which returned to baseline at the last checkpoint. We also detected a significant decrease in sperm count, whereas no significant changes were observed in sperm motility and morphology.
RAI ablative therapy in managing DTC improves outcomes by targeting potential micrometastases.
The treatment's main adverse effects (sialadenitis, gastrointestinal discomfort, leukemia, etc.) mostly involve rapid-cycling cells with many divisions (8).  (13); thus, individuals' adherence to thyroxine hormone replacement can potentially cause an impediment in LH trend assessment. As free testosterone remains in the normal range after RAI therapy, the exocrine functions of the testis seem to be more affected than endocrine roles (7). The impairment of testosterone production is expected at absorptive radiation doses greater than 20 Gy as the Leydig cells are more resistant to radiation (11). Future studies should focus on the exact effect of RAI on LH and testosterone levels.
We also observed changes in sperm count, motility, and morphology, of which sperm count changed significantly with an initial decrease followed by returning to normal after 12 months.

Limitation and suggestions
The most significant limitation of the present study was its small sample size, probably secondary to not considering the psychological burden of the diagnosis on cases. Several cases refrained from participating because they did not receive proper psychological support after the cancer diagnosis, and asking them to participate in a study was relatively premature. Although this small sample size can compromise the validity of our conclusion, as it is mostly in line with similar studies of the female population (in terms of LH and FSH), we believe this effect is negligible.
Other limitations were not including TSH, prolactin, inhibin B, and DNA fragmentation index in our fertility analysis. We suggest further studies in performing baseline hormonal assessment before the cessation of thyroid hormones for RAI therapy.
Assessing baseline and follow-up of TSH levels helps determine individuals' adherence to thyroid hormone replacement and provides more reliable results. Due to insufficient data on the effects of iodine therapy on prolactin, evaluation of this hormone could be considered. Occupational status, previous history of medications, smoking, body mass index, and probable fever episodes in the last 3 months should also be considered.