Effects on Male Fertility

Sperm production in males is maintained by production of FSH by the pituitary and regulated by a negative feedback mechanism by inhibin produced by the seminiferous tubules within the testes. Androgen production is maintained by pituitary production of LH, also controlled by a negative feedback mechanism by production of testosterone by the testicular Leydig cells. Fertility in men is assessed by semen analysis with assessment of sperm concentration, motility, and percentage of abnormal forms. An alternative, although less accurate, method of assessing spermatogenesis is by measuring FSH levels; elevated levels are associated with poor spermatogenesis.

The spermatogonia (germinal epithelium) are very sensitive to radiation and unlike most tissues are not spared by fractionation [14]. Transient suppression of spermatogenesis occurs with doses as low as 0.5Gy. Following a dose of 2-3 Gy there is a period of azoospermia, after which full recovery is expected by 3 years. At doses of 4-6 Gy recovery is not universal and may take up to 5 years [15]. After 6Gy there is a high risk of permanent sterility. The Leydig cells are more resistant to irradiation but doses in excess of 15 Gy may affect their function and production of testosterone.

Following 131I administration, sources of radiation to the testes are the blood, bladder, gut, and functioning metastases close to the testes. Another source of testicular irradiation is derived from organified 131I, which is incorporated into a variety of iodoproteins. These have relatively long half-lives and produce continuous blood-borne irradiation for weeks [16]. The MIRD to the testes is 0.085cGy/37MBq (1mCi) in euthyroid adults [7]. Theoretical models taking into account the hypothyroid status of the patients, which decreases renal clearance of iodine resulting in a more prolonged exposure, suggested a higher testicular dose in the order of 0.5-1 cGy/37MBq [17]. Thus the cumulative radiation dose following a standard ablation iodine activity of 3 GBq (81 mCi) is approximately 40-80 cGy. Using thermoluminescent dosimetry (TLD) we measured the dose in 14 patients; the mean dose to each testis was 6.4cGy, 14.1 cGy, and 21.2cGy following administration of 3, 5.5 and 9.2GBq (81, 149 and 249mCi) of 131I, respectively. Testicular dose was higher following administration of larger iodine activities but still smaller than that estimated [18].All of our 14 patients had persistent uptake of 131I only in the neck and excreted the iodine relatively quickly; both factors would have contributed to the low absorbed testicular dose. Obviously the measured dose on the surface of the scrotum is likely to be less than that absorbed by the testes.

The serum FSH level is the best marker of germinal cell failure and serial measurements have been suggested as a useful prognostic indicator for recovery of spermatogenic function, since falling values indicate stem cell repopulation. We noted an elevation in serum FSH level even with low absorbed testicular doses. Mean FSH levels were lower before than after 131I administration: 6.3 ± 4.1 versus 16.3 ± 4.8, respectively (normal range 3-12IU/L). However, the levels normalized in all patients within 9 months from the last administration. Similar results were reported by Pacini et al., who found an increase in FSH levels in 36.8% of patients treated with high activities of radioiodine, as well as a positive correlation between FSH levels and the cumulative dose of 131I received [19]. They also noted that in most patients FSH levels returned to normal 6-12 months after treatment but remained constantly elevated in four who had been treated with several doses of iodine, indicating permanent damage to the germinal epithelium. In another study a threshold dose of 100 mCi (3.7GBq) 131I for testicular damage was suggested since no elevation in serum FSH was seen in men treated with a single dose up to 100mCi [20].

Fifty-nine patients in our series fathered 106 children 3.5-18 years after iodine treatment and none of the others reported infertility. Because of these results, as well as the low testicular dose measured using TLD, we did not perform semen analysis. There is, however, some evidence that iodine therapy can cause oligo- and even azoospermia which is correlated with cumulative dose [21]. Postmortem findings of testicu-lar atrophy with absent spermatogenesis have been reported in three men aged 53-75 years treated with cumulative 131I doses of 17 to 30.4 GBq (459 to 820 mCi) and external beam radiotherapy [22]. It is not clear whether these postmortem changes were due only to iodine therapy since other factors such as age, hypothy-roidism, and terminal disease might have contributed. The administration of therapeutic doses of ionic forms of longer-lived radionuclides is a possible source of concern because of the appearance of quantities of such radionu-clides in ejaculate and in sperm. It may be prudent, therefore, to advise sexually active males who have been treated with 131I to avoid fathering children for a period of 4 months

(suggested as it is greater than the life of a sperm cell) [13].

Our data as well as those of others indicate that radioiodine treatment for differentiated thyroid cancer may cause a transient impairment of testicular function. For patients who are treated with a single ablation dose, testicular function recovers within months and the risk of infertility seems negligible. However, gonadal damage may be cumulative in those who require multiple administrations for persistent disease. In addition to efforts aimed at reducing radiation exposure such as generous hydration with frequent micturition and avoidance of constipation, sperm banking may need to be considered in these patients [23].

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