Effects of Radiation

The data for gonadal function following fractionated radiotherapy in humans comes from a) patients with cancers who have been treated with either fields near the testes in which there is scatter dose or b) patients with diseases such as testicular cancers or ALL in which the testes are thought to be at risk of harboring disease and therefore irradiated directly. One of the potentially confounding issues is that some of these cancers may themselves be associated with decreased gonadal function independent of irradiation. For ex-ample,Hodgkin's disease is well documented to cause oligospermia in some patients (reviewed in [35]). Patients with testicular tumors may have preexisting gonadal dysfunction [35,70,90].In ALL, the leukemic cells may infiltrate the interstitium of the testis and conceivably affect Leydig cell function.

Ash et al. summarized data from several older studies [25,67,80] that examined testicular function following radiation for patients who were treated for a range of cancers, including Hodgkin's disease, prostate cancer and testicular cancer [4] (see Table 14.4). They found that oligospermia occurred at doses as low as 10cGy and that azoospermia, which was generally reversible, occurred at doses as low as 35 cGy. However, doses of 200-300 cGy could result in azoospermia that did not reverse even years after irradiation.

These results are supported by other reports. In a study of 17 males treated for Hodgkin's disease who received 6-70 cGy of scatter dose to the testes, FSH levels remained normal in patients who received <20 cGy [41]. Those receiving > 20 cGy had a dose-dependent increase in serum FSH levels, with a maximum difference seen at six months following radiation. In all patients,the FSH normalized within 12-24 months. Eight patients had normal pretreatment sperm counts. Most of the patients continued to have high sperm counts following irradiation, although two developed transient oligospermia with complete recovery of sperm count by 18 months. Four patients who had received 23 cGy or less went on to father children. Ortin et al. reported on children treated for Hodgkin's disease [57]. Seven boys received pelvic radiation as part of their treatment without any chemotherapy. Three of them fathered children. Three had azoospermia 10-15 years after irradiation, and one had testicular atrophy diagnosed by biopsy a year after irradiation. However, these results are difficult to interpret because there was no measurement or estimate of dose received to the testes in these children.

Similar data exist for patients treated for soft tissue sarcomas (median age at diagnosis 49 years; range 14-67) [74]. These patients were estimated to have received between 1-2500 cGy (median dose 80 cGy) of scatter dose to the testes. Patients who received 50 cGy or more had a greater elevation in FSH than did those who received less than 50 cGy. Only the latter group showed normalization of FSH levels by 12 months. In the former group, FSH levels remained above baseline as long as 30 months out.

There are also data on germ cell function after treatment for testicular cancer. Hahn et al. examined gonadal function in 14 patients who were irradiated to the paraaortic and ipsilateral pelvic/inguinal lymphatics with a "hockey stick" field following orchiectomy for seminoma [26]. The scatter dose to the remaining testicle in these 14 patients ranged from

32-114 cGy (median 82cGy). Ten patients who received >70 cGy to the testes developed azoospermia 10-30 weeks following radiation. All patients, except two, had recovery of spermatogenesis; and the recovery time from azoospermia was dose-dependent. Centola et al.,in a study of males with seminoma, also showed that the recovery time from oligospermia/ azoospermia was dose-dependent [13].

The previous data includes only patients who received incidental irradiation to the testes; however, there are situations in which children receive direct irradiation to the testes. Sklar et al. examined testicular function in 60 long-term survivors of childhood ALL [77]. All the patients had received identical chemotherapy; however, the RT fields varied significantly and included: 1) craniospinal radiation and 1200 cGy to the abdomen and testes (n = 11), 2) craniospinal RT with 1800 or 2400 cGy (estimated go-nadal dose 36-360 cGy; n = 23) or 3) cranial RT with 1800 or 2400 cGy (negligible testicular dose; n = 26). Based on measurements of serum FSH and testicular volume, which commenced at either 12 years of age or seven years after diagnosis of ALL, gonadal function abnormalities occurred in 55%, 17% and 0% of patients in groups 1,2, and 3, respectively. Because, at the time of testing, many of the patients were adolescents, when evaluation of germ cell function can be difficult, this study probably underestimated the incidence of the problem. Castillo et al. examined 15 boys with ALL who were given 1200-2400 cGy to the testes prior to puberty (median age 6.8 years; range 5-12 years), either as prophylaxis or for testicular relapse [12]. Semen analyses, performed at least nine years following testicular irradiation, showed azoospermia in seven out of seven cases. Six of these patients had received 1200 cGy and one had received 1500 cGy.

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