Pituitary Function after High-Dose 177Lu-DOTATATE Therapy and Long-Term Follow-Up.

INTRODUCTION: The pituitary gland has a high expression of somatostatin receptors and is therefore a potential organ at risk for radiation-induced toxicity after 177Lu-DOTATATE treatment. OBJECTIVE: To study changes in pituitary function in patients with neuroendocrine tumors (NETs) treated with dosimetry-based 177Lu-DOTATATE to detect possible late toxicity. METHODS: 68 patients from a phase II clinical trial of dosimetry-based, individualized 177Lu-DOTATATE therapy were included in this analysis. Patients had received a median of 5 (range 3-9) treatment cycles of 7.4 GBq/cycle. Median follow-up was 30 months (range 11-89). The GH/IGF-1 axis, gonadotropins, and adrenal and thyroid axes were analyzed at baseline and on a yearly basis thereafter. Percent changes in hormonal levels over time were analyzed statistically using a linear mixed model and described graphically using box plots. The absorbed radiation dose to the pituitary was estimated based on post-therapeutic imaging, and the results analyzed versus percent change in IGF-1 levels over time. RESULTS: A statistically significant decrease in IGF-1 levels was found (p < 0.005), which correlated with the number of treatment cycles (p = 0.008) and the absorbed radiation dose (p = 0.03). A similar decrease, although non-significant, was seen in gonadotropins in postmenopausal women, while in men there was an increase during the first years after therapy, after which the levels returned to baseline. No change was observed in the adrenal or thyroid axes. CONCLUSIONS: No signs of severe endocrine disorders were detected, although a significant decrease in the GH/IGF-1 axis was found, where dosimetric analyses indicated radiation-induced damage to the pituitary gland as a probable cause.

Rat models of post-irradiation recovery of spermatogenesis: interstrain differences.

Recently, we reported large differences between rat strains in spermatogenesis recovery at 10 weeks after 5-Gy irradiation suggesting that there are interstrain as well as interspecies differences in testicular radiation response. To determine whether these interstrain differences in sensitivity might be a result of the particular dose and time-point chosen, we performed dose-response and time-course studies on sensitive Brown-Norway (BN) and more resistant spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. Type A spermatogonia were observed in atrophic tubules at 10 weeks after irradiation in all strains indicating that tubular atrophy was caused by a block in their differentiation, but the doses to produce the block ranged from 4.0 Gy in BN to 10 Gy in SD rats. Although the numbers of type A spermatogonial were unaffected at doses below 6 Gy, higher doses reduced their number, indicating that stem cell killing also contributed to the failure of recovery. After 10 weeks, there was no further recovery and even a decline in spermatogonial differentiation in BN rats, but in SHR rats, sperm production returned to control levels by 20 weeks after 5.0 Gy and, after 7.5 Gy, differentiation resumed in 60% of tubules by 30 weeks. Suppression of testosterone and gonadotropins after irradiation restored production of differentiated cells in nearly all tubules in BN rats and in all tubules in SHR rats. Thus, the differences in recovery of spermatogenesis between strains were a result of both quantitative differences in their sensitivities to a radiation-induced, hormone-dependent block of spermatogonial differentiation and qualitative interstrain differences in the progression of post-irradiation recovery. The progression of recovery in SHR rats was similar to the prolonged delays in recovery of human spermatogenesis after cytotoxic agent exposure and thus may be a system for investigating a phenomenon also observed in men.