The overall prevalence of hypopituitarism was 29 per 100,000 cases based on a previous survey [25]. The mechanism of hypopituitarism included dysfunction of the pituitary gland or hypothalamic damage. Various diseases may cause hypopituitarism. The most common causes of primary hypopituitarism are PAs and complications of surgery or radiation therapy for PAs [15]. PAs can cause hypopituitarism because of tumor growth and compression of pituitary gland and stalk. The pituitary gland and hypothalamus can be damaged by pituitary surgery or radiotherapy. One or more factors can result in hypopituitarism. Patients who develop hypopituitarism have a poor quality of life, high risk of morbidity and even mortality [26, 27].

Table 5 summarizes recent literatures describing GKRS for PAs. Previous studies reported a highly heterogeneous incidence rate of hypopituitarism after GKRS for PAs, which ranged from 12.3 to 39% [9, 16,17,18,19,20,21, 28, 29]. Sex, tumor volume, suprasellar extension, prior radiation, mean dose to the pituitary gland, isodose line, margin dose, and maximum dose were reported to be significantly associated with hypopituitarism after GKRS for PAs [9, 16,17,18,19,20,21, 28]. According to Pollock et al. [28], the incidence of new-onset hypopituitarism was 27% based on 62 PAs treated with GKRS. In this study, hypopituitarism was relatively higher for patients with a tumor volume > 4.0 cm3. Sheehan et al. [20] investigated 512 PA patients undergoing GKRS and reported that new-onset hypopituitarism following GKRS was noted in 21% of the patients and prior radiation therapy and greater tumor margin doses were predictive of new-onset hypopituitarism. Xu et al. [21] examined a total of 262 PA patients treated with stereotactic radiosurgery (SRS) and reported a new-onset hypopituitarism rate of 30%. This study investigated that suprasellar extension and higher margin dose (> 16 Gy) increased the risk of hypopituitarism after GKRS. Sicignano et al. [16] enrolled 130 PA patients and reported a new-onset hypopituitarism rate of 12.3%. In this study, they identified that dosimetric (the mean dose and amount of healthy tissue within the high-dose region) parameters were correlated with the risk of new-onset hypopituitarism. In another study, Lee et al. [9] reported that 24% of PAs caused new-onset hypopituitarism, and patients who had received a tumor margin dose of > 18 Gy as well as a maximum dose of > 36 Gy had a higher risk for hypopituitarism. Graffeo et al. [30] found that higher mean pituitary gland dose (> 11 Gy) was associated with new-onset hypopituitarism after SRS. From a multicenter and international study, Cordeiro et al. [17] revealed that 248 of 1023 (24.2%) patients developed new-onset hypopituitarism and they found that a lower isodose line (< 50%) was an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38).

In the present study, we described 241 patients with PA treated with GKRS, in which new-onset hypopituitarism occurred in 50 patients (20.7%). This incidence was comparable with previous published data of hypopituitarism following GKRS (Table 5). In our series, the median time for the occurrence of hypopituitarism after GKRS was 44.1 (range, 13.5–141.4) months, which was apparently similar with that in a previous study. Since 33 cases (13.7%) received two or more times GKRS in the study, we conducted subgroup analyses for a single GKRS and multiple GKRS treatments. In a single GKRS group, our multivariate analysis demonstrated that tumor volume (≥ 5 cm3) and tumor progression were significantly associated with new-onset hypopituitarism after GKRS. New-onset hypopituitarism occurs in 15.9% of patients with tumors < 5 cm3 relative to 43.8% of patients with tumors > 5 cm3. These data suggested that large tumors were associated with high risk for new-onset hypopituitarism after GKRS for PAs. In large tumors, the pituitary gland is compressed more seriously than those in small tumors. Besides, large tumor volumes may make it difficult to deliver an ideal radiation dose to the target volume. The radiation dose and volume of surrounding structures including the pituitary gland, pituitary stalk, and hypothalamus were increased, which might be at risk for new-onset hypopituitarism after GKRS. Tumor progression after GKRS was also a risk factor for new-onset hypopituitarism in a single GKRS group in this study. This may be related to the aggravation of compression on the normal pituitary gland after tumor progression. Among the 4 patients with tumor progression, 3 (75%) developed new-onset hypopituitarism. In the 3 cases of tumor progression and new-onset hypopituitarism, one patient’s tumor progression and new-onset hypopituitarism were detected simultaneously, while the new-onset hypopituitarism in the other 2 cases occurred after the tumor progression. In contrast, only 19.1% of patients with shrinking or stable tumors experienced new-onset hypopituitarism. Although the number of cases in the tumor progression group is small, with only 4 cases, this could limit statistical analysis, but the issue of new-onset hypopituitarism due to tumor progression after GKRS treatment cannot be overlooked. Insufficient GKRS dosage can lead to tumor progression and subsequent pituitary dysfunction, while excessive GKRS dosage may also result in hypopituitarism. How to balance GKRS dosage, local tumor control, and new-onset hypopituitarism warrants careful consideration. For patients (n = 33) who received 2 or more times GKRS, no risk factors associated with new-onset hypopituitarism were found. Besides, the incidence of new-onset hypopituitarism did not differ between a single GKRS and 2 or more times GKRS. This may be related to the small number of cases in the multiple GKRS group.

Three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and fractionated stereotactic radiotherapy are common radiation techniques. However, no clinical trials have compared the efficacy and safety of conventional radiotherapy with SRS. Previous studies reported that new-onset hypopituitarism after conventional radiotherapy can occur in up to 80% of the cases in 10 years [31]. In most studies, the incidence of hypopituitarism after GKRS for PAs ranged from 12.3 to 39% [9, 16,17,18,19,20,21, 28, 29]. Conventional radiotherapy is less precise than SRS, which increases the radiation volume to the pituitary gland, pituitary stalk, and hypothalamus. Therefore, it may convey more risk of adverse effects. Furthermore, SRS has a better dose conformity with only single fraction and is more convenient than conventional radiotherapy. Thus, SRS has been the most commonly used radiation technique in many centers and is an essential part in the treatment of PAs.

In our experience, 20.7% of patients with PAs developed new hypopituitarism after GKRS. Hypopituitarism is not an uncommon complication of GKRS. New hypopituitarism may occur several years after GKRS. Large tumor volume (≥ 5 cm3) and tumor progression after GKRS are risk factors for new-onset hypopituitarism after a single GKRS. Thus, regular endocrine follow-up is necessary. Since tumor progression can also lead to pituitary dysfunction, clinicians must carefully weigh the issues of local tumor control and pituitary dysfunction when determining the appropriate prescription dose, in order to make better clinical decisions. Although uncorrected hypopituitarism is related with early mortality and morbidity, with the help of endocrinologist, it can be treated with hormone replacement.

This study has several limitations. First, this was a single-center retrospective study that was stopped in 2016, and thereby reflected treatment and selection biases. Second, because many patients came from a long distance from nationwide, endocrine tests and MRI evaluations were missing, thus, only 241 patients were included according the inclusion criteria in this study, which might lead to a selection bias. Third, the number of patients is relatively small, and this may limit the statistical power. Four, for some patients located far from the center, endocrine evaluations were mainly taken in the local hospital; thus, there might be slight variation in the definition of hypopituitarism. Finaly, dosimetric parameters on the pituitary stalk or gland were associated with the risk of hypopituitarism after GKRS, however, these dosimetric parameters were not available in this study.