Somatostatin receptors (SSTR) density in normal endocrine organs is not as high as in neuroendocrine tumours (NETs); however, the existence of SSTRs in such organs expose them to some degree of radiation during PRRT [77,115]. The normal anterior pituitary express SSTRs, mainly SSTR2, SSTR5 and SSTR1 [74,75,76]. The expression of different SSTR subtypes varies according to the pituitary cell type, with rat studies suggesting that the highest expression of SSTR2 can be found in somatotrophs and thyrotrophs [74,116]. Consistently, the anterior pituitary shows the uptake on SSTR imaging, suggesting that pituitary cells may be exposed to radiation during peptide receptor radionuclide therapy (PRRT) [6,93]. Hypopituitarism secondary to external beam radiotherapy is widely recognised, and the risk increases proportionally with higher doses and long periods following the irradiation, with GH and gonadotrophin axes being more radiosensitive, whereas ACTH and TSH axes are significantly more resistant [117,118]. Hence, patients who received PRRT may be theoretically at risk of developing hypopituitarism, which has prompted some groups to investigate the effects of PRRT on the pituitary function. Four studies, summarised in Table 1, have assessed the PRRT effects on pituitary function in patients with non-pituitary neuroendocrine neoplasms who received PRRT [33,113,114,115]. Overall, the data from these studies suggest that there is no significant increased risk of clinically relevant hypopituitarism in patients exposed to PRRT [33,113,114,115].

In post-menopausal women, two studies showed a decrease in serum follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels following PRRT [114,115], which may suggest a potential effect of PRRT on gonadotrophs, although hypogonadotropic hypogonadism in post-menopausal women is not clinically relevant. In contrast, a previous study showed unchanged levels of LH and FSH (as well as oestradiol and inhibin B) before and 24 months after PRRT [33], and another study with a longer follow-up showed no differences in secondary hypogonadism rates between PRRT-treated and control females, with no differences in FSH levels between these two subgroups; moreover, none of the PRRT-treated post-menopausal women had inappropriately low levels of FSH and LH [113].

In men, gonadotrophins rise shortly after PRRT, accompanied by a decrease of inhibin B; however, both returned to baseline 18–24 months after PRRT [33,115]. Total testosterone decreases during the follow-up after PRRT [33,115], coincident with a decrease in sex hormone binding globulin (SHBG), but the biochemically active non-SHBG-bound testosterone does not change [115]. Elston et al. found no differences in the rates of secondary hypogonadism between PRRT-treated vs. control males, and PRRT was not a predictor of male hypogonadism [113].

Taking together these data, gonadal function may be subject to subtle changes following PRRT, but in the long-term, clinically relevant secondary hypogonadism seems not to be an issue for PRRT-treated patients. Men undergoing PRRT may suffer from a transient and reversible impairment of spermatogenesis [33,115], similar to male patients with thyroid cancer who undergo radioiodine therapy [119,120]. Although sperm analyses have not been systematically performed in the studies, the observation of remarkable decrease in inhibin B with concomitant raise in FSH, both returning to baseline several months after PRRT [33,115], suggest a temporarily impaired spermatogenesis. In fact, inhibin B, produced by the testicular Sertoli cells, plays a crucial role in the spermatogenesis, and is also a major (negative) feedback regulator of FSH [121,122,123].

The somatotroph axis, recognised as the most radiosensitive and the first pituitary axis to reflect the radiation effects [117,118], was assessed in PRRT-treated patients in two studies [113,114]. Sundlöv et al. showed a decrease in serum insulin-like growth factor 1 (IGF-1) levels following PRRT, estimated at −15% and −30% at 19–24 months and >48 months of follow-up, respectively, which correlated with the number of PRRT cycles and the absorbed radiation doses. This was interpreted as pituitary-related GH deficiency, as albumin levels during the follow-up did not change, making unlikely that IGF-1 decrease would be a result of liver damage; moreover, most patients were already receiving a fixed dose of somatostatin analogues at baseline which remained stable, therefore not explaining either the decrease of IGF-1 during the follow-up [114]. On a different study, 1 of 34 patients (3%) developed GH deficiency 55 months after PRRT, and Elston et al. reported a trend for GH deficiency based on lower IGF-1 Z-scores in PRRT-treated vs. control patients [113]. Whilst the development of GH deficiency may eventually explain constitutional symptoms, such as fatigue or body composition changes that might be reported by PRRT-treated patients, a finding of GH deficiency post-PRRT would not alter the management, as GH replacement therapy is contraindicated in patients with active malignancy [124], and neither should it preclude clinicians prescribing PRRT for a progressive and potentially threating neuroendocrine neoplasm.

Sundlöv et al. and Elston et al. reported no changes in the thyroid axis as a result of PRRT [113,114], while two earlier studies showed that free thyroxine (FT4) levels decrease 3 to 24 months after PRRT with no changes in TSH and T3 [33,115]. The development of primary hypothyroidism is also uncommon in PRRT-treated patients, occurring in only 3% of cases [115]. The levels of reverse triiodothyronine (rT3) also decrease after PRRT [115]. Considering the chronicity and severity of the underlying malignant disease and their impact on the thyroid axis, it is currently unknown as to whether such changes, particularly in serum FT4, are secondary to the effects of PRRT or instead due to a cancer-related non-thyroidal illness [115], neither it is clear if these patients at a longer term will evolve to hypothyroidism requiring thyroxine replacement therapy.

The hypothalamo–pituitary–adrenal axis remained intact in patients submitted to PRRT across three studies investigating the adrenal function post-PRRT [113,114,115]. These studies mainly relied on measuring basal serum ACTH and cortisol, while Teunissen et al. studied the adrenal reserve with low dose ACTH stimulation tests. An adequate cortisol response (>550 nmol/L) on the ACTH stimulation test was seen in all patients before and 24 months after PRRT; however, the mean peak cortisol response before PRRT was higher than that after PRRT (909 ± 57 vs. 822 ± 35 nmol/L; p < 0.001). Whether this subtle difference in the mean peak stimulated cortisol after PRRT reflects any partial radiation-induced adrenal insufficiency or just a less stressful state of patients remains unclear; nevertheless, such a difference is not clinically relevant as any of the patients failed the ACTH stimulation test, and thus none of them would be diagnosed with adrenal insufficiency nor require glucocorticoid replacement therapy [115].