Pituitary neuroendocrine tumours (PitNETs) are usually benign and slow-growing; however, in some cases, they may behave aggressively and become resistant to conventional treatments. Therapeutic options for aggressive or metastatic PitNETs are limited, and currently mainly consist of temozolomide, with little experience of other emerging approaches, including peptide receptor radionuclide therapy (PRRT). Somatostatin receptor expression in PitNETs explains the effectiveness of somatostatin analogues for treating PitNETs, particularly those hypersecreting pituitary hormones, such as growth hormone or adrenocorticotropic hormone. The expression of such receptors in pituitary tumour cells has provided the rationale for using PRRT to treat patients with aggressive or metastatic PitNETs.
1. Introduction
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][1][2]. The normal anterior pituitary express SSTRs, mainly SSTR2, SSTR5 and SSTR1
[74,75,76][3][4][5]. 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][3][6]. 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][7][8]. 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][9][10]. 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][2][11][12][13]. 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][2][11][12][13].
Table 1. Studies investigating the pituitary function following PRRT.
Reference (PMID) |
Study Population |
Gender/Mean Age |
Previous Treatments |
Type of PRRT |
Activity/Number of Cycles |
Follow-Up after PRRT |
Main Findings Regarding the Pituitary Function Post-PRRT |
Kwekkeboom 2005 | J Clin Oncol [33] (PMID: 15837990) | [11] (PMID: 15837990) |
131 pts with metastasized or inoperable gastroentero-pancreatic NETs |
65 M, 66 F/56 years |
48% had surgery; 5% EBRT; 15% chemotherapy; 50% SSA |
177 | Lu-DOTATATE |
600–800 mCi |
24 months |
|
- -
-
Serum TSH did not change during or after PRRT, while FT4 levels decreased significantly (mean 18.3 pmol/L before PRRT; and 15.5 to 17.5 pmol/L 3- to 24-months after PRRT)
- -
-
In women: LH, FSH, estradiol and inhibin B levels did not change
- -
-
In men: serum testosterone decreased in the follow-up period (from a mean of 14.4 nmol/L before PRRT to 10.4 nmol/L 24 months after the last cycle of PRRT; p < 0.01), while LH did not change. Serum inhibin B also decreased (from a mean of 179 ng/L before PRRT to 23 ng/L 3 months after the last cycle) accompanied by a rise in FSH, both returning to baseline at 18–24 months after the last PRRT cycle.
|
|
Teunissen 2009 | Eur J Nucl Med Mol Imaging [115] (PMID: 19471926) | [2] (PMID: 19471926) |
79 pts with various types of endocrine-related cancers (74 NETs, 4 thyroid cancers, 1 paraganglioma) |
38 M, 41 F/54.8 years |
46% had surgery; 8% chemotherapy; 4% EBRT; 46% SSA |
177 | Lu-DOTATATE |
600–800 mCi (3–4 cycles with 6- or 9-week intervals) |
24 months |
|
- -
-
15 of 35 male pts (43%) had hypogonadism prior to PRRT
- -
-
In men: serum inhibin B decreased 3 months after PRRT (205 ± 16 to 25 ± 4 ng/L; p < 0.05), suggesting transient spermatogenesis impairment; there was also an increase in FSH (5.9 ± 0.5 to 22.7 ± 1.4 IU/L; p < 0.05) and LH (5.2 ± 0.6 to 7.7 ± 0.7 IU/L; p < 0.05); these returned later near to the baseline level. Total testosterone and SHBG decreased (respectively, 15.0 ± 0.9 to 10.6 ± 1.0 nmol/L; p < 0.05, and 61.8 ± 8.7 to 33.2 ± 3.7 nmol/L; p < 0.05) while non-SHBG-bound testosterone did not change.
- -
-
In post-menopausal women: serum FSH and LH decreased 24 months after PRRT (respectively, 74.4 ± 5.6 to 62.4 ± 7.7 IU/L; p < 0.05, and 21.1 ± 3.0 to 21.1 ± 3.0 IU/L; p < 0.05)
- -
-
Thyroid axis: FT4 decreased 24 months after PRRT (17.7 ± 0.4 to 15.6 ± 0.6 pmol/L; p < 0.05), but TSH and T3 did not change (although tended to increase and decrease, respectively). rT3 decreased from 0.38 ± 0.03 to 0.30 ± 0.01 nmol/L (p < 0.05). Two of 66 pts (3%) developed primary hypothyroidism.
- -
-
Adrenal axis: adequate cortisol response on ACTH stimulation tests in all pts before and after PRRT. Mean peak cortisol response before PRRT was higher than after PRRT (909 ± 57 vs. 822 ± 35 nmol/L; p < 0.001)
- -
-
GH/IGF-1 axis was not evaluated
|
|
Sundlöv 2021 | Neuroendocrinology [114] (PMID: 32259830) | [13] (PMID: 32259830) |
68 pts with progressive grade 1–2 NETs |
37 M, 31 F/66 years |
80% had SSA; 12% chemotherapy; 15% biologics; 1% MIBG; 40% liver- therapies |
177 | Lu-DOTATATE |
Median 37.0 GBq (IQR: 14.8–66.6) |
Median 30 months (range: 11–89) |
|
- -
-
IGF-1 decreased during follow-up (p < 0.005): a decrease of −15% and −30% at 19–24 months and >48 months of follow-up, respectively.
- -
-
Extent of IGF-1 decrease correlated with the number of cycles (p = 0.008) and with the absorbed radiation dose (p = 0.03)
- -
-
In post-menopausal women, serum LH and FSH tended to decrease (p value NS) during follow-up, while in men, they increased in the first year following PRRT, after which returned to baseline
- -
-
No changes in the adrenal or thyroid axes
|
|
Elston 2021 | Cancer Med [113] (PMID: 34697905) | [12] (PMID: 34697905) |
66 pts with unresectable metastatic NETs: 34 received PRRT vs. 32 controls |
PRRT group: 23 M, 11 F/65.1 years vs. Controls: 15 M, 17 F/61.6 years |
53% had SSA; 50% chemotherapy |
na |
Mean 31.8 GBq (IQR: 31.2–35) |
Median 68 months (IQR: 51.3–102) |
|
- -
-
There were no differences in male hypogonadism or other hormone deficiencies between PRRT-treated pts vs. controls
- -
-
16 of 38 pts (42%) men from the whole cohort had hypogonadism: 7 pts had primary hypogonadism (5 from the PRRT group); 9 pts had secondary hypogonadism (6 from the PRRT group)
- -
-
No differences in the proportion of pts with secondary hypogonadism between PRRT-treated vs. control males (48 vs. 33%; p = 0.51), as well as among PRRT-treated vs. control females (0 vs. 12%; p = 0.51). PRRT did not predict male hypogonadism (OR = 1.8, 95% CI 0.5–7.1).
- -
-
No differences in median FSH between post-menopausal women who had PRRT vs. those who did not (61.5 vs. 66 U/L)
- -
-
No differences in the total dose received between PRRT-treated pts who developed secondary hypogonadism vs. those who did not (32.1 vs. 32.5 GBq; p = 1.000)
- -
-
One of 34 PRRT-treated pts (3%) developed GH deficiency confirmed by both low IGF-1 and glucagon stimulation testing (55 months after PRRT, cumulative dose 33.7 GBq)
- -
-
No differences in the proportion of pts with hyperprolactinaemia between PRRT-treated pts vs. controls (12 vs. 7%; p = 0.67)
- -
-
No diabetes insipidus
|
|
2. Gonadal Axis
In post-menopausal women, two studies showed a decrease in serum follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels following PRRT
[114,115][2][13], 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][11], 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][12].
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][2][11]. Total testosterone decreases during the follow-up after PRRT
[33[2][11],
115], coincident with a decrease in sex hormone binding globulin (SHBG), but the biochemically active non-SHBG-bound testosterone does not change
[115][2]. 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][12].
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[2][11],
115], similar to male patients with thyroid cancer who undergo radioiodine therapy
[119,120][14][15]. 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[2][11],
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][16][17][18].
3. Somatotroph Axis
The somatotroph axis, recognised as the most radiosensitive and the first pituitary axis to reflect the radiation effects
[117[9][10],
118], was assessed in PRRT-treated patients in two studies
[113,114][12][13]. 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][13]. 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][12]. 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][19], and neither should it preclude clinicians prescribing PRRT for a progressive and potentially threating neuroendocrine neoplasm.
4. Thyroid Axis
Sundlöv et al. and Elston et al. reported no changes in the thyroid axis as a result of PRRT
[113[12][13],
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][2][11]. The development of primary hypothyroidism is also uncommon in PRRT-treated patients, occurring in only 3% of cases
[115][2]. The levels of reverse triiodothyronine (rT3) also decrease after PRRT
[115][2]. 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][2], neither it is clear if these patients at a longer term will evolve to hypothyroidism requiring thyroxine replacement therapy.
5. Hypothalamo–Pituitary–Adrenal Axis
The hypothalamo–pituitary–adrenal axis remained intact in patients submitted to PRRT across three studies investigating the adrenal function post-PRRT
[113,114,115][2][12][13]. 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][2].