Effects of therapy with [177Lu-DOTA 0,Tyr 3]octreotate on endocrine function

Abstract

Purpose: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes.

Methods: Hormone levels were measured and adrenal function assessed at baseline and up to 24 months of follow-up.

Results: In 35 men, mean serum inhibin B levels were decreased at 3 months post-therapy (205 +/- 16 to 25 +/- 4 ng/l, p < 0.05) and follicle-stimulating hormone (FSH) levels increased (5.9 +/- 0.5 to 22.7 +/- 1.4 IU/l, p < 0.05). These levels returned to near baseline levels. Total testosterone and sex hormone binding globulin (SHBG) levels decreased (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, p < 0.05), respectively, whereas non-SHBG-bound T did not change. An increase (5.2 +/- 0.6 to 7.7 +/- 0.7 IU/l, p < 0.05) of luteinizing hormone (LH) levels was found at 3 months of follow-up returning to baseline levels thereafter. In 21 postmenopausal women, a decrease in levels of FSH (74.4 +/- 5.6 to 62.4 +/- 7.7 IU/l, p < 0.05) and LH (26.8 +/- 2.1 to 21.1 +/- 3.0 IU/l, p < 0.05) was found. Of 66 patients, 2 developed persistent primary hypothyroidism. Free thyroxine (FT(4)) levels decreased (17.7 +/- 0.4 to 15.6 +/- 0.6 pmol/l, p < 0.05), whereas thyroid-stimulating hormone (TSH) and triiodothyronine (T(3)) levels did not change. Reverse triiodothyronine (rT(3)) levels decreased (0.38 +/- 0.03 to 0.30 +/- 0.01 nmol/l, p < 0.05). Before and after therapy adrenocorticotropic hormone (ACTH) stimulation tests showed an adequate response of serum cortisol (> 550 nmol/l, n = 18). Five patients developed elevated HbA(1c) levels (> 6.5%).

Conclusion: In men (177)Lu-octreotate therapy induced transient inhibitory effects on spermatogenesis, but non-SHBG-bound T levels remained unaffected. In the long term, gonadotropin levels decreased significantly in postmenopausal women. Only a few patients developed hypothyroidism or elevated levels of HbA(1c). Therefore, PRRT with (177)Lu-octreotate can be regarded as a safe treatment modality with respect to short- and long-term endocrine function.

Fig. 1

a, b Longitudinal analyses of mean (± SEM) serum levels of FSH (dotted line with open squares), inhibin B (black line with open circles), LH (dotted line with filled squares) and TT (black line with filled circles) in 35 men with SSTR-positive tumours before, during and up to 24 months after 600–800 mCi ¹⁷⁷Lu-octreotate therapy. Bars along both y-axes represent the reference range (4 SD) values, *p < 0.05. c Longitudinal analyses of mean (± SEM) serum levels of TT (black line with filled circles), SHBG (black line with filled triangles) and non-SHBG-bound testosterone (n-SHBG-bound T, black line with filled diamonds) in 35 men with SSTR-positive tumours before, during and up to 24 months after 600–800 mCi ¹⁷⁷Lu-octreotate therapy. Bars along both y-axes represent the reference range (4 SD) values, *p < 0.05

Fig. 2

Longitudinal analysis of mean (± SEM) serum levels of FSH (dotted line with open squares) and LH (dotted line with filled squares) in 21 postmenopausal women with SSTR-positive tumours before, during and up to 24 months after 600–800 mCi ¹⁷⁷Lu-octreotate therapy. The mean inhibin B and E₂ levels are not shown as these were at normal low postmenopausal levels (<10 ng/l and < 50 pmol/l, respectively). Bars along both y-axes represent the reference range (4 SD) values, *p < 0.05

Fig. 3

Longitudinal analysis of mean (± SEM) serum levels of TSH (dotted line with filled triangles), FT₄ (black line with filled circles), T₃ (black line with filled diamonds), rT₃ (dotted line with open triangles) and T₃/ rT₃ ratio (line with open circles) of 66 patients with SSTR-positive tumours before, during and up to 24 months after 600–800 mCi ¹⁷⁷Lu-octreotate therapy. Bars along both y-axes represent the reference range (4 SD) values, *p < 0.05

Fig. 4

Longitudinal analysis of mean (± SEM) serum levels of rT₃ in patients with SSTR-positive tumours before, during and at 3 months of follow-up after 600–800 mCi ¹⁷⁷Lu-octreotate therapy grouped according to their therapy outcome (minor remission and partial remission, MR & PR, filled circles; stable disease, SD, filled diamonds; progressive disease, PD, filled triangles) at 3 months of follow-up. Bars along the y-axis represent the reference range values, *p < 0.05

Fig. 5

Mean peak cortisol responses with the low-dose (1 μg) ACTH stimulation test in 18 patients before and 12–18 months after ¹⁷⁷Lu-octreotate therapy are shown. Each dotted line connects one individual patient