Effects of oral macimorelin on copeptin and anterior pituitary hormones in healthy volunteers

Sandrine A Urwyler, Sven Lustenberger, Juliana R Drummond, Beatriz Santana Soares, Deborah R Vogt, Nicola Ammer, Kevin C J Yuen, Antonio Ribeiro-Oliveira, Mirjam Christ-Crain, Sandrine A Urwyler, Sven Lustenberger, Juliana R Drummond, Beatriz Santana Soares, Deborah R Vogt, Nicola Ammer, Kevin C J Yuen, Antonio Ribeiro-Oliveira, Mirjam Christ-Crain

Abstract

Purpose: The test with the highest diagnostic accuracy for diabetes insipidus is copeptin measurement after hypertonic saline infusion. However, the procedure is cumbersome and unpleasant due to rapid sodium increase. An oral stimulation test would be highly desirable. Macimorelin, an oral ghrelin agonist, is a newly approved diagnostic test for growth hormone (GH) deficiency, but its effects on copeptin/vasopressin are unknown and the effects on other pituitary hormones only scarcely investigated.

Methods: In this prospective, interventional, proof-of-concept study Copeptin and anterior pituitary hormones were measured in 28 healthy volunteers on two test days at baseline, 30, 45, 60, 90 and 120 min after a single dose of macimorelin (first visit: 0.5 mg/kg, second visit: 0.75 mg/kg).

Results: Baseline copeptin levels were 5.26 pmol/L [1.57, 6.81] and did not change after macimorelin intake (0.5 mg/kg: maximal median change 0.40 [- 0.49, 0.65] pmol/L, p = 0.442; 0.75 mg/kg: - 0.13 [- 0.45, 0.17] pmol/L, p = 0.442. Median GH levels increased from 3.67 mU/L with a maximal median change of 94.66 [IQR 56.5; 110.96] mU/L, p < 0.001. No effect was seen on cortisol, ACTH, LH and FSH levels. Prolactin (max. median change 100 [2.5; 146.5] mU/L, p = 0.004) and free thyroxine (fT4) (0.5 [0.2; 0.8] pmol/L, p < 0.001) increased, whereas TSH decreased (- 0.18 [- 0.22, - 0.09] mU/L, p < 0.001).

Conclusion: We confirm an increase of GH upon macimorelin in healthy volunteers. However, macimorelin did not stimulate copeptin and therefore does not provide an oral test alternative for the diagnosis of diabetes insipidus. Additionally, a stimulatory effect was seen for prolactin and fT4, but not for ACTH and gonadotropic hormones.

Registration: The trial was registered on ClinicalTrials.gov (NCT03844217) on February 18, 2019.

Keywords: Copeptin; Diabetes insipidus; Ghrelin agonist; Macimorelin; Pituitary hormones.

Conflict of interest statement

Nicola Ammer is an employee of Aeterna Zentaris GmbH Frankfurt and Antonio Ribeiro-Oliveira an employee of Ipsen Bioscience in Cambridge/Massachusetts. All other authors have nothing to disclose in relation to this work.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Time course of copeptin after a single oral stimulation with macimorelin 0.5 mg/kg and 0.75 mg/kg
Fig. 2
Fig. 2
Maximum copeptin times, i.e. the measurement time point at which copeptin levels were maximal. Time zero indicates the baseline, i.e. before intake of macimorelin
Fig. 3
Fig. 3
Time course of GH and IGF-1 for each macimorelin dose
Fig. 4
Fig. 4
Time course of ACTH and cortisol for each macimorelin dose
Fig. 5
Fig. 5
Time course of TSH, fT4, prolactin and gonadotropic hormones for each macimorelin dose

References

    1. Christ-Crain M. Diabetes insipidus—new concepts for diagnosis. Neuroendocrinology. 2020;110(9–10):859–867. doi: 10.1159/000505548.
    1. Christ-Crain M, et al. Diabetes insipidus. Nat Rev Dis Primers. 2019;5(1):54. doi: 10.1038/s41572-019-0103-2.
    1. Fenske W, et al. A copeptin-based approach in the diagnosis of diabetes insipidus. N Engl J Med. 2018;379(5):428–439. doi: 10.1056/NEJMoa1803760.
    1. Winzeler B, et al. Arginine-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a prospective diagnostic study. Lancet. 2019;394(10198):587–595. doi: 10.1016/S0140-6736(19)31255-3.
    1. Garcia JM, et al. Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. 2013;98(6):2422–2429. doi: 10.1210/jc.2013-1157.
    1. Garcia JM, et al. Macimorelin as a diagnostic test for adult GH deficiency. J Clin Endocrinol Metab. 2018;103(8):3083–3093. doi: 10.1210/jc.2018-00665.
    1. Korbonits M, et al. The effect of growth hormone secretagogues and neuropeptide Y on hypothalamic hormone release from acute rat hypothalamic explants. J Neuroendocrinol. 1999;11(7):521–528. doi: 10.1046/j.1365-2826.1999.00353.x.
    1. Nemoto T, et al. The effects of ghrelin/GHSs on AVP mRNA expression and release in cultured hypothalamic cells in rats. Peptides. 2011;32(6):1281–1288. doi: 10.1016/j.peptides.2011.04.007.
    1. Ishizaki S, et al. Role of ghrelin in the regulation of vasopressin release in conscious rats. Endocrinology. 2002;143(5):1589–1593. doi: 10.1210/endo.143.5.8804.
    1. Galfi M, et al. Ghrelin-induced enhancement of vasopressin and oxytocin secretion in rat neurohypophyseal cell cultures. J Mol Neurosci. 2016;60(4):525–530. doi: 10.1007/s12031-016-0850-4.
    1. Korbonits M, et al. The growth hormone secretagogue hexarelin stimulates the hypothalamo-pituitary-adrenal axis via arginine vasopressin. J Clin Endocrinol Metab. 1999;84(7):2489–2495. doi: 10.1210/jcem.84.7.5811.
    1. Bancos I, et al. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3(3):216–226. doi: 10.1016/S2213-8587(14)70142-1.
    1. Aeterna Zentaris (2019) Investigator’s Brochure Macimorelin (AEZS-130) Edition no. 7. Charleston, SC (USA), Frankfurt am Main (Germany)
    1. Wasserstein RL, Schirm AL, Lazar NA. Moving to a world beyond "p < 0.005". Am Stat. 2019;73(Suppl 1):1–19. doi: 10.1080/00031305.2019.1583913.
    1. Korbonits M, et al. Hexarelin as a test of pituitary reserve in patients with pituitary disease. Clin Endocrinol. 1999;51(3):369–375. doi: 10.1046/j.1365-2265.1999.00828.x.
    1. Growth Hormone Research S Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab. 2000;85(11):3990–3993.
    1. Vestergaard ET, et al. Acute intravenous acyl ghrelin infusion induces thirst but does not affect sodium excretion: two randomized, double-blind, placebo-controlled crossover studies in hypopituitary patients. Eur J Endocrinol. 2019;181(1):23–30. doi: 10.1530/EJE-19-0027.
    1. Broglio F, et al. EP1572: a novel peptido-mimetic GH secretagogue with potent and selective GH-releasing activity in man. J Endocrinol Invest. 2002;25(8):RC26–RC28. doi: 10.1007/BF03345096.
    1. Piccoli F, et al. Pharmacokinetics and pharmacodynamic effects of an oral ghrelin agonist in healthy subjects. J Clin Endocrinol Metab. 2007;92(5):1814–1820. doi: 10.1210/jc.2006-2160.
    1. Klaus B, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macimorelin in healthy adults: results of a single-dose, randomized controlled study. Growth Horm IGF Res. 2020;52:101321. doi: 10.1016/j.ghir.2020.101321.
    1. Peacey SR, Shalet SM. Insulin-like growth factor 1 measurement in diagnosis and management of acromegaly. Ann Clin Biochem. 2001;38(Pt 4):297–303. doi: 10.1258/0004563011900678.
    1. Poher AL, Tschop MH, Muller TD. Ghrelin regulation of glucose metabolism. Peptides. 2018;100:236–242. doi: 10.1016/j.peptides.2017.12.015.
    1. Kordi F, Khazali H. The effect of ghrelin and estradiol on mean concentration of thyroid hormones. Int J Endocrinol Metab. 2015;13(1):e17988. doi: 10.5812/ijem.17988.
    1. Mahmoudi F, et al. The effect of central injection of ghrelin and bombesin on mean plasma thyroid hormones concentration. Iran J Pharm Res. 2011;10(3):627–632.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner