Abstract
Background: Loss-of-function mutations in immunoglobulin superfamily member 1 (IGSF1) cause an X-linked syndrome of central hypothyroidism, macroorchidism, delayed pubertal testosterone rise, variable prolactin deficiency and variable partial GH deficiency in childhood. The clinical features and gene expression pattern suggest a pivotal role for IGSF1 in the pituitary, but detailed knowledge on pituitary hormone secretion in this syndrome is lacking. We therefore aimed to study the 24-hour pituitary hormone secretion in male patients with IGSF1 deficiency. Methods: We collected blood samples every 10 min for 24 h in eight adult male IGSF1-deficient patients and measured circulating TSH, prolactin and gonadotropins. Deconvolution, modified cosinor and approximate entropy analyses were applied to quantify secretion rates, diurnal rhythmicity and regularity of hormone release. Results were compared to healthy controls matched for age and body mass index. Results: Compared to healthy controls, IGSF1-deficient patients showed decreased pulsatile secretion of TSH with decreased disorderliness and reduced diurnal variation. Basal and pulsatile secretion of FSH was increased by over 200%, while LH secretion did not differ from healthy controls. We observed a bimodal distribution of prolactin secretion, i.e. severe deficiency in three and increased basal and total secretion in the other five patients. Conclusion: The altered TSH secretion pattern is consistent with the previously hypothesized defect in thyrotropin-releasing hormone signaling in IGSF1 deficiency. However, the phenotype is more extensive and includes increased FSH secretion without altered LH secretion as well as either undetectable or increased prolactin secretion.
References
1.
Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, Cambridge E, White JK, le Tissier P, Gharavy SN, Martinez-Barbera JP, Stokvis-Brantsma WH, Vulsma T, Kempers MJ, Persani L, Campi I, Bonomi M, Beck-Peccoz P, Zhu H, Davis TM, Hokken-Koelega AC, Del Blanco DG, Rangasami JJ, Ruivenkamp CA, Laros JF, Kriek M, Kant SG, Bosch CA, Biermasz NR, Appelman-Dijkstra NM, Corssmit EP, Hovens GC, Pereira AM, Dunnen JT, Wade MG, Breuning MH, Hennekam RC, Chatterjee K, Dattani MT, Wit JM, Bernard DJ: Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet 2012;44:1375-1381.
2.
Joustra SD, Schoenmakers N, Persani L, Campi I, Bonomi M, Radetti G, Beck-Peccoz P, Zhu H, Davis TM, Sun Y, Corssmit EP, Appelman-Dijkstra NM, Heinen CA, Pereira AM, Varewijck AJ, Janssen JA, Endert E, Hennekam RC, Lombardi MP, Mannens MM, Bak B, Bernard DJ, Breuning MH, Chatterjee K, Dattani MT, Oostdijk W, Biermasz NR, Wit JM, van Trotsenburg AS: The IGSF1 deficiency syndrome: characteristics of male and female patients. J Clin Endocrinol Metab 2013;98:4942-4952.
3.
Tajima T, Nakamura A, Ishizu K: A novel mutation of IGSF1 in a Japanese patient of congenital central hypothyroidism without macroorchidism. Endocr J 2013;60:245-249.
4.
Nakamura A, Bak B, Silander TL, Lam J, Hotsubo T, Yorifuji T, Ishizu K, Bernard DJ, Tajima T: Three novel IGSF1 mutations in four Japanese patients with X-linked congenital central hypothyroidism. J Clin Endocrinol Metab 2013;98:E1682-E1691.
5.
Fafioffe A, Ethier JF, Fontaine J, JeanPierre E, Taragnat C, Dupont J: Activin and inhibin receptor gene expression in the ewe pituitary throughout the oestrous cycle. J Endocrinol 2004;182:55-68.
6.
Bernard DJ, Chapman SC, Woodruff TK: Mechanisms of inhibin signal transduction. Recent Prog Horm Res 2001;56:417-450.
7.
Roelfsema F, Pereira AM, Veldhuis JD, Adriaanse R, Endert E, Fliers E, Romijn JA: Thyrotropin secretion profiles are not different in men and women. J Clin Endocrinol Metab 2009;94:3964-3967.
8.
Kok SW, Roelfsema F, Overeem S, Lammers GJ, Frolich M, Meinders AE, Pijl H: Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men. Am J Physiol Endocrinol Metab 2005;288:E892-E899.
9.
Roelfsema F, Pijl H, Keenan DM, Veldhuis JD: Prolactin secretion in healthy adults is determined by gender, age and body mass index. PLoS One 2012;7:e31305.
10.
Veldhuis JD, Roelfsema F, Keenan DM, Pincus S: Gender, age, body mass index, and IGF-I individually and jointly determine distinct GH dynamics: analyses in one hundred healthy adults. J Clin Endocrinol Metab 2011;96:115-121.
11.
Roelfsema F, Veldhuis JD: Thyrotropin secretion patterns in health and disease. Endocr Rev 2013;34:619-657.
12.
Keenan DM, Roelfsema F, Biermasz N, Veldhuis JD: Physiological control of pituitary hormone secretory-burst mass, frequency, and waveform: a statistical formulation and analysis. Am J Physiol Regul Integr Comp Physiol 2003;285:R664-R673.
13.
Roelfsema F, Pereira AM, Biermasz NR, Veldhuis JD: Hormone secretion by pituitary adenomas is characterized by increased disorderliness and spikiness but more regular pulsing. J Clin Endocrinol Metab 2014;99:3836-3844.
14.
Liu PY, Keenan DM, Kok P, Padmanabhan V, O'Byrne KT, Veldhuis JD: Sensitivity and specificity of pulse detection using a new deconvolution method. Am J Physiol Endocrinol Metab 2009;297:E538-E544.
15.
Keenan DM, Chattopadhyay S, Veldhuis JD: Composite model of time-varying appearance and disappearance of neurohormone pulse signals in blood. J Theor Biol 2005;236:242-255.
16.
Magner JA: Thyroid-stimulating hormone: biosynthesis, cell biology, and bioactivity. Endocr Rev 1990;11:354-385.
17.
Pincus SM: Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 1991;88:2297-2301.
18.
Pincus SM, Keefe DL: Quantification of hormone pulsatility via an approximate entropy algorithm. Am J Physiol 1992;262:E741-E754.
19.
Pincus SM, Schmidt PJ, Palladino-Negro P, Rubinow DR: Differentiation of women with premenstrual dysphoric disorder, recurrent brief depression, and healthy controls by daily mood rating dynamics. J Psychiatr Res 2008;42:337-347.
20.
Van Someren EJ, Nagtegaal E: Improving melatonin circadian phase estimates. Sleep Med 2007;8:590-601.
21.
Roelfsema F, Pijl H, Kok P, Endert E, Fliers E, Biermasz NR, Pereira AM, Veldhuis JD: Thyrotropin secretion in healthy subjects is robust and independent of age and gender, and only weakly dependent on body mass index. J Clin Endocrinol Metab 2014;99:570-578.
22.
Molitch ME: Drugs and prolactin. Pituitary 2008;11:209-218.
23.
Holub G, Lunglmayr G, Spona J: Effect of cyproterone/acetate (SH-714) on plasma prolactin in patients with prostatic cancer. Urol Res 1981;9:245-247.
24.
Samuels MH, Lillehei K, Kleinschmidt-Demasters BK, Stears J, Ridgway EC: Patterns of pulsatile pituitary glycoprotein secretion in central hypothyroidism and hypogonadism. J Clin Endocrinol Metab 1990;70:391-395.
25.
Adriaanse R, Brabant G, Endert E, Wiersinga WM: Pulsatile thyrotropin release in patients with untreated pituitary disease. J Clin Endocrinol Metab 1993;77:205-209.
26.
Bonomi M, Busnelli M, Beck-Peccoz P, Costanzo D, Antonica F, Dolci C, Pilotta A, Buzi F, Persani L: A family with complete resistance to thyrotropin-releasing hormone. N Engl J Med 2009;360:731-734.
27.
Kalsbeek A, Fliers E, Franke AN, Wortel J, Buijs RM: Functional connections between the suprachiasmatic nucleus and the thyroid gland as revealed by lesioning and viral tracing techniques in the rat. Endocrinology 2000;141:3832-3841.
28.
Roelfsema F, Pereira AM, Keenan DM, Veldhuis JD, Romijn JA: Thyrotropin secretion by thyrotropinomas is characterized by increased pulse frequency, delayed diurnal rhythm, enhanced basal secretion, spikiness, and disorderliness. J Clin Endocrinol Metab 2008;93:4052-4057.
29.
Roelfsema F, Pereira AM, Adriaanse R, Endert E, Fliers E, Romijn JA, Veldhuis JD: Thyrotropin secretion in mild and severe primary hypothyroidism is distinguished by amplified burst mass and basal secretion with increased spikiness and approximate entropy. J Clin Endocrinol Metab 2010;95:928-934.
30.
Weber G, Vigone MC, Stroppa L, Chiumello G: Thyroid function and puberty. J Pediatr Endocrinol Metab 2003;16(suppl 2):253-257.
31.
Bruder JM, Samuels MH, Bremner WJ, Ridgway EC, Wierman ME: Hypothyroidism-induced macroorchidism: use of a gonadotropin-releasing hormone agonist to understand its mechanism and augment adult stature. J Clin Endocrinol Metab 1995;80:11-16.
32.
Castro-Magana M, Angulo M, Canas A, Sharp A, Fuentes B: Hypothalamic-pituitary gonadal axis in boys with primary hypothyroidism and macroorchidism. J Pediatr 1988;112:397-402.
33.
Thompson IR, Kaiser UB: GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. Mol Cell Endocrinol 2014;385:28-35.
34.
Makanji Y, Zhu J, Mishra R, Holmquist C, Wong WP, Schwartz NB, Mayo KE, Woodruff TK: Inhibin at 90: from discovery to clinical application, a historical review. Endocr Rev 2014;35:747-794.
35.
Bernard DJ, Burns KH, Haupt B, Matzuk MM, Woodruff TK: Normal reproductive function in InhBP/p120-deficient mice. Mol Cell Biol 2003;23:4882-4891.
36.
Holsberger DR, Cooke PS: Understanding the role of thyroid hormone in Sertoli cell development: a mechanistic hypothesis. Cell Tissue Res 2005;322:133-140.
37.
Ryan GL, Feng X, d'Alva CB, Zhang M, van Voorhis BJ, Pinto EM, Kubias AE, Antonini SR, Latronico AC, Segaloff DL: Evaluating the roles of follicle-stimulating hormone receptor polymorphisms in gonadal hyperstimulation associated with severe juvenile primary hypothyroidism. J Clin Endocrinol Metab 2007;92:2312-2317.
38.
Collu R, Tang J, Castagne J, Lagace G, Masson N, Huot C, Deal C, Delvin E, Faccenda E, Eidne KA, van Vliet G: A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J Clin Endocrinol Metab 1997;82:1561-1565.
39.
Veldhuis JD, Keenan DM, Pincus SM: Motivations and methods for analyzing pulsatile hormone secretion. Endocr Rev 2008;29:823-864.
40.
Joustra SD, van der Plas EM, Goede J, Oostdijk W, Delemarre-van de Waal HA, Hack WW, van Buuren S, Wit JM: New reference charts for testicular volume in Dutch children and adolescents allow the calculation of standard deviation scores. Acta Paediatr 2015;104:e271-e278.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
