IGSF1 Does Not Regulate Spermatogenesis or Modify FSH Synthesis in Response to Inhibins or Activins

Journal of the Endocrine Society, vol. 5, pp. bvab023

Abstract

Abstract Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene result in central hypothyroidism, often associated with macroorchidism. Testicular enlargement in these patients might be caused by increases in follicle-stimulating hormone (FSH) levels, as IGSF1 has been proposed to function as an inhibin B receptor or as an inhibitor of activin type I receptor (ALK4) activity in pituitary gonadotrope cells. If true, loss of IGSF1 should lead to reduced inhibin B action or disinhibition of activin signaling, thereby increasing FSH synthesis. Here, we show that FSH levels and sperm counts are normal in male Igsf1 knockout mice, although testis size is mildly increased. Sperm parameters are also normal in men with IGSF1 deficiency, although their FSH levels may trend higher and their testes are enlarged. Inhibin B retains the ability to suppress FSH synthesis in pituitaries of Igsf1-knockout mice and IGSF1 does not interact with ALK4 or alter activin A/ALK4 stimulation of FSHβ (Fshb/FSHB) subunit transcription or expression. In light of these results, it is unlikely that macroorchidism in IGSF1 deficiency derives from alterations in spermatogenesis or inhibin/activin regulation of FSH.

Authors 12

1. Charlotte A. Heinen

   Emma Kinderziekenhuis · Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Amsterdam University Medical Centers, University of Amsterdam, Department of Endocrinology & Metabolism, Meibergdreef 9, 1105 Amsterdam, the Netherlands

   Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Department of Pediatric Endocrinology, 1105 Amsterdam, the Netherlands

   Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Department of Pediatric Endocrinology, 1105 Amsterdam, the Netherlands

2. Courtney L. Smith

   McGill University

   Affiliation as printed

   Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada

3. Gauthier Schang

   McGill University

   Affiliation as printed

   Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada

4. Yining Li

   McGill University

   Affiliation as printed

   Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada

5. Xiang Zhou

   McGill University

   Affiliation as printed

   Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada

6. Ying Wang

   McGill University

   Affiliation as printed

   Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada

7. Sjoerd D. Joustra Aachen Department of Medicine Division of Endocrinology, Leiden University Medical Center Department of Pediatrics, Leiden University Medical Center

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2300 Leiden, the Netherlands

   Department of Pediatrics, Leiden University Medical Center, 2300 Leiden, the Netherlands

8. Jan Maarten Wit Aachen Department of Pediatrics, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pediatrics, Leiden University Medical Center, 2300 Leiden, the Netherlands

9. Eric Fliers

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Amsterdam University Medical Centers, University of Amsterdam, Department of Endocrinology & Metabolism, Meibergdreef 9, 1105 Amsterdam, the Netherlands

10. Sjoerd Repping

    Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 Amsterdam, the Netherlands

11. A S Paul van Trotsenburg

    Emma Kinderziekenhuis · Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Department of Pediatric Endocrinology, 1105 Amsterdam, the Netherlands

    Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Department of Pediatric Endocrinology, 1105 Amsterdam, the Netherlands

12. Daniel J. Bernard corresponding

    McGill University

    Affiliation as printed

    Department of Anatomy and Cell Biology, McGill University, Montréal, Québec H3A 0C7, Canada

    Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada