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

Emilie Brûlé; Charlotte A Heinen; Courtney L Smith; Gauthier Schang; Yining Li; Xiang Zhou; Ying Wang; Sjoerd D Joustra; Jan M Wit; Eric Fliers; Sjoerd Repping; A S Paul van Trotsenburg; Daniel J Bernard

doi:10.1210/jendso/bvab023

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

J Endocr Soc. 2021 Feb 20;5(4):bvab023. doi: 10.1210/jendso/bvab023. eCollection 2021 Apr 1.

Authors

Emilie Brûlé¹, Charlotte A Heinen^{2

3}, Courtney L Smith⁴, Gauthier Schang⁴, Yining Li⁴, Xiang Zhou⁴, Ying Wang⁴, Sjoerd D Joustra^{5

6}, Jan M Wit⁶, Eric Fliers³, Sjoerd Repping⁷, A S Paul van Trotsenburg², Daniel J Bernard^{1

4}

Affiliations

¹ Department of Anatomy and Cell Biology, McGill University, Montréal, Québec H3A 0C7, Canada.
² Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Department of Pediatric Endocrinology, 1105 Amsterdam, the Netherlands.
³ Amsterdam University Medical Centers, University of Amsterdam, Department of Endocrinology & Metabolism, Meibergdreef 9, 1105 Amsterdam, the Netherlands.
⁴ Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada.
⁵ Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2300 Leiden, the Netherlands.
⁶ Department of Pediatrics, Leiden University Medical Center, 2300 Leiden, the Netherlands.
⁷ Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 Amsterdam, the Netherlands.

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.

Keywords: FSH; IGSF1; macroorchidism; pituitary.