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Constitutively active follicle-stimulating hormone receptor enables androgen-independent spermatogenesis

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Title: Constitutively active follicle-stimulating hormone receptor enables androgen-independent spermatogenesis
Authors: Oduwole, OO
Peltoketo, H
Poliandri, A
Vengadabady, L
Chrusciel, M
Doroszko, M
Samanta, L
Owen, L
Keevil, B
Rahman, NA
Huhtaniemi, IT
Item Type: Journal Article
Abstract: Spermatogenesis is regulated by the 2 pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This process is considered impossible without the absolute requirement of LH-stimulated testicular testosterone (T) production. The role of FSH remains unclear because men and mice with inactivating FSH receptor (FSHR) mutations are fertile. We revisited the role of FSH in spermatogenesis using transgenic mice expressing a constitutively strongly active FSHR mutant in a LH receptor–null (LHR-null) background. The mutant FSHR reversed the azoospermia and partially restored fertility of Lhr–/– mice. The finding was initially ascribed to the residual Leydig cell T production. However, when T action was completely blocked with the potent antiandrogen flutamide, spermatogenesis persisted. Hence, completely T-independent spermatogenesis is possible through strong FSHR activation, and the dogma of T being a sine qua non for spermatogenesis may need modification. The mechanism for the finding appeared to be that FSHR activation maintained the expression of Sertoli cell genes considered androgen dependent. The translational message of our findings is the possibility of developing a new strategy of high-dose FSH treatment for spermatogenic failure. Our findings also provide an explanation of molecular pathogenesis for Pasqualini syndrome (fertile eunuchs; LH/T deficiency with persistent spermatogenesis) and explain how the hormonal regulation of spermatogenesis has shifted from FSH to T dominance during evolution.
Issue Date: 1-May-2018
Date of Acceptance: 7-Feb-2018
URI: http://hdl.handle.net/10044/1/58024
DOI: https://dx.doi.org/10.1172/JCI96794
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation
Start Page: 1787
End Page: 1792
Journal / Book Title: Journal of Clinical Investigation
Volume: 128
Issue: 5
Copyright Statement: © 2018 Oduwole et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: 063552/A/01/Z
G0600002
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
SERTOLI-CELLS
MAINTAIN SPERMATOGENESIS
FSH
TESTOSTERONE
MUTATION
GENE
MOUSE
MEN
IDENTIFICATION
EXPRESSION
Endocrinology
Fertility
Reproductive Biology
Reproductive biochemistry
11 Medical And Health Sciences
Immunology
Publication Status: Published
Online Publication Date: 2018-03-26
Appears in Collections:Department of Surgery and Cancer