University of Oulu

Oduwole, O., Peltoketo, H., Poliandri, A., Vengadabady, L., Chrusciel, M., Doroszko, M., Samanta, L., Owen, L., Keevil, B., Rahman, N., Huhtaniemi, I. (2018) Constitutively active follicle-stimulating hormone receptor enables androgen-independent spermatogenesis. Journal of Clinical Investigation, 128 (5), 1787-1792. https://doi.org/10.1172/JCI96794.

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

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Author: Oduwole, Olayiwola O.1; Peltoketo, Hellevi1,2; Poliandri, Ariel1,3;
Organizations: 1Institute of Reproductive and Developmental Biology (IRDB), Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom
2Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit/Laboratory Medicine, Biocenter Oulu and Faculty of Medicine, University of Oulu, Oulu, Finland
3Department of Molecular and Clinical Sciences, St. George’s University of London, London, United Kingdom
4Department of Target Sciences, GlaxoSmithKline, London, United Kingdom
5Department of Physiology, University of Turku, Turku, Finland
6Department of Zoology, School of Life Sciences, Ravenshaw University, Cuttack, India
7Biochemistry Department, University Hospital of South Manchester, Manchester, United Kingdom
8Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2018060725487
Language: English
Published: American Society for Clinical Investigation, 2018
Publish Date: 2018-06-07
Description:

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.

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Series: Journal of clinical investigation
ISSN: 0021-9738
ISSN-E: 1558-8238
ISSN-L: 0021-9738
Volume: 128
Issue: 5
Pages: 1787 - 1792
DOI: 10.1172/JCI96794
OADOI: https://oadoi.org/10.1172/JCI96794
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
Subjects:
Funding: This work was supported by Wellcome Trust Programme grant 082101/Z07/Z and MRC Project grant 0600002 (to ITH); Polish National Science Center grant 2015/17/B/NZ5/00636, and the Moikoinen Cancer Research Foundation (to NR).
Copyright information: © 2018 ASCI. 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/.
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