Constitutively active follicle-stimulating hormone receptor enables androgen-independent spermatogenesis
Olayiwola O. Oduwole, … , Nafis A. Rahman, Ilpo T. Huhtaniemi
Olayiwola O. Oduwole, … , Nafis A. Rahman, Ilpo T. Huhtaniemi
Published March 26, 2018
Citation Information: J Clin Invest. 2018;128(5):1787-1792. https://doi.org/10.1172/JCI96794.
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Concise Communication Endocrinology Reproductive biology

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

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.

Authors

Olayiwola O. Oduwole, Hellevi Peltoketo, Ariel Poliandri, Laura Vengadabady, Marcin Chrusciel, Milena Doroszko, Luna Samanta, Laura Owen, Brian Keevil, Nafis A. Rahman, Ilpo T. Huhtaniemi

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Figure 3

Relative mRNA expression in testes.

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Relative mRNA expression in testes. (A) Steroidogenic genes. (B) Hormone...
(A) Steroidogenic genes. (B) Hormones and growth factors. (C) Hormone receptors. (D) Androgen-regulated (Drd5, Rhox5, Eppin, and Tjp1), postmeiotic germ cell–specific (Aqp8), and germ cell–regulated (Gata1) genes in WT, Fshr-CAM, Fshr-CAM/Lhr–/–, and Lhr–/– testes. In contrast with the LC genes downregulated in Lhr–/– testes (A), we identified several upregulated SC-specific genes (B and C). Expression of 3 steroid receptor genes with mixed localization, namely, Esr1, Esr2, and Ar, also resembled that of the SC-specific genes (C). The increased proportion of SC per unit weight in Lhr–/– testes (Table 1 and Supplemental Table 3) apparently explains, at least partly, the enrichment of the SC genes. Expression of these genes became normalized in the Fshr-CAM/Lhr–/– mice, in accordance with the normalization of testis size and proportions of the different cell types. (E) Effect of flutamide treatment on expression of androgen-regulated genes in WT and Fshr-CAM/Lhr–/– mice. Data represent mean ± SEM. n = 3 samples/group. Bars with different symbols differ significantly from each other (P < 0.05; ANOVA/Newman-Keuls).