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.
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
Submitter: Deepa Bhartiya | firstname.lastname@example.org
Authors: Deepa Bhartiya and Hiren Patel
ICMR-National Institute for Research in Reproductive Health, Parel, Mumbai, India
Published April 25, 2018
It is text-book knowledge that LH-stimulated testosterone production is crucial whereas role of FSH during spermatogenesis remains unclear since men and mice with inactivating FSHR mutations are fertile. Crucial role of FSH during spermatogenesis has been demonstrated earlier but lacks consensus. Active immunization of fertile Bonnet monkeys with phage-expressed FSHR peptides results in azoospermia by D100 although testosterone levels remained unaffected (1). Treating with 300IU of rFSH resulted in increased sperm count and improved pregnancy rates in normogonadotropic infertile patients with oligoasthenozoospermia (2). Recent article by Huhtaniemi’s group (3) shows that transgenic mice with constitutively strongly active FSHR point-mutation in LHR-null mice could reverse azoospermia and restore fertility. Authors concluded that spermatogenesis can be solely driven by FSH in LH-independent manner. Increased FSHR expression at mRNA level (>20 folds) in transgenic mice could maintain Sertoli cells gene expression for various growth factors and also testosterone levels were relatively higher in Fshr-CAM/LH-/- compared to LHR-/- mice. Circulatory LH were >10 folds increased whereas FSH showed 1.5 folds increase in Fshr-CAM/LH-/- and LHR-/- mice. Authors have successfully established an in vivo model where they can demonstrate FSH role without LH interference but results obtained may not necessarily be due to increased FSHR expression on Sertoli cells. We have earlier shown that besides Sertoli cells, testicular stem cells also express FSHR (using commercially available FSHR antibody raised against the extracellular region of FSHR which is common to all alternatively spliced FSHR isoforms). Stem cells undergo asymmetric, symmetric cell divisions and clonal expansion (rapid proliferation with incomplete cytokinesis) when treated with FSH and the action is possibly mediated via alternately spliced growth factor type-1 Fshr3 rather than the canonical Fshr1 isoform (Patel and Bhartiya, 2016). Moreover, when the cells isolated from chemoablated (busulphan 25 mg/kg) seminiferous tubules were cultured in the presence of FSH and conditioned medium from Sertoli cells and on a Sertoli cells bed, they recapitulated complete spermatogenesis in vitro (Anand et al, 2015). Spermatogenesis is driven by the direct action of FSH on stem cells that express FSHR and divide to produce spermatogonial cells in addition to paracrine influence of their niche (Sertoli cells) crucial for their differentiation. There is much more to learn about the role of FSHR isoforms and FSH during spermatogenesis. Careful selection of both antibodies and primers to study FSHR expression and mRNA regulation by FSH is crucial.
Rao AJ, Ramachandra SG, Ramesh V, Couture L, Abdennebi L, Salesse R, Remy JJ. Induction of infertility in adult male bonnet monkeys by immunization with phage-expressed peptides of the extracellular domain of FSH receptor. Reprod Biomed Online. 2004;8(4):385-91.
Paradisi R, Natali F, Fabbri R, Battaglia C, Seracchioli R, Venturoli S. Evidence for a stimulatory role of high doses of recombinant human follicle-stimulating hormone in the treatment of male-factor infertility. Andrologia. 2014;46(9):1067-72
Oduwole OO, Peltoketo H, Poliandri A, Vengadabady L, Chrusciel M, Doroszko M, Samanta L, Owen L, Keevil B, Rahman NA, Huhtaniemi IT. Constitutively active follicle-stimulating hormone receptor enables androgen-independent spermatogenesis. J Clin Invest. 2018 Mar 26. pii: 96794. doi: 10.1172/JCI96794.