Follicle-stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles

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madman

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Abstract:

Background:
Human reproduction is regulated by the combined action of the follicle stimulating hormone (FSH) and the luteinizing hormone (LH) on the gonads. Although FSH is largely used in female reproduction, in particular in women attending assisted reproductive techniques to stimulate multi-follicular growth, its efficacy in men with idiopathic infertility is not clearly demonstrated. Indeed, whether FSH administration improves fertility in patients with hypogonadotropic hypogonadism, the therapeutic benefit in men presenting alterations in sperm production despite normal FSH serum levels is still unclear. In the present review, we evaluate the potential pharmacological benefits of FSH administration in clinical practice.

Methods: This is a narrative review, describing the FSH physiological role in spermatogenesis and its potential therapeutic action in men.

Results: The FSH role on male fertility is reviewed starting from the physiological control of spermatogenesis, throughout its mechanism of action in Sertoli cells, the genetic regulation of its action on spermatogenesis, until the therapeutic options available to improve sperm production.

Conclusion: FSH administration in infertile men has potential benefits, although its action should be considered by evaluating its synergic action with testosterone, and well-controlled, powerful trials are required. Prospective studies and new compounds could be developed in the near future.


1. Introduction
2. Physiological Control of Spermatogenesis Spermatogenesis
3. Mechanism of Action of FSH in the Sertoli Cell
4. Genetic Regulation of FSH Action on Spermatogenesis
5. Therapeutic Options to Improve Sperm Production
6. Future Perspectives




7. Conclusions


In conclusion, here we highlight how FSH acts in the sophisticated and not completely understood regulatory process resulting in male fertility. Human spermatogenesis is regulated by FSH and LH-dependent intra-testicular testosterone, with synergistic, partially overlapping mechanisms. Starting from these notions, FSH administration is proposed as a potentially effective therapeutic approach to male infertility. The exogenous FSH administration seems to improve sperm production, although it remains unclear whether it acts as replacement therapy or overstimulating treatment. This latter concept is supported by experimental demonstrations that spermatogenesis could be boosted beyond its physiological rate. However, the FSH-dependent overstimulation on spermatogenesis must still be verified in infertile men with properly designed clinical trials. Similarly, new scientific evidence is needed to confirm the efficacy of FSH administration in male infertility. A really powerful, phase 2 clinical trial is urgently required to produce evidence about FSH therapeutic potential. In this setting, the pharmacogenomic basis of FSH response, as well as the most effective dose and duration, must be addressed.
 

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madman

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Screenshot (1305).png

Figure 1. Schematic representation of a hemi-section of a seminiferous tubule. From the basal membrane to the lumen, spermatogenesis stages are reported up to the mature spermatozoa. This complex process is regulated synergistically by follicle-stimulating hormone (FSH) acting on Sertoli cells and by intra-testicular testosterone, produced by Leydig cells under luteinizing hormone (LH) stimulus. (FSH = follicle-stimulating hormone; n = haploid cell; 2n = diploid cell)
 

madman

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Screenshot (1306).png

Figure 2. Early FSH-dependent signaling and receptor internalization. (A) FSHR extracellular domain is exposed to FSH binding in the cell membrane. (B) FSHRs may form multimers in the cell surface and, upon FSH binding, undergo conformational changes inducing activation of the Gαs protein and subsequent ATP to cAMP conversion by the adenylyl cyclase enzyme. The downstream PKA, pERK1/2, and pCREB activation target CRE sequences, triggering gene expression. (C) The GRK enzyme is recruited via a mechanism involving the βγ dimer of the G protein and mediates FSHR phosphorylation at specific intracellular sites. (D) β-arrestins form a signaling module associated with FSHR and ERK1/2, mediating the assembly of clathrin-coated pits and internalization of the receptor. Besides this β-arrestin/clathrin-related mechanism, the GTPase dynamin may participate in the internalization of FSHR. (E) FSH complexed with the receptor is internalized and routed to endosomal compartments sustaining the prolonged activation of signaling cascades.
 

madman

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Screenshot (1307).png

Figure 3. Triiodothyronine (T3) counteracts the mitotic response to FSH, by inhibiting the transcription of Cdk4, via the JunD transcriptional regulator. Thus, the association of Cdk4 to FSHinduced CycD1 is hampered, and Sertoli cell mitoses cease.
 

madman

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Table 1. Clinical trials available in the literature evaluating the efficacy of follicle-stimulating hormone (FSH) in male idiopathic infertility. Studies are classified considering the study design and the therapeutic dosage applied.
Screenshot (1308).png

Screenshot (1309).png

FSH: follicle-stimulating hormone; RCT: randomized controlled clinical trial. * This study applied human chorionic gonadotropin (hCG) plus human menopausal gonadotropin (hMG). § In these studies, the control group was treated with placebos in a double-blind study design.
 
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