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Commentary: FSH and various forms of FSH receptors: distribution and their functions in gonads and extra-gonadal tissues

The Original Article was published on 30 October 2021

The Original Article was published on 30 October 2021

FSH is central to reproduction and regulates ovarian production of steroid hormones which in turn regulate endometrial growth/receptivity/regeneration/remodeling. However, these well defined boundaries of the 70s and 80s are now blurring with steroid hormone receptors being reported in the hematopoietic system and FSHR on several extragonadal sites including cancers in multiple tissues [1], and in the endometrium, myometrium, cervix, and placental [2] and hematopoietic system [3, 4]. Female patients being subjected to FSH therapy for stimulating their ovaries show effective mobilization of stem cells in their peripheral blood [5].

Bhartiya’s group reported that FSH treatment enhanced hematopoiesis in the bone marrow by almost 72 h in 5-FU treated mice [6]. How does FSH exerts its pleiotropic effects? What is the significance of FSHR3 and how significant it is functionally compared to the canonical FSHR1? Ovarian cancer cells do not exhibit cAMP signaling upon treatment with FSH [7].

Ratajczak and Bhartiya groups have published data to show FSHR expression on very-small embryonic-like stem cells (VSCLs) [4, 8] in reproductive tissues and surprisingly FSH treatment upregulated alternately spliced FSHR3 more significantly compared to the canonical FSHR1. Similarly, Sullivan et al. [9] reported FSHR3 to be the predominant isoform in sheep ovaries. It did not come as a surprise to see a special issue focused on different facets of FSH/FSHR biology published in 2020 wherein experts raised several concerns regarding extragonadal expression of FSHR [10]. They doubt the results and think these to be due to technical shortfalls [11].

Currently held belief written in golden letters in reproductive biology textbooks is the fact that initial follicle growth is gonadotropin independent and FSHR are not expressed on primordial follicles and that FSH acts on granulosa cells in the ovaries and Sertoli cells in the testes [12].

Bhartiya’s group points this as a ‘misconcept’ and points out this discrepancy has surfaced because of initial studies used only FSHR1 specific primers to detect FSHR in various types of follicles which will not detect FSHR3.

We are pleased to publish two review articles in the Journal of Ovarian Research on FSH/FSHR biology authored by Bhartiya’s group from ICMR-National Institute for Research in Reproductive Health, Mumbai, INDIA. The group has attempted to provide explanation to various concerns raised by Rahman’s group [11]. Since these articles question several basic existing paradigms in the field of reproductive biology including ovarian biology, further discussions and comments will be welcome and we will be pleased to publish in JOVR.

References

  1. Radu A, Pichon C, Camparo P, Antoine M, Allory Y, Couvelard A, et al. Expression of follicle-stimulating hormone receptor in tumor blood vessels. N Engl J Med. 2010;363(17):1621–30.

    CAS  Article  Google Scholar 

  2. Stilley JA, Christensen DE, Dahlem KB, Guan R, Santillan DA, England SK, et al. FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice. Biol Reprod. 2014;91(3):74.

    Article  Google Scholar 

  3. Ratajczak MZ. Why are hematopoietic stem cells so 'sexy'? On a search for developmental explanation. Leukemia. 2017;31(8):1671–7.

    CAS  Article  Google Scholar 

  4. Mierzejewska K, Borkowska S, Suszynska E, Suszynska M, Poniewierska-Baran A, Maj M, et al. Hematopoietic stem/progenitor cells express several functional sex hormone receptors-novel evidence for a potential developmental link between hematopoiesis and primordial germ cells. Stem Cells Dev. 2015;24(8):927–37.

    CAS  Article  Google Scholar 

  5. Zbucka-Kretowska M, Eljaszewicz A, Lipinska D, Grubczak K, Rusak M, Mrugacz G, et al. Effective mobilization of very small embryonic-like stem cells and hematopoietic stem/progenitor cells but not endothelial progenitor cells by follicle-stimulating hormone therapy. Stem Cells Int. 2016;2016:8530207.

    Article  Google Scholar 

  6. Shaikh A, Bhartiya D, Kapoor S, Nimkar H. Delineating the effects of 5-fluorouracil and follicle-stimulating hormone on mouse bone marrow stem/progenitor cells. Stem Cell Res Ther. 2016;7(1):59.

    Article  Google Scholar 

  7. Li Y, Ganta S, Cheng C, Craig R, Ganta R, Freeman LC. FSH stimulates ovarian cancer cell growth by action on growth factor variant receptor. Mol Cell Endocrinol. 2007;267(1-2):26–37.

    CAS  Article  Google Scholar 

  8. Sriraman K, Bhartiya D, Anand S, Bhutda S. Mouse ovarian very small embryonic-like stem cells resist chemotherapy and retain ability to initiate oocyte-specific differentiation. Reprod Sci. 2015;22(7):884–903.

    CAS  Article  Google Scholar 

  9. Sullivan RR, Faris BR, Eborn D, Grieger DM, Cino-Ozuna AG, Rozell TG. Follicular expression of follicle stimulating hormone receptor variants in the ewe. Reprod Biol Endocrinol. 2013;11:113.

    Article  Google Scholar 

  10. Simoni M, Huhtaniemi I, Santi D, Casarini L. Editorial: follicle-stimulating hormone: fertility and beyond. Front Endocrinol (Lausanne). 2019;10:610.

    Article  Google Scholar 

  11. Chrusciel M, Ponikwicka-Tyszko D, Wolczynski S, Huhtaniemi I, Rahman NA. Extragonadal FSHR expression and function—is it real? Front Endocrinol. 2019;10:32.

    Article  Google Scholar 

  12. Coss D. Commentary on the recent FSH collection: known Knowns and known unknowns. Endocrinology. 2020;161(1):bqz035.

    Article  Google Scholar 

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Acknowledgements

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Funding

This work was supported by NIH grant T32 HL134644 to SSK and MZR.

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Both SSK and MZR reviewed the both the review articles published by Dr. Bhartiya in the Journal of Ovarian Research and wrote the commentary. The author(s) read and approved the final manuscript.

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Correspondence to Sham S. Kakar.

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Kakar, S.S., Ratajczak, M.Z. Commentary: FSH and various forms of FSH receptors: distribution and their functions in gonads and extra-gonadal tissues. J Ovarian Res 14, 146 (2021). https://doi.org/10.1186/s13048-021-00893-y

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