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The Thickness and Density of the Ovarian Tunica Albuginea Increases with Age in Transgender Patients

  • Reproductive Biology: Original Article
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Abstract

It is known that the extracellular matrix structure and composition changes with aging in many organs. Despite this, knowledge on how does the extracellular part of the ovary change with increasing age in women and how those changes might be related to women’s loss of fertility is still lacking. For this, we propose that recurrent injury and repair events on the outermost layers of the ovary due to ovulation are partly responsible for those changes women experience with aging. The histological analysis of the ovaries from 18 female-to-male transgender patients revealed that the ovarian tunica albuginea (TA) increases its thickness and density correlatively with increasing age of the patient (r = 0.52 and r = 0.55, P < 0.05 respectively). The increase in thickness is independent of the total androgen dose received and occurs because of the appearance of defined fibrotic areas underneath the TA layer which increase the total distance of dense connective tissue from the ovarian surface. In conclusion, the ovarian TA increases in its thickness and density with aging because of the appearance of fibrotic areas underneath the layer in transgender patients. This fact might contribute to reduce oocyte quality and cause ovulation difficulties in older women.

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Abbreviations

GID:

gender identity disorder

ECM:

extracellular matrix

TA:

tunica albuginea

RT:

room temperature

PSR:

picrosirius red

References

  1. Bongaarts J, Potter RG. 2 - natural fertility and its proximate determinants. In: Fertility, biology, and behavior. San Diego: Academic Press; 1983. p. 21–51. https://doi.org/10.1016/B978-0-08-091698-9.50007-5.

    Chapter  Google Scholar 

  2. Gray RH. Biological and social interactions in the determination of late fertility. J Biosoc Sci Suppl. 1979;6:97–115.

    Article  Google Scholar 

  3. Frank O, Bianchi PG, Campana A. The end of fertility: age, fecundity and fecundability in women. J Biosoc Sci. 1994;26(3):349–68.

    Article  CAS  Google Scholar 

  4. Jirge PR. Poor ovarian reserve. J Hum Reprod Sci. 2016;9(2):63–9. https://doi.org/10.4103/0974-1208.183514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Subrat P, Santa SA, Vandana J. The concepts and consequences of early ovarian ageing: a caveat to women’s health. J Reprod Infertil. 2013;14(1):3–7.

    PubMed  PubMed Central  Google Scholar 

  6. Cimadomo D, Fabozzi G, Vaiarelli A, Ubaldi N, Ubaldi FM, Rienzi L. Impact of maternal age on oocyte and embryo competence. Front Endocrinol (Lausanne). 2018;9:327. https://doi.org/10.3389/fendo.2018.00327.

    Article  Google Scholar 

  7. Briley SM, Jasti S, McCracken JM, Hornick JE, Fegley B, Pritchard MT, et al. Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction. 2016;152(3):245–60. https://doi.org/10.1530/REP-16-0129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Exbrayat J-M (2013) Histochemical and Cytochemical Methods of Visualization. Boca Raton: CRC Press. https://doi.org/10.1201/b14967.

  9. Smith RM, Woodruff TK, Shea LD. Designing follicle-environment interactions with biomaterials. Cancer Treat Res. 2010;156:11–24. https://doi.org/10.1007/978-1-4419-6518-9_2.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Phillip JM, Aifuwa I, Walston J, Wirtz D. The mechanobiology of aging. Annu Rev Biomed Eng. 2015;17:113–41. https://doi.org/10.1146/annurev-bioeng-071114-040829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. West ER, Xu M, Woodruff TK, Shea LD. Physical properties of alginate hydrogels and their effects on in vitro follicle development. Biomaterials. 2007;28(30):4439–48. https://doi.org/10.1016/j.biomaterials.2007.07.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xu M, West E, Shea LD, Woodruff TK. Identification of a stage-specific permissive in vitro culture environment for follicle growth and oocyte development. Biol Reprod. 2006;75(6):916–23. https://doi.org/10.1095/biolreprod.106.054833.

    Article  CAS  PubMed  Google Scholar 

  13. Emi Y, Adachi M, Sasaki A, Nakamura Y, Nakatsuka M. Increased arterial stiffness in female-to-male transsexuals treated with androgen. J Obstet Gynaecol Res. 2008;34(5):890–7. https://doi.org/10.1111/j.1447-0756.2008.00857.x.

    Article  PubMed  Google Scholar 

  14. Elbers JM, de Jong S, Teerlink T, Asscheman H, Seidell JC, Gooren LJ. Changes in fat cell size and in vitro lipolytic activity of abdominal and gluteal adipocytes after a one-year cross-sex hormone administration in transsexuals. Metabolism. 1999;48(11):1371–7.

    Article  CAS  Google Scholar 

  15. Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, Gooren LJ, Meyer WJ, Spack NP, et al. Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2009;94(9):3132–54. https://doi.org/10.1210/jc.2009-0345.

    Article  CAS  PubMed  Google Scholar 

  16. Ikeda K, Baba T, Noguchi H, Nagasawa K, Endo T, Kiya T, et al. Excessive androgen exposure in female-to-male transsexual persons of reproductive age induces hyperplasia of the ovarian cortex and stroma but not polycystic ovary morphology. Hum Reprod. 2013;28(2):453–61. https://doi.org/10.1093/humrep/des385.

    Article  CAS  PubMed  Google Scholar 

  17. Espey LL. Ovarian proteolytic enzymes and ovulation. Biol Reprod. 1974;10(2):216–35. https://doi.org/10.1095/biolreprod10.2.216.

    Article  CAS  PubMed  Google Scholar 

  18. Hanna MD, Chizen DR, Pierson RA. Characteristics of follicular evacuation during human ovulation. Ultrasound Obstet Gynecol. 1994;4(6):488–93. https://doi.org/10.1046/j.1469-0705.1994.04060488.x.

    Article  CAS  PubMed  Google Scholar 

  19. Colwell AS, Longaker MT, Lorenz HP. Fetal wound healing. Front Biosci. 2003;8:s1240–8. https://doi.org/10.2741/1183.

    Article  CAS  PubMed  Google Scholar 

  20. Kular JK, Basu S, Sharma RI. The extracellular matrix: structure, composition, age-related differences, tools for analysis and applications for tissue engineering. J Tissue Eng. 2014;5:2041731414557112. https://doi.org/10.1177/2041731414557112.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Jones MG, Andriotis OG, Roberts JJ, Lunn K, Tear VJ, Cao L, et al. Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis. Elife. 2018;7. https://doi.org/10.7554/eLife.36354.

  22. Jun JI, Lau LF. Resolution of organ fibrosis. J Clin Invest. 2018;128(1):97–107. https://doi.org/10.1172/JCI93563.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210. https://doi.org/10.1002/path.2277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Meirow D, Dor J, Kaufman B, Shrim A, Rabinovici J, Schiff E, et al. Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury. Hum Reprod. 2007;22(6):1626–33. https://doi.org/10.1093/humrep/dem027.

    Article  CAS  PubMed  Google Scholar 

  25. McCloskey CW, Cook DP, Kelly BS, Azzi F, Allen CH, Forsyth A, et al. Metformin abrogates age-associated ovarian fibrosis. Clin Cancer Res. 2020;26(3):632–42. https://doi.org/10.1158/1078-0432.CCR-19-0603.

    Article  CAS  PubMed  Google Scholar 

  26. Mara JN, Zhou LT, Larmore M, Johnson B, Ayiku R, Amargant F, et al. Ovulation and ovarian wound healing are impaired with advanced reproductive age. Aging (Albany NY). 2020;12(10):9686–713. https://doi.org/10.18632/aging.103237.

    Article  CAS  Google Scholar 

  27. Vanderhyden BC. Loss of ovarian function and the risk of ovarian cancer. Cell Tissue Res. 2005;322(1):117–24. https://doi.org/10.1007/s00441-005-1100-1.

    Article  PubMed  Google Scholar 

  28. Edmonds CJ, Jasani BM, Smith T. Total body potassium and body fat estimation in relationship to height, sex, age, malnutrition and obesity. Clin Sci Mol Med. 1975;48(5):431–40. https://doi.org/10.1042/cs0480431.

    Article  CAS  PubMed  Google Scholar 

  29. Wells RG. Tissue mechanics and fibrosis. Biochim Biophys Acta. 2013;1832(7):884–90. https://doi.org/10.1016/j.bbadis.2013.02.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Straub JM, New J, Hamilton CD, Lominska C, Shnayder Y, Thomas SM. Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol. 2015;141(11):1985–94. https://doi.org/10.1007/s00432-015-1974-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Woodruff TK, Shea LD. A new hypothesis regarding ovarian follicle development: ovarian rigidity as a regulator of selection and health. J Assist Reprod Genet. 2011;28(1):3–6. https://doi.org/10.1007/s10815-010-9478-4.

    Article  PubMed  Google Scholar 

  32. Spinder T, Spijkstra JJ, van den Tweel JG, Burger CW, van Kessel H, Hompes PG, et al. The effects of long term testosterone administration on pulsatile luteinizing hormone secretion and on ovarian histology in eugonadal female to male transsexual subjects. J Clin Endocrinol Metab. 1989;69(1):151–7. https://doi.org/10.1210/jcem-69-1-151.

    Article  CAS  PubMed  Google Scholar 

  33. Pache TD, Chadha S, Gooren LJ, Hop WC, Jaarsma KW, Dommerholt HB, et al. Ovarian morphology in long-term androgen-treated female to male transsexuals. A human model for the study of polycystic ovarian syndrome? Histopathology. 1991;19(5):445–52. https://doi.org/10.1111/j.1365-2559.1991.tb00235.x.

    Article  CAS  PubMed  Google Scholar 

  34. Caanen MR, Schouten NE, Kuijper EAM, van Rijswijk J, van den Berg MH, van Dulmen-den Broeder E, et al. Effects of long-term exogenous testosterone administration on ovarian morphology, determined by transvaginal (3D) ultrasound in female-to-male transsexuals. Hum Reprod. 2017;32(7):1457–64. https://doi.org/10.1093/humrep/dex098.

    Article  CAS  PubMed  Google Scholar 

  35. Kubota T. Update in polycystic ovary syndrome: new criteria of diagnosis and treatment in Japan. Reprod Med Biol. 2013;12(3):71–7. https://doi.org/10.1007/s12522-013-0145-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This research was partially supported by the Sasakawa Scientific Research Grant from The Japan Science Society (Grant number: 2020-4052).

Author information

Authors and Affiliations

  1. Assisted Reproductive Technology (ART) Center, Okayama University, Okayama, Japan

    Pilar Ferré-Pujol, Junko Otsuki, Hiroaki Funahashi & Mikiya Nakatsuka

  2. Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan

    Junko Otsuki & Hiroaki Funahashi

  3. Okayama University Medical School, Okayama, Japan

    Mikiya Nakatsuka

Authors
  1. Pilar Ferré-Pujol
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  2. Junko Otsuki
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  3. Hiroaki Funahashi
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  4. Mikiya Nakatsuka
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Contributions

PF contributed in the experimental design, performed all the histology experiments and image analysis, analyzed and interpreted all the datasets obtained, and was a major contributor in writing the manuscript.

JO contributed in the experimental design, data analysis, and the writing of the manuscript.

HF contributed in the experimental design, data analysis, and the writing of the manuscript.

MN performed the operations on all the patients, obtained and provided all the data regarding the patients’ medical history, and contributed in the writing of the manuscript.

All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Junko Otsuki or Hiroaki Funahashi.

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The authors declare that there is no conflict of interest.

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Supplementary Information

Supplementary Information 1

A In ovarian samples stained following Masson’s Trichrome method, a moderate positive linear correlation was detected between the thickness of the TA layer and the age of the patients (r = 0.76, P < 0.001). This was congruent with the results obtained when the samples were stained following the PSR method. B From left to right, the picture shows an ovarian section from a young transgender donor (21 years old) and from an older transgender donor (44 years old) stained with Masson’s trichrome method. TA tunica albuginea, r Spearman coefficient, PSR Picrosirius red. Scale bars represent 200 μm (PNG 4361 kb).

High resolution image (TIF 444 kb).

Supplementary Information 2

Image composition depicting one representative ovarian section per each of the 18 patients participating in the study, organized by increasing age, from the lowest to the greatest. Scale bars represent 400 μm (PNG 7303 kb).

High resolution image (TIF 1921 kb).

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Ferré-Pujol, P., Otsuki, J., Funahashi, H. et al. The Thickness and Density of the Ovarian Tunica Albuginea Increases with Age in Transgender Patients. Reprod. Sci. 28, 1339–1346 (2021). https://doi.org/10.1007/s43032-020-00390-5

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  • DOI: https://doi.org/10.1007/s43032-020-00390-5

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