Presence of ovarian stromal aberrations after cessation of testosterone therapy in a transgender mouse model†

Hadrian M Kinnear; Prianka H Hashim; Cynthia Dela Cruz; Faith L Chang; Gillian Rubenstein; Likitha Nimmagadda; Venkateswaran Ramamoorthi Elangovan; Andrea Jones; Margaret A Brunette; D Ford Hannum; Jun Z Li; Vasantha Padmanabhan; Molly B Moravek; Ariella Shikanov

doi:10.1093/biolre/ioad019

Presence of ovarian stromal aberrations after cessation of testosterone therapy in a transgender mouse model†

Biol Reprod. 2023 May 10;108(5):802-813. doi: 10.1093/biolre/ioad019.

Authors

Hadrian M Kinnear^{1

2}, Prianka H Hashim³, Cynthia Dela Cruz³, Faith L Chang⁴, Gillian Rubenstein⁵, Likitha Nimmagadda⁴, Venkateswaran Ramamoorthi Elangovan⁶, Andrea Jones⁴, Margaret A Brunette⁴, D Ford Hannum⁷, Jun Z Li⁷, Vasantha Padmanabhan^{3

6}, Molly B Moravek^{3

8

9}, Ariella Shikanov^{1

3

4}

Affiliations

¹ Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA.
² Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
³ Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁵ Women's and Gender Studies Department, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁸ Division of Reproductive Endocrinology and Infertility, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Urology, University of Michigan, Ann Arbor, MI, USA.

Abstract

Some transmasculine individuals may be interested in pausing gender-affirming testosterone therapy and carrying a pregnancy. The ovarian impact of taking and pausing testosterone is not completely understood. The objective of this study was to utilize a mouse model mimicking transmasculine testosterone therapy to characterize the ovarian dynamics following testosterone cessation. We injected postpubertal 9-10-week-old female C57BL/6N mice once weekly with 0.9 mg of testosterone enanthate or a vehicle control for 6 weeks. All testosterone-treated mice stopped cycling and demonstrated persistent diestrus within 1 week of starting testosterone, while control mice cycled regularly. After 6 weeks of testosterone therapy, one group of testosterone-treated mice and age-matched vehicle-treated diestrus controls were sacrificed. Another group of testosterone-treated mice were maintained after stopping testosterone therapy and were sacrificed in diestrus four cycles after the resumption of cyclicity along with age-matched vehicle-treated controls. Ovarian histological analysis revealed stromal changes with clusters of large round cells in the post testosterone group as compared to both age-matched controls and mice at 6 weeks on testosterone. These clusters exhibited periodic acid-Schiff staining, which has been previously reported in multinucleated macrophages in aging mouse ovaries. Notably, many of these cells also demonstrated positive staining for macrophage markers CD68 and CD11b. Ovarian ribonucleic acid-sequencing found upregulation of immune pathways post testosterone as compared to age-matched controls and ovaries at 6 weeks on testosterone. Although functional significance remains unknown, further attention to the ovarian stroma may be relevant for transmasculine people interested in pausing testosterone to carry a pregnancy.

Keywords: immune; macrophage; mouse; ovary; stroma; testosterone; transgender.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Female
Humans
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Ovary* / metabolism
Pregnancy
Testosterone / metabolism
Transgender Persons*

Substances

Testosterone

Abstract

Publication types

MeSH terms

Substances

Grants and funding