The Ovarian Stroma As a New Frontier

Overview

Journal Reproduction

Specialty Reproductive Medicine

Date 2020 Jul 28

PMID 32716007

Citations 88

Authors

Hadrian M Kinnear

Claire E Tomaszewski

Alexis L Chang

Molly B Moravek

Min Xu

Vasantha Padmanabhan

Ariella Shikanov

Affiliations

Soon will be listed here.

Abstract

Historically, research in ovarian biology has focused on folliculogenesis, but recently the ovarian stroma has become an exciting new frontier for research, holding critical keys to understanding complex ovarian dynamics. Ovarian follicles, which are the functional units of the ovary, comprise the ovarian parenchyma, while the ovarian stroma thus refers to the inverse or the components of the ovary that are not ovarian follicles. The ovarian stroma includes more general components such as immune cells, blood vessels, nerves, and lymphatic vessels, as well as ovary-specific components including ovarian surface epithelium, tunica albuginea, intraovarian rete ovarii, hilar cells, stem cells, and a majority of incompletely characterized stromal cells including the fibroblast-like, spindle-shaped, and interstitial cells. The stroma also includes ovarian extracellular matrix components. This review combines foundational and emerging scholarship regarding the structures and roles of the different components of the ovarian stroma in normal physiology. This is followed by a discussion of key areas for further research regarding the ovarian stroma, including elucidating theca cell origins, understanding stromal cell hormone production and responsiveness, investigating pathological conditions such as polycystic ovary syndrome (PCOS), developing artificial ovary technology, and using technological advances to further delineate the multiple stromal cell types.

Citing Articles

Ultrasound Assessment in Polycystic Ovary Syndrome Diagnosis: From Origins to Future Perspectives-A Comprehensive Review.

Di Michele S, Fulghesu A, Pittui E, Cordella M, Sicilia G, Mandurino G Biomedicines. 2025; 13(2).

PMID: 40002866 PMC: 11853298. DOI: 10.3390/biomedicines13020453.

Metabolic control of ovarian function through the sympathetic nervous system: role of leptin.

Astudillo-Guerrero C, Paredes A, Escobar J, Fernandois D, Barra R, Cruz G Front Endocrinol (Lausanne). 2025; 15:1484939.

PMID: 39963180 PMC: 11830616. DOI: 10.3389/fendo.2024.1484939.

Single-cell RNA sequencing reveals the intercellular crosstalk and the regulatory landscape of stromal cells during the whole life of the mouse ovary.

Jiang W, Sun W, Peng Y, Xu H, Fan H, Jin X Life Med. 2025; 3(6):lnae041.

PMID: 39872151 PMC: 11748273. DOI: 10.1093/lifemedi/lnae041.

Black Garlic Extract Modulates Endothelin Expression and Ovulatory Function in Monosodium Glutamate Treated Rats.

Gezer A, Yediel Aras S, Ozkaraca M, Kilic Baygutalp N, Gundogdu G, Karadag Sari E Food Sci Nutr. 2025; 13(1):e4766.

PMID: 39830904 PMC: 11742640. DOI: 10.1002/fsn3.4766.

Single-Cell RNA Sequencing Reveals That C5AR1 in Follicle Monocyte Cells Could Predict the Development of POI.

Han Y, Diao J, Wang X, Zhang S, Yuan L, Ping Y J Inflamm Res. 2024; 17:11221-11234.

PMID: 39717665 PMC: 11664250. DOI: 10.2147/JIR.S490996.

References

Jabara S, Christenson L, Wang C, McAllister J, Javitt N, Dunaif A . Stromal cells of the human postmenopausal ovary display a distinctive biochemical and molecular phenotype. J Clin Endocrinol Metab. 2003; 88(1):484-92. DOI: 10.1210/jc.2002-021274. View

MATOUSEK M, Carati C, Gannon B, Brannstrom M . Novel method for intrafollicular pressure measurements in the rat ovary: increased intrafollicular pressure after hCG stimulation. Reproduction. 2001; 121(2):307-14. DOI: 10.1530/rep.0.1210307. View

Spinder T, Spijkstra J, van den Tweel J, Burger C, van Kessel H, Hompes P . 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. DOI: 10.1210/jcem-69-1-151. View

Rowley J, Amargant F, Zhou L, Galligos A, Simon L, Pritchard M . Low Molecular Weight Hyaluronan Induces an Inflammatory Response in Ovarian Stromal Cells and Impairs Gamete Development In Vitro. Int J Mol Sci. 2020; 21(3). PMC: 7036885. DOI: 10.3390/ijms21031036. View

Brown H, Russell D . Blood and lymphatic vasculature in the ovary: development, function and disease. Hum Reprod Update. 2013; 20(1):29-39. DOI: 10.1093/humupd/dmt049. View

Johnson J, Canning J, Kaneko T, Pru J, Tilly J . Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004; 428(6979):145-50. DOI: 10.1038/nature02316. View

Berkholtz C, Shea L, Woodruff T . Extracellular matrix functions in follicle maturation. Semin Reprod Med. 2006; 24(4):262-9. PMC: 2648384. DOI: 10.1055/s-2006-948555. View

Belosi C, Selvaggi L, Apa R, Guido M, Romualdi D, Fulghesu A . Is the PCOS diagnosis solved by ESHRE/ASRM 2003 consensus or could it include ultrasound examination of the ovarian stroma?. Hum Reprod. 2006; 21(12):3108-15. DOI: 10.1093/humrep/del306. View

Pepe G, Locati M, Della Torre S, Mornata F, Cignarella A, Maggi A . The estrogen-macrophage interplay in the homeostasis of the female reproductive tract. Hum Reprod Update. 2018; 24(6):652-672. DOI: 10.1093/humupd/dmy026. View

10.

Scott J, Carlsson I, Bavister B, Hovatta O . Human ovarian tissue cultures: extracellular matrix composition, coating density and tissue dimensions. Reprod Biomed Online. 2004; 9(3):287-93. DOI: 10.1016/s1472-6483(10)62143-8. View

11.

Liu R, Zhang X, Fan Z, Wang Y, Yao G, Wan X . Human amniotic mesenchymal stem cells improve the follicular microenvironment to recover ovarian function in premature ovarian failure mice. Stem Cell Res Ther. 2019; 10(1):299. PMC: 6775662. DOI: 10.1186/s13287-019-1315-9. View

12.

Zhang Y, Yan Z, Qin Q, Nisenblat V, Chang H, Yu Y . Transcriptome Landscape of Human Folliculogenesis Reveals Oocyte and Granulosa Cell Interactions. Mol Cell. 2018; 72(6):1021-1034.e4. DOI: 10.1016/j.molcel.2018.10.029. View

13.

Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S . Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci U S A. 2013; 110(43):17474-9. PMC: 3808580. DOI: 10.1073/pnas.1312830110. View

14.

Wu R, Fujii S, Ryan N, Van der Hoek K, Jasper M, Sini I . Ovarian leukocyte distribution and cytokine/chemokine mRNA expression in follicular fluid cells in women with polycystic ovary syndrome. Hum Reprod. 2006; 22(2):527-35. DOI: 10.1093/humrep/del371. View

15.

Kaaijk E, Sasano H, Suzuki T, Beek J, van der Veen F . Distribution of steroidogenic enzymes involved in androgen synthesis in polycystic ovaries: an immunohistochemical study. Mol Hum Reprod. 2000; 6(5):443-7. DOI: 10.1093/molehr/6.5.443. View

16.

Di Pietro M, Pascuali N, Parborell F, Abramovich D . Ovarian angiogenesis in polycystic ovary syndrome. Reproduction. 2018; 155(5):R199-R209. DOI: 10.1530/REP-17-0597. View

17.

Rotgers E, Jorgensen A, Hung-Chang Yao H . At the Crossroads of Fate-Somatic Cell Lineage Specification in the Fetal Gonad. Endocr Rev. 2018; 39(5):739-759. PMC: 6173476. DOI: 10.1210/er.2018-00010. View

18.

Suzuki T, Sasano H, Takaya R, Fukaya T, Yajima A, Date F . Leukocytes in normal-cycling human ovaries: immunohistochemical distribution and characterization. Hum Reprod. 1998; 13(8):2186-91. DOI: 10.1093/humrep/13.8.2186. View

19.

Zhang Z, Schlamp F, Huang L, Clark H, Brayboy L . Inflammaging is associated with shifted macrophage ontogeny and polarization in the aging mouse ovary. Reproduction. 2020; 159(3):325-337. PMC: 7066623. DOI: 10.1530/REP-19-0330. View

20.

Briley S, Jasti S, McCracken J, Hornick J, Fegley B, Pritchard M . Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction. 2016; 152(3):245-260. PMC: 4979755. DOI: 10.1530/REP-16-0129. View