Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries
Abstract
To test the hypothesis that the hyperandrogenemia associated with polycystic ovary syndrome (PCOS) results from an intrinsic abnormality in ovarian theca cell steroidogenesis, we examined steroid hormone production, steroidogenic enzyme activity, and mRNA expression in normal and PCOS theca cells propagated in long-term culture. Progesterone (P4), 17alpha-hydroxyprogesterone (17OHP4), and testosterone (T) production per cell were markedly increased in PCOS theca cell cultures. Moreover, basal and forskolin-stimulated pregnenolone, P4, and dehydroepiandrosterone metabolism were increased dramatically in PCOS theca cells. PCOS theca cells were capable of substantial metabolism of precursors into T, reflecting expression of an androgenic 17beta-hydroxysteroid dehydrogenase. Forskolin-stimulated cholesterol side chain cleavage enzyme (CYP11A) and 17alpha-hydroxylase/17,20-desmolase (CYP17) expression were augmented in PCOS theca cells compared with normal cells, whereas no differences were found in steroidogenic acute regulatory protein mRNA expression. Collectively, these observations establish that increased CYP11A and CYP17 mRNA expression, as well as increased CYP17, 3beta-hydroxysteroid dehydrogenase, and 17beta-hydroxysteroid dehydrogenase enzyme activity per theca cell, and consequently increased production of P4, 17OHP4, and T, are stable properties of PCOS theca cells. These findings are consistent with the notion that there is an intrinsic alteration in the steroidogenic activity of PCOS thecal cells that encompasses multiple steps in the biosynthetic pathway.
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Available data document constitutively increased androgen production and CYP17A1 expression in cultured theca cells isolated from PCOS ovaries.
“Available data document constitutively increased androgen production and CYP17A1 expression in cultured theca cells isolated from PCOS ovaries [24–26].”
From Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls (2019) · cites this paper as [26]
Cites
Franks, S. (1995) · New England Journal of Medicine · doi:10.1056/nejm199509283331307 · Cited by 2,463 · see citing works
Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome
Legro, R. S., Driscoll, D., Strauss, J. F., Fox, J., & Dunaif, A. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14956 · Cited by 699 · see citing works
Self-citationREVIEW ARTICLE: THE POLYCYSTIC OVARY SYNDROME
Yen, S. S. C. (1980) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1980.tb02132.x · Cited by 697 · see citing works
Barbieri, R. L., Makris, A., Randall, R. W., Daniels, G. H., Kistner, R. W., & Ryan, K. J. (1986) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-62-5-904 · Cited by 629 · see citing works
Nestler, J. E., Jakubowicz, D. J., Falcon de Vargas, A., Brik, C., Quintero, N., & Medina, F. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.6.4886 · Cited by 617 · see citing works
The Ovarian Androgen Producing Cells: A Review of Structure/Function Relationships1,2
Erickson, G. F., Magoffin, D. A., Dyer, C. A., & Hofeditz, C. (1985) · Endocrine Reviews · doi:10.1210/edrv-6-3-371 · Cited by 569 · see citing works
Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries
Gilling‐Smith, C., Willis, D., Beard, R. W., & Franks, S. (1994) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.79.4.7962289 · Cited by 436 · see citing works
The Polycystic Ovary. I. Clinical and Histologic Features
Goldzieher, J. W., & Green, J. (1962) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-22-3-325 · Cited by 369 · see citing works
McNATTY, K. P., MAKRIS, A., DEGRAZIA, C., RAPIN, O., & RYAN, K. J. (1979) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-49-5-687 · Cited by 367 · see citing works
Pituitary-Ovarian Responses to Nafarelin Testing in the Polycystic Ovary Syndrome
Barnes, R. B., Rosenfield, R. L., Burstein, S., & Ehrmann, D. A. (1989) · New England Journal of Medicine · doi:10.1056/nejm198903023200904 · Cited by 308 · see citing works
Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome
Gilling‐Smith, C., Story, H., Rogers, V., & Franks, S. (1997) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1997.2321049.x · Cited by 301 · see citing works
Wallach, E. E., & Goldzieher, J. W. (1981) · Fertility and Sterility · doi:10.1016/s0015-0282(16)45429-4 · Cited by 296 · see citing works
The genetic basis of polycystic ovary syndrome
Franks, S., Gharani, N., Waterworth, D. M., Batty, S., White, D. M., Williamson, R., & McCarthy, M. I. (1997) · Human Reproduction · doi:10.1093/humrep/12.12.2641 · Cited by 289 · see citing works
ERICKSO, G. F., Hsueh, A. J. W., QUIGLEY, M. E., Rebar, R. W., & Yen, S. S. C. (1979) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-49-4-514 · Cited by 250 · see citing works
Dysregulation of cytochrome P450c17α as the cause of polycystic ovarian syndrome
Rl, R., Barnes, R., Cara, J., & Lucky, A. W. (1991) · International Journal of Gynecology & Obstetrics · doi:10.1016/0020-7292(91)90373-d · Cited by 222 · see citing works
Granulosa cells of polycystic ovaries: are they normal or abnormal?
Erickson, G. F., Magoffin, D. A., Garzo, V. G., Cheung, A. P., & Chang, R. J. (1992) · Human Reproduction · doi:10.1093/oxfordjournals.humrep.a137638 · Cited by 162 · see citing works
Insulin regulation of human ovarian androgens
Nestler, J. E. (1997) · Human Reproduction · doi:10.1093/humrep/12.suppl_1.53 · Cited by 161 · see citing works
Erickson, G. F., Magoffin, D. A., Cragun, J. R., & Chang, R. J. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-70-4-894 · Cited by 157 · see citing works
Expression of steroidogenic acute regulatory protein (StAR) in the human ovary
Kiriakidou, M., McAllister, J. M., Sugawara, T., & Strauss, J. F. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.11.8923870 · Cited by 152 · see citing works
Self-citationPhenotype and genotype in polycystic ovary syndrome
Legro, R. S. (2001) · Cambridge University Press eBooks · doi:10.1017/cbo9780511545191.003 · Cited by 147 · see citing works
Self-citationMoon, Y. S., Tsang, B. K., SIMPSON, C., & Armstrong, D. T. (1978) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-47-2-263 · Cited by 144 · see citing works
Jakubowicz, D. J., & Nestler, J. E. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.2.3753 · Cited by 137 · see citing works
McAllister, J. M., Byrd, W. E., & Simpson, E. R. (1994) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.79.1.8027214 · Cited by 69 · see citing works
Self-citationMcAllister, J. M., Kerin, J. F., Trant, J. M., Estabrook, R. W., Mason, J. I., Waterman, M. R., & Simpson, E. R. (1989) · Endocrinology · doi:10.1210/endo-125-4-1959 · Cited by 68 · see citing works
Self-citationMason, H. D., Margara, R. A., Winston, R. M. L., Beard, R. W., Reed, M. J., & Franks, S. (1990) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1990.tb03888.x · Cited by 65 · see citing works
McAllister, J. M., Mason, J. I., BYRD, W., Trant, J. M., Waterman, M. R., & Simpson, E. R. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-71-1-26 · Cited by 51 · see citing works
Self-citationHuman ovarian expression of 17 beta-hydroxysteroid dehydrogenase types 1, 2, and 3
ZHANG, Y. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.81.10.3594 · Cited by 48 · see citing works
Franks, S., & Mason, H. D. (1991) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(91)90208-m · Cited by 19 · see citing works
Tamura, T., Kitawaki, J., Yamamoto, T., et al. (1993) · Journal of Endocrinology · doi:10.1677/joe.0.1390503 · Cited by 18 · see citing works
Functional, long-term human theca and granulosa cell cultures from polycystic ovaries
McAllister, J. M. (1995) · Endocrine · doi:10.1007/bf02990066 · Cited by 12 · see citing works
Self-citationThe polycystic ovary syndrome: nature or nurture?
Ben‐Shlomo, I., Franks, S., & Adashi, E. Y. (1995) · Fertility and Sterility · doi:10.1016/s0015-0282(16)57529-3 · Cited by 12 · see citing works
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- Authors
- Nelson, V. L., Legro, R. S., Strauss, J. F., & McAllister, J. M.
- Affiliations
- Pennsylvania State University (US)
- University of Pennsylvania (US)
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1999-06
- Volume
- 13
- Issue
- 6
- Pages
- 946-957
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W1995994721
- Cited by
- 556
- References
- 31
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 22 · 2023: 25 · 2022: 27 · 2021: 24 · 2020: 24 · 2019: 30 · 2018: 21 · 2017: 16 · 2016: 23 · 2015: 25 · 2014: 24 · 2013: 26 · 2012: 21
- FWCI
- 13.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54-HD34449, R01HD33852, R01HD033852, U54HD034449)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- polycystic ovary syndrome, theca cells, steroidogenesis, hyperandrogenemia, progesterone, testosterone, 17-hydroxyprogesterone, CYP11A, CYP17, 17β-hydroxysteroid dehydrogenase, 3β-hydroxysteroid dehydrogenase, steroidogenic enzymes, steroidogenic acute regulatory protein, long-term cell culture
- MeSH terms
- Steroidogenic Acute Regulatory Protein, Adult, Androgens, Cells, Cultured, Cholesterol Side-Chain Cleavage Enzyme, Dehydroepiandrosterone, Female, Colforsin, Gene Expression Regulation, Humans, Phenotype, Phosphoproteins, Polycystic Ovary Syndrome, Pregnenolone, Progesterone, Reference Values, Steroid 17-alpha-Hydroxylase, Theca Cells, 17-Hydroxysteroid Dehydrogenases
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