Insulin Stimulates Testosterone Biosynthesis by Human Thecal Cells from Women with Polycystic Ovary Syndrome by Activating Its Own Receptor and Using Inositolglycan Mediators as the Signal Transduction System1
Abstract
To determine whether insulin stimulates human ovarian testosterone production in the polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system, thecal cells from polycystic ovary syndrome women were isolated and cultured. Insulin and insulin-like growth factor I stimulated thecal testosterone biosynthesis. Antibody blockade of the insulin receptor abolished insulin's stimulatory action, whereas effective antibody blockade of the insulin-like growth factor I receptor did not alter insulin's stimulation of thecal testosterone biosynthesis. A chiro-inositol containing glycan (INS-2) increased thecal testosterone biosynthesis. Preincubation of cells with an antiinositolglycan antibody (A23939 or alpha IGP) abolished insulin's stimulatory effect, but not that of hCG. These findings suggest that inositolglycans serve as the signal transduction system for insulin's stimulation of human thecal testosterone biosynthesis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
At the pituitary level, insulin stimulates LH secretion, which, in association with insulin itself, acts synergistically on theca cells, increasing androgen biosynthesis.
“Furthermore, at pituitary level, insulin stimulates LH secretion, which, in association with insulin itself, acts synergistically on theca cells, increasing androgen biosynthesis [4, 23].”
From From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management (2020) · cites this paper as [4]
Insulin directly stimulates androgen production from ovaries, enhancing the activity of CYP17α and other steroidogenic enzymes with increased androgen production.
“Insulin in fact directly stimulates androgen production from ovaries, enhancing the activity of CYP17α and other steroidogenic enzymes with increased androgen production.”
From From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management (2020) · cites this paper as [4]
Insulin inhibits hepatic synthesis of SHBG and secretion of IGFBP-1, resulting in elevated levels of free IGF and androgens.
“It also inhibits the hepatic synthesis of SHBG and the secretion of the insulin-like growth factor-binding protein (IGFBP-1) resulting in elevated levels of free IGF and androgens.”
From From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management (2020) · cites this paper as [4]
Insulin resistance results in hyperinsulinemia, which has a central role in the pathogenesis of androgen excess in PCOS.
“The result of IR is hyperinsulinemia, which has a central role in the pathogenesis of androgen excess in PCOS.”
From From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management (2020) · cites this paper as [4]
Cites
Velazquez, E. M., Mendoza, S., Hamer, T., Sosa, F., & Glueck, C. J. (1994) · Metabolism · doi:10.1016/0026-0495(94)90209-7 · Cited by 865 · see citing works
Franks, S. (1997) · Archives of Disease in Childhood · doi:10.1136/adc.77.1.89 · Cited by 802 · see citing works
Nestler, J. E., & Jakubowicz, D. J. (1996) · New England Journal of Medicine · doi:10.1056/nejm199608293350902 · Cited by 743 · see citing works
Self-citationBarbieri, 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
Dunaif, A. E., Scott, D., Finegood, D. T., Quintana, B., & Whitcomb, R. W. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.9.8784087 · Cited by 530 · see citing works
New chromosome techniques in the study of human neoplasia
Yunis, J. J. (1981) · Human Pathology · doi:10.1016/s0046-8177(81)80068-8 · Cited by 311 · see citing works
On the Paradox of Insulin-Induced Hyperandrogenism in Insulin-Resistant States
Poretsky, L. (1991) · Endocrine Reviews · doi:10.1210/edrv-12-1-3 · Cited by 258 · see citing works
Willis, D., & Franks, S. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.80.12.8530637 · Cited by 203 · see citing works
Phosphatidylinositol-Glycan Anchors of Membrane Proteins: Potential Precursors of Insulin Mediators
Romero, G. G., Luttrell, L. M., Rogol, A. D., et al. (1988) · Science · doi:10.1126/science.3282305 · Cited by 198 · see citing works
Metabolic regulation of androgen production by human thecal cells in vitro
Nahum, R., Thong, K. J., & Hillier, S. G. (1995) · Human Reproduction · doi:10.1093/humrep/10.1.75 · Cited by 172 · see citing works
Second Messengers of Insulin Action
Saltiel, A. R. (1990) · Diabetes Care · doi:10.2337/diacare.13.3.244 · Cited by 148 · see citing works
Polycystic ovarian disease: US features in 104 patients.
Yeh, H., Futterweit, W., & Thornton, J. C. (1987) · Radiology · doi:10.1148/radiology.163.1.3547491 · Cited by 140 · 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
Self-citationRoth, R. A., Cassell, D. J., Wong, K. Y., Maddux, B. A., & Goldfine, I. D. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.23.7312 · Cited by 120 · see citing works
Larner, J. (1988) · Diabetes · doi:10.2337/diab.37.3.262 · Cited by 97 · see citing works
Romero, G. G., Gámez, G., Huang, L. C., et al. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.4.1476 · Cited by 83 · see citing works
Richards, J. S., & Kersey, K. A. (1979) · Biology of Reproduction · doi:10.1095/biolreprod21.5.1185 · Cited by 76 · see citing works
Nestler, J. E., Romero, G. G., HUANG, L. C., ZHANG, C., & Larner, J. (1991) · Endocrinology · doi:10.1210/endo-129-6-2951 · Cited by 50 · see citing works
Self-citationFonteles, M., Huang, L.-C., & Larner, J. (1996) · Diabetologia · doi:10.1007/bf00418546 · Cited by 45 · see citing works
Mediators of postreceptor action of insulin
Larner, J. (1983) · The American Journal of Medicine · doi:10.1016/0002-9343(83)90653-8 · Cited by 41 · see citing works
Romero, G. G., Garmey, J. C., & Veldhuis, J. D. (1993) · Endocrinology · doi:10.1210/endo.132.4.8462454 · Cited by 29 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Azziz, R., Carmina, E., Dewailly, D., Diamanti-Kandarakis, E., Escobar-Morreale, H. F., Futterweit, W., Janssen, O. E., Legro, R. S., Norman, R. J., Taylor, A. E., et al. (2009) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.06.035 · Cited by 2,132 · see citing works
Polycystic Ovary Syndrome: Definition, Aetiology, Diagnosis and Treatment
Escobar-Morreale, H. F. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2018.24 · Cited by 2,083 · see citing works
Diamanti-Kandarakis, E., & Dunaif, A. (2012) · Endocrine Reviews · doi:10.1210/er.2011-1034 · Cited by 1,947 · see citing works
Azziz, R., Carmina, E., Chen, Z., Dunaif, A., Laven, J. S. E., Legro, R. S., Lizneva, D., Natterson-Horowtiz, B., Teede, H. J., & Yildiz, B. O. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.57 · Cited by 2,005 · see citing works
Rosenfield, R. L., & Ehrmann, D. A. (2016) · Endocrine Reviews · doi:10.1210/er.2015-1104 · Cited by 1,603 · see citing works
Dumesic, D. A., Oberfield, S. E., Stener-Victorin, E., Marshall, J. C., Laven, J. S., & Legro, R. S. (2015) · Endocrine Reviews · doi:10.1210/er.2015-1018 · Cited by 1,020 · see citing works
Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus
Foretz, M., Guigas, B., & Viollet, B. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0242-2 · Cited by 686 · see citing works
DeUgarte, C. M., Bartolucci, A. A., & Azziz, R. (2005) · Fertility and Sterility · doi:10.1016/j.fertnstert.2004.11.070 · Cited by 589 · see citing works
Nelson, V. L., Legro, R. S., Strauss, J. F., & McAllister, J. M. (1999) · Molecular Endocrinology · doi:10.1210/mend.13.6.0311 · Cited by 556 · see citing works
Genetic, hormonal and metabolic aspects of PCOS: an update
De Leo, V., Musacchio, M. C., Cappelli, V., Massaro, M. G., Morgante, G., & Petraglia, F. (2016) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-016-0173-x · Cited by 484 · see citing works
Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus
Ovalle, F., & Azziz, R. (2002) · Fertility and Sterility · doi:10.1016/s0015-0282(02)03111-4 · Cited by 428 · see citing works
Zhao, H., Zhang, J., Cheng, X., Nie, X., & He, B. (2023) · Journal of Ovarian Research · doi:10.1186/s13048-022-01091-0 · Cited by 408 · see citing works
Metformin for the treatment of the polycystic ovary syndrome
Nestler, J. E. (2008) · New England Journal of Medicine · doi:10.1056/nejmct0707092 · Cited by 313 · see citing works
Self-citationMolecular mechanisms of insulin resistance in polycystic ovary syndrome
Diamanti-Kandarakis, E., & Papavassiliou, A. G. (2006) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2006.05.006 · Cited by 301 · see citing works
Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome
Lewy, V. D., Danadian, K., Witchel, S. F., & Arslanian, S. (2001) · The Journal of Pediatrics · doi:10.1067/mpd.2001.109603 · Cited by 298 · see citing works
Polycystic ovarian syndrome: Pathophysiology, molecular aspects and clinical implications
Diamanti-Kandarakis, E. (2008) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399408000598 · Cited by 294 · see citing works
Arslanian, S. A., Lewy, V., Danadian, K., & Saad, R. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.4.8398 · Cited by 272 · see citing works
Sir-Petermann, T., Codner, E., Pérez, V., Echiburú, B., Maliqueo, M., Ladrón de Guevara, A., Preisler, J., Crisosto, N., Sánchez, F., Cassorla, F., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2836 · Cited by 260 · see citing works
Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype
McAllister, J. M., Modi, B., Miller, B. A., Biegler, J., Bruggeman, R., Legro, R. S., & Strauss, J. F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1400574111 · Cited by 250 · see citing works
The Effects of a Low-Carbohydrate, Ketogenic Diet on the Polycystic Ovary Syndrome: A Pilot Study
Mavropoulos, J. C., Yancy, W. S., Hepburn, J., & Westman, E. C. (2005) · Nutrition & Metabolism · doi:10.1186/1743-7075-2-35 · Cited by 226 · see citing works
Metabolic Syndrome and PCOS: Pathogenesis and the Role of Metabolites
Chen, W., & Pang, Y. (2021) · Metabolites · doi:10.3390/metabo11120869 · Cited by 228 · see citing works
Farrell, K., & Antoni, M. H. (2010) · Fertility and Sterility · doi:10.1016/j.fertnstert.2010.03.081 · Cited by 209 · see citing works
Insulin resistance and PCOS: chicken or egg?
Moghetti, P., & Tosi, F. (2021) · Journal of Endocrinological Investigation · doi:10.1007/s40618-020-01351-0 · Cited by 209 · see citing works
Corbould, A. (2007) · Journal of Endocrinology · doi:10.1677/joe.1.07070 · Cited by 184 · see citing works
Barrea, L., Marzullo, P., Muscogiuri, G., Di Somma, C., Scacchi, M., Orio, F., Aimaretti, G., Colao, A., & Savastano, S. (2018) · Nutrition Research Reviews · doi:10.1017/s0954422418000136 · Cited by 171 · see citing works
Nelson-Degrave, V. L., Wickenheisser, J. K., Hendricks, K. L., Asano, T., Fujishiro, M., Legro, R. S., Kimball, S. R., Strauss, J. F., & McAllister, J. M. (2005) · Molecular Endocrinology · doi:10.1210/me.2004-0178 · Cited by 167 · see citing works
Tong, C., Wu, Y., Zhang, L., & Yu, Y. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1091147 · Cited by 157 · see citing works
Inositols: From Established Knowledge to Novel Approaches
Dinicola, S., Unfer, V., Facchinetti, F., Soulage, C. O., Greene, N. D., Bizzarri, M., Laganà, A. S., Chan, S.-Y., Bevilacqua, A., Pkhaladze, L., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910575 · Cited by 154 · see citing works
Self-citationEvidence of proatherogenic inflammation in polycystic ovary syndrome
González, F., Rote, N. S., Minium, J., & Kirwan, J. P. (2009) · Metabolism · doi:10.1016/j.metabol.2009.02.022 · Cited by 135 · see citing works
Polycystic Ovary Syndrome: Pathophysiology and Therapeutic Opportunities
Dong, J., & Rees, D. A. (2023) · BMJ Medicine · doi:10.1136/bmjmed-2023-000548 · Cited by 123 · see citing works
Adrenal Androgens and Androgen Precursors-Definition, Synthesis, Regulation and Physiologic Actions
Turcu, A., Smith, J. M., Auchus, R., & Rainey, W. E. (2014) · Comprehensive physiology · doi:10.1002/cphy.c140006 · Cited by 113 · see citing works
Unfer, V., Carlomagno, G., Papaleo, E., Vailati, S., Candiani, M., & Baillargeon, J.-P. (2014) · Reproductive Sciences · doi:10.1177/1933719113518985 · Cited by 105 · see citing works
Inositols in polycystic ovary syndrome: An overview on the advances
Facchinetti, F., Unfer, V., Dewailly, D., Kamenov, Z. A., Diamanti-Kandarakis, E., Laganà, A. S., Nestler, J. E., & Soulage, C. O. (2020) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2020.02.002 · Cited by 102 · see citing works
Self-citationGheller, B. J. F., Riddle, E. S., Lem, M. R., & Thalacker-Mercer, A. E. (2016) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071715-050901 · Cited by 98 · see citing works
Kamenov, Z., & Gateva, A. (2020) · Molecules · doi:10.3390/molecules25235566 · Cited by 100 · see citing works
“Increased insulin levels act synergistically with LH to stimulate ovarian production of androgens [38,48] and suppresses SHBG production from the liver [49], that leads to increased free testosterone levels.”
BackgroundThecal Cell Sensitivity to Luteinizing Hormone and Insulin in Polycystic Ovarian Syndrome
Cadagan, D., Khan, R., & Amer, S. (2016) · Reproductive Biology · doi:10.1016/j.repbio.2015.12.006 · Cited by 92 · see citing works
Steegers-Theunissen, R. P. M., Wiegel, R. E., Jansen, P. W., Laven, J. S. E., & Sinclair, K. D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218211 · Cited by 82 · see citing works
Jakubowicz, D., Barnea, M., Wainstein, J., & Froy, O. (2013) · Clinical Science · doi:10.1042/cs20130071 · Cited by 81 · see citing works
Self-citationReinecke, H., Bogdanski, J., Woltering, A., Breithardt, G. Ü., Assmann, G., Kerber, S., & von Eckardstein, A. (2002) · The American Journal of Cardiology · doi:10.1016/s0002-9149(02)02490-6 · Cited by 78 · see citing works
Moret, M., Stettler, R., Rodieux, F., Gaillard, R. C., Waeber, G., Wirthner, D., Giusti, V., Tappy, L., & Pralong, F. P. (2009) · Neuroendocrinology · doi:10.1159/000160911 · Cited by 72 · see citing works
Tosi, F., Di Sarra, D., Kaufman, J.-M., Bonin, C., Moretta, R., Bonora, E., Zanolin, E., & Moghetti, P. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2786 · Cited by 70 · see citing works
Inositol and human reproduction. From cellular metabolism to clinical use
Milewska, E. M., Czyzyk, A., Meczekalski, B., & Genazzani, A. D. (2016) · Gynecological Endocrinology · doi:10.1080/09513590.2016.1188282 · Cited by 69 · see citing works
González, F., Nair, K. S., Daniels, J. K., Basal, E., & Schimke, J. M. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00416.2011 · Cited by 70 · see citing works
Li, X.-J., Yu, Y.-X., Liu, C.-Q., Zhang, W., Zhang, H.-J., Yan, B., Wang, L.-Y., Yang, S.-Y., & Zhang, S.-H. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2010.03917.x · Cited by 67 · see citing works
Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood
Abbott, D. H., & Bacha, F. (2013) · Fertility and Sterility · doi:10.1016/j.fertnstert.2013.05.023 · Cited by 67 · see citing works
Reproductive tissues maintain insulin sensitivity in diet-induced obesity
Wu, S., Divall, S., Wondisford, F., & Wolfe, A. (2012) · Diabetes · doi:10.2337/db11-0956 · Cited by 65 · see citing works
Cardiometabolic Risk in PCOS: More than a Reproductive Disorder
Torchen, L. C. (2017) · Current Diabetes Reports · doi:10.1007/s11892-017-0956-2 · Cited by 65 · see citing works
Facchinetti, F., Appetecchia, M., Aragona, C., Bevilacqua, A., Bezerra Espinola, M. S., Bizzarri, M., D’Anna, R., Dewailly, D., Diamanti-Kandarakis, E., Hernández Marín, I., et al. (2020) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2020.1737675 · Cited by 63 · see citing works
Self-citationHigh-fat high-sugar diet induces polycystic ovary syndrome in a rodent model†
Roberts, J. S., Perets, R. A., Sarfert, K. S., Bowman, J. J., Ozark, P. A., Whitworth, G. B., Blythe, S. N., & Toporikova, N. (2017) · Biology of Reproduction · doi:10.1095/biolreprod.116.142786 · Cited by 58 · see citing works
Hyperinsulinaemic androgen excess in adolescent girls
Ibáñez, L., Ong, K. K., López-Bermejo, A., Dunger, D. B., & de Zegher, F. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2014.58 · Cited by 56 · see citing works
Mario, F. M., Graff, S. K., & Spritzer, P. M. (2017) · Journal of Endocrinological Investigation · doi:10.1007/s40618-016-0570-1 · Cited by 47 · see citing works
Pani, A., Gironi, I., Di Vieste, G., Mion, E., Bertuzzi, F., & Pintaudi, B. (2020) · International Journal of Endocrinology · doi:10.1155/2020/6276187 · Cited by 38 · see citing works
Modeling Endocrine Control of the Pituitary–Ovarian Axis: Androgenic Influence and Chaotic Dynamics
Hendrix, A. O., Hughes, C. L., & Selgrade, J. F. (2014) · Bulletin of Mathematical Biology · doi:10.1007/s11538-013-9913-7 · Cited by 19 · see citing works
Cheang, K. I., Sistrun, S. N., Morel, K. S., & Nestler, J. E. (2016) · International Journal of Endocrinology · doi:10.1155/2016/7631804 · Cited by 2 · see citing works
Self-citation
- Authors
- Nestler, J. E., Jakubowicz, D. J., Falcon de Vargas, A., Brik, C., Quintero, N., & Medina, F.
- Affiliations
- Virginia Commonwealth University (US)
- Hospital Clínico Universitario de Caracas (VE)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1998-06
- Volume
- 83
- Issue
- 6
- Pages
- 2001-2005
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2091336289
- Cited by
- 617
- References
- 21
- Citations by year
- 2026: 4 · 2025: 19 · 2024: 25 · 2023: 29 · 2022: 24 · 2021: 33 · 2020: 32 · 2019: 21 · 2018: 20 · 2017: 20 · 2016: 35 · 2015: 29 · 2014: 25 · 2013: 24 · 2012: 28
- FWCI
- 12.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Virginia
- Insmed
- National Institutes of Health (5r01ca064500-03)
- National Cancer Institute (R01-CA-64500)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD035629)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- insulin, testosterone production, polycystic ovary syndrome, theca cells, insulin receptor, insulin-like growth factor I, signal transduction, chiro-inositol, human chorionic gonadotropin, ovarian steroidogenesis
- MeSH terms
- Adult, Antibodies, Female, Humans, Inositol, Insulin, Insulin-Like Growth Factor I, Polycystic Ovary Syndrome, Polysaccharides, Receptor, Insulin, Testosterone, Theca Cells, Signal Transduction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
