Decreases in Ovarian Cytochrome P450c17α Activity and Serum Free Testosterone after Reduction of Insulin Secretion in Polycystic Ovary Syndrome

Nestler, John E.; Jakubowicz, Daniela J.

doi:10.1056/nejm199608293350902

Cited by 743Ovarian function and disordersDiabetes, Cardiovascular Risks, and LipoproteinsAdrenal Hormones and Disorders

Decreases in Ovarian Cytochrome P450c17α Activity and Serum Free Testosterone after Reduction of Insulin Secretion in Polycystic Ovary Syndrome

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Nestler, John E., Jakubowicz, Daniela J.·1996·New England Journal of Medicine

DOI 10.1056/nejm199608293350902

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Abstract

BACKGROUND: Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome. P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity. METHODS: We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotrophin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome. RESULTS: In the 11 women given metformin, the mean (+/- SE) area under the serum insulin curve after oral glucose administration decreased from 9303 +/- 1603 to 4982 +/- 911 microU per milliliter per minute (56 +/- 10 to 30 +/- 6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17 alpha-hydroxyprogesterone concentration from 135 +/- 21 to 66 +/- 7 ng per deciliter (4.1 +/- 0.6 to 2.0 +/- 0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone concentration from 455 +/- 54 to 281 +/- 52 ng per deciliter (13.7 +/- 1.6 to 8.5 +/- 1.6 nmol per liter) (P = 0.01). The serum 17 alpha-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5 +/- 2.2 to 2.8 +/- 0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34 +/- 0.07 to 0.19 +/- 0.05 ng per deciliter (12 +/- 3 to 7 +/- 2 pmol per liter) (P = 0.009), and the serum sex hormone-binding globulin concentration increased from 0.8 +/- 0.2 to 2.3 +/- 0.6 microgram per deciliter (29 +/- 7 to 80 +/- 21 nmol per liter) (P < 0.001). None of these values changed significantly in the placebo group. CONCLUSIONS: In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism.

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Insulin acting on ovarian theca cells increases androgen synthesis by increasing activity of cytochrome P450C17α.
“Insulin acting on ovarian theca cells increases androgen synthesis by increasing activity of the cytochrome P450C17α, which has 17-hydroxylase and 17,20-lyase activities [62].”
From The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome (2022) · cites this paper as [62]

Polycystic Ovary Syndrome
Franks, S. (1995) · New England Journal of Medicine · doi:10.1056/nejm199509283331307 · Cited by 2,463 · see citing works
Profound Peripheral Insulin Resistance, Independent of Obesity, in Polycystic Ovary Syndrome
Dunaif, A., Segal, K. R., Futterweit, W., & Dobrjansky, A. (1989) · Diabetes · doi:10.2337/diab.38.9.1165 · Cited by 1,967 · see citing works
Improvement in Endocrine and Ovarian Function during Dietary Treatment of Obese Women with Polycystic Ovary Syndrome
Kiddy, D. S., Hamilton‐Fairley, D., Bush, A., Short, F., Anyaoku, V., Reed, M. J., & Franks, S. (1992) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1992.tb02909.x · Cited by 921 · see citing works
Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy
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
A Direct Effect of Hyperinsulinemia on Serum Sex Hormone-Binding Globulin Levels in Obese Women with the Polycystic Ovary Syndrome*
NESTLER, J. E., POWERS, L. P., MATT, D. W., STEINGOLD, K. A., PLYMATE, S. R., RITTMASTER, R. S., CLORE, J. N., & BLACKARD, W. G. (1991) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-72-1-83 · Cited by 815 · see citing works
Self-citation
Insulin resistance in nonobese patients with polycystic ovarian disease
CHANG, R. J., NAKAMURA, R. M., JUDD, H. L., & KAPLAN, S. A. (1983) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-57-2-356 · Cited by 704 · see citing works
Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin.
PLYMATE, S. R., MATEJ, L. A., JONES, R. E., & FRIEDL, K. E. (1988) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-67-3-460 · Cited by 693 · see citing works
Insulin Stimulates Androgen Accumulation in Incubations of Ovarian Stroma Obtained from Women with Hyperandrogenism*
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
Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome.
Dunaif, A., Xia, J., Book, C. B., Schenker, E., & Tang, Z. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118126 · Cited by 561 · see citing works
Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome
Dunaif, A. E., Segal, K. R., Futterweit, W., et al. (1989) · Diabetes · doi:10.2337/diabetes.38.9.1165 · Cited by 518 · see citing works
Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome?
Carmina, E., Koyama, T., Chang, L., Stanczyk, F. Z., & Løbo, R. A. (1992) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(92)91779-a · Cited by 441 · see citing works
Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus.
Ehrmann, D. A., Sturis, J., Byrne, M. M., Karrison, T., Rosenfield, R. L., & Polonsky, K. S. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118064 · Cited by 426 · see citing works
Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects
DEFRONZO, R. A., BARZILAI, N., & SIMONSON, D. C. (1991) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-73-6-1294 · Cited by 408 · see citing works
Insulin receptors in the central nervous system: Localization, signalling mechanisms and functional aspects
UNGER, J., Livingston, J. H., & Moss, A. (1991) · Progress in Neurobiology · doi:10.1016/0301-0082(91)90015-s · Cited by 403 · see citing works
Insulin Enhancement of Luteinizing Hormone and Follicle-Stimulating Hormone Release by Cultured Pituitary Cells*
ADASHI, E. Y., HSUEH, A. J. W., & YEN, S. S. C. (1981) · Endocrinology · doi:10.1210/endo-108-4-1441 · Cited by 366 · see citing works
Effects of Metformin on Insulin Resistance, Risk Factors for Cardiovascular Disease, and Plasminogen Activator Inhibitor in NIDDM Subjects: A study of two ethnic groups
Nagi, D. K., & Yudkin, J. S. (1993) · Diabetes Care · doi:10.2337/diacare.16.4.621 · Cited by 353 · see citing works
Suppression of Serum Insulin by Diazoxide Reduces Serum Testosterone Levels in Obese Women with Polycystic Ovary Syndrome*
NESTLER, J. E., BARLASCINI, C. O., MATT, D. W., STEINGOLD, K. A., PLYMATE, S. R., CLORE, J. N., & BLACKARD, W. G. (1989) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-68-6-1027 · Cited by 338 · see citing works
Self-citation
Cellular mechanisms of insulin resistance in polycystic ovarian syndrome
Ciaraldi, T. P. (1992) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.75.2.577 · Cited by 336 · see citing works
Insulin-Like Growth Factor I and Insulin Potentiate Luteinizing Hormone-Induced Androgen Synthesis by Rat Ovarian Thecal-Interstitial Cells*
Cara, J. F., & Rosenfield, R. L. (1988) · Endocrinology · doi:10.1210/endo-123-2-733 · Cited by 333 · see citing works
Detection of Functional Ovarian Hyperandrogenism in Women with Androgen Excess
Ehrmann, D. A., Rosenfield, R. L., Barnes, R. B., Brigell, D. F., & Sheikh, Z. (1992) · New England Journal of Medicine · doi:10.1056/nejm199207163270304 · Cited by 322 · see citing works
Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women
Crave, J. C., Fimbel, S., Lejeune, H., Cugnardey, N., Déchaud, H., & Pugeat, M. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.80.7.7608255 · Cited by 301 · see citing works
Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin
Bergh, C., Carlsson, B., Olsson, J., Selleskog, U., & Hillensjø, T. (1993) · Fertility and Sterility · doi:10.1016/s0015-0282(16)55675-1 · Cited by 253 · see citing works
The Effects of Long Term Testosterone Administration on Pulsatile Luteinizing Hormone Secretion and on Ovarian Histology in Eugonadal Female to Male Transsexual Subjects
Spinder, T., Spijkstra, J. J., van den Tweel, J. G., Burger, C. W., van Kessel, H. I., Hompes, P. G. A., & Gooren, L. J. (1989) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-69-1-151 · Cited by 206 · see citing works
Suppression of Hyperandrogenism Does not Improve Peripheral or Hepatic Insulin Resistance in the Polycystic Ovary Syndrome*
Dunaif, A. E., Green, G., Futterweit, W., & Dobrjansky, A. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-70-3-699 · Cited by 198 · see citing works
Insulin infusion amplifies 17 alpha-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity
Moghetti, P., Castello, R., Negri, C., Tosi, F., Spiazzi, G., Brun, E., Balducci, R., Toscano, V., & Muggeo, M. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.3.8772544 · Cited by 196 · see citing works
Diet-Induced Changes in Sex Hormone Binding Globulin and Free Testosterone in Women with Normal or Polycystic Ovaries: Correlation with Serum Insulin and Insulin-like Growth Factor-I
KIDDY, D. S., HAMILTON‐FAIRLEY, D., SEPPÄLÄ, M., KOISTINEN, R., JAMES, V. H. T., REED, M. J., & FRANKS, S. (1989) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1989.tb01297.x · Cited by 182 · 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
Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism
Apter, D. L., Bützow, T. L., Laughlin, G. A., & YEN, S. S. C. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.80.10.7559882 · Cited by 167 · 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
Studies of the nature of 17-hydroxyprogesterone hyperresonsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism
Rosenfield, R. L., Barnes, R. B., & Ehrmann, D. A. (1994) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.79.6.7989476 · Cited by 119 · see citing works
Source localization of androgen excess in adolescent girls
Ibáñez, L., Potau, N., Zampolli, M., Prat, N., Gussinyé, M., Saenger, P. H., Vicens-Calvet, E., & Carrascosa, A. (1994) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.79.6.7989484 · Cited by 88 · see citing works
Do Androgens Directly Regulate Gonadotropin Secretion in the Polycystic Ovary SyndromeÓ*
ANDREA, D. (1986) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-63-1-215 · Cited by 83 · see citing works
Effects of a reduction in circulating insulin by metformin on serum dehydroepiandrosterone sulfate in nondiabetic men
Nestler, J. E., Beer, N., Jakubowicz, D. J., & Beer, R. M. (1994) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.78.3.8126125 · Cited by 74 · see citing works
Self-citation
Increased luteinizing hormone and alpha-subunit secretion in women with hyperandrogenic anovulation.
Berga, S. L., Guzick, D. S., & Winters, S. J. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.77.4.7691863 · Cited by 71 · see citing works
Gonadotrophin and gonadal steroid response to a single dose of a long‐acting agonist of gonadotrophin‐releasing hormone in ovulatory and anovulatory women with polycystic ovary syndrome
White, D., Leigh, A., Wilson, C. A., Donaldson, A., & Franks, S. (1995) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1995.tb02665.x · Cited by 68 · see citing works
Interface between Extra‐ and Intraovarian Factors in Polycystic Ovarian Syndrome
YEN, S. S. C., LAUGHLIN, G. A., & MORALES, A. J. (1993) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1993.tb43858.x · Cited by 36 · see citing works
Variations of steroid hormone metabolites in serum and urine in polycystic ovary syndrome after nafarelin stimulation: evidence for an altered corticoid excretion
Luppa, P. B., Müller, B., Jacob, K., Kimmig, R., Strowitzki, T., Höß, C., Weber, M. M., Engelhardt, D., & Løbo, R. A. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.80.1.7829627 · Cited by 28 · see citing works
Ovulation Induction: Basic Science and Clinical Advances
Filicori, M. (1994) · Cited by 28 · see citing works
Detection of Functional Ovarian Hyperandrogenism in Women With Androgen Excess
Ehrmann, D. A., Rosenfield, R. L., Barnes, R. B., Brigell, D. F., & Sheikh, Z. (1993) · Obstetrical & Gynecological Survey · doi:10.1097/00006254-199301000-00020 · Cited by 27 · see citing works
Changing Pituitary Reactivity to Follicle-Stimulating Hormone and Luteinizing Hormone-Releasing Hormone After Induced Ovulatory Cycles and After Anovulation in Patients With Polycystic Ovarian Disease
Blankstein, J., Rabinovici, J., Goldenberg, M., et al. (1987) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-65-6-1164 · Cited by 25 · see citing works
Increased luteinizing hormone and alpha-subunit secretion in women with hyperandrogenic anovulation
Berga, S. L. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.77.4.895 · Cited by 19 · see citing works

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Slap*, G. B. (2003) · Best Practice & Research Clinical Obstetrics & Gynaecology · doi:10.1053/ybeog.2002.0342 · Cited by 140 · see citing works
Favourable metabolic effects of a eucaloric lower‐carbohydrate diet in women with <scp>PCOS</scp>
Gower, B. A., Chandler‐Laney, P. C., Ovalle, F., Goree, L. L., Azziz, R., Desmond, R. A., Granger, W. M., Goss, A. M., & Bates, G. W. (2013) · Clinical Endocrinology · doi:10.1111/cen.12175 · Cited by 108 · see citing works
Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism
Ibáñez, L., Ong, K., Ferrer, A., Amin, R., Dunger, D., & de Zegher, F. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-022002 · Cited by 100 · see citing works
Inositols in PCOS
Kamenov, Z., & Gateva, A. (2020) · Molecules · doi:10.3390/molecules25235566 · Cited by 100 · see citing works
“Hyperinsulinemia appears to play an important pathogenic role in the hyperandrogenism and anovulation of both obese and lean women with PCOS [33,34].”
Background
Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome
Sam, S., & Ehrmann, D. A. (2017) · Diabetologia · doi:10.1007/s00125-017-4306-3 · Cited by 93 · see citing works
MENSTRUAL DISORDERS IN ADOLESCENTS
Gordon, C. M. (1999) · Pediatric Clinics of North America · doi:10.1016/s0031-3955(05)70135-8 · Cited by 92 · see citing works
Thecal 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
Clinical, metabolic, and endocrine parameters in response to metformin and lifestyle intervention in women with polycystic ovary syndrome: a randomized, double-blind, and placebo control trial
Fux Otta, C., Wior, M., Iraci, G. S., Kaplan, R., Torres, D., Gaido, M. I., & Wyse, E. P. (2010) · Gynecological Endocrinology · doi:10.3109/09513590903215581 · Cited by 85 · see citing works
Uterine effects of metformin administration in anovulatory women with polycystic ovary syndrome
Palomba, S., Russo, T., Orio, F., Falbo, A., Manguso, F., Cascella, T., Tolino, A., Carmina, E., Colao, A., & Zullo, F. (2006) · Human Reproduction · doi:10.1093/humrep/dei351 · Cited by 85 · see citing works
Effects of Caloric Intake Timing on Insulin Resistance and Hyperandrogenism in Lean Women with Polycystic Ovary Syndrome
Jakubowicz, D., Barnea, M., Wainstein, J., & Froy, O. (2013) · Clinical Science · doi:10.1042/cs20130071 · Cited by 81 · see citing works
Self-citation
The effects of rosiglitazone and metformin on insulin resistance and serum androgen levels in obese and lean patients with polycystic ovary syndrome
Yilmaz, M., Biri, A., Karakoç, A., Törüner, F., Bingöl, B., Çakir, N., Tiras, B., Ayvaz, G., & Arslan, M. (2005) · Journal of Endocrinological Investigation · doi:10.1007/bf03345339 · Cited by 77 · see citing works
Metabolic and Hormonal Changes Induced by Pioglitazone in Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Clinical Trial
Aroda, V. R., Ciaraldi, T. P., Burke, P., Mudaliar, S., Clopton, P., Phillips, S., Chang, R. J., & Henry, R. R. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1133 · Cited by 71 · see citing works
Effects of increased dietary protein-to-carbohydrate ratios in women with polycystic ovary syndrome
Sørensen, L. B., Søe, M., Halkier, K. H., Stigsby, B., & Astrup, A. (2012) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.020693 · Cited by 70 · see citing works
Evaluation of Ovarian Functionality after a Dietary Treatment in Obese Women with Polycystic Ovary Syndrome
Tolino, A., Gambardella, V., Caccavale, C., D’Ettore, A., Giannotti, F., D’Antò, V., & De Falco, C. L. (2005) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2004.06.043 · Cited by 69 · see citing works
Metformin vs thiazolidinediones for treatment of clinical, hormonal and metabolic characteristics of polycystic ovary syndrome: a meta-analysis: Metformin vs thiazolidinediones for PCOS
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
Metformin induces a prompt decrease in LH-stimulated testosterone response in women with PCOS independent of its insulin-sensitizing effects
Kurzthaler, D., Hadziomerovic-Pekic, D., Wildt, L., & Seeber, B. E. (2014) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-12-98 · Cited by 66 · see citing works
Naltrexone treatment in clomiphene resistant women with polycystic ovary syndrome
Ahmed, M. I., Duleba, A. J., El Shahat, O., Ibrahim, M. E., & Salem, A. (2008) · Human Reproduction · doi:10.1093/humrep/den273 · Cited by 58 · see citing works
Increased Luteinizing Hormone Secretion in Women with Polycystic Ovary Syndrome Is Unaltered by Prolonged Insulin Infusion
Patel, K., Coffler, M. S., Dahan, M. H., Yoo, R. Y., Lawson, M. A., Malcom, P. J., & Chang, R. J. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030816 · Cited by 60 · see citing works
Retention of Estradiol Negative Feedback Relationship to LH Predicts Ovulation in Response to Caloric Restriction and Weight Loss in Obese Patients with Polycystic Ovary Syndrome
van Dam, E. W. C. M., Roelfsema, F., Veldhuis, J. D., Hogendoorn, S., Westenberg, J., Helmerhorst, F. M., Frölich, M., Krans, H. M. J., Meinders, A. E., & Pijl, H. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00377.2003 · Cited by 51 · see citing works
Is there a dose-response relationship of metformin treatment in patients with polycystic ovary syndrome? Results from a multicentric study
Fulghesu, A. M., Romualdi, D., Di Florio, C., Sanna, S., Tagliaferri, V., Gambineri, A., Tomassoni, F., Minerba, L., Pasquali, R., & Lanzone, A. (2012) · Human Reproduction · doi:10.1093/humrep/des262 · Cited by 48 · see citing works
Luteinizing Hormone Secretion Is Not Influenced by Insulin Infusion in Women with Polycystic Ovary Syndrome Despite Improved Insulin Sensitivity during Pioglitazone Treatment
Mehta, R. V., Patel, K. S., Coffler, M. S., Dahan, M. H., Yoo, R. Y., Archer, J. S., Malcom, P. J., & Chang, R. J. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1040 · Cited by 47 · see citing works
Effect of hyperinsulinaemia and insulin resistance on endocrine, metabolic and fertility outcomes in women with polycystic ovary syndrome undergoing ovulation induction
Zhang, D., Yang, X., Li, J., Yu, J., & Wu, X. (2019) · Clinical Endocrinology · doi:10.1111/cen.14050 · Cited by 40 · see citing works
Genetically defined forms of diabetes in children
Taylor, S. I., & Arioglu, E. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.12.6237 · Cited by 38 · see citing works
Substituting Poly- and Mono-Unsaturated Fat for Dietary Carbohydrate Reduces Hyperinsulinemia in Women with Polycystic Ovary Syndrome
Perelman, D., Coghlan, N., Lamendola, C., Carter, S., Abbasi, F., & McLaughlin, T. (2017) · Gynecological Endocrinology · doi:10.1080/09513590.2016.1259407 · Cited by 18 · see citing works
Non-traditional metabolic pathways of adrenal steroids
Auchus, R. J. (2009) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-008-9095-z · Cited by 17 · see citing works

Insulin resistance 'and polycystic ovary syndrome (PCOS) ': Part 1. The impact of insulin resistance
McEwen, B. J., & Hartmann, G. (2018) · Journal of the Australian Traditional-Medicine Society · Cited by 2 · see citing works
The relationship between epicardial fat thickness and insulin resistance in women with polycystic ovarian disease
Shahebrahimi, K., Rahimi, M., Salehi, N., et al. (2017) · Majallah-i dānishgāh-i ̒ulūm-i pizishkī-i Kirmānshāh · doi:10.22110/jkums.v21i1.2715
Insulin Resistance in Polycystic Ovary Syndrome Mechanism and Treatment Methods
Pei-pe, M. (2010) · Medical Recapitulate
Hyperandrogenaemia and the ovary
Norman, R. J. (2002) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(02)00062-x · Cited by 21 · see citing works
Plasma Free Testosterone—is An Index Sufficient?
Nanjee, M. N., & Wheeler, M. J. (1985) · Annals of Clinical Biochemistry: International Journal of Laboratory Medicine · doi:10.1177/000456328502200410 · Cited by 114 · see citing works

Authors: Nestler, J. E., & Jakubowicz, D. J.
Affiliations: Virginia Commonwealth University (US)
Hospital Clínico Universitario de Caracas (VE)
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 1996-08-29
Volume: 335
Issue: 9
Pages: 617-623
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejm199608293350902
OpenAlex: W2043939998
Semantic Scholar: ceef65efd08206a29d0d02f8f4fe634915c1d731
Cited by: 743
References: 41
Citations by year: 2026: 4 · 2025: 9 · 2024: 6 · 2023: 7 · 2022: 15 · 2021: 19 · 2020: 10 · 2019: 7 · 2018: 15 · 2017: 12 · 2016: 13 · 2015: 17 · 2014: 15 · 2013: 28 · 2012: 25
FWCI: 34.35
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
VCU Scholars Compass (Virginia Commonwealth University) (submittedVersion)
Funders: National Institutes of Health (5r01ag011227-03, 5r01ca064500-03)
National Institute on Aging (R01-AG11227)
National Cancer Institute (R01-CA-64500)
Topics: Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords: polycystic ovary syndrome, 17α-hydroxylase, 17,20-lyase, androgen production, insulin resistance, hyperinsulinemia, metformin, insulin secretion, 17-hydroxyprogesterone, luteinizing hormone, free testosterone
MeSH terms: Adolescent, Adult, Blood Glucose, Female, Humans, Hydroxyprogesterones, Hypoglycemic Agents, Insulin, Luteinizing Hormone, Metformin, Obesity, Polycystic Ovary Syndrome, Steroid 17-alpha-Hydroxylase, Testosterone, Leuprolide, Hyperandrogenism, 17-alpha-Hydroxyprogesterone

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Decreases in Ovarian Cytochrome P450c17α Activity and Serum Free Testosterone after Reduction of Insulin Secretion in Polycystic Ovary Syndrome

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