The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism

Wallach, Edward E.; Barbieri, Robert L.; Smith, Samuel; Ryan, Kenneth J.

doi:10.1016/s0015-0282(16)60060-2

Cited by 348Ovarian function and disordersDiabetes, Cardiovascular Risks, and LipoproteinsAdrenal Hormones and Disorders

The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism

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Wallach, Edward E., Barbieri, Robert L., Smith, Samuel, Ryan, Kenneth J.·1988·Fertility and Sterility

DOI 10.1016/s0015-0282(16)60060-2

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Abstract

The evidence that supports the hypothesis that insulin and LH both regulate ovarian androgen production was presented. The most dramatic clinical example of the association between hyperinsulinemia and hyperandrogenism is the HAIR-AN syndrome. Our hypothesis is that, in the HAIR-AN syndrome, the severe insulin resistance causes a compensatory hyperinsulinemia, which stimulates ovarian androgen production if adequate LH is present. The acanthosis nigricans is an epiphenomenon of the syndrome. Acanthosis nigricans is a dermatologic manifestation of severe insulin resistance. In vitro evidence suggests that insulin and IGF-I stimulate androgen production in incubations of human stroma and theca. The stromatropic effects of insulin may sensitize the stroma to the stimulatory effects of LH. In some hyperandrogenic-insulin-resistant women, a glucose load appears to produce an acute rise in circulating androgens. The magnitude of the rise in circulating androgens is proportional to the magnitude of the insulin response to the glucose load. These data suggest that hyperinsulinemia may play a central role in the development of ovarian hyperandrogenism.

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Insulin suppresses hepatic SHBG secretion and acts on the ovary to promote thecal cell androgen synthesis, increasing circulating free testosterone.
“Insulin suppresses hepatic SHBG secretion and acts on the ovary to promote thecal cell androgen synthesis 58 with the net effect of increasing circulating free testosterone concentrations.”
From The impact of metformin with or without lifestyle modification versus placebo on polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [58]

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Insulin Binding to Monocytes in Obese Patients Treated with Carbohydrate Restriction and Changes in Physical Activity*
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INSULIN RESISTANCE IN A CHILD WITH ACANTHOSIS NIGRICANS TYPE A*
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A 13-Year-Old Premenarchal Female with the Stein-Leventhal Syndrome
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Acanthosis Nigricans with Endocrinopathy
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Congenital lipodystrophy and polycystic ovarian disease.
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1 of the 108 references couldn’t be matched to a known paper.

Sorted by citations

Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review.
Kaaks, R., Lukanova, A., & Kurzer, M. S. (2002) · PubMed · Cited by 1,038 · see citing works
Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy
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Symptoms of menopause — global prevalence, physiology and implications
Monteleone, P., Mascagni, G., Giannini, A., Genazzani, A. R., & Simoncini, T. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.180 · Cited by 819 · see citing works
The Insulin-Related Ovarian Regulatory System in Health and Disease
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Insulin Resistance — Mechanisms, Syndromes, and Implications
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Hormonal Etiology of Epithelial Ovarian Cancer, With a Hypothesis Concerning the Role of Androgens and Progesterone
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Energy balance and cancer: the role of insulin and insulin-like growth factor-I
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Acne vulgaris: a disease of Western civilization
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Coronary Heart Disease Risk Factors in Women With Polycystic Ovary Syndrome
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Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features
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Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet
Crosignani, P. G. (2003) · Human Reproduction · doi:10.1093/humrep/deg367 · Cited by 359 · see citing works
Nutrition, hormones, and breast cancer: Is insulin the missing link?
Kaaks, R. (1996) · Cancer Causes & Control · doi:10.1007/bf00051703 · Cited by 361 · see citing works
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
Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries.
Willis, D., Mason, H., Gilling-Smith, C., & Franks, S. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.1.8550768 · Cited by 371 · see citing works
Menstrual Cyclicity After Metformin Therapy in Polycystic Ovary Syndrome
M, E., Acosta, A., & Mendoza, S. (1997) · Obstetrics and Gynecology · doi:10.1016/s0029-7844(97)00296-2 · Cited by 310 · see citing works
Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective
Kumariya, S., Ubba, V., Jha, R. K., & Gayen, J. R. (2021) · Autophagy · doi:10.1080/15548627.2021.1938914 · Cited by 306 · 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
Metformin directly inhibits androgen production in human thecal cells
Attia, G. R., Rainey, W. E., & Carr, B. R. (2001) · Fertility and Sterility · doi:10.1016/s0015-0282(01)01975-6 · Cited by 254 · 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
Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women
Guzick, D. S., Wing, R., Smith, D., Berga, S. L., & Winters, S. J. (1994) · Fertility and Sterility · doi:10.1016/s0015-0282(16)56632-1 · Cited by 246 · see citing works
Epigenetic inheritance of polycystic ovary syndrome — challenges and opportunities for treatment
Stener‐Victorin, E., & Deng, Q. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00517-x · Cited by 223 · see citing works
Carotid atherosclerosis in women with polycystic ovary syndrome: Initial results from a case-control study
Guzick, D. S., Talbott, E. O., Sutton-Tyrrell, K., Herzog, H. C., Kuller, L. H., & Wolfson, S. K. (1996) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(96)70665-8 · Cited by 210 · see citing works
Hyperinsulinemic diseases of civilization: more than just Syndrome X
Cordain, L., Eades, M. R., & Eades, M. D. (2003) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/s1095-6433(03)00011-4 · Cited by 209 · see citing works
“Both insulin and IGF-1 stimulate the synthesis of androgens in ovarian (Barbieri et al., 1988; Cara, 1994) and testicular (De Mellow et al.”
Background
The Follicle-Deplete Mouse Ovary Produces Androgen1
Mayer, L. P., Devine, P. J., Dyer, C. A., & Hoyer, P. B. (2004) · Biology of Reproduction · doi:10.1095/biolreprod.103.016113 · Cited by 209 · see citing works
Insulin action and insulin resistance: diseases involving defects in insulin receptors, signal transduction, and the glucose transport effector system
Hunter, S. J., & Garvey, W. T. (1998) · The American Journal of Medicine · doi:10.1016/s0002-9343(98)00300-3 · Cited by 200 · see citing works
Polycystic ovary syndrome and environmental toxins
Rutkowska, A. Z., & Diamanti‐Kandarakis, E. (2016) · Fertility and Sterility · doi:10.1016/j.fertnstert.2016.08.031 · Cited by 191 · see citing works
The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women
Holte, J., Bergh, T., Gennarelli, G., & WIDE, L. E. (1994) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1994.tb02578.x · Cited by 178 · see citing works
Can metformin reduce insulin resistance in polycystic ovary syndrome?
Açbay, Ö., & Gündoğdu, S. (1996) · Fertility and Sterility · doi:10.1016/s0015-0282(16)58266-1 · Cited by 173 · see citing works
Menopause in Type 1 Diabetic Women
Dorman, J. S., Steenkiste, A. R., Foley, T. P., Strotmeyer, E. S., Burke, J. P., Kuller, L. H., & Kwoh, C. K. (2001) · Diabetes · doi:10.2337/diabetes.50.8.1857 · Cited by 171 · see citing works
Expression of the genes encoding the insulin-like growth factors and their receptors in the human ovary.
Hernández, E. R., Hurwitz, A., VERA, A., Pellicer, A., Adashi, E. Y., LeRoith, D., & Roberts, C. T. (1992) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.74.2.1309838 · Cited by 160 · see citing works
The Effects of Insulin and Insulin-Like Growth Factors-I and -II on Estradiol Production by Granulosa Cells of Polycystic Ovaries*
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
High Prevalence of Polycystic Ovaries and Associated Clinical, Endocrine, and Metabolic Features in Women with Previous Gestational Diabetes Mellitus
Holte, J., Gennarelli, G., WIDE, L. E., Lithell, H., & Berne, C. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.4.4707 · Cited by 149 · see citing works
Interrelation between plasma sex hormone-binding globulin and plasma insulin in healthy adult women: the telecom study
Preziosi, P., Barrett-Connor, E. L., Papoz, L., Roger, M., Saint-Paul, M., NAHOUL, K., & Simon, D. (1993) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.76.2.8432770 · Cited by 145 · see citing works
Polycystic ovaries and levels of gonadotrophins and androgens in recurrent miscarriage: prospective study in 50 women
Tulppala, M., Stenman, U., Cacciatore, B., & Ylikorkala, O. (1993) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1993.tb12978.x · Cited by 144 · see citing works
Implications for the Role of Diet in Acne
Cordain, L. (2005) · Seminars in Cutaneous Medicine and Surgery · doi:10.1016/j.sder.2005.04.002 · Cited by 140 · see citing works
Diabetes and endometrial cancer in the Iowa women's health study.
Anderson, K. E., Anderson, E. L., Mink, P. J., Hong, C. P., Kushi, L. H., Sellers, T. A., Lazovich, D., & Folsom, A. R. (2001) · PubMed · Cited by 139 · see citing works
Advanced glycation end products and their relevance in female reproduction
Merhi, Z. O. (2013) · Human Reproduction · doi:10.1093/humrep/det383 · Cited by 137 · see citing works
“Both insulin-like growth factor-1 (IGF-1) and insulin are potent stimulators of ovarian androgen production, an action likely mediated via the insulin receptor (Burghen et al., 1980; Barbieri et al., 1988).”
Background
Insulin Resistance in PCOS
Diamanti‐Kandarakis, E. (2006) · Endocrine · doi:10.1385/endo:30:1:13 · Cited by 136 · see citing works
Juvenile acanthosis nigricans
Sinha, S., & Schwartz, R. A. (2007) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2006.08.016 · Cited by 134 · see citing works
Insulin as an Effector of Human Ovarian and Adrenal Steroid Metabolism
Nestler, J. E., & Strauss, J. F. (1991) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(18)30245-7 · Cited by 133 · see citing works
Hyperinsulinemia is common in family members of women with polycystic ovary syndrome
Norman, R. J., Masters, S. C., & Hague, W. M. (1996) · Fertility and Sterility · doi:10.1016/s0015-0282(16)58687-7 · Cited by 132 · see citing works
Effects of Rosiglitazone in Obese Women with Polycystic Ovary Syndrome and Severe Insulin Resistance
Sepilian, V., & Nagamani, M. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1376 · Cited by 130 · see citing works
Randomized Placebo-Controlled Trial of Metformin for Adolescents With Polycystic Ovary Syndrome
Bridger, T., MacDonald, S., Baltzer, F., & Rodd, C. (2006) · Archives of Pediatrics & Adolescent Medicine · doi:10.1001/archpedi.160.3.241 · Cited by 126 · see citing works
“Although the pathogenesis is not fully understood, evidence suggests insulin resistance and hyperinsulinemia play a key pathophysiologic role by promoting excess androgen production from both the ovaries and adrenal glands.(10,11) Many studies have demonstrated improvement of hyperinsulinemia, hyperandrogenemia, and c…”
Obstetric and neonatal outcome in women with a history of recurrent miscarriage: a cohort study
Jivraj, S., Anstie, B., Cheong, Y. C., Fairlie, F., Laird, S. M., & Li, T. C. (2001) · Human Reproduction · doi:10.1093/humrep/16.1.102 · Cited by 126 · see citing works
Hormonal treatment of acne vulgaris: an update
Elsaie, M. L. (2016) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s114830 · Cited by 122 · see citing works
“Insulin has a direct stimulant effect on androgenesis besides inhibiting the SHBG synthesis by the liver.(26) Of interest, 50% of cases with ovarian hyperandrogenism experience an existing functional adrenal hyperandrogenism.”
The Impact of Insulin Secretion on the Ovarian Response to Exogenous Gonadotropins in Polycystic Ovary Syndrome
Fulghesu, A. M., Villa, P., Pavone, V., Guido, M., Apa, R., Caruso, A., Lanzone, A., Rossodivita, A., & Mancuso, S. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.2.3727 · Cited by 128 · see citing works
A Systematic Review of the Effects of Exercise on Hormones in Women with Polycystic Ovary Syndrome
Shele, G., Genkil, J., & Speelman, D. L. (2020) · Journal of Functional Morphology and Kinesiology · doi:10.3390/jfmk5020035 · Cited by 131 · see citing works
Diagnosis and management of the dermatologic manifestations of the polycystic ovary syndrome
Lowenstein, E. J. (2006) · Dermatologic Therapy · doi:10.1111/j.1529-8019.2006.00077.x · Cited by 111 · see citing works
“The hyperandrogenism, insulin resistance and AN syndrome (HAIR-AN) is considered a severe variant or subphenotype of PCOS, often with genetic and familial predisposition (53).”
Background
The Relation of Type 2 Diabetes and Cancer
Strickler, H. D., Wylie‐Rosett, J., Rohan, T. E., Hoover, D. R., Smoller, S., Burk, R. D., & Yu, H. (2001) · Diabetes Technology & Therapeutics · doi:10.1089/152091501300209633 · Cited by 114 · see citing works
Clinical Manifestations and Treatment of Dysfunctional Uterine Bleeding
Bayer, S. R. (1993) · JAMA · doi:10.1001/jama.1993.03500140075039 · Cited by 113 · see citing works
Dietary glycemic index and glucose, insulin, insulin-like growth factor-I, insulin-like growth factor binding protein 3, and leptin levels in patients with acne
Kaymak, Y., Adisen, E., Ilter, N., Bideci, A., Gurler, D., & Celik, B. (2007) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2007.06.028 · Cited by 113 · see citing works
Direct Thiazolidinedione Action in the Human Ovary: Insulin-Independent and Insulin-Sensitizing Effects on Steroidogenesis and Insulin-Like Growth Factor Binding Protein-1 Production
Seto‐Young, D., Paliou, M., Schlosser, J., Avtanski, D. B., Park, A., Patel, P., Holcomb, K., Chang, P., & Poretsky, L. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0469 · Cited by 107 · see citing works
Comparison of nonspecific indications and quantitative methods for the assessment of insulin resistance in horses and ponies.
Kronfeld, D., Treiber, K., & Geor, R. (2005) · Journal of the American Veterinary Medical Association · doi:10.2460/javma.2005.226.712 · Cited by 109 · see citing works
Menstrual Irregularity in Women with Acromegaly
Kaltsas, G., Mukherjee, J. J., Jenkins, P. J., Satta, M. A., Islam, N., Monson, J. P., BESSER, G. M., & Grossman, A. B. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.8.5858 · Cited by 108 · see citing works
“Acromegaly induces hyperinsulinemia and an insulin-resistant state (21), and excessive GH levels can increase androgen secretion (13, 22, 23), whereas the severity of the clinical expression of PCOS is affected by both the degree of hyperandrogenism and insulin resistance (24).”
Background
Adipose tissue expandability and the early origins of PCOS
de Zegher, F., López‐Bermejo, A., & Ibáñez, L. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.06.003 · Cited by 108 · see citing works
Effect of insulin-like growth factor-I treatment on serum androgens and testicular and penile size in males with Laron syndrome (primary growth hormone resistance)
Laron, Z., & Klinger, B. (1998) · European Journal of Endocrinology · doi:10.1530/eje.0.1380176 · Cited by 107 · see citing works
Hormone Profiles in Young Adults with Epilepsy Treated with Sodium Valproate or Lamotrigine Monotherapy
Stephen, L. J., Kwan, P., Shapiro, D., Dominiczak, M. H., & Brodie, M. J. (2001) · Epilepsia · doi:10.1046/j.1528-1157.2001.0420081002.x · Cited by 106 · see citing works
“Affected women can also have an elevated serum luteinising hormone (LH)/ follicle-stimulating hormone (FSH) ratio, but this is a less sensitive marker (12,15).”
Background
Ovarian stromal hypertrophy in hyperandrogenic women
Dewailly, D., Robert, Y., Helln, I., Ardaens, Y., Thomas‐Desrousseaux, P., Lemaltre, L., & Fossati, P. (1994) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1994.tb01818.x · Cited by 107 · see citing works
“Insulin resistance with its compensatory hyperinsulinism is a common finding in women with PCOS (Barbieri et al., 1988).”
Background
MANAGEMENT OF ENDOCRINE DISEASE: Hyperandrogenism after menopause
Markopoulos, M. C., Kassi, E., Alexandraki, K., Mastorakos, G. P., & Kaltsas, G. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0468 · Cited by 106 · see citing works
The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome
Ünlühızarcı, K., Keleştimur, F., Bayram, F., Şahin, Y., & Tutuş, A. (1999) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1999.00786.x · Cited by 104 · see citing works
“…to obesity (Changet al., 1983; Barbieriet al.,1988; Nestleret al.,1989a) and appears to play a key pathogenetic role in the ovarian androgen overproduction (Barbieri et al., 1988; Willis et al., 1996) and glucose intolerance in PCOS (Ciaraldiet al., 1992; Ehrmannet al., 1995; Dunaifet al., 1996).”
Background
The central role of obesity (hyperinsulinemia) in the pathogenesis of the polycystic ovary syndrome
Nestler, J. E., Clore, J. N., & Blackard, W. G. (1989) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(89)90640-6 · Cited by 103 · see citing works
Ethnic differences in insulin and glucose response to glucose between white and Indian women with polycystic ovary syndrome
Norman, R. J., Mahabeer, S., & Masters, S. C. (1995) · Fertility and Sterility · doi:10.1016/s0015-0282(16)57297-5 · Cited by 102 · see citing works
The Effect of a Desogestrel-Containing Oral Contraceptive on Glucose Tolerance and Leptin Concentrations in Hyperandrogenic Women
Nader, S., Riad, M. G., & Saad, M. F. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.9.4192 · Cited by 100 · see citing works
A pilot study to determine the short-term effects of a low glycemic load diet on hormonal markers of acne: a nonrandomized, parallel, controlled feeding trial
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Authors: Wallach, E. E., Barbieri, R. L., Smith, S., & Ryan, K. J.
Affiliations: Brigham and Women's Hospital (US)
ORCID: Barbieri, Robert L.
Ryan, Kenneth J.
Venue: Fertility and Sterility
Publisher: Elsevier BV
Published: 1988-08
Volume: 50
Issue: 2
Pages: 197-212
ISSN: 0015-0282 (ISSN-L)
DOI: 10.1016/s0015-0282(16)60060-2
OpenAlex: W194639418
Cited by: 348
References: 108
Citations by year: 2026: 4 · 2025: 6 · 2024: 3 · 2023: 9 · 2022: 9 · 2021: 8 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 6 · 2015: 5 · 2014: 7 · 2013: 4 · 2012: 2
FWCI: 10.95
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 12352 d)
Locations: Fertility and Sterility (publishedVersion)
PubMed (publishedVersion)
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: hyperinsulinemia, ovarian hyperandrogenism, polycystic ovary syndrome, androgen overproduction, PCOS pathogenesis, insulin resistance, hypothalamic-pituitary-ovarian axis, adrenal androgen production
MeSH terms: Acanthosis Nigricans, Androgens, Female, Humans, Hyperinsulinism, Insulin Resistance, Ovary, Polycystic Ovary Syndrome, Syndrome

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The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism

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