A Direct Effect of Hyperinsulinemia on Serum Sex Hormone-Binding Globulin Levels in Obese Women with the Polycystic Ovary Syndrome*

NESTLER, JOHN E.; POWERS, LINDA P.; MATT, DENNIS W.; STEINGOLD, KENNETH A.; PLYMATE, STEPHEN R.; RITTMASTER, ROGER S.; CLORE, JOHN N.; BLACKARD, WILLIAM G.

doi:10.1210/jcem-72-1-83

Cited by 816Ovarian function and disordersHormonal and reproductive studiesDiabetes, Cardiovascular Risks, and Lipoproteins

A Direct Effect of Hyperinsulinemia on Serum Sex Hormone-Binding Globulin Levels in Obese Women with the Polycystic Ovary Syndrome*

NESTLER, JOHN E., POWERS, LINDA P., MATT, DENNIS W., STEINGOLD, KENNETH A., PLYMATE, STEPHEN R., RITTMASTER, ROGER S., CLORE, JOHN N., BLACKARD, WILLIAM G.·1991·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jcem-72-1-83

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Abstract

To determine whether hyperinsulinemia can directly reduce serum sex hormone-binding globulin (SHBG) levels in obese women with the polycystic ovary syndrome, six obese women with this disorder were studied. Before study, ovarian steroid production was suppressed in each woman by the administration of 7.5 mg of a long-acting GnRH agonist, leuprolide depot, im, on days -56, -28, and 0. This resulted in substantial reductions in serum concentrations of testosterone (from 1.72 +/- 0.29 nmol/L on day -56 to 0.32 +/- 0.09 nmol/L on day 0), non-SHBG-bound testosterone (from 104 +/- 16 pmol/L on day -56 to 19 +/- 5 pmol/L on day 0), androstenedione (from 7.25 +/- 1.65 nmol/L on day -56 to 2.78 +/- 0.94 nmol/L on day 0), estrone (from 371 +/- 71 pmol/L on day -56 to 156 +/- 29 pmol/L on day 0), estradiol (from 235 +/- 26 pmol/L on day -56 to 90 +/- 24 pmol/L on day 0), and progesterone (from 0.28 +/- 0.12 nmol/L on day -56 to 0.08 +/- 0.02 nmol/L on day 0). Serum SHBG levels, however, did not change (18.8 +/- 2.8 nmol/L on day -56 vs. 17.8 +/- 2.6 nmol/L on day 0). While continuing leuprolide treatment, the women were administered oral diazoxide (300 mg/day) for 10 days to suppress serum insulin levels. Diazoxide treatment resulted in suppressed insulin release during a 100-g oral glucose tolerance test (insulin area under the curve, 262 +/- 55 nmol/min.L on day 0 vs. 102 +/- 33 nmol/min.L on day 10; P less than 0.05) and deterioration of glucose tolerance. Serum testosterone, androstenedione, estrone, estradiol, and progesterone levels did not change during combined diazoxide and leuprolide treatment. In contrast, serum SHBG levels rose by 32% from 17.8 +/- 2.6 nmol/L on day 0 to 23.5 +/- 2.0 nmol/L on day 10 (P less than 0.003). Due primarily to the rise in serum SHBG levels, serum non-SHBG-bound testosterone levels fell by 43% from 19 +/- 5 pmol/L on day 0 to 11 +/- 4 pmol/L on day 10 (P = 0.05). These observations suggest that hyperinsulinemia directly reduces serum SHBG levels in obese women with the polycystic ovary syndrome independently of any effect on serum sex steroids.

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Hyperinsulinaemia indirectly inhibits hepatic SHBG production, thus increasing free testosterone.
“Hyperinsulinaemia also plays an indirect role in hyperandrogenism by inhibiting hepatic sex hormone-binding globulin (SHBG) production, thus increasing free testosterone (Kiddy et al., 1989;Nestler et al., 1991).”
From Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic–hyperinsulinaemic clamp studies (2016) · cites this paper as Nestler et al., 1991
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 [6]

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Suppression of Serum Insulin by Diazoxide Reduces Serum Testosterone Levels in Obese Women with Polycystic Ovary Syndrome*
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Suppression of serum insulin level by diazoxide does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese women
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Authors: NESTLER, J. E., POWERS, L. P., MATT, D. W., STEINGOLD, K. A., PLYMATE, S. R., RITTMASTER, R. S., CLORE, J. N., & BLACKARD, W. G.
Affiliations: Madigan Army Medical Center (US)
ORCID: PLYMATE, STEPHEN R.
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 1991-01
Volume: 72
Issue: 1
Pages: 83-89
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jcem-72-1-83
OpenAlex: W2008509267
Cited by: 815
References: 38
Citations by year: 2026: 13 · 2025: 22 · 2024: 25 · 2023: 25 · 2022: 28 · 2021: 38 · 2020: 27 · 2019: 25 · 2018: 18 · 2017: 25 · 2016: 25 · 2015: 30 · 2014: 22 · 2013: 27 · 2012: 18
FWCI: 10.34
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (DK-18904)
National Center for Research Resources (RR 00065, M01RR000065)
Topics: Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: hyperinsulinemia, sex hormone-binding globulin, polycystic ovary syndrome, obesity, insulin resistance, diazoxide, leuprolide, GnRH agonist, testosterone, androstenedione, estradiol, estrone, glucose tolerance, insulin secretion, ovarian steroidogenesis, glucose-insulin interaction, insulin sensitivity index, insulin resistance index
MeSH terms: Adult, Androstenedione, Diazoxide, Estradiol, Estrone, Female, Glucose Tolerance Test, Humans, Insulin, Insulin Resistance, Gonadotropin-Releasing Hormone, Obesity, Polycystic Ovary Syndrome, Progesterone, Sex Hormone-Binding Globulin, Testosterone, Androstane-3,17-diol, Leuprolide

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A Direct Effect of Hyperinsulinemia on Serum Sex Hormone-Binding Globulin Levels in Obese Women with the Polycystic Ovary Syndrome*

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