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SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance

Background Patients with severe insulin resistance have ovarian hyperthecosis, high testosterone (T) and minimal adipose tissue. Recent studies have found elevated levels of 11-oxygenated (11-oxy) androgens in women with polycystic ovary syndrome (PCOS) compared to age and sex-matched controls. 11-o...

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Autores principales: Jha, Smita, Turcu, Adina, Brookner, Brittany, Abel, Brent Samuel, Startzell, Megan, Auchus, Richard Joseph, Brown, Rebecca J, Merke, Deborah P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209492/
http://dx.doi.org/10.1210/jendso/bvaa046.2298
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author Jha, Smita
Turcu, Adina
Brookner, Brittany
Abel, Brent Samuel
Startzell, Megan
Auchus, Richard Joseph
Brown, Rebecca J
Merke, Deborah P
author_facet Jha, Smita
Turcu, Adina
Brookner, Brittany
Abel, Brent Samuel
Startzell, Megan
Auchus, Richard Joseph
Brown, Rebecca J
Merke, Deborah P
author_sort Jha, Smita
collection PubMed
description Background Patients with severe insulin resistance have ovarian hyperthecosis, high testosterone (T) and minimal adipose tissue. Recent studies have found elevated levels of 11-oxygenated (11-oxy) androgens in women with polycystic ovary syndrome (PCOS) compared to age and sex-matched controls. 11-oxy-androgens are produced by CYP11B1, an enzyme expressed predominantly in the adrenal, with minor ovarian expression. We analyzed 11-oxy-androgens in women with severe insulin resistance. Methods We performed retrospective analysis of women with severe insulin resistance (lipodystrophy or insulin receptor defects) seen at the NIH and identified 19 patients with testosterone ≥ 80 ng/dl (immunoassay) and available serum samples. Quantitation of androgens was performed by LC-MS/ MS and compared to age, sex and BMI-matched controls. Data between groups was compared using non-parametric Mann-Whitney U test. Correlation analyses utilized the Pearson and Spearman’s rho. Results Median patient age was 18yrs (IQR 17-26) with median fasting insulin of 63mcU/ mL (IQR 40-184). Serum insulin correlated strongly with fold elevation of T in patients relative to controls (r= 0.47, P=0.04). Median levels of all androgens except 11-hydroxytestosterone (11OHT) were significantly higher in patients than controls, including 11-ketotestosterone (11KT), a clinically relevant androgen in both congenital adrenal hyperplasia and PCOS [69 ng/dl (IQR 27-82) vs 24 ng/dl (IQR 16-40), P < 0.001]. 11KT/ T was lower in patients (0.30, IQR 0.12-1.15) compared to controls (1.1, IQR 0.41-1.5, P = 0.04). All 11-oxy-androgens correlated with each other (r(s) range: 0.6-0.8, P < .05) in both groups. There was no difference in the proportionate contribution of 11-oxy-androgens to the total circulating androgenic pool in patients vs. controls. Conclusion: Elevated 11-oxy-androgens in patients with severe insulin resistance suggests that both adrenal and ovarian androgens are upregulated by hyperinsulinemia. Lower 11KT/T in patients compared to controls despite higher 11-oxy-androgens than in controls is consistent with predominant ovarian T excess in patients with severe IR. Correlation between insulin and fold elevation of T relative to controls supports hyperinsulinemia as the cause of high T in states of hyperinsulinism. Acknowledgement: This research was supported by the Intramural Program of NIH Clinical Center and NIDDK.
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spelling pubmed-72094922020-05-13 SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance Jha, Smita Turcu, Adina Brookner, Brittany Abel, Brent Samuel Startzell, Megan Auchus, Richard Joseph Brown, Rebecca J Merke, Deborah P J Endocr Soc Reproductive Endocrinology Background Patients with severe insulin resistance have ovarian hyperthecosis, high testosterone (T) and minimal adipose tissue. Recent studies have found elevated levels of 11-oxygenated (11-oxy) androgens in women with polycystic ovary syndrome (PCOS) compared to age and sex-matched controls. 11-oxy-androgens are produced by CYP11B1, an enzyme expressed predominantly in the adrenal, with minor ovarian expression. We analyzed 11-oxy-androgens in women with severe insulin resistance. Methods We performed retrospective analysis of women with severe insulin resistance (lipodystrophy or insulin receptor defects) seen at the NIH and identified 19 patients with testosterone ≥ 80 ng/dl (immunoassay) and available serum samples. Quantitation of androgens was performed by LC-MS/ MS and compared to age, sex and BMI-matched controls. Data between groups was compared using non-parametric Mann-Whitney U test. Correlation analyses utilized the Pearson and Spearman’s rho. Results Median patient age was 18yrs (IQR 17-26) with median fasting insulin of 63mcU/ mL (IQR 40-184). Serum insulin correlated strongly with fold elevation of T in patients relative to controls (r= 0.47, P=0.04). Median levels of all androgens except 11-hydroxytestosterone (11OHT) were significantly higher in patients than controls, including 11-ketotestosterone (11KT), a clinically relevant androgen in both congenital adrenal hyperplasia and PCOS [69 ng/dl (IQR 27-82) vs 24 ng/dl (IQR 16-40), P < 0.001]. 11KT/ T was lower in patients (0.30, IQR 0.12-1.15) compared to controls (1.1, IQR 0.41-1.5, P = 0.04). All 11-oxy-androgens correlated with each other (r(s) range: 0.6-0.8, P < .05) in both groups. There was no difference in the proportionate contribution of 11-oxy-androgens to the total circulating androgenic pool in patients vs. controls. Conclusion: Elevated 11-oxy-androgens in patients with severe insulin resistance suggests that both adrenal and ovarian androgens are upregulated by hyperinsulinemia. Lower 11KT/T in patients compared to controls despite higher 11-oxy-androgens than in controls is consistent with predominant ovarian T excess in patients with severe IR. Correlation between insulin and fold elevation of T relative to controls supports hyperinsulinemia as the cause of high T in states of hyperinsulinism. Acknowledgement: This research was supported by the Intramural Program of NIH Clinical Center and NIDDK. Oxford University Press 2020-05-08 /pmc/articles/PMC7209492/ http://dx.doi.org/10.1210/jendso/bvaa046.2298 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Reproductive Endocrinology
Jha, Smita
Turcu, Adina
Brookner, Brittany
Abel, Brent Samuel
Startzell, Megan
Auchus, Richard Joseph
Brown, Rebecca J
Merke, Deborah P
SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance
title SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance
title_full SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance
title_fullStr SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance
title_full_unstemmed SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance
title_short SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance
title_sort sun-lb4 androgenic profiles of patients with severe insulin resistance
topic Reproductive Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209492/
http://dx.doi.org/10.1210/jendso/bvaa046.2298
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