Insulin Resistance, Hyperinsulinemia, and LH: Relative Roles in Peripubertal Obesity-Associated Hyperandrogenemia

Abstract

Context: Peripubertal obesity is associated with variable hyperandrogenemia, but precise mechanisms remain unclear.

Objective: To assess insulin resistance, hyperinsulinemia, and LH roles in peripubertal obesity-associated hyperandrogenemia.

Design: Cross-sectional analysis.

Setting: Academic clinical research unit.

Participants: Eleven obese (body mass index for age ≥95%) peripubertal girls.

Intervention: Blood samples were taken during a mixed-meal tolerance test (1900 to 2100), overnight (2100 to 0700), while fasting (0700 to 0900), and during an 80 mU/m2/min hyperinsulinemic-euglycemic clamp (0900 to 1100).

Main outcome measures: The dependent variable was morning free testosterone level; independent variables were insulin sensitivity index (ISI), estimated 24-hour insulin, and estimated 24-hour LH levels.

Results: All participants demonstrated insulin resistance and hyperinsulinemia. ISI, but not estimated 24-hour insulin level, correlated positively with morning free testosterone level when correcting for estimated 24-hour LH level and Tanner stage (rs = 0.68, P = 0.046). The correlation between estimated 24-hour LH and free testosterone levels approached significance after adjusting for estimated 24-hour insulin level and Tanner stage (rs = 0.63, P = 0.067). Estimated 24-hour insulin level did not correlate with free testosterone level after adjusting for estimated 24-hour LH level and Tanner stage (rs = 0.47, P = 0.20).

Conclusion: In insulin-resistant obese girls with hyperinsulinemia, free testosterone levels correlated positively with insulin sensitivity and, likely, circulating LH concentrations but not with circulating insulin levels. In the setting of relatively uniform hyperinsulinemia, variable steroidogenic-cell insulin sensitivity may correlate with metabolic insulin sensitivity and contribute to variable free testosterone concentrations.

Trial registration: ClinicalTrials.gov NCT00928759.

Figures

Figure 1.

Study protocol and insulin levels. (a) Schematic of the study protocol. (b) Insulin levels achieved during study (mean ± SEM). Specifically, insulin was measured before and after mixed-meal ingestion, during an observed overnight fast, and during a hyperinsulinemic-euglycemic clamp.

Figure 2.

Potential predictors of free T (simple relationships). Simple relationship between (a) ISI and morning free-T level; (b) estimated 24-hour mean insulin and morning free-T levels; and (c) estimated 24-hour mean LH and morning free-T levels. Numbers associated with data points denote participant numbers that correspond to participant-level data.

Figure 3.

Adiposity, insulin sensitivity, and insulin secretion. ISI was not significantly correlated with either (a) BMI z-scores or (b) estimated average 24-hour insulin concentrations. (c) A plot of ISI vs insulinogenic index during the MMTT did not clearly demonstrate the expected curvilinear relationship.

Figure 4.

A hypothetical model. This model stipulates steroidogenic cell insulin sensitivity is a determinant of androgen production, and that although steroidogenic-cell insulin sensitivity is substantially greater than peripheral (muscle) metabolic insulin sensitivity (in keeping with the insulin paradox), it correlates positively with peripheral metabolic insulin sensitivity. The figure denotes how plasma insulin levels generally increase as a function of worsening ISI [i.e., increasing peripheral (muscle) metabolic insulin resistance], but insulin concentrations may plateau (i.e., may not vary as a simple function of insulin sensitivity) due to emerging β-cell failure. The shaded area labeled “A” represents the putative range within which the strong relationship between insulin and T concentrations masks a positive correlation between insulin sensitivity and T. The shaded area labeled “B” represents the putative range within which hyperinsulinemia may be marked but may not vary as a simple function of insulin sensitivity, thus unmasking a positive correlation between insulin sensitivity and T.