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Context Insulin resistance (IR) is associated with polycystic ovaries and hyperandrogenism, but underpinning mechanisms are poorly understood and therapeutic options are limited. Objective To characterize hyperandrogenemia and ovarian pathology in primary severe IR (SIR), using IR of defined molecular etiology to interrogate disease mechanism. To extend evaluation of gonadotropin-releasing hormone (GnRH) analogue therapy in SIR. Methods Retrospective case note review in 2 SIR national referral centers. Female patients with SIR with documented serum total testosterone (TT) concentration. Results Among 185 patients with lipodystrophy, 65 with primary insulin signaling disorders, and 29 with idiopathic SIR, serum TT ranged from undetectable to 1562 ng/dL (54.2 nmol/L; median 40.3 ng/dL [1.40 nmol/L]; n = 279) and free testosterone (FT) from undetectable to 18.0 ng/dL (0.625 nmol/L; median 0.705 ng/dL [0.0244 nmol/L]; n = 233). Higher TT but not FT in the insulin signaling subgroup was attributable to higher serum sex hormone–binding globulin (SHBG) concentration. Insulin correlated positively with SHBG in the insulin signaling subgroup, but negatively in lipodystrophy. In 8/9 patients with available ovarian tissue, histology was consistent with polycystic ovary syndrome (PCOS). In 6/6 patients treated with GnRH analogue therapy, gonadotropin suppression improved hyperandrogenic symptoms and reduced serum TT irrespective of SIR etiology. Conclusion SIR causes severe hyperandrogenemia and PCOS-like ovarian changes whether due to proximal insulin signaling or adipose development defects. A distinct relationship between IR and FT between the groups is mediated by SHBG. GnRH analogues are beneficial in a range of SIR subphenotypes.

Background: There is an association between insulin resistance (IR) and hyperuricemia but the direction of causalityand mechanisms are unclear. In obesity and lipodystrophy, IR is “selective”, with lack of insulin signalingcausing hyperglycemia, but enhanced insulin signaling causing dyslipidemia and possibly hyperuricemia. Rare human conditions exist in which there is extreme, non-selective, IR impairing all insulin signalingpathways (e.g. mutations of the insulin receptor, INSR). We hypothesized that hyperinsulinemia withenhanced signaling through the insulin receptor causes hyperuricemia in selective IR, whereas lack ofinsulin signaling through its receptor despite hyperinsulinemia results in normal uricemia in non-selective IR. Method: Cross-sectional retrospective analysis comparing fasting insulin and serum uric acid in patients withsevere IR that was either selective (due to lipodystrophy) or non-selective (due to INSR mutation orautoantibody to the insulin receptor). Visits were chosen based on availability of serum uric acid andinsulin. If multiple visits were available, the visit with the highest insulin value was chosen. Results: We analyzed data of 68 patients with selective IR and 14 patients with non-selective IR. Fasting seruminsulin median [interquartile range] was 23.4 [14, 53] mcU/mL in selective IR vs 215 [73.7, 604] in non-selective IR, p