Ovarian Hyperandrogenism and Response to Gonadotropin-releasing Hormone Analogues in Primary Severe Insulin Resistance.

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Huang-Doran, Isabel  ORCID logo  https://orcid.org/0000-0002-0573-6557
Kinzer, Alexandra B 
Jimenez-Linan, Mercedes 
Thackray, Kerrie 
Harris, Julie 

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.

GnRH analogue, Polycystic ovary syndrome, androgen, hyperinsulinemia, insulin receptor, lipodystrophy, Adolescent, Adult, Aged, Child, Child, Preschool, Female, Fertility Agents, Female, Gonadotropin-Releasing Hormone, Humans, Hyperandrogenism, Infant, Insulin, Insulin Resistance, Lipodystrophy, Middle Aged, Ovary, Polycystic Ovary Syndrome, Retrospective Studies, Sex Hormone-Binding Globulin, Testosterone, Young Adult
Journal Title
J Clin Endocrinol Metab
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The Endocrine Society
Wellcome Trust (100574/Z/12/Z)
Wellcome Trust (107064/Z/15/Z)
MRC (MC_UU_00014/5)
Wellcome Trust (095515/Z/11/Z)
Wellcome Trust (214274/Z/18/Z)