Ovarian Hyperandrogenism and Response to Gonadotropin-releasing Hormone Analogues in Primary Severe Insulin Resistance.
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Authors
Kinzer, Alexandra B
Jimenez-Linan, Mercedes
Thackray, Kerrie
Harris, Julie
Adams, Claire L
de Kerdanet, Marc
Stears, Anna
O'Rahilly, Stephen
Savage, David B
Gorden, Phillip
Publication Date
2021-07-13Journal Title
J Clin Endocrinol Metab
ISSN
0021-972X
Publisher
The Endocrine Society
Volume
106
Issue
8
Pages
2367-2383
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
Huang-Doran, I., Kinzer, A. B., Jimenez-Linan, M., Thackray, K., Harris, J., Adams, C. L., de Kerdanet, M., et al. (2021). Ovarian Hyperandrogenism and Response to Gonadotropin-releasing Hormone Analogues in Primary Severe Insulin Resistance.. J Clin Endocrinol Metab, 106 (8), 2367-2383. https://doi.org/10.1210/clinem/dgab275
Abstract
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.
Keywords
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
Sponsorship
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)
Identifiers
External DOI: https://doi.org/10.1210/clinem/dgab275
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333539
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