AKR1C3-mediated adipose androgen generation drives lipotoxicity in polycystic ovary syndrome

Sex hormones, adiposity, and metabolic traits in men and women: a Mendelian randomisation study

“…Exposure to chronic androgen excess in women with PCOS was shown to suppress SAT lipolysis in some studies (13,35,36) and to impair SAT lipoprotein lipase activity, which controls the delivery of fatty acids from circulating triglyceride-rich lipoproteins to AT (13).…”

“…AT is also capable of androgen generation and might contribute to the higher BioT levels associated with obesity. Specifically, the androgen-activating enzyme aldoketoreductase type 1C3 (AKR1C3), generates testosterone from the androgenic precursor androstenedione, is abundantly expressed in AT and its SAT expression is induced in obesity, PCOS, and hyperinsulinaemia (35,45). Indeed, increased SAT AKR1C3 activity was shown to contribute to circulating androgen levels in PCOS women (35).…”

“…Specifically, the androgen-activating enzyme aldoketoreductase type 1C3 (AKR1C3), generates testosterone from the androgenic precursor androstenedione, is abundantly expressed in AT and its SAT expression is induced in obesity, PCOS, and hyperinsulinaemia (35,45). Indeed, increased SAT AKR1C3 activity was shown to contribute to circulating androgen levels in PCOS women (35). We further show that genetically instrumented android fat distribution is also associated with raised BioT, with direct effects of genetic variants on insulin resistance, circulating leptin levels, and reproductive tract tumour susceptibility potentially accounting for the horizontal pleiotropy detected for this link.…”

Development of a LC-MS/MS method to measure serum 3-sulfate and 3-glucuronide 25-hydroxyvitamin D3 metabolites; comparisons to unconjugated 25OHD in pregnancy and polycystic ovary syndrome

“…Pregnancy and healthy control serum sample collection and ethical approval has been described previously (NHS REC approval 06/Q2707/12 and 13/WM/0178 [2014-2024]) (23). Women with PCOS aged between 18 and 40 years were recruited from outpatient clinics at University Hospitals Birmingham and Birmingham Women's Hospital as previously reported (25) Exclusion criteria for the study were as follows: recent glucocorticoid treatment (within 3 months), pregnancy, age younger than 18 or older than 45 years, recent oral contraceptive use (within 3 months), hyperprolactinemia, thyroid disorders, and dysglycemia (impaired fasting glucose, impaired glucose tolerance or overt diabetes mellitus). PCOS women were also excluded if they had received prior treatment with metformin, insulin sensitizers or androgen receptor blockers.…”

“…Vitamin D3 is produced from 7-dehydrocholestorol following UV radiation of skin. Then twostep hydroxylation generates the vitamin D receptor (VDR)-binding metabolite 1,25dihydroxyvitamin D3 (1,25(OH)2D3) (1)(2)(3). The first metabolite formed from vitamin D by the action of the enzyme vitamin D-25-hydroxylase (CYP2R1 and CYP27A1) (4, 5) is 25hydroxyvitamin D3 (25OHD3), the most abundant serum metabolite of vitamin D. Because of its long half-life and high abundance in circulation, the serum measurement of 25OHD (combining 25OHD3 and 25OHD2) is currently considered to be the most reliable estimation of vitamin D status for any given individual, even though 25OHD3 is not the biologically active form of vitamin D (6,7).…”