11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome

Abstract

Background/context Polycystic ovary syndrome (PCOS) is common and diagnosis requires an elevated testosterone. The clinical importance of adrenal 11-oxyandrogens in PCOS is unclear. We sought to determine if 11-oxyandrogens: 1) better identify PCOS diagnosis compared to testosterone 2) predict clinical comorbidities of PCOS, 3) are altered with combined oral contraceptive pill (COCP) or metformin therapy. Methods Data from 200 adolescent females aged 12-21 years, most with obesity, enrolled across 6 studies in pediatric endocrinology were included: 70 non-PCOS controls, 115 untreated PCOS, 9 PCOS+obesity treated with COCP, 6 PCOS+obesity treated with metformin. 11-hydroxyandrostenedione (11OHA4), 11-hydroxytestosterone (1-OHT), 11-ketotestosterone (11KT) and testosterone were measured with LC/MSMS. Data between 1) untreated PCOS and controls and 2) untreated PCOS and the 2 treatment groups were compared. Results Untreated girls with PCOS had higher 11OHA4 (p=0.003) and 11OHT (p=0.005) compared to controls, but not 11KT (p=0.745). Elevated 11OHA4 remained significant after controlling for obesity. Testosterone better predicted PCOS status compared to 11-oxyandrogens (ROC analysis: 11OHA4 AUC=0.620, 11OHT AUC=0.638; testosterone AUC=0.840). Among untreated PCOS, all three 11-oxyandrogens correlated with hirsutism severity. 11KT (p=0.039) and testosterone (p<0.006) was lower in those on COCP treatment compared to untreated PCOS). Metformin treatment had no effect on 11-oxyandrogens, although testosterone was lower (p=0.01). Conclusions/Relevance While 11-oxyandrogens do not aid in the diagnosis of PCOS, they relate to excess hair growth. COCP treatment may related to 11-KT, however, further work is needed to determine causality, relationship with metabolic outcomes, and the clinical utility of measuring these androgens in PCOS.

Case report: 11-ketotestosterone may potentiate advanced bone age as seen in some cases of Wiedemann-Steiner Syndrome

“…Early elevated 11KT may reflect the premature onset of adrenal gland maturation. The recent elucidation of conditions such as premature adrenarche and polycystic ovary syndrome manifesting with elevated 11KT ( 26 ), supports the notion of a mechanistic role for 11KT in premature adrenarche and conditions causing androgen excess. It is unclear if the increasing 11KT has a specific androgenic affinity for peripheral tissues such as bone and promotes skeletal maturation.…”

11-Oxygenated androgens are not secreted by the human ovary: in-vivo data from four different cases of hyperandrogenism

“…There was no difference in 11-KT levels obtained from the different sampling sites, again challenging the idea of a primarily ovarian 11-KT biosynthesis. While all published studies on PCOS and 11-oxygenated androgens ( 19 , 20 , 27 ) showed elevated levels of 11-OHA4 in comparison to controls, 11-KT seems only to be elevated in some ( 19 , 20 ), but not all women with PCOS ( 19 , 27 ). An elevation of 11-KT seems to be primarily found in women with PCOS who are obese but not in those who are only over- or normal-weighted ( 19 , 20 ).…”

“…It has been shown that 11-oxygenated androgens are elevated in adrenal-related androgen excess as congenital adrenal hyperplasia (CAH) or premature adrenarche and Cushing's disease [14,17,18]. In addition, they may also be elevated in some [19,20], but not all patients [21] with PCOS. However, as there is also in-vitro data claiming that there is a relevant production of 11-KT derived from the gonads [15], details of the biosynthesis of 11-oxygenated androgens in humans are debatable as direct evidence in terms of in-vivo data of localized secretion patterns is absent.…”

Criteria for Diagnosis of Polycystic Ovary Syndrome during Adolescence: Literature Review

“…The presence of hirsutism and acne was similar among the adolescents with PCOS diagnosed using Rotterdam or NIH criteria [ 68 ]. Lower mean mFG scores (6–8.5) were reported in cohorts of adolescents with PCOS in the USA including Hispanics and black adolescents [ 69 , 70 ]. Hirsutism defined as mFG score higher than 6 and higher than 8 was reported in 60–70% and 50% of adolescents with PCOS respectively [ 8 , 68 , 70 ].…”

“…Hirsutism defined as mFG score higher than 6 and higher than 8 was reported in 60–70% and 50% of adolescents with PCOS respectively [ 8 , 68 , 70 ]. Higher hirsutism scores are related to higher testosterone levels according to population and cross-sectional studies of adolescents [ 59 , 60 , 69 , 71 , 72 ]. Hirsutism must also be distinguished from hypertrichosis, which is defined as excessive vellus hair distributed in a non-sexual pattern.…”