Endocrine Abstracts

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is associated with metabolic disorders such as obesity, dyslipidemia, systemic insulin resistance (IR), and adipose IR. Hyperandrogenism is prevalent in PCOS and is linked to metabolic dysfunction in multiple tissues, including WAT. However, data on the disease onset and progression of WAT mediated metabolic derangements in PCOS women are lacking. Therefore, we aim to test the hypothesis that the androgen dihydrotestosterone (DHT) induces time-dependent progression of WAT and metabolic dysfunction on both the molecular and functional levels in PCOS. This hypothesis was tested using a well-characterized DHT-induced PCOS mouse model after 2, 4, 8 and 12 wks of DHT administration.

Methods: Three-week old female mice (C57BL/6N) were implanted with Silastic tubes filled with DHT (8 mg, s.c.) or vehicle (n=6/grp) for 2, 4, 8 and 12 weeks. Weekly body weight (BW, gravimetry), body composition (EchoMRI), subcutaneous fat (SCF)- a WAT depot mass (gravimetry) were assessed. Serum leptin, adiponectin, and insulin were measured by ELISA, while non-esterified free fatty acid (NEFA) and cholesterol by using a clinical chemistry analyzer. Adipose IR (insulin×NEFA) was calculated. SCF androgen receptor (AR), lipolytic marker adipose triglyceride lipase (ATGL), and adipogenesis marker peroxisome proliferator-activated receptor-γ (PPAR-γ) protein levels were assessed by Western blot.

Results: DHT mice showed significant (P<0.05) increases in BW (1.15-fold) and lean mass (1.14-fold) starting 2 weeks following DHT-exposure where higher cholesterol (1.3-fold), insulin (2.3-fold) and adipose IR (2.5-fold) as well as lower insulin-sensitizing adipokine adiponectin levels (50%) were also observed compared to vehicle. The increases in SCF mass (1.5-fold) and total fat mass (2.2-fold) were only significant starting at 8 weeks. DHT significantly increased NEFA (1.3- and 1.2-fold, 8- and 12-weeks post-DHT, respectively) and leptin (1.5-fold, 12 weeks post-DHT). On the molecular level, DHT mice had an upregulation in SCF AR expression (1.5-fold) at 2 weeks and an upregulation of ATGL and PPARγ expression by 50% and 40% at 4 weeks post-DHT.

Conclusion and significance: Our findings suggest that some of the associated metabolic traits such as serum adiponectin, insulin, cholesterol and adipo-IR, occur very early following the induction of hyperandrogenemia that may be drivers of disease progression. Therefore, actively screening and managing risk factors for metabolic derangements from early on in PCOS is critical for disease management.