Polycystic
Ovary Syndrome is a frequent cause of female infertility and is associated with
a range of metabolic disorders. Hyperandrogenism is a key feature of PCOS, but
the role of androgen actions via the androgen receptor (AR) in its development
is unclear. To investigate their role, we combined our optimal PCOS mouse model
[1] with our global and granulosa cell-specific AR knockout models (ARKO &
GCARKO, respectively), as granulosa cells are a major site for AR-mediated
actions in the follicle. DHT treated wild-type (WT) mice from both lines
exhibited disrupted (fewer) estrous cycles (0±0 vs 2.6±0.2cycles/14days and
0.3±0.2 vs 2.8±0.2cycles/14days, respectively, p<0.01) and reduced corpora
lutea (CL) numbers (1±1 vs 9.7±3 and 0±0 vs 9.3±1.8, p<0.05) compared to
non-DHT treated controls, while also exhibiting increased body weight over 13
weeks (151.4±21.3% vs 124.6±21.8%, p<0.01 and 202.1±10.9% vs 167.7±11.2%,
p=0.05), and fat pad weights (intra-abdominal: 4.53±0.42 vs 2.71±0.34 mg/BW and
6.18±0.86 vs 3.77±0.50 mg/BW, p<0.01; subcutaneous: 12.29±0.83 vs 8.79±0.73
mg/BW and 11.9±0.56 vs 9.6±0.47 mg/BW, p<0.01). Globally inactivated AR
(ARKO) rescued the DHT induced effects, however, when AR inactivation was
confined to the granulosa cells (GCARKO) mice displayed persistent DHT effects
of reduced number of estrous cycles in 14 days (1.0±0.2 vs 2.7±0.2,
p<0.001), a trend to reduced CL numbers (1.7±1.7 vs 5.7±0.7, p=0.09),
increased body weight (187.0±14.5% vs 159.1±11.4%, p<0.05) and increased fat
pad weights (intra-abdominal: 5.80±0.80 vs 3.05±0.37 mg/BW, p<0.01;
subcutaneous: 10.58±0.49 vs 8.82±0.40 mg/BW, p<0.01). There was no
difference in fasting glucose levels, glucose tolerance or blood pressure in
any groups. Our results support a role for hyperandrogenism in the development
of PCOS features, and indicate that these effects are not mediated via the
granulosa cells but rather via other cells within the ovary or via
extra-ovarian (neuroendocrine) sites.
- Caldwell A.S.L, Middleton L.J, Jimenez M, Desai R, McMahon A.C, Allan C.M, Handelsman D.J, and Walters K.A. Characterization of reproductive, metabolic and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models. Endocrinology DOI: 10.1210/en.2014-1196 (In Press)