ER-mediated actions, even in the absence of AR actions, can induce reproductive features of PCOS

Background: Hyperandrogenism is a key defining feature of polycystic ovary syndrome (PCOS). Clinical and animal experimental studies have provided strong evidence to support an important role for androgens in driving the development of PCOS. Testosterone (T) and dihydrotestosterone (DHT) are the two bioactive forms of androgens which can act directly through the androgen receptor (AR). Additionally, T, unlike DHT, can also be converted to estradiol and act via the estrogen receptor (ER).Objective: To determine if ER-mediated actions are involved in the development of different features of PCOS.Materials and Methods: ARKO mice were generated using Cre/LoxP technology. WT and ARKO prepubertal mice were implanted with a blank, T or DHT implant and examined after 12 weeks.Results: Both T and DHT induced anovulation in WT mice as there were no corpora lutea (CL) in their ovaries (CL number: WT+blank: 9.5±2.1; WT+DHT: 0±0; WT+T: 0±0, p<0.01). In contrast, ARKO mice treated with blank or DHT implants ovulated, but those with T implants still displayed ovulatory disruption (CL number: ARKO+blank: 2.3±0.3; ARKO+DHT: 3.25±0.4; ARKO+T: 0.4±0.4, p<0.05). This finding suggests that ER actions even in the absence of AR actions can induce disrupted ovulation. In WT mice, DHT but not T induced metabolic features of PCOS (e.g. body weight (WT+blank: 23.4g±0.5; WT+DHT: 27.1g±0.6; WT+T: 22.5g±0.67, p<0.01)), however neither androgen had an effect in ARKO mice (body weight, ARKO+blank: 23.1g±0.4; ARKO+DHT: 24.1g±0.7; ARKO+T: 23.5g±0.4). Indicating the role of AR, but not ER, in the development of metabolic features of PCOS.Conclusion: These results show a key role for AR signalling in the establishment of reproductive and metabolic traits of PCOS, but also implying that ER-mediated actions may contribute to the development of reproductive features of PCOS. Suggesting that non-hyperandrogenic PCOS patients (phenotype D) may have a different etiology and prognosis from hyperandrogenic-PCOS patients.

Keywords:

PCOS , Androgen receptor , Estrogen receptor , ARKO