Androgen signaling pathways driving reproductive and metabolic phenotypes in a PCOS mouse model

Abstract

As the mechanistic basis of polycystic ovary syndrome (PCOS) remains unknown, current management relies on symptomatic treatment. Hyperandrogenism is a major PCOS characteristic and evidence supports it playing a key role in PCOS pathogenesis. Classically, androgens can act directly through the androgen receptor (AR) or, indirectly, following aromatization, via the estrogen receptor (ER). We investigated the mechanism of androgenic actions driving PCOS by comparing the capacity of non-aromatizable dihydrotestosterone (DHT) and aromatizable testosterone to induce PCOS traits in WT and Ar-knockout (ARKO) mice. DHT and testosterone induced the reproductive PCOS-like features of acyclicity and anovulation in WT females. In ARKO mice, DHT did not cause reproductive dysfunction; however, testosterone treatment induced irregular cycles and ovulatory disruption. These findings indicate that direct AR actions and indirect, likely ER, actions of androgens are important mediators of PCOS reproductive traits. DHT, but not testosterone, induced an increase in body weight, body fat, serum cholesterol and adipocyte hypertrophy in WT mice, but neither androgen induced these metabolic features in ARKO mice. These data infer that direct AR-driven mechanisms are key in driving the development of PCOS metabolic traits. Overall, these findings demonstrate that differing PCOS traits can be mediated via different steroid signaling pathways and indicate that a phenotype-based treatment approach would ensure effective targeting of the underlying mechanisms.

Reversibility of testosterone-induced acyclicity after testosterone cessation in a transgender mouse model

“…Our previous study, investigating the effects of injectable T enanthate on postpubertal female mice, demonstrated Tinduced persistent diestrus with a lack of corpora lutea (15). Other studies also noted T-induced persistent diestrus with a lack of corpora lutea in peripubertal mice treated with silastic T implants for 12 weeks (18). One recent study found that female mice injected weekly with T cypionate experienced persistent diestrus with a significant reduction in corpora lutea (19).…”

Constitutive expression of Steroidogenic factor‐1 (NR5A1) disrupts ovarian functions, fertility, and metabolic homeostasis in female mice

“…Studies of testosterone and non-aromatizable dihydrotestosterone (DHT) treatments in control and AR knockout mice demonstrated that an indirect action of androgen through ER could contribute to reproductive defects such as irregular cycles. 37 A direct action through androgen receptor was required to induce the metabolic defects, and global AR knockout can prevent the development of metabolic defects in mice exposed to DHT. 37,38 Our results support that excess androgen in our mouse model is directly due to NR5A1 overexpression in the ovary.…”

“…37 A direct action through androgen receptor was required to induce the metabolic defects, and global AR knockout can prevent the development of metabolic defects in mice exposed to DHT. 37,38 Our results support that excess androgen in our mouse model is directly due to NR5A1 overexpression in the ovary. NR5A1 can indeed directly control the expression of steroidogenic enzymes, 5 and various steroidogenic enzymes, including known direct targets of NR5A1, 39 were significantly upregulated in the ovary, concomitant with the significant upregulation of androgen serum levels.…”

“…Androgens can act directly through the androgen receptor (AR) as well as indirectly through its aromatized product estrogens via estrogen receptor (ER). Studies of testosterone and non‐aromatizable dihydrotestosterone (DHT) treatments in control and AR knockout mice demonstrated that an indirect action of androgen through ER could contribute to reproductive defects such as irregular cycles 37 . A direct action through androgen receptor was required to induce the metabolic defects, and global AR knockout can prevent the development of metabolic defects in mice exposed to DHT 37,38 .…”

The Effects of Salvia miltiorrhiza on Reproduction and Metabolism in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

“…Beyond its effects on lipid profiles, S. miltiorrhiza has positive effects on other aspects of PCOS patients' health. PCOS is closely related to metabolic syndrome [ 47 , 48 ], and several studies have demonstrated the different effects of S. miltiorrhiza on hypoglycemia and hypoinsulinemia. Adiponectin (APN) and leptin are closely related to obesity [ 49 ].…”