Endocrine Abstracts

The human endometrium is a complex multicellular tissue the prime function of which is to provide a receptive environment during a fertile cycle. The tissue responds to steroid hormones exhibiting dynamic cyclical regeneration, angiogenesis, differentiation (decidualisation) and inflammation. In the absence of an embryo the inner surface is shed and repaired without scarring (menstruation). The endometrium exhitbits spatial and temporal expression of androgen receptors (AR) in stromal fibroblasts and endothelial cells: upregulation of AR in epithelial cells occurs in reponse to progesterone withdrawal (cycle) or administration of PR antagonists.

We used primary cells (human endometrial stromal cells:) and mouse models to investigate the impact of androgens (T, DHT), AR antagonists (Flutamide) and selective AR modulators (SARMs) on key endometrial cell functions.

We discovered that local ‘intracrine’ biosynthesis of T/DHT by human stromal cells regulates AR and expression of receptivity factors. Notably DHT inhibited cell migration but increased resistance to apoptosis with SARMs exhibiting a range of activities on these functions and on expression of AR-regulated genes.

Administration of DHT to steroid-depleted (ovariectomised) female mice promoted a significant increase in uterine size, induced epithelial cell proliferation, expansion of the glandular epithelium and altered uterine AR immunoexpression. Administration of DHT in a mouse model of endometrial repair (‘menstruation’) altered regulation of restoration of endometrial tissue homeostasis following endometrial shedding at the time of menstruation. We have used these mouse models to test the impact of SARMs on endometrial proliferation and repair and found evidence for selective effects of different SARMs on these functional processes.

In summary, our studies demonstrate a key role for AR in regulation of endometrial function in health and disease. We believe SARMs may offer a novel way to target the AR for therapeutic benefit.

DOI: 10.1530/endoabs.54.IS6