Identifying the role of androgens in endometrial function
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Date
29/11/2016Item status
Restricted AccessEmbargo end date
31/12/2100Author
Simitsidellis, Ioannis
Metadata
Abstract
The endometrium is a complex multicellular tissue that undergoes dynamic alterations under
the control of ovarian-derived sex steroid hormones. During the proliferative phase of the
human menstrual cycle, oestrogen induces proliferation of the endometrial epithelium while
during the progesterone-dominated secretory phase, the endometrial stromal compartment
differentiates in preparation for pregnancy. This differentiation event is termed decidualisation
and it is accompanied by immune cell infiltration, vascular remodelling and secretion of
cytokines and growth factors, as well as a newfound capacity of active steroid synthesis in the
endometrium. Defective decidualisation has been described in several endometrial-associated
disorders such as endometriosis, a pathology of ectopic endometrial tissue in the peritoneal
cavity, often associated with infertility. Rodent models have been used for the investigation of
endometrial physiology and pathology due to the similarity in uterine tissue architecture,
appropriate endometrial responses to steroid hormones and the opportunity to inform cellular
mechanisms using genetic manipulation.
While the impact of 17β-oestradiol and progesterone on endometrial function have been
extensively studied, androgens have only recently emerged as potent potential regulators of
the endometrium, however, their impact on cell function has not been fully elucidated.
The aims of this study were to:
Identify the impact of androgens on endometrial function using a mouse model of steroid
depletion (ovariectomy) followed by administration of the potent androgen
dihydrotestosterone (DHT).
Investigate the capacity of endometrial stromal cells to synthesise androgens during
decidualisation using human primary endometrial stromal cells (hESCs) decidualised in vitro.
Elucidate the decidualisation response of hESCs from women with endometriosis after
modulation of androgen receptor (AR) function during decidualisation.
Novel results obtained provided evidence of a role for androgens in inducing a trophic effect
in the mouse uterus characterised by: pronounced endometrial epithelial proliferation, altered
expression pattern of AR, changes in the expression of genes involved in cell-cycle
progression and stromal-epithelial cross-talk. In addition, androgen treatment resulted in a
striking and unexpected increase in the number of endometrial glands. Decidualisation of
hESCs resulted in time-dependent changes in expression of the androgen synthesising
enzymes AKR1C3 and 5α-reductase (accompanied by biosynthesis of both testosterone and
DHT in a dynamic time-dependent manner). Notably, blocking of AR action arising from local
androgen signalling during decidualisation of hESCs culminates in sub-optimal
decidualisation as detected by the expression of the classical decidualisation markers IGFBP1
and PRL.
Women with endometriosis are reported to exhibit defective decidualisation, which may be
accompanied with infertility. Treatment of hESCs from women with endometriosis with an
AR agonist (DHT) or antagonist (flutamide) during decidualisation resulted in striking
differences in decidualisation response as demonstrated in a case-study approach.
Taken together, these findings highlight novel roles of androgens in regulating endometrial
function by impacting on cell proliferation, gland formation and decidualisation. These
striking new findings have implications for endometrial disorders such as endometriosis.
Future studies will focus on the use of selective androgen receptor modulators, a novel class
of compounds, with tissue-selective actions and without the undesired side-effects of potent
androgens. The use of AR modulators would benefit from a personalised medicine approach,
instructed by patient profiling to direct therapeutic targeting of endometrial disorders.