Fluctuating endocrine hormones are essential regulators underpinning normal placental and fetal development, including maternal immune tolerance mediated by T regulatory (Treg) cells. Androgen receptors are expressed in decidualised uterus, but the role of androgen signalling in early pregnancy remains undefined. Therefore, we aimed to assess the effects of androgen blockade on immune tolerance and late-gestation outcome.
To block androgen signalling, female C57Bl/6 mice mated to Balb/c stud males were treated with 30mg/kg injections of androgen receptor (AR) inhibitor Enzalutamide on days 0.5 and 2.5 post-coitum (Dpc). On D17.5pc (late-gestation) pregnancy rate, total and viable implantation sites, fetal and placental weights were measured. Masson’s trichrome staining was used to assess placental structure (n=16-17 dams/group). To assess the impact of dysregulated androgen signalling on immune tolerance, uterus, uterus-draining lymph nodes (udLN), spleen, and thymus were weighed, and T cells were measured using flow cytometry on D3.5pc (pre-implantation) (n=13 mice/group).
Plug:pregnancy rate was unaffected by AR-blockade and there were no significant differences in the number of total implantation sites, viable fetuses or percentage of fetal resorptions on D17.5pc. A 10.9% reduction in fetal weight was observed in Enzalutamide-treated dams, with no dissimilarities in placental weight or structure. This led to a 31.2% decrease in fetal:placental weight ratio in the Enzalutamide-treated group. On D3.5pc flow cytometry data showed no changes in total Treg cell numbers yet a slight increase in the peripherally-induced Treg cells in uterus, udLN and spleen. In thymus, immature T cells were increased in proportion while proliferation of CD4/CD8 double-positive, CD4 single-positive and CD8 single-positive cells was decreased after AR-blockade.
In conclusion, dysregulated maternal androgen signalling in early pregnancy leads to placental insufficiency and fetal growth restriction despite minimal changes in the Treg cell population. These data imply a subtle but significant role of maternal androgen signalling in fetal growth.