Utero-placental expression and functional implications of HSD11B1 and HSD11B2 in canine pregnancy

Abstract

Glucocorticoids modulate the feto-maternal interface during the induction of parturition. In the dog, the prepartum rise of cortisol in the maternal circulation appears to be erratic, and information about its contribution to the prepartum luteolytic cascade is scarce. However, the local placental upregulation of glucocorticoid receptor (GR/NR3C1) at term led to the hypothesis that species-specific regulatory mechanisms might apply to the involvement of cortisol in canine parturition. Therefore, here, we assessed the canine uterine/utero-placental spatio-temporal expression of hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1; reduces cortisone to cortisol), and − 2 (HSD11B2; oxidizes cortisol to the inactive cortisone). Both enzymes were detectable throughout pregnancy. Their transcriptional levels were elevated following implantation, with a strong increase in HSD11B2 post-implantation (days 18–25 of pregnancy), and then a decrease towards parturition, while HSD11B1 was the highest at mid-gestation (days 35–40) and remained unchanged at prepartum luteolysis (P < 0.05). A custom-made species-specific antibody generated against HSD11B2 confirmed its decreased expression at prepartum luteolysis. Moreover, in mid-pregnant dogs treated with aglepristone, HSD11B1 was significantly higher than −2 (P < 0.05). HSD11B2 (protein and transcript) was localized mostly in the syncytiotrophoblast, whereas HSD11B1 mRNA was mainly localized in cytotrophoblast cells. Finally, in a functional approach using placental microsomes, a reduced conversion capacity to deactivate cortisol into cortisone was observed during prepartum luteolysis, fitting well with the diminished HSD11B2 levels. In particular, the latter findings support the presence of local increased cortisol availability at term in the dog, contrasting with an enhanced inactivation of cortisol during early pregnancy.

Advances in understanding canine pregnancy: Endocrine and morpho‐functional regulation

“…As a further peculiarity of canine reproductive endocrinology, the circulating estradiol (E2) levels drop prepartum, as a result of both the lack of placental steroidogenesis and the prepartum luteolysis (Hoffmann et al, 1994). As shown in our studies, glucocorticoids appear to play a role at the placental level, perhaps being involved in the feto‐maternal interplay during the termination of pregnancy (Gram et al, 2016; Tavares Pereira et al, 2023). The glucocorticoid receptor (GR/NR3C1) is localized in foetal trophoblast and is increased during the natural withdrawal of P4 (Gram et al, 2016; Figure 1).…”

“…Yet, the circulating cortisol levels are very variable and are not indicative of the approach of parturition. Interestingly, the lack of an increase in the expression of GR/NR3C1 following the antigestagen‐mediated withdrawal of P4 indicates that it is not required for the initiation of PGF2α production (Gram et al, 2016) and other local roles of glucocorticoids may apply, as discussed previously (Gram et al, 2016; Tavares Pereira et al, 2023). Accordingly, in clinical settings, application of glucocorticoids does not appear to mimic the natural prepartum signalling cascade, as prolonged treatments are required for the termination of pregnancy and strong side effects occur (Wanke et al, 1997).…”

“…Below, some of our most recent in vivo and in vitro observations are highlighted and collectively discussed in detail. These include selected functional clues from our transcriptomic approach (Nowak et al, 2019; Tavares Pereira et al, 2022), insights into immunomodulatory effects (Tavares Pereira, Nowaczyk, Aslan, et al, 2021; Tavares Pereira, Nowaczyk, Payan Carreira, et al, 2021), and implications for the local role of glucocorticoids (Tavares Pereira et al, 2023). In particular, the in vitro studies include deeper insights into species‐specific decidualization and PGR‐mediated effects, as well as offering perspectives for future investigations including translational research.…”

“…The presence of dexamethasone among the important regulators of the luteolytic process drew our attention as it points towards an involvement of glucocorticoids in the luteolytic cascade in the dog. This relatively poorly understood area of canine reproductive physiology has been addressed in more detail in our recent studies (discussed below and in [Tavares Pereira et al, 2023]). PPARγ is an interesting regulatory candidate expressed in the foetal trophoblast, and its importance in the maintenance of canine pregnancy was discussed previously (Kowalewski, Meyer, et al, 2011).…”

Female Autoimmune Disorders with Infertility: A Narrative Review

“…Pre-implanted embryos can express histo-compatibility antigens (MHC) which theoretically can induce an immune response. Thus, the possibility of maternal immune responses playing a role in the failure of http://doi.org/10.33091/amj.2023.138475.1022 implantation is accepted [6,7].…”