Placenta progesterone and its receptor in HIV-associated pre-eclampsia.

Abstract

Background: The maintenance of a healthy pregnancy is dependent upon the placental production of progesterone, which interacts with progesterone receptors (PR) to stimulate trophoblast invasion. Pre-eclampsia (PE) is associated with defective trophoblast invasion, and due to the high prevalence of HIV infection and pre-eclampsia in South Africa, this study examined the expression of placental progesterone and PR in HIV-infected women with PE. Methods: Placental tissue from 180 women were grouped into normotensive (N) (n = 60) and PE (n =120). The PE group was further stratified by gestational age into early-onset pre-eclampsia (EOPE) and late-onset pre-eclampsia (LOPE) (n = 60 per group). Both normotensive and PE groups were stratified by HIV status (HIV positive+ and HIV negative-) into N- (n=30), N+ (n=30), EOPE- (n=30), EOPE+ (n=30), LOPE- (n=30) and LOPE+ (n=30). Immunohistochemistry and morphometric image analysis were used to assess placental progesterone and PR immuno-expression in exchange and conducting villi. The Mann Whitney test was used to compare the effects of pregnancy type (normotensive vs. pre-eclamptic), HIV status (HIV+ vs. HIV-) and PE subtype (EOPE vs LOPE). For comparative analysis across all six study groups, a one-way ANOVA non-parametric Kruskal-Wallis test was used, followed by Dunn's Multiple Comparisons test. A two-way ANOVA was used to compare villi type (exchange vs conducting) and pregnancy type. Results: Progesterone was immunoexpressed within endothelial, mesenchymal and trophoblast cells within conducting and exchange villi whilst PR was mainly expressed on cytotrophoblasts and syncytiotrophoblasts. Progesterone and PR immuno-expression in exchange villi were significantly lower in the following groups: PE compared to the normotensive group (p = <0.0001 and p = <0.0001, respectively) and EOPE compared to the LOPE group (p = <0.0001 and p = <0.0001). Progesterone immuno-expression in the HIV+ group compared to the HIV- group was significantly lower (p = <0.0001), whilst PR expression was non-significant (p = 0.4291). Progesterone and PR immuno-expression in conducting villi were downregulated in the following groups: EOPE group compared to the LOPE group (p = <0.0001 and p = <0.0001) and in the HIV+ group compared to the HIV- group (p = <0.0001 and p = 0.0009). Progesterone immunoexpression was higher in the PE group compared to normotensive (p = 0.0326) and PR immunoexpression was non-significant (p = 0.6935). xiii There was a significant difference in progesterone and PR in exchange vs conducting villi (p = <0.0001 and p = <0.0001, respectively) and villi type accounted for 34.47% and 15.28% of total variance for progesterone and PR, respectively. Conclusion: This study observed a reduction in progesterone and PR immunoexpression in the exchange villi of pre-eclamptic placenta. Progesterone and PR immuno-expression were also significantly reduced in HIV+ placentas, with the EOPE+ group displaying the lowest immunoexpression. We postulate that HIV infection combined with cART may cause mitochondrial dysfunction that compromises progesterone synthesis. Progesterone deficiency results in minimal binding to PRs, which affects signalling pathways (PI3K/AKT, JAK-STAT, and MAPK cascades) and impairs trophoblast invasion. Notably, the EOPE group has the lowest immunoexpression of progesterone and PRs which links the downregulation of progesterone to defective placentation. This study links HIV infection to reduced progesterone production during pregnancy and associates decreased progesterone and PR immuno-expression with PE.

Isendlalelo: Ukugcinwa kokukhulelwa okunempilo kuncike ekukhiqizweni kwe-placenta yeprogesterone, esebenzisana nama-progesterone receptors (PR) ukuze kuvuse ukuhlasela kwetrophoblast. I-Pre-eclampsia (PE) ihlotshaniswa nokuhlasela kwe-trophoblast enesici, futhi ngenxa yokusabalala okuphezulu kokutheleleka nge-HIV kanye ne-pre-eclampsia eNingizimu Afrika, lolu cwaningo luhlole ukuvezwa kwe-placental progesterone kanye ne-PR kwabesifazane abane-HIV abane-PE. Izindlela: Izicubu ze-placental ezivela kwabesifazane abangu-180 zahlanganiswa zaba yinormotensive (n = 60) ne-PE (n = 120). Iqembu le-PE laphinde lahlukaniswa ngeminyaka yokukhulelwa yaba yi-PE yokuqala kanye ne-PE yokufika sekwephuzile (n = 60 iqembu ngalinye). Womabili amaqembu e-normotensive kanye ne-PE ahlukaniswa ngesimo se-HIV (HIV+ ne-HIV negative-) aba yi-N- (n=30), N+ (n=30), EOPE- (n=30), EOPE+ (n=30), LOPE - (n=30) kanye ne-LOPE+ (n=30). I-Immunohistochemistry kanye nokuhlaziywa kwesithombe semorphometric kwasetshenziselwa ukuhlola i-placenta progesterone kanye ne-PR immunoexpression ekushintsheni nasekuqhubeni i-villi. Imiphumela: I-progesterone yayingabonakali ngaphakathi kwamaseli e-endothelial, mesenchymal kanye ne-trophoblast ngaphakathi kokuqhuba nokushintshanisa i-villi ngenkathi i- PR iboniswa ikakhulukazi kuma-cytotrophoblasts nama-syncytiotrophoblasts. I-progesterone ne- PR immuno-expression ekushintsheni i-villi yayiphansi kakhulu kumaqembu alandelayo: I-PE uma iqhathaniswa neqembu le-normotensive (p = <0.0001 kanye ne-p = <0.0001, ngokulandelana) kanye ne-EOPE uma kuqhathaniswa neqembu le-LOPE (p = <0.0001 kanye p = <0.0001). I-progesterone immuno-expression eqenjini le-HIV+ uma iqhathaniswa neqembu le- HIV yayiphansi kakhulu (p = <0.0001), kuyilapho inkulumo ye-PR yayingabalulekile (p = 0.4291). I-progesterone ne-PR immuno-expression ekuqhubeni i-villi yehlisiwe emaqenjini alandelayo: Iqembu le-EOPE uma liqhathaniswa neqembu le-LOPE (p = <0.0001 kanye ne-p = <0.0001) naseqenjini le-HIV+ uma liqhathaniswa neqembu le-HIV (p = <0.0001 futhi p = 0.0009). Iprogesterone immuno-expression yayiphezulu eqenjini le-PE uma kuqhathaniswa nenormotensive (p = 0.0326) kanye ne-PR immuno-expression yayingabalulekile (p = 0.6935). xv Kunomehluko omkhulu ku-progesterone ne-PR ekuhwebeni ngokuqhudelana nokuqhuba i-villi (p = <0.0001 kanye ne-p = <0.0001, ngokulandelana) kanye nohlobo lwe-villi lubalelwa ku- 34.47% no-15.28% wokuhluka okuphelele kwe-progesterone ne-PR, ngokulandelana. Isiphetho: Lolu cwaningo lubone ukuncipha kwe-progesterone kanye ne-PR immunoexpression ku-villi yokushintshanisa ye-pre-eclamptic placenta. I-progesterone ne-PR immuno-expression nazo zehliswa kakhulu kuma-placenta e-HIV+, neqembu le-EOPE+ libonisa ukubonakaliswa okuphansi kokuzivikela komzimba. Sibeka umbono wokuthi ukutheleleka nge-HIV kuhlanganiswe ne-cART kungase kubangele ukungasebenzi kahle kwe-mitochondrial okuphazamisa ukwakheka kwe-progesterone. Ukuntuleka kwe-progesterone kubangela ukubophezela okuncane kuma-PRs, okuthinta izindlela zokubonisa (PI3K/AKT, JAK-STAT, kanye ne-MAPK cascades) futhi kulimaze ukuhlasela kwe-trophoblast. Ngokuphawulekayo, iqembu le-EOPE line-immuno-expression ephansi kakhulu ye-progesterone kanye ne-PRs exhumanisa ukulawulwa kwe-progesterone nokuzala okungalungile. Lolu cwaningo luxhumanisa ukutheleleka nge-HIV nokuncipha kokukhiqizwa kwe-progesterone ngesikhathi sokukhulelwa kanye nokuhlotshaniswa nokuncipha kwe-progesterone kanye ne-PR immuno-expression ne-PE.