Placenta progesterone and its receptor in HIV-associated pre-eclampsia.
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Date
2022
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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).
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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).
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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.
Description
Masters Degree. University of KwaZulu-Natal, Durban.