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HIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction.

Papp E, Mohammadi H, Loutfy MR, Yudin MH, Murphy KE, Walmsley SL, Shah R, MacGillivray J, Silverman M, Serghides L - J. Infect. Dis. (2014)

Bottom Line: In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight.Progesterone supplementation resulted in a significant improvement in fetal weight.In HIV-infected women, progesterone levels correlated significantly with birth weight percentile.

View Article: PubMed Central - PubMed

Affiliation: Toronto General Research Institute, University Health Network.

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Related in: MedlinePlus

Protease inhibitors decrease trophoblast progesterone production in vitro. A, BeWo cells, a human cytotrophoblast cell line, were treated for 24 hours with 10 times the minimal effective dose (see Methods) of zidovudine (ZDV), lamivudine (3TC), nevirapine (NVP), ritonavir (RTV), atazanavir (ATV), darunavir (DRV), or lopinavir (LPV). B, BeWo cells were treated for 24 hours with combinations of ZDV plus 3TC and RTV-boosted ATV (ATV/r), DRV (DRV/r), or LPV (LPV/r). Control cells (Ctr) were treated with dimethyl sulfoxide at a final concentration of <0.1%. Cells incubated in hypoxic conditions (1% oxygen; Hyp) were used as a positive control. Progesterone levels were measured by competitive enzyme immunoassay and were corrected for the number of cells per well. Progesterone levels are expressed as percentage of the median control value. Data displayed are means±standard errors of the mean for 3–6 independent experiments. *P < .05 and **P < .01 for comparisons of each value with the control, by analysis of variance with the Dunnett post hoc test.
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JIU393F1: Protease inhibitors decrease trophoblast progesterone production in vitro. A, BeWo cells, a human cytotrophoblast cell line, were treated for 24 hours with 10 times the minimal effective dose (see Methods) of zidovudine (ZDV), lamivudine (3TC), nevirapine (NVP), ritonavir (RTV), atazanavir (ATV), darunavir (DRV), or lopinavir (LPV). B, BeWo cells were treated for 24 hours with combinations of ZDV plus 3TC and RTV-boosted ATV (ATV/r), DRV (DRV/r), or LPV (LPV/r). Control cells (Ctr) were treated with dimethyl sulfoxide at a final concentration of <0.1%. Cells incubated in hypoxic conditions (1% oxygen; Hyp) were used as a positive control. Progesterone levels were measured by competitive enzyme immunoassay and were corrected for the number of cells per well. Progesterone levels are expressed as percentage of the median control value. Data displayed are means±standard errors of the mean for 3–6 independent experiments. *P < .05 and **P < .01 for comparisons of each value with the control, by analysis of variance with the Dunnett post hoc test.

Mentions: We first investigated the impact of HIV antiretrovirals on progesterone levels in vitro, using BeWo cells, a third-trimester human cytotrophoblast cell line capable of sex steroid production [28]. Antiretrovirals were tested singly and in clinically relevant combinations, at 10 times the MEC for 24 hours. These conditions did not result in cytotoxicity or inhibition of proliferation. Of the 3 different classes of drugs tested—NRTIs, nonnucleoside reverse transcriptase inhibitors (NNRTIs), and PIs—only PIs resulted in reduced progesterone levels (Figure 1A). RTV, known for its significant impact on CYP enzymes [20], had the strongest inhibitory effect on progesterone levels. ATV and LPV also decreased progesterone levels, while darunavir (DRV) was the only PI tested that did not significantly affect progesterone release. Nevirapine, ZDV, and 3TC had no effect on progesterone levels.Figure 1.


HIV protease inhibitor use during pregnancy is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction.

Papp E, Mohammadi H, Loutfy MR, Yudin MH, Murphy KE, Walmsley SL, Shah R, MacGillivray J, Silverman M, Serghides L - J. Infect. Dis. (2014)

Protease inhibitors decrease trophoblast progesterone production in vitro. A, BeWo cells, a human cytotrophoblast cell line, were treated for 24 hours with 10 times the minimal effective dose (see Methods) of zidovudine (ZDV), lamivudine (3TC), nevirapine (NVP), ritonavir (RTV), atazanavir (ATV), darunavir (DRV), or lopinavir (LPV). B, BeWo cells were treated for 24 hours with combinations of ZDV plus 3TC and RTV-boosted ATV (ATV/r), DRV (DRV/r), or LPV (LPV/r). Control cells (Ctr) were treated with dimethyl sulfoxide at a final concentration of <0.1%. Cells incubated in hypoxic conditions (1% oxygen; Hyp) were used as a positive control. Progesterone levels were measured by competitive enzyme immunoassay and were corrected for the number of cells per well. Progesterone levels are expressed as percentage of the median control value. Data displayed are means±standard errors of the mean for 3–6 independent experiments. *P < .05 and **P < .01 for comparisons of each value with the control, by analysis of variance with the Dunnett post hoc test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264589&req=5

JIU393F1: Protease inhibitors decrease trophoblast progesterone production in vitro. A, BeWo cells, a human cytotrophoblast cell line, were treated for 24 hours with 10 times the minimal effective dose (see Methods) of zidovudine (ZDV), lamivudine (3TC), nevirapine (NVP), ritonavir (RTV), atazanavir (ATV), darunavir (DRV), or lopinavir (LPV). B, BeWo cells were treated for 24 hours with combinations of ZDV plus 3TC and RTV-boosted ATV (ATV/r), DRV (DRV/r), or LPV (LPV/r). Control cells (Ctr) were treated with dimethyl sulfoxide at a final concentration of <0.1%. Cells incubated in hypoxic conditions (1% oxygen; Hyp) were used as a positive control. Progesterone levels were measured by competitive enzyme immunoassay and were corrected for the number of cells per well. Progesterone levels are expressed as percentage of the median control value. Data displayed are means±standard errors of the mean for 3–6 independent experiments. *P < .05 and **P < .01 for comparisons of each value with the control, by analysis of variance with the Dunnett post hoc test.
Mentions: We first investigated the impact of HIV antiretrovirals on progesterone levels in vitro, using BeWo cells, a third-trimester human cytotrophoblast cell line capable of sex steroid production [28]. Antiretrovirals were tested singly and in clinically relevant combinations, at 10 times the MEC for 24 hours. These conditions did not result in cytotoxicity or inhibition of proliferation. Of the 3 different classes of drugs tested—NRTIs, nonnucleoside reverse transcriptase inhibitors (NNRTIs), and PIs—only PIs resulted in reduced progesterone levels (Figure 1A). RTV, known for its significant impact on CYP enzymes [20], had the strongest inhibitory effect on progesterone levels. ATV and LPV also decreased progesterone levels, while darunavir (DRV) was the only PI tested that did not significantly affect progesterone release. Nevirapine, ZDV, and 3TC had no effect on progesterone levels.Figure 1.

Bottom Line: In pregnant mice, PI-based cART but not dual-NRTI therapy was associated with significantly lower progesterone levels that directly correlated with fetal weight.Progesterone supplementation resulted in a significant improvement in fetal weight.In HIV-infected women, progesterone levels correlated significantly with birth weight percentile.

View Article: PubMed Central - PubMed

Affiliation: Toronto General Research Institute, University Health Network.

Show MeSH
Related in: MedlinePlus