title: Low Prolactin and High 20-α-Hydroxysteroid Dehydrogenase Levels Contribute to Lower Progesterone Levels in HIV-Infected Pregnant Women Exposed to Protease Inhibitor-Based Combination Antiretroviral Therapy.
abstract: BACKGROUND
  It has been reported that pregnant women receiving protease inhibitor (PI)-based combination antiretroviral therapy (cART) have lower levels of progesterone, which put them at risk of adverse birth outcomes, such as low birth weight. We sought to understand the mechanisms involved in this decline in progesterone level.
  
  
  METHODS
  We assessed plasma levels of progesterone, prolactin, and lipids and placental expression of genes involved in progesterone metabolism in 42 human immunodeficiency virus (HIV)-infected and 31 HIV-uninfected pregnant women. In vitro studies and a mouse pregnancy model were used to delineate the effect of HIV from that of PI-based cART on progesterone metabolism.
  
  
  RESULTS
  HIV-infected pregnant women receiving PI-based cART showed a reduction in plasma progesterone levels (P= .026) and an elevation in placental expression of the progesterone inactivating enzyme 20-α-hydroxysteroid dehydrogenase (20α-HSD; median, 2.5 arbitrary units [AU]; interquartile range [IQR], 1.00-4.10 AU), compared with controls (median, 0.89 AU; IQR, 0.66-1.26 AU;P= .002). Prolactin, a key regulator of 20α-HSD, was lower (P= .012) in HIV-infected pregnant women. We observed similar data in pregnant mice exposed to PI-based cART. In vitro inhibition of 20α-HSD activity in trophoblast cells reversed PI-based cART-induced decreases in progesterone levels.
  
  
  CONCLUSIONS
  Our data suggest that the decrease in progesterone levels observed in HIV-infected pregnant women exposed to PI-based cART is caused, at least in part, by an increase in placental expression of 20α-HSD, which may be due to lower prolactin levels observed in these women.
authors.affiliation: Toronto General Research Institute, University Health Network.
authors.forename: Eszter
authors.initials: E
authors.lastname: Papp
authors.affiliation: Toronto General Research Institute, University Health Network.
authors.forename: Kayode
authors.initials: K
authors.lastname: Balogun
authors.affiliation: Toronto General Research Institute, University Health Network.
authors.forename: Nicole
authors.initials: N
authors.lastname: Banko
authors.affiliation: Toronto General Research Institute, University Health Network.
authors.forename: Hakimeh
authors.initials: H
authors.lastname: Mohammadi
authors.affiliation: Women's College Research Institute, Women's College Hospital Department of Medicine.
authors.forename: Mona
authors.initials: M
authors.lastname: Loutfy
authors.affiliation: Department of Medicine St. Michael's Hospital.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Yudin
authors.affiliation: St. Michael's Hospital.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Shah
authors.affiliation: St. Michael's Hospital.
authors.forename: Jay
authors.initials: J
authors.lastname: MacGillivray
authors.affiliation: Department of Medicine Mount Sinai Hospital, Toronto.
authors.forename: Kellie E
authors.initials: KE
authors.lastname: Murphy
authors.affiliation: Toronto General Research Institute, University Health Network Department of Medicine.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Walmsley
authors.affiliation: University of Western Ontario, London, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Silverman
authors.affiliation: Toronto General Research Institute, University Health Network Women's College Research Institute, Women's College Hospital Department of Immunology, University of Toronto.
authors.forename: Lena
authors.initials: L
authors.lastname: Serghides
mesh_terms: D043607:20-alpha-Hydroxysteroid Dehydrogenase / Q000378:metabolism*; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D061466:Lopinavir / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy / Q000201:enzymology; D011374:Progesterone / Q000097:blood*; D011388:Prolactin / Q000097:blood*; D019438:Ritonavir / Q000627:therapeutic use; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism; D015215:Zidovudine / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D061466:Lopinavir; D019259:Lamivudine; D015215:Zidovudine; D011374:Progesterone; D011388:Prolactin; D043607:20-alpha-Hydroxysteroid Dehydrogenase; D019438:Ritonavir
keywords: 20-α-hydroxysteroid dehydrogenase; HIV; adverse birth outcomes; antiretrovirals; birth weight; pregnancy; progesterone; prolactin; protease inhibitors