title: Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage.
abstract: BACKGROUND
  Preclinical evidence suggests that progesterone improves recovery after intracerebral hemorrhage (ICH); however, gonadal hormones have sex-specific effects. Therefore, an experimental model of ICH was used to assess recovery after progesterone administration in male and female rats.
  
  
  METHODS
  ICH was induced in male and female Wistar rats via stereotactic intrastriatal injection of clostridial collagenase (0.5 U). Animals were randomized to receive vehicle or 8 mg/kg progesterone intraperitoneally at 2 h, then subcutaneously at 5, 24, 48, and 72 h after injury. Outcomes included relevant physiology during the first 3 h, hemorrhage and edema evolution over the first 24 h, proinflammatory transcription factor and cytokine regulation at 24 h, rotarod latency and neuroseverity score over the first 7 days, and microglial activation/macrophage recruitment at 7 days after injury.
  
  
  RESULTS
  Rotarod latency (p = 0.001) and neuroseverity score (p = 0.01) were improved in progesterone-treated males, but worsened in progesterone-treated females (p = 0.028 and p = 0.008, respectively). Progesterone decreased cerebral edema (p = 0.04), microglial activation/macrophage recruitment (p < 0.001), and proinflammatory transcription factor phosphorylated nuclear factor-x03BA;B p65 expression (p = 0.0038) in males but not females, independent of tumor necrosis factor-α, interleukin-6, and toll-like receptor-4 expression. Cerebral perfusion was increased in progesterone-treated males at 4 h (p = 0.043) but not 24 h after injury. Hemorrhage volume, arterial blood gases, glucose, and systolic blood pressure were not affected.
  
  
  CONCLUSIONS
  Progesterone administration improved early neurobehavioral recovery and decreased secondary neuroinflammation after ICH in male rats. Paradoxically, progesterone worsened neurobehavioral recovery and did not modify neuroinflammation in female rats. Future work should isolate mechanisms of sex-specific progesterone effects after ICH.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Hsieh
authors.forename: Beilei
authors.initials: B
authors.lastname: Lei
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
authors.forename: Talagnair
authors.initials: T
authors.lastname: Venkatraman
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lascola
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.forename: Michael L
authors.initials: ML
authors.lastname: James
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000000981:diagnostic imaging / Q000178:diet therapy* / Q000503:physiopathology; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D011374:Progesterone / Q000627:therapeutic use*; D011372:Progestins / Q000627:therapeutic use*; D011596:Psychomotor Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D012737:Sex Factors; D013997:Time Factors; D051193:Toll-Like Receptors / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008840:Microfilament Proteins; D011372:Progestins; D051193:Toll-Like Receptors; D011374:Progesterone