Progesterone Treatment for Experimental Stroke: An Individual Animal Meta-Analysis

Abstract

Preclinical studies suggest progesterone is neuroprotective after cerebral ischemia. The gold standard for assessing intervention effects across studies within and between subgroups is to use meta-analysis based on individual animal data (IAD). Preclinical studies of progesterone in experimental stroke were identified from searches of electronic databases and reference lists. Corresponding authors of papers of interest were contacted to obtain IAD and, if unavailable, summary data were obtained from the publication. Data are given as standardized mean differences (SMDs, continuous data) or odds ratios (binary data), with 95% confidence intervals (95% CIs). In an unadjusted analysis of IAD and summary data, progesterone reduced standardized lesion volume (SMD À 0.766, 95% CI À 1.173 to À 0.358, Po0.001). Publication bias was apparent on visual inspection of a Begg's funnel plot on lesion volume and statistically using Egger's test (P ¼ 0.001). Using individual animal data alone, progesterone was associated with an increase in death in adjusted analysis (odds ratio 2.64, 95% CI 1.17 to 5.97, P ¼ 0.020). Although progesterone significantly reduced lesion volume, it also appeared to increase the incidence of death after experimental stroke, particularly in young ovariectomized female animals. Experimental studies must report the effect of interactions on death and on modifiers, such as age and sex.

Intranasal delivery of progesterone after transient ischemic stroke decreases mortality and provides neuroprotection

“…Progesterone was administered at 1, 6, and 24 h after MCAO. This dose and treatment regimen have been shown to be neuroprotective in previous studies using intraperitoneal or subcutaneous injections of progesterone (Wong et al, 2013). …”

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 progesterone treatment in male mice (Gibson and Murphy, 2004) while another study showed no effect of progesterone on mortality rate in ovariectomised females and in aged females (Gibson et al, 2011). A recent meta-analysis based on individual animal data concluded that progesterone was associated with an increase in death (Wong et al, 2013). Our results show that progesterone oleogel administered by intranasal route decreased the mortality rate.…”

“…Indeed, intranasal delivery of progesterone decreased mortality rate, decreased the early BBB disruption, improved motor functions, reduced lesion volume and increased neuronal density in the infarct and peri-infarct. Several studies have shown the neuroprotective effects of progesterone after stroke (Wong et al, 2013). Most of them reported a beneficial effect in reducing lesion volume and increasing motor functions.…”

“…A number of studies have demonstrated neuroprotective efficacy of progesterone in experimental models of stroke, and in particular after MCAO (Gibson et al, 2008;Liu et al, 2012a Q1 ; Schumacher et al, 2007;Stein, 2008;Wong et al, 2013). However, they have only investigated the efficacy of intraperitoneal and subcutaneous administrations (Wong et al, 2013), which would not be the most appropriate mode of administration in stroke patients since progesterone injection has a short half-life in both plasma and brain.…”

“…However, they have only investigated the efficacy of intraperitoneal and subcutaneous administrations (Wong et al, 2013), which would not be the most appropriate mode of administration in stroke patients since progesterone injection has a short half-life in both plasma and brain. Before clinical trials, refining of treatment protocols is needed.…”