Overview of Studies Utilizing Progesterone in the Developing Brain
There are few studies which evaluated the effects of progesterone in the developing brain. One of the important questions regarding progesterone treatment is whether TBI leads to alterations in the levels of progesterone or its receptor. Although this has not been examined after pediatric TBI, experimental studies in immature seizure and ischemia models report changes in progesterone and its receptor levels early after injury depending on the insult and time after injury. For example, when postnatal day 7 (P7) old female rats were exposed to hypoxia only (6.5% oxygen for 50 min) or hypoxia plus ischemia (HI, ligature of the right carotid artery), progesterone receptor levels decreased at 48 hours after hypoxia and markedly increased at 7 days after hypoxia and HI versus control. Progesterone and estradiol secretion at 3 and 8 months were unaffected by HI, but levels were not evaluated at earlier times. González-Ramírez et al showed that serum progesterone levels increase 5- to 6-fold at 30 minutes and 24 hours after pentylenetetrazol-induced seizures in P10 male and female rats. These limited studies of progesterone and progesterone receptor levels after brain injury would suggest that the mechanism of injury and timing after injury are important considerations when evaluating progesterone for treatment.
A recent study in adult TBI show that compared with controls, cerebrospinal fluid (CSF) progesterone levels were significantly and persistently elevated during the first 2 days after TBI, and high CSF progesterone levels were associated with worse Glasgow Outcome Scale (GOS) at 6 months in bivariate analysis. In multivariate analysis, high CSF progesterone was indirectly associated with worse outcome through its interactions with cortisol as progesterone is a precursor to cortisol. Thus, it is possible that brain interstitial and CSF levels of progesterone and its physiologically active metabolites (such as allopregnanolone) may be an important determinant of recovery in the injured brain. Progesterone and its metabolites have been associated with anticonvulsant effects,[77,78] most likely by acting as powerful positive modulators of GABAA receptors in the brain.[79,80] Corroborating this finding, Holmes and Weber demonstrated that while progesterone does not have effect on kindling in the adult animal, it markedly inhibits kindling in immature animals and prevents generalization of seizures.
As discussed in the previous section, GABA is excitatory for immature neurons, whereas it is inhibitory for mature neurons. Consistent with this, a recent study reported that exogenous administration of progesterone and allopregnanolone exacerbated brain injury in an age-dependent manner. Progesterone (10 mg/kg), allopregnanolone (10 mg/kg), or vehicle was intraperitoneally administered immediately before and then subcutaneously at 6 and 24 hours after hypoxia-ischemia, using the Rice-Vannucci model, to P7, P14, and P21 male and female rats. Both progesterone and allopregnanolone exacerbated hemispheric volume loss and histopathological injury score in P7 and P14 rats but not in P21 rats. Coadministration of the GABAA receptor antagonist, bicuculline, partially mitigated the exacerbating effect of allopregnanolone. The authors concluded that the detrimental effects of progesterone were most likely due to GABAergic neuroexcitatory activity of allopregnanolone. Although the authors identified a potential mechanism for the detrimental effects of progesterone and allopregnanolone in their model, levels of progesterone, allopregnanolone in serum and brain, and their corresponding receptors in the brain were not analyzed. It is possible that if the levels of progesterone receptor are decreased after injury as shown previously, one might observe off-target effects of the drug more often. Nevertheless, this study suggests that caution is required when considering progesterone and its metabolites for neuroprotection in the immature brain.
Two recent studies evaluated the neuroprotective effect of progesterone alone or in combination with magnesium after TBI in the developing brain.[84,85] Mixed gender 7-day-old Wistar rats were exposed to weight drop injury, and progesterone or magnesium sulfate was administered intraperitoneally immediately after TBI. Combination therapy was found to be superior to progesterone alone for improving long-term (3 wk) neuronal survival in the dentate gyrus, while treatment with progesterone alone, magnesium alone, or the two in combination reduced the extent of apoptotic cell death profiles. Furthermore, spatial learning and memory retention at 3 weeks after injury were improved by treatment with progesterone alone, magnesium alone, or the two in combination. In a separate study, the authors reported that progesterone decreased TBI-induced anxiety in the immature rat, thought to be related to attenuation of TBI-induced changes in circulating corticosterone and insulin-like growth factor levels by progesterone. Further studies in different models of TBI in the immature brain are needed to determine whether progesterone is beneficial in contusional head injury.
Interestingly, studies performed in a single center in extremely preterm infants report improved neurodevelopmental outcome with exogenous combined estrogen and progesterone administration.[86,87] The initial aim of these studies was to evaluate the impact of estradiol and progesterone replacement on postnatal bone mineral accretion.[86,88] Male and female infants less than 1,000 g were randomized to receive either estradiol and progesterone emulsion or placebo containing same amount of lipids for 4 weeks after birth. The authors followed circulating estrogen and progesterone levels in the patients and aimed to maintain plasma levels equaling intrauterine levels. At the follow-up examination at 5-year corrected age, a significant time-response relationship was found: every day of treatment with estrogen and progesterone was associated with a reduced risk for cerebral palsy, spasticity, and ametropia. Although these results are promising, multicenter trials are necessary to test beneficial effects of estrogen and progesterone on neurodevelopmental outcome in extremely preterm infants.
Pediatr Crit Care Med. 2015;16(3):236-244. © 2015 Lippincott Williams & Wilkins