Abstract
IntroductionThe neurosteroid allopregnanolone modulates oxytocin expression in the brain, and its effects arise from its action on the GABAA receptor. Whether neurosteroid levels and the function of the GABAA receptor are involved in the risk of preterm labour in pregnant women is unknown.MethodsPregnant women with (n = 16) or without (n = 20) threatened preterm labour (TPL) in gestational week 33 + 6 days to 37 + 0 days were studied prospectively with procedures including foetal heart rate monitoring, vaginal examination, ultrasound examination and blood tests to determine allopregnanolone, progesterone and oxytocin levels. The GABAA receptor function in both groups was measured with a saccadic eye velocity test (SEVT).ResultsPlasma oxytocin levels were higher in the TPL group than in the control group (41.5 vs. 37.0 pmol/L, respectively, p = .021). Although the allopregnanolone and progesterone levels in both groups did not differ, there was a negative association between blood oxytocin and allopregnanolone (as predictor) levels in the TPL group (B: −3.2, 95% confidence interval (CI): −5.5 to −0.9, p = .012). As a predictor of TPL, progesterone was associated with cervix maturity (odds ratio: 1.02, 95% CI: 1.00–1.04, p = .038). SEVT showed that the women in both groups had similar GABAA receptor functions. In both groups, body mass index correlated with peak saccadic eye velocity (r = .34, p = .044) and negatively with allopregnanolone (r = −.41, p = .013).ConclusionsNeurosteroid levels were unchanged in the peripheral blood of women with TPL, despite the increase in available oxytocin. Although the function of the GABAA receptor was unchanged in women with TPL, to ensure reliable results, saccadic eye velocity should be investigated during a challenge test with a GABAA receptor agonist.
Highlights
The neurosteroid allopregnanolone modulates oxytocin expression in the brain, and its effects arise from its action on the GABAA receptor
We investigated the involvement of the GABA-active neurosteroid allopregnanolone and oxytocin in the mechanism underlying threatened preterm labour (TPL)
Our main findings were that women with TPL had higher oxytocin levels in the blood than the control group, whereas their blood levels of allopregnanolone and progesterone were similar
Summary
Preterm birth, defined as birth before 37 weeks of gestation, is a significant public health problem. Oxytocin and allopregnanolone are both secreted in response to stress,[13] but the premature activation of oxytocin secretion by stressors in late pregnancy is hindered by the activation of a central endogenous opioid mechanism.[14] For example, acute morphine treatment inhibits the oxytocin release stimulated by parturition,[15] and when the actions of endogenous opioids are antagonized with naloxone, the oxytocin response to the immune stressor interleukin-1β is potentiated.[14] When the pregnancy levels of progesterone were simulated in virgin rats, opioid inhibition of the oxytocin response to stress was induced.[16] These activities may be attributed to increased production of the neurosteroid allopregnanolone, which is abundant in the brain during late pregnancy and reduces stress-induced hypothalamus-pituitary-adrenal axis activity.[9,17] Allopregnanolone is produced from progesterone by the sequential action of the enzymes 5α-reductase and 3α-hydroxysteroid dehydrogenase, and in late pregnancy, the amounts of both enzymes increase in brain regions known to be critical in regulating the oxytocin responses to stress.[17,18] Changes in serum allopregnanolone levels in healthy women are not fully dependent on variations in progesterone.[19] Several studies have shown that the neurosteroid allopregnanolone modulates oxytocin expression in the brain and induces the endogenous opioid-induced inhibition of the oxytocin responses.[20,21] the mechanism by which allopregnanolone induces inhibitory opioid tone is still unclear, it may involve an interaction with the GABAA receptor.
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