1 Departments of Obstetrics and Gynecology and 2 Physiology, Shimane Medical University, 891 Enya, Izumo 693-8501 and 3 Department of Perinatology, Kagawa Medical University, Kagawa, Japan
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Abstract |
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Key words: dehydroepiandrosterone sulphate/nitric oxide/oestrogen/term pregnancy/vasodilative effect
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Introduction |
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Dehydroepiandrosterone sulphate (DHEA-S) of both maternal and fetal origin is converted to oestrogen in the placenta. The metabolic clearance rate of DHEA-S in normal pregnant women is markedly elevated compared with that of non-pregnant subjects (Gant et al., 1971). The blood oestradiol concentration rapidly increases after an i.v. injection of DHEA-S to women in late pregnancy (Tulchinsky et al., 1976
). DHEA-S induces a significant decrease in the uterine artery pulsatility index (PI), which suggests a possible decrease in uterine vascular impedance in term pregnancy (Hata et al., 1995
). Oestrogen induces notable uterine vasodilation in non-pregnant sheep (Killam et al., 1973
; Resnik et al., 1974
; Van Buren et al., 1992
; Rosenfeld et al., 1996
). Van Buren et al. (1992) showed that oestradiol-induced increases in uterine blood flow in non-pregnant sheep are mediated mainly by NO. A more recent study also found that placental blood flow increased markedly after DHEA-S injection using power Doppler imaging in term human pregnancy (Hata et al., 1998b
).
In this study it is postulated that a rapid decrease in uterine artery vascular impedance after bolus injection of DHEA-S may be mediated by a rapid increase of NO after an increase of oestradiol.
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Materials and methods |
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Statistical analysis for comparison of maternal age, gestational age at examination, mean arterial pressure, birth age, birth weight, Apgar score and blood pH of umbilical artery between both groups were done using an unpaired t-test. Data for experimental values for oestradiol and nitrite and nitrate were analysed by KruskalWallis one-way analysis of variance by ranks, and multiple comparisons. P < 0.05 was considered significant.
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Results |
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Discussion |
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In this investigation, there were no significant changes in maternal blood pressure and heart rate after DHEA-S administration, regardless of the vasodilative effect of DHEA-S. A previous report showed that maternal cardiac output increased by 20% and mean increase in stroke volume was 25% after DHEA-S administration (Hata et al., 1996). One possible explanation is that DHEA-S might increase cardiac output and stroke volume, without altering blood pressure and heart rate, by a change in the systemic vascular resistance.
The effect of oestrogens on NO metabolism has already been investigated (Rosenfeld et al., 1996; Cicinelli et al., 1998
). In post-menopausal women, plasma concentrations of NO metabolites 24 h after transdermal oestradiol administration were significantly higher than baseline concentrations (Cicinelli et al., 1998
). In non-pregnant ewes, acute oestrogen-induced increases in the uterine blood flow were associated with NO-dependent increases in cyclic GMP synthesis (Rosenfeld et al., 1996
). In this investigation, bolus injection of DHEA-S in full-term pregnant women increased significantly the NO metabolites at 10 and 30 min respectively. However, nitrate and nitrite concentrations returned to baseline (i.e. no statistical difference over pre-injection) at 60 min after injection, while the peak oestradiol concentration occurred at 60 min. If it is suggested that the sequence of events is DHEA-S converted to oestradiol which stimulates production of NO, then one would expect the peak of NO metabolites (nitrate and nitrite) to occur after the oestradiol peak. The reason for this discrepancy between oestradiol peak and the peak of NO metabolites is currently unknown. One possibility is that DHEA-S may alter peak nitrate and nitrite concentrations by a mechanism other than via oestradiol. In our previous investigation (Hata et al., 1995
), uterine artery pulsatility index decreased from baseline by 26% after 5 min, and the mean reduction was 36% after 10 min and 15% after 30 min. The pulsatility index returned to the baseline value 60 min later. Moreover, increased power Doppler enhancements of the placenta after DHEA-S injection were evident in each case studied; however, these power Doppler enhancements returned to the baseline imaging within 60 min (Hata et al., 1998b
).
These results suggest that a rapid decrease in uterine artery vascular impedance (Hata et al., 1995) after bolus injection of DHEA-S should be mediated by a rapid increase of NO following an increase of oestradiol. This improved uterine perfusion after DHEA-S administration might play an important role for the preservation of the pregnancy and in the outcome of the fetus. It seems that this vasodilative effect of DHEA-S is expected to be a new possible therapeutic agent in high-risk fetuses with decreased uteroplacental blood flows. However, the direct effect of DHEA-S on uterine vascular tone is still unknown, and further study is needed to clarify the direct effect of DHEA-S on uterine circulation during pregnancy. Caution should be exercised since DHEA-S (Sasaki et al., 1982
), oestradiol (Gordon and Calder, 1977
; Allen et al., 1989
; Magann et al., 1995
), and NO (Chwalisz et al., 1997
; Thomson et al., 1997
; Thomson et al., 1998
), can each produce effective ripening of the pregnant human cervix. Recently, NO donors have been shown to improve uteroplacental blood flow in severe fetal growth restriction and pre-eclampsia (Ramsay et al., 1994
; Cacciatore et al., 1998
).
Further study is needed to clarify the relationship between oestradiol production and NO synthesis after DHEA-S injection in human pregnancy.
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Notes |
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References |
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Submitted on January 25, 1999; accepted on April 30, 1999.