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Effect of dehydroepiandrosterone sulfate on uterine artery flow velocity waveforms in term pregnancy
Effect of Dehydroepiandrosterone Sulfate o n Uterine Artery Flow Velocity Waveforms in Term Pregnancy TOSHIYUKI HATA, MD, PhD, DAISAKU SENOH, MD, KOHKICHI HATA, MD, PhD, MANABU KITAO, MD, PhD, AND SUMIO MASUMURA, MD, PhD Objective: To investigate the interrelation b e t w e e n estrogen s y n t h e s i s b y the fetoplacental unit and uteroplacental hemod y n a m i c s in term pregnancy. Methods: Transvaginal color D o p p l e r flow i m a g i n g and p u l s e d D o p p l e r ultrasonographic a s s e s s m e n t s were made on ten normal full-term pregnant w o m e n before and 3, 5, 10, 30, and 60 m i n u t e s after the administration of a 200-mg intrav e n o u s dose of d e h y d r o e p i a n d r o s t e r o n e sulfate ( D H A S ) in 20 mL of 5% dextrose. Ten normal full-term pregnant w o m e n received 20 mL of 5% dextrose as controls. The pulsatility index (PI) values for the uterine artery, heart rate, and m e a n arterial pressure were recorded. Plasma estradiol (E2) w a s measured before and 10 m i n u t e s after the infusion. Results: In the D H A S group, uterine artery PI decreased from baseline b y 26% (P K .05) after 5 minutes, and the m e a n reduction w a s 36% (P K .05) after 10 m i n u t e s and 15% (P .05) after 30 minutes. The PI returned to the baseline value 60 m i n u t e s later. In the control group, there w a s no change in uterine artery PI. N o change w a s f o u n d in heart rate or m e a n arterial b l o o d pressure in the control or D H A S groups. The mean plasma E2 increased from 22.3 + 6.6 to 56.2 ± 24.1 ng/mL (P ~ .05) 10 m i n u t e s after the i n f u s i o n in D H A S subjects, w h e r e a s there w a s no significant change in plasma E2 in the controls. Conclusion: D e h y d r o e p i a n d r o s t e r o n e sulfate induces a significant decrease in the uterine artery PI, w h i c h suggests a p o s s i b l e decrease in uterine vascular i m p e d a n c e in term pregnancy. (Obstet Gynecol 1995;85:118-21)
Dehydroepiandrosterone sulfate (DHAS) of both maternal and fetal origin is converted to estrogen in the placenta. The metabolic clearance rate of DHAS in normal pregnant w o m e n is markedly elevated compared with that of nonpregnant subjects) The blood estradiol (E2) level increases rapidly after intravenous (IV) injection of DHAS to w o m e n in late pregnancy. 2 In From the Departments of Obstetrics and Gynecologyand Physiology, Shimane Medical University, Izumo, Japan.
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the pregnant ewe, the m a x i m u m concentration of estrogens occur approximately 30 minutes after the administration of DHAS, and uterine blood flow increases approximately 90 minutes after the m a x i m u m concentration of estrogens. 3 However, we are not aware of any report of the acute effect of DHAS on the uteroplacental circulation in humans. Transvaginal ultrasonography produces detailed images in the female pelvis. 4 Transvaginal Doppler ultrasound has facilitated the measurement of blood flow in the female pelvis 5 and is an easy, noninvasive method of assessing uteroplacental circulation in both normal and abnormal pregnancies. 6 In this investigation, our objective was to evaluate the effect of DHAS on uterine artery flow velocity waveforms in term pregnancy, using transvaginal color Doppler flow imaging and pulsed Doppler ultrasonography.
Materials and Methods For this study, we selected 20 normal pregnant w o m e n (ten normal controls and ten treated with DHAS) ranging from 37-41 weeks' gestation. These w o m e n were nonsmokers with no evidence of maternal complications or substance abuse. Gestational age was estimated from the first day of the last menstrual period and confirmed by first-trimester and early second-trimester ultrasound examinations (crown-rump length, biparietal diameter, and femur length measurements). Doppler studies were performed before and 3, 5, 10, 30, and 60 minutes after the administration of a 200-mg IV dose of DHAS dissolved in 20 mL of 5% dextrose for the experimental group, or a 20 mL dose of 5% dextrose for the control group. Mean arterial pressure and heart rate were recorded before and after the infusion. Blood samples were collected before and 10 minutes
Obstetrics & Gynecology
Table 1. Cardiovascular and Hormonal Changes in Response to Bolus Injection of Dehydroepiandrosterone Sulfate Time after injection
Uterine artery pulsatility index
Heart rate (bpm)
Mean arterial pressure (mmHg)
Estradiol (ng/mL)
(rain)
Control
DHAS
Control
DHAS
Control
DHAS
Control
DHAS
0 3 5 10 30 60
1.70 ~ 0.30 1.71 ± 0.32 1.73 ± 0.37 1.73 ± 0.36 1.70 ± 0.38 1.69 ± 0.30
1.64 ÷ 0.19 1.43 ± 0.39 1.21 + 0.35* 1.05 ± 0.28* 1.40 ± 0.20* 1.59 + 0.30
76 ± 7.6 75 ± 7.5 75 ± 7.6 76 + 7.1 76 ± 6.8 77 ± 6.5
77 ± 6.9 73 -+ 7.2 75 ± 5.9 75 ± 6.8 77 -+ 8.1 77 ± 5.0
85 ± 5.9 84 ± 4.6 82 ± 3.6 82 -+ 3.9 84 ± 4.3 85 ± 5.9
86 ± 7.9 87 ± 6.8 86 ± 6.4 87 ± 6.0 87 ~ 6.1 87 ± 5.3
21.8 ± 4.4
22.3 ± 6.6
22.3 ± 3.8
56.2 ± 24.1"
bpm = beats per minute; DHAS - dehydroepiandrosterone sulfate. Data are presented as mean + standard deviation. * P K .05
after the a d m i n i s t r a t i o n of D H A S or placebo. P l a s m a w a s frozen at - 8 0 ° C until a s s a y e d . P l a s m a E2 w a s m e a s u r e d b y r a d i o i m m u n o a s s a y (Diagnostic P r o d u c t s Co., Los Angeles, CA). The s t u d y w a s a p p r o v e d b y the local ethical c o m m i t t e e of S h i m a n e M e d i c a l University, a n d s t a n d a r d i z e d i n f o r m e d consent w a s o b t a i n e d f r o m each w o m a n . All infants w e r e d e l i v e r e d in o u r u n i v e r sity h o s p i t a l after 37 w e e k s ' gestation, a n d birth w e i g h t s w e r e in the n o r m a l r a n g e ( b e t w e e n the tenth a n d 90th percentiles) of the s t a n d a r d i n t r a u t e r i n e g r o w t h curve for J a p a n e s e neonates. 7 N o n e of the fetuses h a d evid e n c e of congenital m a l f o r m a t i o n s or genetic diseases. An end-viewing, 90°-angled, real-time, convex 5 - M H z t r a n s v a g i n a l t r a n s d u c e r ( A l o k a UST-964P-5; A l o k a Co., Tokyo, Japan) w a s c o n n e c t e d to an SSD-680 D o p p l e r u n i t (Aloka Co.). In the color a n d p u l s e d D o p p l e r m o d e s , the l o w e s t p o s s i b l e m e a s u r a b l e velocity w a s 1.54 c m / s e c o n d . Pulse r e p e t i t i o n frequencies w e r e 1-25 k H z , the m a x i m u m p e n e t r a t i o n d e p t h w a s 12 cm, a n d the gate w i d t h w a s 1-10 m m . W a l l filters (50 Hz) e l i m i n a t e d l o w - f r e q u e n c y signals occurring from v e s s e l - w a l l motion. The spatial p e a k t e m p o r a l a v e r a g e intensity at the m a x i m u m a m p l i t u d e a n d mini m u m gate w i d t h in s i m u l t a n e o u s color a n d p u l s e d D o p p l e r m o d e s w a s less t h a n 80 m W / c m 2, a c c o r d i n g to the m a n u f a c t u r e r ' s specifications. Before the e x a m i n a t i o n , each w o m a n w a s a s k e d to v o i d a n d then p l a c e d in the l i t h o t o m y position. Ultras o u n d gel w a s a p p l i e d to the h e a d of the t r a n s d u c e r , w h i c h w a s c o v e r e d w i t h a c o m m e r c i a l l y available cond o m . A n a d d i t i o n a l c o u p l i n g a g e n t w a s p l a c e d on the p r o b e to facilitate insertion into the vagina. O n the color D o p p l e r u l t r a s o n o g r a m , the s a m p l i n g p o i n t on the line of the p u l s e d D o p p l e r b e a m w a s p o s i t i o n e d w h e r e the c o l o r e d left u t e r i n e arterial flow w a s noted. The samp l i n g v o l u m e e m b r a c e d the entire l u m e n of the vessel, a n d the t i m e - v e l o c i t y w a v e f o r m s of the arterial flow w e r e d i s p l a y e d w h e n s w i t c h i n g to the D o p p l e r m o d e . A l t h o u g h the direction of flow w a s a l w a y s a w a y f r o m the t r a n s d u c e r (negative flow), it w a s also p o s s i b l e in
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m a n y instances to identify flow t o w a r d the transducer; this flow o r i g i n a t e d f r o m the cervical b r a n c h of the u t e r i n e artery. The p u l s a t i l i t y i n d e x (PI) (the rate of difference b e t w e e n p e a k systolic velocity a n d e n d diastolic velocity to t i m e - a v e r a g e d m e a n p e a k velocity) w a s calculated as the a v e r a g e v a l u e o b t a i n e d from five consecutive r e p r o d u c i b l e w a v e f o r m s . All e x a m i n a t i o n s w e r e p e r f o r m e d b y one e x a m i n e r (TH). The intrao b s e r v e r coefficient of v a r i a t i o n for the m e a s u r e m e n t of PI w a s 8.4%, d e t e r m i n e d b y p e r f o r m i n g five consecutive e x a m i n a t i o n s on ten p a t i e n t s w i t h i n 30 minutes. Statistical a n a l y s e s u s e d w e r e p a i r e d t test, a n a l y s i s of variance, a n d N e w m a n - K e u l s m u l t i p l e c o m p a r i s o n test. P K .05 w a s c o n s i d e r e d statistically significant.
Results In the D H A S g r o u p , u t e r i n e a r t e r y PI d e c r e a s e d f r o m b a s e l i n e b y 12% at 3 m i n u t e s , 26% (P < .05) at 5 m i n u t e s , 36% (P K .05) at 10 m i n u t e s , a n d 15% (P K .05) at 30 m i n u t e s , a n d r e t u r n e d to the b a s e l i n e v a l u e 60 m i n u t e s later (Table 1). In the controls, there w a s no c h a n g e in u t e r i n e a r t e r y PI. There w a s no significant c h a n g e in h e a r t rate or m e a n arterial b l o o d p r e s s u r e , nor d i d the w o m e n h a v e side effects in either g r o u p . M e a n p l a s m a E2 i n c r e a s e d 10 m i n u t e s after the i n f u s i o n in the D H A S g r o u p (P ~ .05), w h e r e a s there w a s no significant c h a n g e in p l a s m a E2 in the control g r o u p (Table 1).
Discussion The p l a c e n t a uses D H A S of b o t h m a t e r n a l a n d fetal origin for the p r o d u c t i o n of E2. In the final w e e k s of p r e g n a n c y , 40% or m o r e m a t e r n a l - c i r c u l a t i n g D H A S m a y be i r r e v e r s i b l y c o n v e r t e d b y the p l a c e n t a to E2, a n d an a d d i t i o n a l 35-40% to estriol (E3) v i a the i n t e r m e d i acy of 1 6 ~ - h y d r o x y DHAS. Thus, in late p r e g n a n c y , 75-80% of m a t e r n a l - c i r c u l a t i n g D H A S is m e t a b o l i z e d w i t h i n the placenta. 1 Late in p r e g n a n c y , the b l o o d E2
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119
level increases r a p i d l y after IV injection of DHAS2; h o w e v e r , there is a l m o s t no c h a n g e in b l o o d E3 level after D H A S injection. 8 A n IV injection of D H A S has b e e n u s e d clinically to e v a l u a t e placental b i o s y n t h e t i c capabilities a n d i d e n t i f y h i g h - r i s k fetuses 2 or to p r o m o t e cervical r i p e n i n g in t e r m p r e g n a n c y . 9 The fetoplacental u n i t of the e w e is c a p a b l e of increasing the b i o s y n t h e s i s of e s t r o g e n s after the e x o g e n o u s a d m i n i s tration of D H A S to the fetus. The m a x i m u m concentration of estrogens a p p e a r e d a p p r o x i m a t e l y 30 m i n u t e s after the a d m i n i s t r a t i o n of D H A S , a n d u t e r i n e b l o o d flow i n c r e a s e d a p p r o x i m a t e l y 90 m i n u t e s after the m a x i m u m c o n c e n t r a t i o n of estrogens. 3 Estrogen p r o d u c t i o n b y the fetoplacental unit a n d u t e r o p l a c e n t a l b l o o d flow p l a y i m p o r t a n t roles in the p r e s e r v a t i o n of p r e g n a n c y a n d in the o u t c o m e of the fetus. H o w e v e r , v e r y little is k n o w n a b o u t the relation b e t w e e n t h e m in h u m a n subjects, a n d there h a v e b e e n no r e p o r t s of the acute effects of D H A S on u t e r o p l a c e n t a l h e m o d y n a m ics. Therefore, this s t u d y w a s d e s i g n e d to i n v e s t i g a t e the i n t e r r e l a t i o n b e t w e e n e s t r o g e n s y n t h e s i s b y the fetoplacental u n i t a n d u t e r o p l a c e n t a l circulation in t e r m pregnant women. In this investigation, b o l u s injection of D H A S in full-term p r e g n a n t w o m e n r e d u c e d the PI of the u t e r i n e a r t e r y b y a p p r o x i m a t e l y 36% after 10 m i n u t e s , w h e r e a s there w a s no c h a n g e in u t e r i n e a r t e r y PI in the control g r o u p . The PI is b e l i e v e d to r e p r e s e n t i m p e d a n c e to b l o o d flow d o w n s t r e a m f r o m the p o i n t of s a m p l i n g . 1° Therefore, o u r results s u g g e s t a l o w e r i n g of the resistance in the v a s c u l a r b e d d i s t a l to the r e g i o n of ins o n a t i o n in u t e r i n e circulation after D H A S a d m i n i s t r a tion. H o w e v e r , this r e d u c t i o n in u t e r i n e a r t e r y PI lasted no l o n g e r t h a n 60 minutes, w h e n the PI r e t u r n e d to b a s e l i n e values. In a n i m a l e x p e r i m e n t s , 3 u t e r i n e b l o o d flow r e m a i n e d u n c h a n g e d for 90 m i n u t e s after D H A S infusion a n d i n c r e a s e d r a p i d l y thereafter. The r e a s o n for this d i s c r e p a n c y o n the effect of D H A S in u t e r i n e circulation b e t w e e n a n i m a l a n d h u m a n subjects is curr e n t l y u n k n o w n . O n e p o s s i b l e e x p l a n a t i o n is that the PI r e p r e s e n t s i m p e d a n c e to b l o o d flow d o w n s t r e a m from the p o i n t of D o p p l e r s a m p l i n g 1° a n d d o e s not correlate w i t h b l o o d f l o w , 11 The b l o o d E2 level increases r a p i d l y after IV injection of D H A S in w o m e n in late p r e g n a n c y . 2"~2 In this investigation, the b l o o d E2 level also increased 10 m i n u t e s after D H A S a d m i n i s t r a t i o n at the time of m a x i m u m r e d u c t i o n of the PI in the u t e r i n e artery. Estrogen i n d u c e s n o t a b l e u t e r i n e v a s o d i l a t i o n in n o n p r e g n a n t sheep, 13A4 a n d similar estrogenic effects on arterial tone h a v e b e e n r e p o r t e d in the h u m a n aorta ~5 a n d the h u m a n internal carotid artery. 16 Van Buren et a117 s h o w e d that E 2 - i n d u c e d increases in u t e r i n e b l o o d flow are m e d i a t e d m a i n l y b y nitric oxide. Nitric o x i d e a n d
120 Hata et al
DHAS in Term Pregnancy
e n d o t h e l i u m - d e r i v e d relaxing factor h a v e similar c h e m ical a n d p h a r m a c o l o g i c p r o p e r t i e s , l e a d i n g to the suggestion that e n d o t h e l i u m - d e r i v e d relaxing factor m a y be nitric oxide. 1~ E n d o t h e l i u m - d e r i v e d nitric o x i d e m a y p l a y a n i m p o r t a n t role in the m a i n t e n a n c e of l o w b a s a l v a s c u l a r tone in the p l a c e n t a at term. 19 A r a p i d d e c r e a s e in u t e r i n e a r t e r y v a s c u l a r i m p e d a n c e after b o l u s injection of D H A S m a y be m e d i a t e d b y a r a p i d increase of e n d o t h e l i u m - d e r i v e d relaxing factor after an increase of E2. Therefore, e n d o c r i n e r e g u l a t i o n of u t e r o p l a c e n t a l circulation in t e r m p r e g n a n c y w a s s u g g e s t e d s t r o n g l y in h u m a n subjects. This v a s o d i l a t i v e effect of D H A S is e x p e c t e d for a n e w t h e r a p e u t i c a g e n t in a h i g h - r i s k p r e g n a n c y w i t h u t e r o p l a c e n t a l insufficiency. H o w e v e r , the direct effect of D H A S on u t e r i n e v a s c u l a r tone is still u n k n o w n , a n d further s t u d y is n e e d e d to clarify the effect of D H A S on u t e r i n e circulation in n o n p r e g n a n t and pregnant women.
References 1. Gant NF, Hutchinson HT, Suteri PK, MacDonald PC. Study of the metabolic clearance rate of dehydroepiandrosterone sulfate in pregnancy. Am J Obstet Gynecol 1971;111:555-63. 2. Tulchinsky D, Osathanondh R, Finn A. Dehydroepiandrosterone sulfate loading test in the diagnosis of complicated pregnancies. N Engl J Med 1976;294:517-22. 3. Pupkin MJ, Schomberg DW, Nagey DA, Crenshaw C. Effect of exogenous dehydroepiandrosterone upon the fetoplacental biosynthesis of estrogens and its effect upon uterine blood flow in the term pregnant ewe. Am J Obstet Gynecol 1975;121:227-32. 4. Hata K, Hata T, Aoki S, et al. Efficiencyof transvaginal scanning in obstetrics and gynecology. Gynecol Obstet Invest 1990;29:41-6. 5. Bourne TH, Campbell S, Steer CV, Royston P, Whitehead MI, Collins WP. Detection of endometrial cancer by transvaginal ultrasonography with color flow imaging and blood flow analysis: A preliminary report. Gynecol Oncol 1991;40:253-9. 6. Thaler I, Manor D, Itskovitz J, et al. Changes in uterine blood flow during human pregnancy. Am J Obstet Gynecol 1990;162:121-5. 7. Sato A, Akama M, Yamanobe H, Hoshi K, Suzuki M. Intrauterine growth of live-born Japanese infants between 28 and 42 weeks of gestation. Nippon Sanka Fujinka Gakkai Zasshi 1982;34:1535-8. 8. Strecker JR, Killus CM, Lauritzen C, Neumann GK. The clinical value of the dehydroepiandrosterone sulfate loading test in normal and pathologic pregnancies. Am J Obstet Gynecol 1978;131:23949. 9. Sasaki K, Nakano R, Kadoya Y, Iwao M, Shima K, Sowa M. Cervical ripening with dehydroepiandrosterone sulfate. Br J Obstet Gynaecol 1982;89:195-8. 10. Thompson RS, Trudinger BJ, Cook CM. Doppler ultrasound waveform indicies: A/B ratio, pulsatility index, Pourcelot ratio. Br J Obstet Gynaecol 1988;95:581-8. 11. Hansen NB, Stonestreet BS, Rosenkrantz TS, Oh W. Validity of Doppler measurements of anterior cerebral artery blood flow velocity: Correlation with brain blood flow in piglets. Pediatrics 1983;72:526-31. 12. Klopper A, Varela-Torres R, Jandial V. Placental metabolism of dehydroepiandrosterone sulfate in normal pregnancy. Br J Obstet Gynaecol 1976;83:478-83. 13. Killam AP, Rosenfeld CR, Battagulia FC, Makowski EL, Meschia G.
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14.
15.
16.
17.
18.
19.
Effect of estrogens on the uterine blood of oophorectomized ewes. Am J Obstet Gynecol 1973;115:1045-52. Resnik R, Killam AP, Battaglia FC, Makowski EL, Meschia G. The stimulation of uterine blood flow by various estrogens. Endocrinology 1974;94:1192-6. Pines A, Fiwsman EZ, Averbuch M, et al. The effects of hormone replacement therapy in normal postmenopausal women: Measurements of Doppler-derived parameters of aortic flow. Am J Obstet Gynecol 1991;164:806-12. Gangar KF, Vyas S, Whitehead MI, Crook D, Miere H, Campbell S. Pulsatility index in the internal carotid artery is influenced by transdermal estradiol and time since menopause. Lancet 1991;338: 839-42. Van Buren G, Yang D, Clark KE. Estrogen-induced uterine vasodilatation is antagonized by L-nitroarginine methyl ester, an inhibitor of nitric oxidase synthesis. Am J Obstet Gynecol 1992;167: 828 -33. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-6. Gude NM, King RG, Brennecke SP. Role of endothelium-derived
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nitric oxide in maintenance of low fetal vascular resistance in placenta. Lancet 1990;336:1589-90.
A d d r e s s r e p r i n t r e q u e s t s to:
Toshiyuki Hata, MD, PhD Department of Obstetrics and Gynecology Shimane Medical University Izumo 693
lapan
Received May 27, 1994. Received in revised form July 20, 1994. Accepted August 1, 1994.
Copyright © 1995 by The American College of Obstetricians and Gynecologists.
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Dehydroepiandrosterone sulfate (DHAS) of both maternal and fetal origin is converted to estrogen in the placenta. The metabolic clearance rate of DHAS in normal pregnant w o m e n is markedly elevated compared with that of nonpregnant subjects) The blood estradiol (E2) level increases rapidly after intravenous (IV) injection of DHAS to w o m e n in late pregnancy. 2 In From the Departments of Obstetrics and Gynecologyand Physiology, Shimane Medical University, Izumo, Japan.
118 0029-7844/95/$9.50 0029-7844(94)00295-0
the pregnant ewe, the m a x i m u m concentration of estrogens occur approximately 30 minutes after the administration of DHAS, and uterine blood flow increases approximately 90 minutes after the m a x i m u m concentration of estrogens. 3 However, we are not aware of any report of the acute effect of DHAS on the uteroplacental circulation in humans. Transvaginal ultrasonography produces detailed images in the female pelvis. 4 Transvaginal Doppler ultrasound has facilitated the measurement of blood flow in the female pelvis 5 and is an easy, noninvasive method of assessing uteroplacental circulation in both normal and abnormal pregnancies. 6 In this investigation, our objective was to evaluate the effect of DHAS on uterine artery flow velocity waveforms in term pregnancy, using transvaginal color Doppler flow imaging and pulsed Doppler ultrasonography.
Materials and Methods For this study, we selected 20 normal pregnant w o m e n (ten normal controls and ten treated with DHAS) ranging from 37-41 weeks' gestation. These w o m e n were nonsmokers with no evidence of maternal complications or substance abuse. Gestational age was estimated from the first day of the last menstrual period and confirmed by first-trimester and early second-trimester ultrasound examinations (crown-rump length, biparietal diameter, and femur length measurements). Doppler studies were performed before and 3, 5, 10, 30, and 60 minutes after the administration of a 200-mg IV dose of DHAS dissolved in 20 mL of 5% dextrose for the experimental group, or a 20 mL dose of 5% dextrose for the control group. Mean arterial pressure and heart rate were recorded before and after the infusion. Blood samples were collected before and 10 minutes
Obstetrics & Gynecology
Table 1. Cardiovascular and Hormonal Changes in Response to Bolus Injection of Dehydroepiandrosterone Sulfate Time after injection
Uterine artery pulsatility index
Heart rate (bpm)
Mean arterial pressure (mmHg)
Estradiol (ng/mL)
(rain)
Control
DHAS
Control
DHAS
Control
DHAS
Control
DHAS
0 3 5 10 30 60
1.70 ~ 0.30 1.71 ± 0.32 1.73 ± 0.37 1.73 ± 0.36 1.70 ± 0.38 1.69 ± 0.30
1.64 ÷ 0.19 1.43 ± 0.39 1.21 + 0.35* 1.05 ± 0.28* 1.40 ± 0.20* 1.59 + 0.30
76 ± 7.6 75 ± 7.5 75 ± 7.6 76 + 7.1 76 ± 6.8 77 ± 6.5
77 ± 6.9 73 -+ 7.2 75 ± 5.9 75 ± 6.8 77 -+ 8.1 77 ± 5.0
85 ± 5.9 84 ± 4.6 82 ± 3.6 82 -+ 3.9 84 ± 4.3 85 ± 5.9
86 ± 7.9 87 ± 6.8 86 ± 6.4 87 ± 6.0 87 ~ 6.1 87 ± 5.3
21.8 ± 4.4
22.3 ± 6.6
22.3 ± 3.8
56.2 ± 24.1"
bpm = beats per minute; DHAS - dehydroepiandrosterone sulfate. Data are presented as mean + standard deviation. * P K .05
after the a d m i n i s t r a t i o n of D H A S or placebo. P l a s m a w a s frozen at - 8 0 ° C until a s s a y e d . P l a s m a E2 w a s m e a s u r e d b y r a d i o i m m u n o a s s a y (Diagnostic P r o d u c t s Co., Los Angeles, CA). The s t u d y w a s a p p r o v e d b y the local ethical c o m m i t t e e of S h i m a n e M e d i c a l University, a n d s t a n d a r d i z e d i n f o r m e d consent w a s o b t a i n e d f r o m each w o m a n . All infants w e r e d e l i v e r e d in o u r u n i v e r sity h o s p i t a l after 37 w e e k s ' gestation, a n d birth w e i g h t s w e r e in the n o r m a l r a n g e ( b e t w e e n the tenth a n d 90th percentiles) of the s t a n d a r d i n t r a u t e r i n e g r o w t h curve for J a p a n e s e neonates. 7 N o n e of the fetuses h a d evid e n c e of congenital m a l f o r m a t i o n s or genetic diseases. An end-viewing, 90°-angled, real-time, convex 5 - M H z t r a n s v a g i n a l t r a n s d u c e r ( A l o k a UST-964P-5; A l o k a Co., Tokyo, Japan) w a s c o n n e c t e d to an SSD-680 D o p p l e r u n i t (Aloka Co.). In the color a n d p u l s e d D o p p l e r m o d e s , the l o w e s t p o s s i b l e m e a s u r a b l e velocity w a s 1.54 c m / s e c o n d . Pulse r e p e t i t i o n frequencies w e r e 1-25 k H z , the m a x i m u m p e n e t r a t i o n d e p t h w a s 12 cm, a n d the gate w i d t h w a s 1-10 m m . W a l l filters (50 Hz) e l i m i n a t e d l o w - f r e q u e n c y signals occurring from v e s s e l - w a l l motion. The spatial p e a k t e m p o r a l a v e r a g e intensity at the m a x i m u m a m p l i t u d e a n d mini m u m gate w i d t h in s i m u l t a n e o u s color a n d p u l s e d D o p p l e r m o d e s w a s less t h a n 80 m W / c m 2, a c c o r d i n g to the m a n u f a c t u r e r ' s specifications. Before the e x a m i n a t i o n , each w o m a n w a s a s k e d to v o i d a n d then p l a c e d in the l i t h o t o m y position. Ultras o u n d gel w a s a p p l i e d to the h e a d of the t r a n s d u c e r , w h i c h w a s c o v e r e d w i t h a c o m m e r c i a l l y available cond o m . A n a d d i t i o n a l c o u p l i n g a g e n t w a s p l a c e d on the p r o b e to facilitate insertion into the vagina. O n the color D o p p l e r u l t r a s o n o g r a m , the s a m p l i n g p o i n t on the line of the p u l s e d D o p p l e r b e a m w a s p o s i t i o n e d w h e r e the c o l o r e d left u t e r i n e arterial flow w a s noted. The samp l i n g v o l u m e e m b r a c e d the entire l u m e n of the vessel, a n d the t i m e - v e l o c i t y w a v e f o r m s of the arterial flow w e r e d i s p l a y e d w h e n s w i t c h i n g to the D o p p l e r m o d e . A l t h o u g h the direction of flow w a s a l w a y s a w a y f r o m the t r a n s d u c e r (negative flow), it w a s also p o s s i b l e in
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m a n y instances to identify flow t o w a r d the transducer; this flow o r i g i n a t e d f r o m the cervical b r a n c h of the u t e r i n e artery. The p u l s a t i l i t y i n d e x (PI) (the rate of difference b e t w e e n p e a k systolic velocity a n d e n d diastolic velocity to t i m e - a v e r a g e d m e a n p e a k velocity) w a s calculated as the a v e r a g e v a l u e o b t a i n e d from five consecutive r e p r o d u c i b l e w a v e f o r m s . All e x a m i n a t i o n s w e r e p e r f o r m e d b y one e x a m i n e r (TH). The intrao b s e r v e r coefficient of v a r i a t i o n for the m e a s u r e m e n t of PI w a s 8.4%, d e t e r m i n e d b y p e r f o r m i n g five consecutive e x a m i n a t i o n s on ten p a t i e n t s w i t h i n 30 minutes. Statistical a n a l y s e s u s e d w e r e p a i r e d t test, a n a l y s i s of variance, a n d N e w m a n - K e u l s m u l t i p l e c o m p a r i s o n test. P K .05 w a s c o n s i d e r e d statistically significant.
Results In the D H A S g r o u p , u t e r i n e a r t e r y PI d e c r e a s e d f r o m b a s e l i n e b y 12% at 3 m i n u t e s , 26% (P < .05) at 5 m i n u t e s , 36% (P K .05) at 10 m i n u t e s , a n d 15% (P K .05) at 30 m i n u t e s , a n d r e t u r n e d to the b a s e l i n e v a l u e 60 m i n u t e s later (Table 1). In the controls, there w a s no c h a n g e in u t e r i n e a r t e r y PI. There w a s no significant c h a n g e in h e a r t rate or m e a n arterial b l o o d p r e s s u r e , nor d i d the w o m e n h a v e side effects in either g r o u p . M e a n p l a s m a E2 i n c r e a s e d 10 m i n u t e s after the i n f u s i o n in the D H A S g r o u p (P ~ .05), w h e r e a s there w a s no significant c h a n g e in p l a s m a E2 in the control g r o u p (Table 1).
Discussion The p l a c e n t a uses D H A S of b o t h m a t e r n a l a n d fetal origin for the p r o d u c t i o n of E2. In the final w e e k s of p r e g n a n c y , 40% or m o r e m a t e r n a l - c i r c u l a t i n g D H A S m a y be i r r e v e r s i b l y c o n v e r t e d b y the p l a c e n t a to E2, a n d an a d d i t i o n a l 35-40% to estriol (E3) v i a the i n t e r m e d i acy of 1 6 ~ - h y d r o x y DHAS. Thus, in late p r e g n a n c y , 75-80% of m a t e r n a l - c i r c u l a t i n g D H A S is m e t a b o l i z e d w i t h i n the placenta. 1 Late in p r e g n a n c y , the b l o o d E2
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level increases r a p i d l y after IV injection of DHAS2; h o w e v e r , there is a l m o s t no c h a n g e in b l o o d E3 level after D H A S injection. 8 A n IV injection of D H A S has b e e n u s e d clinically to e v a l u a t e placental b i o s y n t h e t i c capabilities a n d i d e n t i f y h i g h - r i s k fetuses 2 or to p r o m o t e cervical r i p e n i n g in t e r m p r e g n a n c y . 9 The fetoplacental u n i t of the e w e is c a p a b l e of increasing the b i o s y n t h e s i s of e s t r o g e n s after the e x o g e n o u s a d m i n i s tration of D H A S to the fetus. The m a x i m u m concentration of estrogens a p p e a r e d a p p r o x i m a t e l y 30 m i n u t e s after the a d m i n i s t r a t i o n of D H A S , a n d u t e r i n e b l o o d flow i n c r e a s e d a p p r o x i m a t e l y 90 m i n u t e s after the m a x i m u m c o n c e n t r a t i o n of estrogens. 3 Estrogen p r o d u c t i o n b y the fetoplacental unit a n d u t e r o p l a c e n t a l b l o o d flow p l a y i m p o r t a n t roles in the p r e s e r v a t i o n of p r e g n a n c y a n d in the o u t c o m e of the fetus. H o w e v e r , v e r y little is k n o w n a b o u t the relation b e t w e e n t h e m in h u m a n subjects, a n d there h a v e b e e n no r e p o r t s of the acute effects of D H A S on u t e r o p l a c e n t a l h e m o d y n a m ics. Therefore, this s t u d y w a s d e s i g n e d to i n v e s t i g a t e the i n t e r r e l a t i o n b e t w e e n e s t r o g e n s y n t h e s i s b y the fetoplacental u n i t a n d u t e r o p l a c e n t a l circulation in t e r m pregnant women. In this investigation, b o l u s injection of D H A S in full-term p r e g n a n t w o m e n r e d u c e d the PI of the u t e r i n e a r t e r y b y a p p r o x i m a t e l y 36% after 10 m i n u t e s , w h e r e a s there w a s no c h a n g e in u t e r i n e a r t e r y PI in the control g r o u p . The PI is b e l i e v e d to r e p r e s e n t i m p e d a n c e to b l o o d flow d o w n s t r e a m f r o m the p o i n t of s a m p l i n g . 1° Therefore, o u r results s u g g e s t a l o w e r i n g of the resistance in the v a s c u l a r b e d d i s t a l to the r e g i o n of ins o n a t i o n in u t e r i n e circulation after D H A S a d m i n i s t r a tion. H o w e v e r , this r e d u c t i o n in u t e r i n e a r t e r y PI lasted no l o n g e r t h a n 60 minutes, w h e n the PI r e t u r n e d to b a s e l i n e values. In a n i m a l e x p e r i m e n t s , 3 u t e r i n e b l o o d flow r e m a i n e d u n c h a n g e d for 90 m i n u t e s after D H A S infusion a n d i n c r e a s e d r a p i d l y thereafter. The r e a s o n for this d i s c r e p a n c y o n the effect of D H A S in u t e r i n e circulation b e t w e e n a n i m a l a n d h u m a n subjects is curr e n t l y u n k n o w n . O n e p o s s i b l e e x p l a n a t i o n is that the PI r e p r e s e n t s i m p e d a n c e to b l o o d flow d o w n s t r e a m from the p o i n t of D o p p l e r s a m p l i n g 1° a n d d o e s not correlate w i t h b l o o d f l o w , 11 The b l o o d E2 level increases r a p i d l y after IV injection of D H A S in w o m e n in late p r e g n a n c y . 2"~2 In this investigation, the b l o o d E2 level also increased 10 m i n u t e s after D H A S a d m i n i s t r a t i o n at the time of m a x i m u m r e d u c t i o n of the PI in the u t e r i n e artery. Estrogen i n d u c e s n o t a b l e u t e r i n e v a s o d i l a t i o n in n o n p r e g n a n t sheep, 13A4 a n d similar estrogenic effects on arterial tone h a v e b e e n r e p o r t e d in the h u m a n aorta ~5 a n d the h u m a n internal carotid artery. 16 Van Buren et a117 s h o w e d that E 2 - i n d u c e d increases in u t e r i n e b l o o d flow are m e d i a t e d m a i n l y b y nitric oxide. Nitric o x i d e a n d
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e n d o t h e l i u m - d e r i v e d relaxing factor h a v e similar c h e m ical a n d p h a r m a c o l o g i c p r o p e r t i e s , l e a d i n g to the suggestion that e n d o t h e l i u m - d e r i v e d relaxing factor m a y be nitric oxide. 1~ E n d o t h e l i u m - d e r i v e d nitric o x i d e m a y p l a y a n i m p o r t a n t role in the m a i n t e n a n c e of l o w b a s a l v a s c u l a r tone in the p l a c e n t a at term. 19 A r a p i d d e c r e a s e in u t e r i n e a r t e r y v a s c u l a r i m p e d a n c e after b o l u s injection of D H A S m a y be m e d i a t e d b y a r a p i d increase of e n d o t h e l i u m - d e r i v e d relaxing factor after an increase of E2. Therefore, e n d o c r i n e r e g u l a t i o n of u t e r o p l a c e n t a l circulation in t e r m p r e g n a n c y w a s s u g g e s t e d s t r o n g l y in h u m a n subjects. This v a s o d i l a t i v e effect of D H A S is e x p e c t e d for a n e w t h e r a p e u t i c a g e n t in a h i g h - r i s k p r e g n a n c y w i t h u t e r o p l a c e n t a l insufficiency. H o w e v e r , the direct effect of D H A S on u t e r i n e v a s c u l a r tone is still u n k n o w n , a n d further s t u d y is n e e d e d to clarify the effect of D H A S on u t e r i n e circulation in n o n p r e g n a n t and pregnant women.
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nitric oxide in maintenance of low fetal vascular resistance in placenta. Lancet 1990;336:1589-90.
A d d r e s s r e p r i n t r e q u e s t s to:
Toshiyuki Hata, MD, PhD Department of Obstetrics and Gynecology Shimane Medical University Izumo 693
lapan
Received May 27, 1994. Received in revised form July 20, 1994. Accepted August 1, 1994.
Copyright © 1995 by The American College of Obstetricians and Gynecologists.
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