Evaluation of the feto-placental function by means of intraamniotic administration of dehydroepiandrosterone-sulphate

Dell'Acqua et al., Intraamniotic administration of DHEA-S

149

j. Perinat. Med. Evaluation of the feto-placental function by means of intraamniotic 7 (1979) 149 administration of dehydroepiandrosterone-sulphate

S. Dell'Acqua, E. Parlati, A. Lucisano, G. Plotti, F. Serri, A. Bompiani

Universita Cattolica del Sacro Cuore, Rome, Italy

l Introduction

The estriol or estrogens determination in maternal urine is a well established test of feto-placental function, extensively used for the diagnosis of pregnancy at risk.

It is know that the most important precursor of estriol (representirig 90% of the total estrogens excreted in maternal urines) is fetal 16-hydroxy- lated dehydroepiandrosterone-sulphate.

In the last trimester of gestation about 80—90%

of the estriol precursors are produced by the fetal adrenals and about 10—20% by the maternal ones;

about 50% of the precursors of estrone and 170- estradiol are produced by the fetus and about 50% by the mother (for a review, see DICZFALUSY [3]).

The predictive value of urinary estriol or estrogens determinations concerning fetal outcome in differ- ent pathological conditions seems to be only about 70% correct [7].

In recent years several investigators have proposed the use of dynamic tests, which could complement and improve the diagnostic pössibilities provided by the simple estriol or estrogens assay, also in terms of long-term prognosis of fetal'conditions The conversion of DHEA-S into estrogens takes [8].

place mainly in the placenta [3].

Such tests are based upon supplying a large amount of DHEA-S to the placenta, to evaluate its steroid- metabolizing capacity under load conditions.

Curricuhim vitae

SERGIO DELL'ACQUA born 1936, graduated from the University of Milan (Italy) in 1962. Training in obstetrics and gynecology at the University of Milan.

Guest scientist from Fe- bruary 1964 to October 1965 at the Reproductive Endocrinology Research Unit, Karolinska sjnkhuset, Stockholm, äs a holder ofa special Ford Foundation Fellowship in Reproductive

Endocrinology. At present associate professor of Ob- stet. Gynecol. Endocrinology, Universita Cattolica del Sacro Cuore, Rome, Italy. Research in thefieldof human reproductive endocrinology, both in pregnant and in non pregnant women, especially in the steroids synthesis and metabolism in the ovary and in the foeto-placental unit.

The purpose of the present investigation was to establish the clinical Utility ofa dynamic test based on the administration of DHEA-S into the amniotic cavity.

2 Material and method

The test was performed in 12 cases of normal pregnancies, ranging from the 33 th to the 37 th week of gestation and in 33 cases of pathological pregnancies (10 intrauterine fetal growth retar- dation, 3 diabetes, 3 cardiopaty, 4 chronic hyper- 0300-5577/79/0007-0149S02.00

© by Walter de Gruyter & Co. · Berlin · New York

150

Dell'Acqua et al., Intraamniotic administration of DHEA-S

tension, 2 toxemia, 3 idiopathic jaundice of pregnancy, 2 anaemia, 2 Rh-isoimmunisation, 2 fetal anencephalia, l myomectomy in pregnancy, l plastic unification of a double Uterus before pregnancy) ranging from the 32th to the 38th week of gestation.

Two hundred mg of DHEA-S were rapidly injected into the amniotic cavity, after localization of the placental area using IN

¹¹³

[ 12].

The increment of maternal urinary excretion of total estrogens over the 24 hrs following the DHEA-S injection was assessed äs the percentage of the mean of the two 24 hr excretion values before DHEA-S administration.

By means of urinary assays performed every 2—4

v

hrs, it was established that the increase in urinary estrogens Starts 6-8 hrs after DHEA-S admini- stration (Fig. 3).

For the above reason it seems more convenient to begin the evaluation of the increment 8 hrs after DHEA-S injection.

As daily urines collection in our department Starts at 6 a.m., the intraamniotic injection of DHEA-S was given to 10 p.m. on the pfevious day.

Total urinary estrogens were measured according to the BROWN, BEISHER and SMITH [1] method, modified by MENINI and BOMPIANI [11].

DHEA-S was kindly supplied by RÖCHE, Basel.

3 Results

Fig. l illustrates the profiles of total urinary estro- gens excretion in 8 cases of normal pregnancies before and after intraamniotic administration of DHEA-S.

In all the 12 cäses.examined, an increment of total urinary estrogens exceeding 100% was obtained, with an average of 147.6% ± 46.6 S.D. (Tab. I).

Fig. 2 illustrates the profiles of total urinary estro- gens excretion in 8 cases of pathological pregnan- cies.

In 28 out of 33 cases of pathological pregnancies examined the increment never reached 100% with an average of 48.6% ± 19.2 S.D. (Tabs.il, III).

It is interesting to note that in normal pregnancies the increase is contained over the first 24hrperiod, but persists in the following days.

Fig. 3 shows two profiles of urinary assays of total estrogens, performed every 4 hrs, in two cases, one normal and one pathological. The two profiles clearly exhibit a different increment curve. Further- more no significant increase in the excretion is found to occur in either profile over the first 8 hrs period following DHEA-S administration.

Tabs. I-IV show a comparison of the results ob- tained using the intraamniotic DHEA-S test with the values of the

r

daily urinary estrogens determined serially during the last trimester of gestation.

Tab. I illustrates the 12 normal cases, in which the urinary estrogens values were all within the normal ränge and the increase after DHEA-S administration always exceeded 100%.

In this group all the deliveries were normal and the newborn weight and the APGAR score were within normal limits.

Tab. II shows 4 pathological pregnancies, in which the urinary estrogens values were below the nor- mal ränge and the increase after DHEA-S admini- stration never reached 100%.

Two of these patients were submitted to cesarian section for fetal distress and the newborns were underweight.

Tab. III illustrates 24 pathological cases, in which the urinary estrogens values were within the normal ränge or at border line, but the increment after DHEA-S administration never reached 100%.

In this group we can observe 6 cesarian sections for fetal distress and one in utero fetal death.

In Tab. IV 5 pathological cases have been collected, in which the urinary estrogens values were below the normal ränge, but the increment after DHEA-S administration always exceeded 100%. We have no explanation for the first case, where the abnormal increment could be due to a technical error, but in the other four cases one newborn was mongoloid, the second was affected with congenital nanism and the other two were anencephalic.

4 Discussion

Intraamniotic injection of DHEA-S rather than maternal intravenous administration was favored, assuming that a higher concentration of the steroid would thus feach the feto-placental unit.

J. Perinat. Med. 7 (1979)

DelTAcqua et al., Intraamniotic administration of DHEA-S

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The results obtained confirm this assumption:

LAURITZEN [6], who first used DHEA-S intra- venous administration to the mother to test the steroid-metabolizing capacity of the fetoplacental unit, obtains a much lower increase of urinary estrogens.

Even when very high doses of DHEA-S (500 mg) are administrated intravenously to the mother, the increase of urinary estrogens is lower than that obtained by us [4].

By using intraamniotic administration a more significant correlation between the percentage of

the increase and the functional condition of the steroid-synthetizing enzymatic complex can be established.

We introduce in the amniotic compartment the rather high dose of 20Q mg DHEA-S to be sure that the enzymatic complex was completely saturated.

It was found that normal pregnant women exhibit an average increase of 147.6 ± 46,6 S.D., in any case exceeding 100%.

We can assume this limit äs an indication of a good functional reserve of the enzymatic complex.

J.Perinat. Med.7 (1979)

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On the other hand the average increase of patho- logical pregnancy with primary or secondary

placental insufficiency was 48.6% ± 19.2 S.D.

From a clinical standpoint too it is interesting to determine whether injected DHEA-S ismetabolized mainly by the placenta, or by the feto-placental unit.

JEFFERY et al. [4] have shown that the estriol/

estrone+estradiol ratio in maternal urine after intravenous administration of DHEA-S to the mother is much lower during estrogens increment than before DHEA-S administration and conclu- ded that this precursor is metabolized mainly by the placenta, rather than by the feto-placental unit.

Some conclusions were reached by LAURITZEN [8], who administered tritiated DHEA-S intra- venously to 6 pregnant women at term shortly before delivery and measured the distribution of

labelled steroids in fetal umbilical vein and arteries, in the amniotic fluid äs well äs in maternal venous blood and urines at 10—20 and 30 min. following injection.

Only 20% of the DHEA-S injected goes to the fetus. The bulk is converted by the placenta to estrone and estradiol: estrone is the most im- portant estrogenic metabolite excreted in the

urine.

MANGO et al. [10] reached a similar conclusion after careful investigation of the metabolic fate of 200 mg of DHEA-S injected into the amniotic compartment, with the determination in maternal urines of estriol, estradiol, estrone, DHEA, etiocholanolone and androsterone, before and after DHEA-S injection.

Different results were obtained by LEHMANN and STRECKER, who injected a mixture of cold DHEA and radioactive DHEA-S into the amniotic

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cavity, but in different experimental conditions (at 20th week of gestation, 5 mg of DHEA).

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steroid that rise in the maternal circulation [9].

The high increment of urinary estrogens after DHEA-S administration in the cases illustrated in Tab. IV could be explained by the fact that in these patients the fetus synthetized insufficient quantities of DHEA-S, whereas the placental function was normal.

In many pathological cases (Tab. III) the results demonstrated that the predictive values of the intraamniotic DHEA-S test can improve those

Summary

It is well know that in pregnancy dehydroepiandroste- rone-sulphate (DHEAS) (90% synthetized by the fetal adrenals, 10% by the maternal ones) is converted into estrogens mainly in the placenta.

In order to eyaluate the steroid metabolizing capacity of the placental enzymatic complex under load conditions,

obtained by the simple urinary estrogen assay.

These findings agreed with those obtained by LAURITZEN [8], STEMBERA and HERZMANN [13], KELLER [5], VAN DER CRABBEN et al. [2], by injecting DHEA-S intravenously to the mother.

In conclusion weconsider the intraamniotic DHEA- S test very reliable and maybe more significant than the analogous maternal intravenous DHEA-S test.

It can be used in the case of pregnancies at risk where the urinary estrogen values are questionable, particularly when a pathological pregnancy is sus- pected, but the urinary estrogens values are within the normal ränge.

a test was devised based upon a rapid introduction of 200 mg of DHEAS into the amniotic compartment during the third trimester of gestation.

The purpose of the present investigation was to establish the clinical utüity of such a test in comparison with the simple urinary estrogen determination test.

J. Perinat. Med. 7(1979)

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J.Perinat.Med.7(1979)

158

DelTAcqua et al., Intraamniotic administration of DHEA-S

After DHEAS administration an increment in maternal urinary excretion of total estrogens was obtained: this increment over the 24 hrs foUowing the DHEA-S in- jection was assessed äs the percentage of the mean of the two 24 hrs excretion values before DHEA-S administration.

The test was performed in 45 pregnancies (12 normal, 33 pathological). In all the normal pregnancies an increment of total urinary estrogens in the first 24 hrs urine ex- ceeding 100% was obtained, with an average of 147,6% ± 46,6 S.D. (Fig. 1).

Conventionally, an increment exceeding 100% was con- sidered an indication of normality. In these 12 cases the values of the daily urinary estrogens determinations were within the normal ränge (Tab. I). In 4 of the cases of pathological pregnancies considered, both daily urinary estrogens excretion and estrogens increment after DHEA- S administration were below the normal ränge (Tab. II).

In 24 cases the daily urinary estrogens excretion was within the normal ränge or at border line, but the in-

crement after DHEA-S administration neverreached 100%

(Tab. UI).

The last 5 cases presented low daily urinary estrogens ex- cretion, but a normal increment after DHEA-S administra- tion (Tab. IV).

This group collected cases of fetal pathology, in which the synthesis of DHEA-S by the fetal adrenals was probably insufficient, whereas the placental function was normal.

In conclusion we consider the intraamniotic DHEA-S test very reliable and maybe more significant than the analogous maternal intravenous DHEA-S test, because utilizing the intraamniotic administration it is possible to obtain a higher increment in estrogens synthetised by the placenta and excreted in maternal urines.

It can be used in the case of pregnancies at risk, where the urinary estrogens values are questionable, particulary where there is suspicion of fetal distress, but the urinary estrogens values are within the normal ränge.

NKeywords: Dehydroepiandrosterone sulphate, feto-placental function, injection intraamniotic.

Zusammenfassung

Bestimmung der feto-plazentaren Funktion durch intra- amniale Gabe von Dehydroepiandrosteron-Sulfat

Es ist bekannt, daß Dehydroepiandrosteron-Sulfat (DHEA- S), von dem 90% in der fetalen und 10% in der mütter- lichen Nebenniere synthetisiert wird, während der Schwangerschaft hauptsächlich in der Plazenta in Östro- gene umgewandelt wird. Um die Fähigkeit des plazentaren Enzymapparates für den Steroidstoffwechsel bei Belastung zu bestimmen, wurde ein Test angewendet, der auf einer raschen Injektion von 200 mg DHEA-S in das Frucht- wasser während des letzten Drittels der Schwangerschaft beruht. Das Ziel der vorliegenden Untersuchung war da- bei, die klinische Brauchbarkeit eines solchen Tests im Vergleich mit der herkömmlichen Östrogenbestimmung im Urin aufzuzeigen.

Nach DHEA-S-Injektion wurde ein Anstieg der Gesamt- östrogene im Urin beobachtet. Die Zunahme, die während der nächsten 24 Stunden nach DHEA-S-Gabe erfolgte, ließ sich als prozentualer Anstieg gegenüber dem Mittel von 2 Gesamtöstrogenbestimmungen in den 24 Stunden vor der DHEA-S-Injektion berechnen. Der Test wurde bei 45 Schwangeren durchgeführt (12 normale und 33 pathologische Schwangerschaften). Bei allen normalen Schwangerschaften betrug der Anstieg der Gesamt- östrogene im ersten 24-Stunden-Urin über 100%. Die Zu- nahme lag im Mittel bei 147,6% mit einer Standardab- weichung von ± 46,6 (Fig. 1). Gewöhnlich bedeutet ein Anstieg, der über 100% liegt, daß eine normale Funktion vorhanden ist. Auch die Östrogenausscheidung war bei

diesen 12 Fällen innerhalb der Norm (Tab. I). In 4 Schwangerschaften, die als pathologisch eingestuft waren, lag sowohl die Östrogenausscheidung wie auch der An- stieg nach DHEA-S-Gabe unterhalb der Norm (Tab. II).

Bei 24 der untersuchten Fälle zeigte sich, daß die Gesamt- östrogenbestimmung im Urin normale Werte oder Grenz- werte lieferte, die Zunahme nach DHEA-S-Injektion je- doch in keinem Fall 100% erreichte (Tab. ). In den 5 übrigen Schwangerschaften waren die Gesamtöstrogen- werte im Urin niedrig, während aber nach DHEA-S-Gabe ein normaler Anstieg gemessen werden konnte (Tab. IV).

Diese Gruppe faßt Fälle zusammen, in denen die DHEA-S- Synthese durch die fetale Nebenniere möglicherweise zu gering war, wohingegen die Plazentafunktion als normal anzusehen ist.

Abschließend kann gesagt werden, daß ein Belastungstest, der auf einer intraamnialen DHEA^S-Gabe beruht, eine gute und möglicherweise bedeutsamere Aussage liefert als der analoge Test nach intravenöser Applikation von DHEA-S an die Mutter. Nach intraamnialer Verabreichung kann man einen höheren Anstieg der von der Plazenta syn- thetisierten und im mütterlichen Urin ausgeschiedenen Östrogene beobachten.

Der Test sollte bei Risikoschwangerschaften eingesetzt werden, in denen unsichere Östro^enwerte im Urin vor- liegen und insbesondere in Fällen, wo der Verdacht einer fetalen Gefährdung besteht, die Östrogenausscheidung aber normal ist.

Schlüsselwörter: Dehydroepiandrosteron-Sulfat, Fetoplazentare Einheit, intraamniale Injektionen.

J. Perinat. Med. 7 (1979)

Dell'Acqua et al, Intraamniotic administration of DHEA-S

159

Resume

Evaluation de la fonction foeto-placentaire par l.admini- stration intra-amniotique de dehydroepiandrosterone- sulphate

11 est bien connu que, dans la grossesse, le dehydroepian- drosterone-sulphate (DHEAS) (90% synthetises par les glandes surrenales du foetus, 10% par celles de la mere) se transforme en oestrogenes principalement dans le placenta.

Afin d'evaluer la capacite metabolisante de steroide du complexe enzymatique placentaire sous les conditions de Charge, un test a ete etabli, base sur une introduction rapide de 200 mg de DHEAS dans le compartiment am- niotique pendant le troisieme trimestre de gestation.

Le but de l'investigation presente a ete d'etablir l'utilite clinique d'un tel test en comparaison avec le simple test de determination d'oestrogene dans l'urine. A la suite de administration de DHEA-S, on a obtenu un in cremen t de l'excretion urinaire maternelle des oestrogenes totals:

cet increment des 24 h. consecutives a l'injection de DHEA-S a ete evalue comme le pourcentage de lamoyenne des deux valeurs d'excretion de 24 h. avant Fadministration de DHEA-S.

Le test a ete effectue dans 45 grossesses (12 normales, 33 pathologiques). Dans toutes les grossesses normales, on a obtenu un increment d'oestrogenes urinaire s complets dans les urines des premieres 24 h. excedant 100%, avec une moyenne de 147,6% ± 46,6 S.D. (Fig' 1).

On avait convenu qu'un increment depassant 100%pouvait etre considere comme normal. Dans ces 12 cas, les valeurs

des determinations d'oestrogenes dans les urines quoti- diennes sont restees dans les limites normales (Tab. I)!

Dans 4 des cas de grossesse pathologique, l'excretion d'oestrogenes des urines quotidiennes et l'increment d'oestrogenes apres administration de DHEA-S ont ete inferieurs ä la normale (Tab. H).

Dans 24 cas, l'excretion d'oestrogenes des urines quoti- diennes a ete normale ou ä la limite des normes, mais l'increment apres administration de DHEA-S n'a jamais atteint 100% (Tab. III).

Les 5 derniers cas ont presente une excretion basse d'oestrogenes des urines quotidiennes, mais un increment normal apres administration de DHEA-S (Tab. IV).

Ce groupe a rassemble des cas de pathologie foetale ou la synthese de DHEA-S par les glandes surrenales du foetus a ete probablement insuffisante, tandis que la fonction placentaire etait normale.

En conclusion, nous considerons que le test de DHEA-S intraamniotique presente un degre d'infaillibilite tres eleve et peut etre plus significatif que le test de DHEA-S intra- veineux maternel analogique parce qu'ayant recours a l'administration intra-amniotique, on peut obtenir un increment plus eleve d'oestrogenes synthetises par le placenta et excretes dans les urines maternelles.

Le test peut etre utilise dans les cas de grossesses ä risque ou les valeurs d'oestrogenes de l'urine restent contestables, particulierement quand on suspecte un distress foetal, bien que les valeurs d'oestrogenes de Furine se situent dans les limites normales.

Mots-cles: dehydroepiandrosterone-sulphate, fonction foetoplacentaire, intra-amniotique.

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[11]MENINI, E., A. BOMPIANI: Automatione nella [13] STEMBERA, Z. K., J. tt$RZMANN: Estriol-Unter- clinica analitica. Simposio Internazionale Techni- suchung nach DHEA-S als Test für plazentare In- con. Roma 1969 suffizienz, Cslka, Gyneak. 26 (1971) 597

[12JMONETA, E., G. GALLI, L. TRONCONE, N.

GARCEA: La scintigrafia della placenta con Indio

radioattivo. Aspetti clinico-biologici. Min. Gineco- Received November 11, 1977. Revised January 7, 1979.

logica 22 (1970) 48 Accepted January 23,1979.

Prof. Sergio Dell'Acqua

Istituto di Clinica Ostetrica e Ginecologica Policlinico Agostino Gemelli

Universita Cattolica del Sacro Cuore Largo Gemelli, 8

ROMA/Italy

J.Perinat.Med.7(1979)