METABOLISM OF OESTRONE GLUCOSIDURONATE AT MIDPREGNANCY

1967 ◽  
Vol 56 (1) ◽  
pp. 71-84 ◽  
Author(s):  
G. Zucconi ◽  
U. Goebelsmann ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Intravenous Infusion ◽  
Isotopic Ratio ◽  
Umbilical Vein ◽  
Radioactive Material ◽  
Therapeutic Abortion ◽  
Maternal Circulation ◽  
Glucuronidase Activity ◽  
Oestrone Sulphate ◽  
Foetal Liver ◽  
Unchanged Form

ABSTRACT Oestrone-6,7-3H-glucosiduronate-14C (OE1-3H-Gl-14C) has been prepared biosynthetically and its metabolism studied in two cases of therapeutic abortion following the administration of the tracer at laparotomy into the umbilical vein. The bulk of the radioactive material recovered was in the foetus and placenta; only small amounts were present in the urine of the mother. Minute quantities of the radioactive material recovered from any of these sources were in an unconjugated form. Following reduction with KBH4 of the extract of the foetal liver oestriol-3-glucosiduronate (OE3-3Gl) was isolated from this source with the same isotopic ratio as that of the injected material. Following hydrolysis with β-glucuronidase, 3H-labelled oestrone, 17β-oestradiol and oestriol were isolated in a radiochemically homogeneous form from the foetal liver and from the urine of the mother, and oestrone and 17β-oestradiol from the placenta. From the urine of the mothers OE1-3H-Gl-14C was also isolated. It exhibited the same isotopic ratio as the injected material. Following the intravenous infusion to two women at midpregnancy of a combination of 3H-labelled OE1-Gl and 14C-labelled oestrone sulphate (OE1-S), the tracer administered as OE1-Gl was eliminated in the urine far more rapidly than that infused in the form of OE1-S. It is concluded that at midpregnancy a) the foetus is capable of metabolizing OE1-Gl without any preceding hydrolysis, b) the placenta exhibits no β-glucuronidase activity, c) only a limited amount of OE1-Gl is transferred from the foeto-placental circulation to the mother and exclusively in an unchanged form, and d) OE1-Gl is eliminated from the maternal circulation much more rapidly than OE1-S.

METABOLISM OF OESTRONE AND OESTRADIOL IN THE HUMAN FOETO-PLACENTAL UNIT AT MIDPREGNANCY

1965 ◽  
Vol 49 (1) ◽  
pp. 65-82 ◽  
Author(s):  
J. Schwers ◽  
G. Eriksson ◽  
E. Diczfalusy
Keyword(s):  
Isotopic Ratio ◽  
Umbilical Vein ◽  
Radioactive Material ◽  
Isotopic Ratios ◽  
Therapeutic Abortion ◽  
Main Site ◽  
Foetal Liver ◽  
Different Sources

ABSTRACT In four cases of therapeutic abortion by laparotomy, tracer amounts of oestrone-6,7-3H and 17β-oestradiol-16-14C were injected into the umbilical vein 20 minutes prior to the interruption of gestation, and the radioactive material recovered from the placenta and various foetal tissues was analysed. More than 92 per cent of the radioactive material recovered from the foetus, but less than 15 per cent of that present in the placenta, was in a conjugated form. Among the foetal tissues studied, the highest percentage of unconjugated (free) radioactive material (25 per cent) occurred in the adrenals. Determination of the isotopic ratios revealed that complete interconversion of injected material was approached only by the oestrone and 17β-oestradiol isolated from the conjugated fraction of the liver. Approximately 10 per cent of the radioactive material recovered from the foetal liver and smaller amounts of that found in the placenta and residual foetal tissues were isolated and identified as oestriol. The isotopic ratio of oestriol isolated from different sources approached very closely that of conjugated oestrone and 17β-oestradiol in the foetal liver, but was distinctly different from the isotopic ratio of free and conjugated oestrone and 17β-oestradiol in all other tissues. At least 9 additional metabolites were detected in the conjugated fraction of the foetal liver. One of them was identified as 15α-hydroxy-17β-oestradiol, another one as 16- (or possibly 17-) epioestriol, and two were ring D ketolic oestrogens, most probably 16α-hydroxyoestrone and 16-oxo-17β-oestradiol. The isotopie ratios of all identified compounds were similar to those of oestrone and 17β-oestradiol isolated from the same fraction. It is concluded that in the foeto-placental unit at midpregnancy, the liver is the main site of oestrone and 17β-oestradiol metabolism and that this metabolism takes place predominantly in a conjugated form, most probably in form of 3-sulphates.

METABOLISM OF OESTRONE SULPHATE BY THE PREVIABLE HUMAN FOETUS

1965 ◽  
Vol 50 (4) ◽  
pp. 597-610 ◽  
Author(s):  
J. Schwers ◽  
Myriam Govaerts-Videtsky ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Isotopic Ratio ◽  
Radioactive Material ◽  
List Type ◽  
Human Foetus ◽  
Oestrone Sulphate ◽  
Foetal Liver ◽  
Polar Metabolites ◽  
Free Material ◽  
Uptake And Metabolism ◽  
Conjugated Metabolites

ABSTRACT Two previable foetuses (20th week of gestation) were perfused with a combination of oestrone-6,7-3H and oestrone-16-14C sulphate. Approximately 80 per cent of the perfused radioactive material was recovered from the various foetal tissues and perfusates in both experiments. In contrast to the 3H-labelled material, very little 14C-labelled material was recovered from the various foetal tissues, except from the liver, which showed an approximately equal uptake of the two isotopes. Thirty-six per cent of the 3H- and as much as 68 per cent of the 14C-labelled material administered was recovered from the perfusate. No 14C-labelled material was detected in any of the extracts of the foetal tissues and perfusates as unconjugated (free) material. No oestriol or 15α-hydroxy-17β-oestradiol could be isolated from the extracts of any of the foetal tissues, except from the liver, where these compounds were present mainly, if not exclusively, as conjugated material. Approximately 10 per cent of the 3H- and 14C-labelled conjugated material recovered from the liver was isolated as oestriol and some 5 per cent of it as 15α-hydroxy-17β-oestradiol. The isotopic ratio (3H/14C) of these compounds was lower than that of oestrone and 17β-oestradiol isolated from the same fraction. Very little, if any oestriol or 15α-hydroxy-17β-oestradiol was detected in the extracts of perfusates. On the other hand, large quantities of some ketonic precursors of oestriol, 15α-hydroxy-17β-oestradiol and of additional highly polar metabolites were present. Following reduction, oestriol was isolated and 15α-hydroxy-17β-oestradiol identified in the extracts of perfusates. The isotopie ratio of these two compounds was similar to the isotopie ratio of those found in the liver. It is concluded that the midterm human foetus is not capable of hydrolysing oestrogen sulphates in the foetal organism oestrone sulphate is mostly taken up by the foetal liver, where the extent of its uptake and metabolism is at least as great as that of oestrone 15α- and 16α-hydroxylation of oestrone takes place mainly, if not exclusively, in the foetal liver and predominantly in form of conjugated material the 15α- and 16α-hydroxylated conjugated metabolites formed from oestrone sulphate are released by the foetal liver into the foetoplacental circulation mainly as ketonic intermediates, rather than completely reduced compounds.

METABOLISM OF DEHYDROEPIANDROSTERONE SULPHATE AND OESTRONE SULPHATE FOLLOWING IN SITU PLACENTAL PERFUSION AT MIDPREGNANCY

1971 ◽  
Vol 66 (4) ◽  
pp. 637-647 ◽  
Author(s):  
J. Schwers ◽  
T. Vancrombreucq ◽  
M. Govaerts ◽  
G. Eriksson ◽  
E. Diczfalusy
Keyword(s):  
Radioactive Material ◽  
Dehydroepiandrosterone Sulphate ◽  
Placental Perfusion ◽  
Carbon 14 ◽  
Maternal Urine ◽  
Oestrone Sulphate ◽  
Unchanged Form ◽  
Urine Specimens

ABSTRACT Two midgestation placentas were perfused in situ with a combination of [7α-3H] dehydroepiandrosterone sulphate and [4-14C] oestrone sulphate and metabolites were isolated from the placentas, perfusates and maternal urine specimens. Approximately 70 per cent of the perfused radioactive material was recovered from these three sources. The bulk of the administered radioactive material was recovered in an unchanged form from the perfusates; some 2–4 per cent was excreted in the urine and less than 0.5% was found in the placentas. The tritium to carbon-14 ratio of the unconjugated material isolated from the perfusates and placentas was higher, and that of the conjugated material recovered from the same sources was lower than the ratio of the administered material. In addition, more tritium than carbon-14 labelled material was present in the urine. Approximately 2 per cent of the perfused dehydroepiandrosterone sulphate was recovered in the form of phenolic steroids, mostly from the urine. From this source double labelled oestrone, oestriol, 16α-hydroxy-oestrone and 16-epioestriol were isolated. The tritium to carbon-14 ratio of all oestrogens isolated from the urine was higher than that of the perfused material. From the urine specimens 10 to 15 times more double labelled oestriol than oestrone was isolated.

FATE OF OESTRIOL-3-SULPHATE AND OESTRIOL-16-GLUCOSIDURONATE IN THE INTACT FOETO-PLACENTAL UNIT AT MIDPREGNANCY

1966 ◽  
Vol 53 (3) ◽  
pp. 391-400 ◽  
Author(s):  
U. Goebelsmann ◽  
G. Eriksson ◽  
E. Diczfalusy ◽  
M. Levitz ◽  
G. P. Condon
Keyword(s):  
Umbilical Vein ◽  
The Other ◽  
Radioactive Material ◽  
Therapeutic Abortion ◽  
Maternal Urine ◽  
Other Hand

ABSTRACT In two cases of therapeutic abortion by laparotomy, tracer amounts of 3H-labelled oestriol-3-sulphate (OE3-3S) and 14C-labelled oestriol-16-glucosiduronate (OE3-16GI) were injected into the umbilical vein 15 minutes prior to the interruption of gestation and the radioactive material recovered from the maternal urine, placenta, various foetal tissues and urine was analysed. Some four times more 3H- than 14C-labelled material was excreted in the urine of the mothers. Approximately 90% of both isotopes was identified as OE3-16GI. From the placentas more than twice as much 14C- as 3H-labelled meterial was recovered. All the 14C-labelled material was present in the form of glucosiduronate. Approximately 40% of the 3H-labelled material was identified as unconjugated oestriol (OE3), some 2% was present in the form of unidentified unconjugated material, and the rest was OE3-3S.3-3S. All the 3H-labelled material present in the foetal organism was identified as OE3-3S, indicating lack of metabolism of this conjugate by the foetus. On the other hand, the 14C-labelled OE3-16GI was metabolised by the foetus. A small part of it was converted into OE3-3S, which was present only in the liver. In addition, all foetal tissues contained considerable quantities of 14C-labelled oestriol-3-sulphate,16-glucosiduronate (OE3-3S,16GI) accompanied by smaller amounts of a 14C-labelled glucosiduronate of OE3, which was considerably more polar than OE3-16GI. The foetal urine contained only 14C-labelled glucosiduronates of OE3.

STUDIES ON THE AROMATISATION OF NEUTRAL STEROIDS IN PREGNANT WOMEN

1964 ◽  
Vol 45 (4) ◽  
pp. 576-599 ◽  
Author(s):  
E. Bolté ◽  
S. Mancuso ◽  
G. Eriksson ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Pregnant Women ◽  
Specific Activity ◽  
Umbilical Vein ◽  
Radioactive Material ◽  
Placental Barrier ◽  
Therapeutic Abortion ◽  
Antecubital Vein

ABSTRACT In connection with therapeutic abortion, in two patients tracer amounts of dehydroepiandrosterone-4-14C sulphate (DHAS-4-14C) were injected into the umbilical vein and tracer amounts of dehydroepiandrosterone-7α-3H sulphate (DHAS-7α-3H) into an antecubital vein. The over-all aromatisation of the two labelled compounds in the presence of viable foetuses was studied by analysing the radioactive metabolites excreted in the urine during a period of 6 days. More than 25 per cent of the 3H-labelled metabolites and more than 75 per cent of the 14C-labelled metabolites recovered from the urine were phenolic in character. More than half of this phenolic radioactive material behaved as oestrone (OE1), 17β-oestradiol (OE2) and oestriol (OE3) when analysed by a modified Brown (1955) method. The OE3 to OE1 + OE2 ratio expressed as 14C incorporated into these three fractions was significantly higher in both patients than the corresponding ratio of 3H. Also the 3H to 14C ratio of urinary OE1 significantly exceeded that of OE3. The specific activity (S. A.) of OE3-7α-3H was by far lower than that of OE1-7α-3H, whereas the S. A. of OE3-4-14C differed much less from that of OE1-4-14C. A concept is presented describing the placental barrier to circulating androgen and the role of the placenta in the formation of OE1, OE2 and OE3.

STUDIES ON THE METABOLISM OF C19 STEROIDS IN THE FOETO-PLACENTAL UNIT

1971 ◽  
Vol 66 (4) ◽  
pp. 653-665 ◽  
Author(s):  
G. Benagiano ◽  
M. Ermini ◽  
B. de la Torre ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Sodium Salt ◽  
Human Placenta ◽  
Major Part ◽  
Isotopic Ratio ◽  
Water Soluble ◽  
Radioactive Material ◽  
Considerable Part ◽  
Maternal Urine ◽  
Unchanged Form ◽  
Urine Specimens

ABSTRACT Three midgestation placentas were perfused at laparotomy during fifteen minutes with tracer amounts of [1,2-3H] testosterone [35S] sulphate sodium salt, and metabolites present in the placentas, perfusates and maternal urine specimens were analyzed. Most of the radioactive material administered was present in the placentas and perfusates; approximately 2% of it was recovered from the urine. More than 99.5% of the radioactive material recovered from the placentas and the perfusates was in a water soluble (conjugated) form. No unconjugated testosterone was found in these sources. Radiochemically homogeneous [1,2-3H] testosterone [35S] sulphate was isolated from the placentas, perfusates and urine specimens collected during the first 24 hours of experiment. The isotopic ratio of the conjugate isolated from these sources was very similar to that of the perfused material. Seventy per cent of the double labelled radioactive material recovered from the Day 1 urine samples was radiochemically homogeneous testosterone sulphate. The relative amounts of testosterone sulphate present in the Day 2 and Day 3 urine specimens showed a gradual decrease. This decrease was associated with an increase in tritium to sulphur-35 ratio. From the pooled extracts of all urine specimens, small amounts of exclusively tritium labelled conjugated 5α-androsterone and 5β-androsterone were also isolated. No 17β-oestradiol 17-sulphate was detected in any of the sources studied. It is concluded that little, if any, testosterone sulphate is hydrolyzed by the midgestation human placenta, and that a considerable part of the testosterone sulphate secreted by the foetus is transferred across the placenta to the mother in an unchanged form. The major part of the transferred testosterone sulphate is excreted in the urine; a smaller part of it undergoes hydrolysis with a subsequent metabolism of the steroid moiety.

OESTRADIOL METABOLISM IN THE PREVIABLE HUMAN FOETUS AND IN THE FOETO-PLACENTAL UNIT

1964 ◽  
Vol 45 (2) ◽  
pp. 297-320 ◽  
Author(s):  
R. C. Haynes ◽  
G. Mikhail ◽  
G. Eriksson ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Complex Mixture ◽  
Total Radioactivity ◽  
The Other ◽  
Radioactive Material ◽  
Maternal Circulation ◽  
Oestrone Sulphate ◽  
Perfusion Experiment ◽  
Distribution Studies ◽  
Additional Support

ABSTRACT Five normal previable foetuses were perfused with tracer amounts of oestradiol-4-14C and the metabolism of the compound was investigated. This study was completed by 3 experiments in which the oestradiol-4-14C was introduced in situ into the intact foeto-placental unit via the umbilical circulation. More than 80 per cent of the radioactive material present in the various foetal organs in both types of experiments was in a conjugated form. In contrast, in the placentas, less than 10 per cent of the total radioactivity present was in a conjugated form. The bulk of the radioactive material present in the foetal tissues was identified as oestradiol 3-sulphate and oestrone sulphate. In addition, two minor fractions were detected in the perfused foetuses, one of which behaved in countercurrent distribution studies as »glucosiduronates«; the other resembled »sulphates«. The oestrogen moiety of these two fractions was neither oestradiol nor oestrone, but it appeared to be a complex mixture. Although some radioactive material was found which closely resembled oestriol, it was not possible to detect oestriol with certainty. No glucosiduronate-like material was found in the foetal tissues following the injection of oestradiol-4-14C into the intact foeto-placental unit. Also the quantity of the »sulphate-like« material different from oestradioland oestrone sulphates was greatly reduced: A number of unconjugated metabolites were also detected, among which oestrone was identified. A perfusion experiment with an anencephalic foetus indicated that this foetus was capable of forming conjugated metabolites from oestradiol-4-14C. The results obtained do not favour the view that oestriol is a major and instantaneously formed foetal metabolite of oestradiol. On the other hand, they lend additional support to the concept that oestrogens reaching the foetus are extensively sulphurylated by the foetus and that these oestrogen sulphates are hydrolysed by the placenta before transfer of the oestrogen moiety to the maternal circulation.

STUDIES ON THE AROMATISATION OF NEUTRAL STEROIDS IN PREGNANT WOMEN

1964 ◽  
Vol 45 (4) ◽  
pp. 535-559 ◽  
Author(s):  
E. Bolté ◽  
S. Mancuso ◽  
G. Eriksson ◽  
N. Wiqvist ◽  
E. Diczfalusy
Keyword(s):  
Pregnant Women ◽  
Comparative Studies ◽  
Chorionic Gonadotrophin ◽  
Human Chorionic Gonadotrophin ◽  
Radioactive Material ◽  
Placental Barrier ◽  
Therapeutic Abortion ◽  
Limited Ability ◽  
Better Than

ABSTRACT In 15 cases of therapeutic abortion by laparotomy the placenta was disconnected from the foetus and perfused in situ with tracer amounts of radioactive dehydroepiandrosterone (DHA), dehydroepiandrosterone sulphate (DHAS), androst-4-ene-3,17-dione (A), testosterone (T) and 17β-oestradiol (OE2). Analysis of the placentas, perfusates and urine samples revealed an extensive aromatisation of DHA, A and T; more than 70% of the radioactive material recovered was phenolic, and at least 80 % of this phenolic material was identified as oestrone (OE1), 17β-oestradiol (OE2) and oestriol (OE3), the latter being detected only in the urine. Comparative studies indicated that A and T were aromatised somewhat better than DHA and that all three unconjugated steroids were aromatised to a much greater extent than DHAS. Radioactive OE1 and OE2 were isolated and identified in the placentas and perfusates, but no OE3, epimeric oestriols, or ring D ketols could be detected in these sources, not even when human chorionic gonadotrophin (HCG) was added to the blood prior to perfusion. Lack of placental 16-hydroxylation was also apparent when OE2 was perfused. Regardless of the precursor perfused, there was three times more OE2 than OE1 in the placenta and three times more OE1 than OE2 in the perfusate. This was also the case following perfusion with OE2. The results are interpreted as suggesting the existence in the pregnant human of a placental »barrier« limiting the passage of circulating androgen. The barrier consists of a) limited ability to transfer directly DHAS and b) an enzymic mechanism resulting in the rapid and extensive aromatisation of the important androgens DHA, A and T.

Determination of insulin-like growth factor-2 in feto-maternal circulation during human pregnancy

1992 ◽  
Vol 127 (4) ◽  
pp. 359-365 ◽  
Author(s):  
Toshiro Kubota ◽  
Shusaku Kamada ◽  
Makoto Taguchi ◽  
Takeshi Aso
Keyword(s):  
Amniotic Fluid ◽  
Umbilical Vein ◽  
Maternal Plasma ◽  
Cross Reactivity ◽  
Main Peak ◽  
Gel Chromatography ◽  
High Concentration ◽  
Maternal Circulation ◽  
Human Pregnancy ◽  
Fetal Plasma

In order to clarify the roles of insulin-like growth factors (IGFs) on the human maternal-fetal environment, IGF-2 and IGF-1 levels were investigated in human plasma and amniotic fluid during pregnancy. Initially, new radio-immunoassay (RIA) systems for human IGF-2 could be developed. The sensitivity of this assay was 17.5 pg/tube and the cross-reactivity with IGF-1 was 0.64%. The pattern of change of maternal plasma IGF-2 in early pregnancy differed from that of IGF-1, but both IGF levels increased progressively in the second half of gestation, and decreased to non-pregnancy levels in the puerperium. Maternal levels of IGF-2 were approximately seven times greater than those of IGF-1. The ratio of IGF-2 to IGF-1 was 3.2 in amniotic fluid. The IGF concentrations in amniotic fluid obtained in the second trimester were significantly greater than those of term specimens, and closely related to those of prolactin (PRL) in amniotic fluid. The highest IGF-2 to IGF-1 ratio (1 5.9) was found in umbilical vein plasma. On Sephadex G-150 gel-chromatography of maternal and fetal plasma at term, two apparent peaks of unsaturated IGF-2 binding protein (BP) could be detected in both 150 and 40 kilo dalton (kD) regions. One main peak of unsaturated IGF-2 BP could be determined in the 40 kD region in the amniotic fluid at term. High concentration of IGF-2 could be detected in feto-maternal circulation during human pregnancy. Moreover, it is strongly suggested that the releasing systems of IGFs in amniotic fluid are different from those in maternal or umbilical circulation.

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