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Origin of Estrogen in Women Pregnant with an Anencephalic Fetus

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Origin of Estrogen in Women Pregnant with an Anencephalic Fetus Origin of Estrogen in Women Pregnant with an Anencephalic Fetus Paul C. MacDonald, Pentti K. Siiteri J Clin Invest. 1965;44(3):465-474. https://doi.org/10.1172/JCI105160. Research Article Find the latest version: https://jci.me/105160/pdf Journal of Clinical Investigation Vol. 44, No. 3, 1965 Origin of Estrogen in Women Pregnant with an Anencephalic Fetus * PAUL C. MACDONALD t AND PENTTI K. SIITERI (From the Department of Obstetrics-Gynecology, the University of Texas, Southwestern Medical School, and Parkland Memorial Hospital, Dallas, Texas) While maternal estrogen excretion increases Indeed, more recent in vivo studies have shown markedly during the course of pregnancy with a that several C19 steroids are converted to estro- normal fetus, Frandsen and Stakeman found that gen when introduced into the circulation of preg- women pregnant with an anencephalic fetus ex- nant women. Previous studies in these labora- crete relatively smaller amounts of urinary estro- tories have demonstrated that dehydroisoandros- gens (1). Pointing to the characteristic absence terone (D), present in the maternal circulation as of the fetal zone of the adrenal cortex in anen- a sulfate ester [dehydroisoandrosterone sulfate cephaly, these authors postulated that the normal (DS)], serves as a quantitatively important pre- fetal adrenal produces a substance that serves as cursor of estrogen during normal and abnormal a precursor for estrogen biosynthesis by the pla- pregnancy (5-7). In addition to D and DS, the centa (2). Several other lines of evidence sug- conversion of testosterone and androstenedione to gest that estrogen production in the placenta urinary estrogens by pregnant women has been arises from the utilization of externally supplied demonstrated by Baulieu and Dray (8). Simi- steroidal precursors rather than by de novo syn- larly, Bolte and associates (9, 10) as well as thetic mechanisms. Levitz, Emerman, and Dan- Warren and Timberlake (11) found radioactive cis were unable to demonstrate estrogen forma- urinary estrogens after the administration of iso- tion in placental systems in vitro from simple pre- tope-labeled DS to pregnant women. In addition cursors such as acetate (3). On the other hand, Bolte and co-workers have also demonstrated the conversion of preformed neutral steroids such aromatization of radioactive D, DS, androstene- as testosterone,' androstenedione, and dehydroiso- dione, and testosterone when these were perfused androsterone to estrone and/or estradiol by pla- through the in situ placenta via the fetal vessels cental preparations in vitro is remarkably efficient after disconnecting the fetus in early pregnancy as first demonstrated by Ryan (4). (12). All of these studies support the concept of pla- * Submitted for publication August 10, 1964; accepted cental estrogen production from externally sup- December 1, 1964. plied precursors. Of the circulating steroids A preliminary report of a portion of this study was known to be available for this process, DS, which presented to the Workshop on Estrogens, Orcas Island, Wash., June 1963. has recently been shown to be a normal adrenal This study was supported, in part, by grants AM 06912- secretory product (13), appears to be most im- 02 and HD 00107-01, U. S. Public Health Service. portant in view of its presence in high concentra- t Address requests for reprints to: Dr. Paul C. Mac- tion in both maternal and fetal blood (14, 15). Donald, The University of Texas, Southwestern Medical However, the relative quantitative importance of School, Dallas, Texas 75235. these two sources (maternal and fetal) of pre- 1 Trivial names are used in the text for the following compounds: testosterone, 1758-hydroxy-androst-4-en-3- cursor DS for placental estrogen formation re- one; androstenedione, androst-4-en-3,17-dione; dehydro- mains to be evaluated. isoandrosterone, 3f8-hydroxy-androst-5-en-17-one; dehy- Women pregnant with an anencephalic fetus droisoandrosterone sulfate, 17-oxo-androst-5-en-3#-yl- represent an interesting biological circumstance sulfate; 16a-hydroxydehydroisoandrosterone, 3,8,16a-dihy- droxy-androst-5-en-17-one; estrone, 3-hydroxy-estra-1, for study of this problem since the amount of DS 3,5 (10) -trien-17-one; estradiol, estra-1,3,5 (10) -trien-3, arising in the fetal compartment is minimal as 17j5-diol; estriol, estra-1,3,5(10)-trien-3,16a,17f-triol. evidenced by the absence of DS in the cord blood 465 466 PAUL C. MACDONALD AND PENTTI K. SIITERI of anencephalic monsters studied by Nichols, dose of E2H' and DC'4S was administered before urine Lescure, and Migeon (16). The purpose of the collection. Experiments IVa and IVb were performed in subject present experiments was to determine the source L.B., a 21-year-old Negro, 33 weeks pregnant with a and mechanism of origin of estrogen in four live anencephalic fetus (LB-33). First, a tracer dose of women pregnant with an anencephalic fetus. The E21-3 and DC714S was administered (experiment IVa). results of this study indicate that the bulk (50 After the fifth day of urine collection, this patient re- to 100%o) of the estrogen entering the maternal ceived dexamethasone, 0.75 mg by mouth every 6 hours for 17 days. On day 11 of treatment with dexametha- compartment in these subjects was derived from sone, a second tracer dose of E2H' and DC"4S was ad- dehydroisoandrosterone sulfate circulating in the ministered (experiment IVb). maternal plasma. In addition, it is shown that Experiments Va and Vb were performed in subject the administration of dexamethasone (1 1/,,17a,21- J.V., a 24-year-old Caucasian, 35 weeks pregnant with trihydroxy-9a-fluoro - 16a-methyl-pregn-1 ,4-dien-3, a live anencephalic fetus (JV-35). Experiment Va in- volved the administration of a tracer dose of E2H' and 20-dione) to one of these subjects resulted in a DC14S after which the usual 5-day urine collection was decrease in the dehydroisoandrosterone sulfate achieved. After the completion of experiment Va, 30 U production rate and a concomitant decrease in the of ACTH was administered intramuscularly to this sub- estradiol production rate.' Conversely, the ad- ject every 12 hours for 9 days. On day 4 of treatment ministration of ACTH to another of these sub- with ACTH, a second tracer dose of E2H3 and DC'4S was given intravenously, and urine was collected as be- jects resulted in an increase in the daily produc- fore (experiment Vb). tion rate of dehydroisoandrosterone sulfate and In each experiment urinary estrone (El), estradiol a proportionate increase in the production rate of (E2), and estriol (E3) were isolated, and their specific estradiol. activities relative to tritium and to C"4 were determined. Similarly, in all studies except experiment I, urinary Methods dehydroisoandrosterone was isolated, and its specific ac- tivity relative to C4 was determined. Expcrinmcntal design. In each study the radioactive The methods of tracer preparation, urine processing, hormone tracers were dissolved in 10 ml of 10% ethanol and hydrolysis, as well as extraction and purification of in water and administered intravenously. Thereafter, the urinary metabolites, dehydroisoandrosterone (sul- in each case, the subject's urine was collected for 5 days fate), estrone, estradiol, and estriol (glucuronosides), into an iced container. At the end of the collection and determination of their specific activities have been period the urine samples were processed as described described in detail (17). below. Preliminary studies indicated that more than In each experiment, 80%o of the 5-day urine pool was 95% of the radioactive urinary metabolites under study adjusted to pH 5.0 and incubated with p-glucuronidase 3 are excreted within 5 days. for 72 hours at 370 C. The liberated steroids were ex- Experiments I and II were performed in subject M.M., tracted with ethyl acetate. After removal of the sol- a 34-year-old Negro, 38 weeks pregnant with a live vent, neutral and phenolic steroids were separated by anencephalic fetus (MM-38). The first study (experi- partition between diethyl ether and 2 N NaOH. Es- ment I) involved the administration of a tracer dose of trogens present in the phenolic fraction were purified 6,7-H8-estradiol (E2"3) and 4-C'4-progesterone followed by chromatographic procedures previously described. by urine collection as described above. Five days after First a gradient elution partition chromatographic sys- the completion of experiment I, a tracer dose of E211' tem employing Celite as support for the stationary phase, and 4-C14-dehydroisoandrosterone suLfate (DC'4S) was ethylene glycol, and utilizing 2,2,4-trimethylpentane (iso- administered, and urine was again collected as before octane) containing progressively increasing quantities of (experiment II). ethyl acetate as mobile phase effected initial separation Experiment III was performed in subject A.B., a of the estrogen metabolites. The fractions containing 37-year-old Caucasian, 35 weeks pregnant with a live estrone, estradiol, and estriol were separately combined anencephalic fetus (AB-35). For this study, a tracer and rechromatographed by liquid-liquid partition chro- matography on Celite by systems containing isooctane, 2 By the techniques used in this study the placental t-butanol, methanol, and water in various ratios as conversion of dehydroisoandrosterone sulfate to estradiol applicable to each estrogen metabolite. After further cannot be distinguished from its conversion to estrone. purification by thin-layer chromatography (TLC), spe- For convenience, the conversion of DS to estrone and/or cific activities of each of the urinary estrogen metabo- estradiol and the production rate of estrone-estradiol are lites were determined by the double isotope derivative referred to in the text as simply the conversion to or technique after acetylation of separate samples of each production of estradiol. In all cases almost identical results were obtained if the values for either urinary 3 Ketodase, Warner-Chilcott Laboratories, Morris estrone or estradiol were used for the calculations.
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