A Brief Account of the Discovery of the Fetal/Placental Unit for Estrogen Production in Equine and Human Pregnancies: Relation to Human Medicine.
Abstract: The role of steroids in human medicine is well recognized, but the major contributions made by the large domestic animals as a source of material in the discovery, isolation, and determination of the structure of the steroid hormones is less well appreciated. After a brief reminder of the early efforts to obtain a reliable source of steroids for clinical use, the narrative here is to outline one example where success was ultimately achieved for estrogen replacement therapy. Whereas knowledge of the high concentrations of estrogens in urine of pregnant women and mares dates from the late 1920s, it was not until the 1940s that the latter was shown to be a practical source. Initially, the placenta was held to be responsible, but the involvement of the fetus in each case was eventually established. The remarkable enlargement of the human fetal adrenal glands and the fetal gonads in the horse, with characteristic features of steroid secreting tissues, suggested their participation. Ultimately, it was 16-hydroxylation by the fetal liver that resulted in estriol being the major estrogen type, by far, in late human pregnancy. In the mare, the pattern of estrogen production reflected that of the growth and later regression of the fetal gonads. The characteristic production ring-B, unsaturated estrogens in the mare is derived from an alternative pathway involving retention of the additional double bond in the biosynthesis of equilin.
Publication Date: 2017-09-25 PubMed ID: 28955183PubMed Central: PMC5612187
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Summary
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The research article reviews the discovery and understanding that the fetal-placental unit in both equine and human pregnancy is a key source of estrogen production. It details the crucial role of large domestic animals in the history of steroid hormone research and highlights the importance of this biological process for estrogen replacement therapy in human medicine.
Background
- The study sets the context by highlighting the importance of steroids in human medicine, specifically the role of steroid hormones.
- It points out that the substantial contributions of large domestic animals in steroid hormone research and development are often overlooked.
- The paper serves to outline an instance where breakthrough was achieved in estrogen replacement therapy, a vital aspect of human medicine.
Early Research and Significant Discoveries
- The article mentions the recognition, from as early as the 1920s, of high estrogen concentrations in the urine of pregnant women and mares.
- However, it wasn’t until the 1940s that the urine of pregnant mares was confirmed to be a practical source of estrogen.
- Researchers initially thought the placenta was solely responsible for estrogen production, but shifting understandings eventually established that both the fetus and placenta are involved in this process.
Role of Human and Equine Fetal Tissues
- The research recounts the discovery of the large size of the human fetal adrenal glands and horse fetal gonads, which suggested their involvement in steroid production.
- The major estrogen type during late human pregnancy, estriol, was found to be a result of 16-hydroxylation by the fetal liver.
- In mares, estrogen production was seen to correlate with the growth and later regression of the fetal gonads.
Understanding the Biochemical Processes
- Notably, the research discusses the process through which the unique production ring-B, unsaturated estrogens in mares, is derived from an alternative pathway involving retention of the additional double bond in the synthesis of equilin, an estrogen hormone.
Impact of the Study
- This research offers significant insights into the evolution of understanding estrogen production, mainly its source and process, and its application in human medicine for estrogen replacement therapy.
Cite This Article
APA
Raeside JI.
(2017).
A Brief Account of the Discovery of the Fetal/Placental Unit for Estrogen Production in Equine and Human Pregnancies: Relation to Human Medicine.
Yale J Biol Med, 90(3), 449-461.
Publication
Researcher Affiliations
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada.
MeSH Terms
- Adrenal Glands / embryology
- Adrenal Glands / metabolism
- Animals
- Estrogens / metabolism
- Estrone / metabolism
- Female
- Gonads / embryology
- Gonads / metabolism
- Horses
- Humans
- Placenta / embryology
- Placenta / metabolism
- Pregnancy
- Steroids / metabolism
References
This article includes 64 references
- Butenandt A, Von Ziegner E. Uber des physiologische Wirksamkeit des krystallisierten weiblichen Sexualhormones im Allen-Doisy Test. Untersuchungen über das weibliche Sexualhormone (3. Mitteilung).. Hoppe Seylers Z Physiol Chem 1930;188:1–10.
- Doisy EA, Veler CD, Thayer S. The preparation of the crystalline ovarian hormone from the urine of pregnant women.. J Biol Chem 1930;86:499–509.
- Marrian GF. The chemistry of oestrin: An improved method of preparation and the isolation of crystalline material.. Biochem J 1930;24(2):435-45.
- Zondek B. Hormonale schwangerschaftreaktion aus dem harn bei mensch und tier.. Klin Wochenschr 1930;9:1207–9.
- Marrian GF. The chemistry of oestrin: The chemical nature of crystalline preparations.. Biochem J 1930;24(4):1021-30.
- Butenandt A. Uber die chemische untersuchung der sexualhormone.. Z Angew Chem 1931;44(46):905–8.
- MacQuorquodale DW, Thayer S, Doisy EA. The isolation of the principal estrogenic substance of the liquor folliculi.. J Biol Chem 1936;115:435–49.
- Butenandt A. Neure Ergebnisse auf dem Gebiet der Sexualhormone.. Wien Klin Wochenschr 1934;47:936.
- Slotta KH, Ruschig H, Fels E. Ȕber der Hormon aus dem Corpus-luteum.. Ber Chem Ges 1934;67:1270.
- Hartmann M, Wettstein A. Ein krystallisiertes Hormon aus Corpus-luteum.. Helv Chim Acta 1934;17:878.
- Allen WM, Wintersteiner O. CRYSTALLINE PROGESTIN.. Science 1934 Aug 24;80(2069):190-1.
- David K, Dingemanse E, Freud J, Laqueur E. Über krystallinisches männliches Hormon aus Hoden (Testosteron), wirksamer als aus Harn oder aus Cholesterin bereitetes Androsteron.. Hoppe Seylers Z Physiol Chem 1935;233:281–3.
- Reichstein T, Shoppee CW. The Hormones of the Adrenal Cortex, in Harris, R S, Thimann, KV.. Vitamins and Hormones, New York 1943;1:345–413.
- SIMPSON SA, TAIT JF, BUSH IE. Secretion of a salt-retaining hormone by the mammalian adrenal cortex.. Lancet 1952 Aug 2;2(6727):226-8.
- Tait SA, Tait JF. The correspondence of S.A.S. Simpson and J.F. Tait with T. Reichstein during their collaborative work on the isolation and elucidation of the structure of electrocortin (later aldosterone).. Steroids 1998 Sep;63(9):440-53.
- Freed SC, Eisin WM, Greenhill JP. The oral effectiveness of estrone sulfate (conjugated estrogens-equine) in women.. J Clin Endocrinol Metab 1943;3(2):89–91.
- DICZFALUSY E. Chorionic gonadotrophin and oestrogens in the human placenta.. Acta Endocrinol Suppl (Copenh) 1953;11(12):1-175.
- Fellner OO. Experimentell erzeugte Wachstumveraenderungen am weiblichen Genitale der Kanichen.. Centrl allg Path Anat 1912;23:673-676.
- Huffman MN, Thayer SA, Doisy EA. The isolation of α-dihydrotheelin from human placenta.. J Biol Chem 1940;133:567–71.
- Campbell AD, Collip JB. ON THE CLINICAL USE OF THE OVARY-STIMULATING HORMONE OF THE PLACENTA: Preliminary Report.. Can Med Assoc J 1930 Feb;22(2):219-20.
- Allen E, Pratt JP, Doisy EA. The ovarian follicular hormone; its distribution in human genital tissues.. JAMA 1925;85(6):399–405.
- Allen E, Doisy EA. Ovarian and placental hormones.. Physiol Rev 1927;7(4):600–50.
- LELONG M, VANDEL S, BORNICHE P, JAYLE MF. [Determination of estrogens in placenta and organs of still-born infants].. Ann Endocrinol (Paris) 1951;12(5):922-5.
- MARRIAN GF, LOKE KH, WATSON EJ, PANATTONI M. 16alpha-Hydroxyoestrone in the urine of pregnant women.. Biochem J 1957 May;66(1):60-5.
- LAYNE DS, MARRIAN GF. The isolation of 16 beta-hydroxyoestrone and 16-oxo-oestradiol-17 beta from the urine of pregnant women.. Biochem J 1958 Oct;70(2):244-8.
- DAVIS ME, GOULD RG, LEROY GV, PLOTZ EJ, WERBIN H. Hormones in human reproduction. I. Metabolism of progesterone.. Am J Obstet Gynecol 1956 Oct;72(4):740-55.
- NICHOLS J, LESCURE OL, MIGEON CJ. Levels of 17-hydroxycorticosteroids and 17-ketosteroids in maternal and cord plasma in term anencephaly.. J Clin Endocrinol Metab 1958 May;18(5):444-52.
- BAULIEU EE. Three sulfate esters of 17-ketosteroids in the plasma of normal subjects and after administration of ACTH.. J Clin Endocrinol Metab 1960 Jun;20:900-4.
- FRANDSEN VA, STAKEMANN G. The site of production of oestrogenic hormones in human pregnancy. Hormone excretion in pregnancy with anencephalic foetus.. Acta Endocrinol (Copenh) 1961 Nov;38:383-91.
- FRANDSEN VA, STAKEMANN G. The site or production of oestrogenic hormones in human pregnancy. II. Experimental investigations on the role of the foetal adrenal.. Acta Endocrinol (Copenh) 1963 Jun;43:184-94.
- FRANDSEN VA, STAKEMANN G. The site or production of oestrogenic hormones in human pregnancy. II. Experimental investigations on the role of the foetal adrenal.. Acta Endocrinol (Copenh) 1963 Jun;43:184-94.
- DICZFALUSY E, CASSMER O, ALONSO C, DE MIQUEL M. Estrogen metabolism in the human fetus and newborn.. Recent Prog Horm Res 1961;17:147-206.
- BAULIEU EE, DRAY F. CONVERSION OF H3-DEHYDROISOANDROSTERONE (3BETA-HYDROXY-DELTA5-ANDROSTEN-17-ONE) SULFATE TO H3-ESTROGENS IN NORMAL PREGNANT WOMEN.. J Clin Endocrinol Metab 1963 Dec;23:1298-301.
- DICZFALUSY E. ENDOCRINE FUNCTIONS OF THE HUMAN FETOPLACENTAL UNIT.. Fed Proc 1964 Jul-Aug;23:791-8.
- Diczfalusy E. Steroid metabolism in pregnancy and the foeto-placental unit.. Proc 2nd Inter Congr Horm Steroids, Exc Med Int Congr Ser 1966;111:82-95.
- Telegdy G, Diczfalusy E. Steroid metabolism in human foeto-placental unit at mid-gestation.. Proc 3rd Inter Congr Horm Steroids, Exc Med Int Congr 1971:496-503.
- Zondek B. Hormonale schwangerschaftsreaktion auf dem harn bei mensch und tier.. Klin Wochenschr 1930;9:2285–9.
- Cole HH, Hart GH. The potency of blood serum in mares in progressive stages of pregnancy in effecting the sexual maturity of the immature rat.. Am J Physiol 1930;93:57–68.
- Cole HH, Hart GH, Lyons WR, Catchpole HH. The development and hormonal content of fetal horse gonads.. Anat Rec 1933;56:275–93.
- DAVIES J, DEMPSEY EW, WISLOCKI GB. Histochemical observations on the fetal ovary and testis of the horse.. J Histochem Cytochem 1957 Nov;5(6):584-90.
- Flood PF, Marrable AW. A histochemical study of steroid metabolism in the equine fetus and placenta.. J Reprod Fertil Suppl 1975 Oct;(23):569-73.
- González-Angulo A, Hernández-Jáuregui P, Martínez-Zedilo G. Fine structure of the gonads of the horse and its functional implications.. J Reprod Fertil Suppl 1975 Oct;(23):563-7.
- MacArthur E, Short RV, O'Donnell VJ. Formation of steroids by the equine foetal testis.. J Endocrinol 1967 Jul;38(3):331-6.
- Raeside JI, Liptrap RM, Milne FJ. Relationship of fetal gonads to urinary estrogen excretion by the pregnant mare.. Am J Vet Res 1973 Jun;34(6):843-5.
- Pashen RL, Allen WR. The role of the fetal gonads and placenta in steroid production, maintenance of pregnancy and parturition in the mare.. J Reprod Fertil Suppl 1979;(27):499-509.
- Raeside JI. Dehydroepiandrosterone in the fetal gonads of the horse.. J Reprod Fertil 1976 Mar;46(2):423-5.
- Raeside JI, Liptrap RM, McDonell WN, Milne FJ. A precursor role for DHA in a feto-placental unit for oestrogen formation in the mare.. J Reprod Fertil Suppl 1979;(27):493-7.
- Girard A, Sandulesco G. Sur une nouvelle série de réactifs du groupe carbonyle, leur utilisation à l’extraction des substances cétoniques et à la caractérisation microchimique des aldéhydes et cétones.. Helv Chim Acta 1936;19:1095–107.
- Heard RD, Jacobs R, O’Donnell V, Peron FG, Saffran JC, Solomon SS. The application of C14 to the study of the metabolism of the sterols and steroid hormones.. Recent Prog Horm Res 1954;9:383–410.
- HEARD RD, O'DONNELL VJ. Biogenesis of the estrogens: the failure of cholesterol-4-C14 to give rise to estrone in the pregnant mare.. Endocrinology 1954 Feb;54(2):209-15.
- SALHANICK HA, BERLINER DL. Isolation of steroids from a feminizing adrenal carcinoma.. J Biol Chem 1957 Aug;227(2):583-90.
- Stárka L, Breuer H, Cedard L. Biosynthesis of equilin and related ring B unsaturated oestrogens in perfused human placenta.. J Endocrinol 1966 Apr;34(4):447-56.
- CHAPPEL C, DUBUC J, DVORNIK D, GIVNER M, HUMBER L, KRAML M, VOITH K, GAUDRY R. AN INHIBITOR OF CHOLESTEROL BIOSYNTHESIS.. Nature 1964 Feb 1;201:497-8.
- Bhavnani BR. The saga of the ring B unsaturated equine estrogens.. Endocr Rev 1988 Nov;9(4):396-416.
- Raeside JI, Renaud RL. Identification of 3 beta-hydroxy-5,7-androstadien-17-one as a secretory product of the fetal horse gonad in vivo and in vitro.. J Endocrinol 1985 Dec;107(3):415-9.
- Tait AD, Hodge LC, Allen WR. Production of an equilin precursor by the fetal horse gonad.. IRCS Med Sci 1982;10:346–7.
- Tait AD, Santikarn S, Allen WR. Identification of 3 beta-hydroxy-5,7-pregnadien-20-one and 3 beta-hydroxy-5,7-androstadien-17-one as endogenous steroids in the fetal horse gonad.. J Endocrinol 1983 Oct;99(1):87-92.
- Tait AD, Hodge LC, Allen WR. The biosynthesis of 3 beta-hydroxy-5,7-androstadien-17-one by the horse fetal gonad.. FEBS Lett 1985 Mar 11;182(1):107-10.
- Bhavnani BR, Stanczyk FZ. Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action.. J Steroid Biochem Mol Biol 2014 Jul;142:16-29.
- SMITH DW, LEMLI L, OPITZ JM. A NEWLY RECOGNIZED SYNDROME OF MULTIPLE CONGENITAL ANOMALIES.. J Pediatr 1964 Feb;64:210-7.
- Correa-Cerro LS, Porter FD. 3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome.. Mol Genet Metab 2005 Feb;84(2):112-26.
- Shackleton CH, Roitman E, Kratz LE, Kelley RI. Equine type estrogens produced by a pregnant woman carrying a Smith-Lemli-Opitz syndrome fetus.. J Clin Endocrinol Metab 1999 Mar;84(3):1157-9.
- BROWN JB. Urinary excretion of oestrogens during pregnancy, lactation, and the re-establishment of menstruation.. Lancet 1956 May 19;270(6925):704-7.
- Ginther OJ. Reproductive Biology of the Mare.. 2nd ed. Cross Plains (WI): Equiservices Publishing; 1992.
Citations
This article has been cited 5 times.- Schuler G, Fürbass R, Klisch K. Placental contribution to the endocrinology of gestation and parturition.. Anim Reprod 2018 Jul-Sep;15(Suppl 1):822-842.
- Dembitsky VM. In Silico Prediction of Steroids and Triterpenoids as Potential Regulators of Lipid Metabolism.. Mar Drugs 2021 Nov 22;19(11).
- Swink JM, Rings LM, Snyder HA, McAuley RC, Burns TA, Dembek KA, Gilsenan WF, Browne N, Toribio RE. Dynamics of androgens in healthy and hospitalized newborn foals.. J Vet Intern Med 2021 Jan;35(1):538-549.
- Liang L, Rasmussen MH, Piening B, Shen X, Chen S, Röst H, Snyder JK, Tibshirani R, Skotte L, Lee NC, Contrepois K, Feenstra B, Zackriah H, Snyder M, Melbye M. Metabolic Dynamics and Prediction of Gestational Age and Time to Delivery in Pregnant Women.. Cell 2020 Jun 25;181(7):1680-1692.e15.
- Sovio U, Goulding N, McBride N, Cook E, Gaccioli F, Charnock-Jones DS, Lawlor DA, Smith GCS. A maternal serum metabolite ratio predicts fetal growth restriction at term.. Nat Med 2020 Mar;26(3):348-353.
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