Placental steroids

The absence of progesterone is incompatible with the gravid state. Progesterone acts in three ways to maintain pregnancy  

It maintains placental viability, thus ensuring adequate exchange of substances between maternal and fetal compartments  

It maintains perfusion of the decidua basalis (maternal placenta), presumably by inhibiting the formation of vasoconstrictive prostaglandins and 

Small amounts of estrogen are required for maintenance of pregnancy because estrogen maintains tissue responsiveness to progesterone. The placenta forms estrogen from androgenic steroids. The major androgen used is 

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J.F. Strauss, 3rd, F. Martinez, and M. Kiriakidou. Placental steroid hormone synthesis Unique features and unanswered questions. Biol Reprod. 54 303-311 (1996). 

L12. Levitz, M., Conjugation and transfer of fetal-placental steroid hormones. J. Clin. Endocrinol. Meted). 26, T7dr-777 (1966). 

W4. Wiener, M., and Allen, S. H. G., Inhibition of placental steroid synthesis by steroid metabolites Possible feedback control. Steroids 9, 567-582 (1967). 

Dibbelt, L., and Kuss, E., Human placental steroid sulfatase solubilized with a cholic acid derivative Molecular mass, kinetic properties and susceptability to glycosidases. Hoppe-SeylersZ. Physiol. Chem. 365, 1145-1153 (1984). 

Harkness, R. A., Gurrent clinical problem in placental steroid or arylsul tase C deficiency and the related cervical dystrocia and X-linked icthyosis. J. Inherited Metab. Dis. 5, 142—144 (1982). 

Noel, H., Plante, L., Bleau, G., Chapdelaine, A., and Robert, K. D., Human placental steroid sulfatase Purification and properties. ]. Steroid Biochem. 19, 1591-1598 (1983). 

Within the OAT family, OAT4 is the only transporter expressed at appreciable levels in both the placenta and in the kidney [54]. The membrane localization of OAT4 within these tissues has not been examined. Steroid sulfates, and ochratoxinA are efficient transport substrates of OAT4, whereas PAH is weakly transported [54]. The functional importance of OAT4 in regulating placental permeability and renal drug elimination is currently unknown. 

Burton, PJ. and Waddell, B.J., Dual function of 1 lP-hydroxysteroid dehydrogenase in placenta Modulating placental glucocorticoid passage and local steroid action, Biol. Reprod., 60, 234, 1999. 

Young There are some answers provided by Roger Smith s work. He looked at corticotropin-releasing hormone (CRH) of the fetus, placental conversion of steroids and up-regulation of a whole lot of machinery in myocytes. But I have no way to address these questions with my work. 

The interaction between the adrenal cortex of the foetus and the placenta in production of steroid hormones is complex. In outline, the placenta produces progesterone from cholesterol (which is available from the maternal blood) whereas the foetal adrenal cortex produces corticosteroids and androgens from the progesterone produced in the placenta. The placenta then converts some of these androgens into oestrogens. The interplay between the placenta and the foetal adrenal cortex is acknowledged by the use of the term foeto-placental unit to describe steroido-... 

Fig. 5.3.7 Disorders that affect the placental/maternal synthesis of estriol and diagnostic analytes for serum and urine. ORD Oxidoreductase deficiency, STS steroid sulfatase deficiency...

Estriol (estra-1,3,5(10)-trien-3,16-a,17-8 -triol) is the major estrogen metabolite found in the urine. It is excreted in the form of its conjugate with glucuronic acid. The determination of this steroid as an index of placental function has become one of the most widely used endocrine determinations. As pregnancy progresses, the excretion increases and reaches very high levels near term. In abnormal fetoplacental function, the levels of estriol will fall in some cases. The fall is usually progressive, and, because of this, serial determinations of urinary estriol must be carried out. The drop in estriol can be taken as evidence of placental insufficiency, and close watch by the physician is indicated, as a continued drop may necessitate Cesarean section to save the life of the infant. 

Concerning the metabolism of triterpenes and steroids, quite a number of P450 catalyzed transformations are very important, namely the 14a-demethyla-tion of lanosterol [50], the side-chain cleavage of cholesterol [51]and pregnenes [52], and the desaturation of ring A of androgens with concomitant oxidative removal of C(19) [53]. The latter reaction is catalyzed by human placental aromatase, associated with a NADPH-dependent reductase, and requires three moles of oxygen and three moles of NADPH in order to oxidize andro-stenedione 45 to formic acid and estrone 46, Fig. 10. 

Pepe GJ, Albrecht ED Actions of placental and fetal adrenal steroid hormones in primate pregnancy. Endocr Rev 16 608-648,1995. 

A growing number of oestrogens and related metabolites in various body fluids, e.g. [234,235] and in placental tissue [236] have been identified. In the latter study, care was taken to remove as much foetal blood as possible to minimise contamination of the extracts. In addition to the three principal oestrogens, oestrone, oestradiol and oestriol, other unconjugated oestriols, 16-hydroxyoestrone, 16-oxo-oestradiol, 2-methoxyoestrone, 16-epioestratriol, 17-epioestriol and 15a-hydroxy-oestrone were identified and semiquantitated. These results coupled with the levels of foetal and maternal oestrogens help to establish the complex interrelationships in steroid metabolism obtained in the mother, foetus and placenta. 

Metabolism studies. GC-MS is a powerful technique for following and identifying the metabolic products from the in vitro incubation of tissue preparations with steroid substrates. Examples of such studies include the 16a-hydroxylation of 18-hydroxydeoxycorticosterone by human adrenal gland [254], the eiromatization of 3jS,15, 16 -trihydroxy-5-androsten-17-one by placental homogenates [255], and the demonstration of 1/3, 12/3, 6a and 6/3 hydroxylase enzyme activities in microsomal preparations of human foetal hepatic tissue [256]. In the latter study, testosterone was used as substrate and in addition to the hydroxylated metabolites isolated, several other testosterone derivatives indicated the presence of 3a, 3/3 and 17/3-hydroxysteroid oxidoreductase in the adrenal gland preparation. 

The application of the twin ion technique [257] is also of importance in metabolism studies. The doubly labelled steroids [4- C+ 7-l- Ho.44]-androstenedione and [4- C + 7/3- Ho.42]-testosterone, were incubated with human placental microsomes and the resulting metabolites quantitated by counting C and identified by GC-MS [258]. The identified metabolites 17/8,19-dihydroxyandrost-4-en-3-one, 19-hydroxyandrost-4-en-3,17-dione, 17/8-hydroxy-3-oxo-androst-4-en-3-one, 3,17-dioxoandrost-4-en-19-al, oestradiol-17/3 and oestrone were easily recognisable from the double sets of relevant ions in their spectra due to the mixture of hydrogen and deuterium substitution at C-7. Hence the presence of the aromatizing enzymes in the placental preparation and the intermediates in oestrogen biosynthesis were confirmed. 

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