Is maternal progesterone actually independent of the fetal steroids?
Progesterone and estradiol are the foremost steroid hormones in human pregnancy. However, the origin of maternal progesterone has still not been satisfactorily explained, despite the generally accepted opinion that maternal LDL-cholesterol is a single substrate for placental synthesis of maternal progesterone. The question remains why the levels of progesterone are substantially higher in fetal as opposed to maternal blood. Hence, the role of the fetal zone of fetal adrenal (FZFA) in the synthesis of progesterone precursors was addressed. The FZFA may be directly regulated by placental CRH inducing an excessive production of sulfated 3beta-hydroxy-5-ene steroids such as sulfates of dehydroepiandrosterone (DHEAS) and pregnenolone (PregS). Due to their excellent solubility in plasma these conjugates are easily transported in excessive amounts to the placenta for further conversion to the sex hormones. While the significance of C19 3beta-hydroxy-5-ene steroid sulfates originating in FZFA for placental estrogen formation is mostly recognized, the question "Which maternal and/or fetal functions may be served by excessive production of PregS in the FZFA?" - still remains open. Our hypothesis is that, besides the necessity to synthesize de novo all the maternal progesterone from cholesterol, it may be more convenient to utilize the fetal PregS. The activities of sulfatase and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) are substantially higher than the activity of cytochrome P450scc, which is rate-limiting for the placental progesterone synthesis from LDL-cholesterol. However, as in the case of progesterone synthesis from maternal LDL-cholesterol, the relative independence of progesterone levels on FZFA activity may be a consequence of substrate saturation of enzymes converting PregS to progesterone. Some of the literature along with our current data (showing no correlation between fetal and maternal progesterone but significant partial correlations between fetal and maternal 20alpha-dihydroprogesterone (Prog20alpha) and between Prog20alpha and progesterone within the maternal blood) indicate that the localization of individual types of 17beta-hydroxysteroid dehydrogenase is responsible for a higher proportion of estrone and progesterone in the fetus, but also a higher proportion of estradiol and Prog20alpha in maternal blood. Type 2 17beta-hydroxysteroid dehydrogenase (17HSD2), which oxidizes estradiol to estrone and Prog20alpha to progesterone, is highly expressed in placental endothelial cells lining the fetal compartment. Alternatively, syncytium, which is directly in contact with maternal blood, produces high amounts of estradiol and Prog20alpha due to the effects of type 1, 5 and 7 17?-hydroxysteroid dehydrogenases (17HSD1, 17HSD5, and 17HSD7, respectively). The proposed mechanisms may serve the following functions: 1) providing substances which may influence the placental production of progesterone and synthesis of neuroprotective steroids in the fetus; and 2) creating hormonal milieu enabling control of the onset of labor.
Hill
M
M
Institute of Endocrinology, Prague, Czech Republic. mhill@endo.cz
Pařízek
A
A
Jirásek
J E
JE
Jirkovská
M
M
Velíková
M
M
Dušková
M
M
Klímková
M
M
Pasková
A
A
Zizka
Z
Z
Germanová
A
A
Koucký
M
M
Kalousová
M
M
Stárka
L
L
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism*; D000328:Adult; D000074425:Aldo-Keto Reductase Family 1 Member C3; D008078:Cholesterol, LDL / Q000378:metabolism*; D004394:Dydrogesterone / Q000031:analogs & derivatives / Q000097:blood; D004958:Estradiol / Q000097:blood; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D007745:Labor Onset / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000096:biosynthesis* / Q000097:blood; D043266:Steryl-Sulfatase / Q000378:metabolism; D014471:Umbilical Veins; D055815:Young Adult
D008078:Cholesterol, LDL; C094637:dihydroxydydrogesterone; D011374:Progesterone; D004958:Estradiol; D004394:Dydrogesterone; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D043266:Steryl-Sulfatase