Is Maternal Progesterone Actually Independent of the Fetal Steroids?

Progesterone and estradiol are the foremost steroid hormones inhuman pregnancy. However, the origin of maternal progesteronehas still not been satisfactorily explained, despite the generallyaccepted opinion that maternal LDL-cholesterol is a singlesubstrate for placental synthesis of maternal progesterone. Thequestion remains why the levels of progesterone are substantiallyhigher in fetal as opposed to maternal blood. Hence, the role ofthe fetal zone of fetal adrenal (FZFA) in the synthesis ofprogesterone precursors was addressed. The FZFA may bedirectly regulated by placental CRH inducing an excessiveproduction of sulfated 3β-hydroxy-5-ene steroids such as sulfatesof dehydroepiandrosterone (DHEAS) and pregnenolone (PregS).Due to their excellent solubility in plasma these conjugates areeasily transported in excessive amounts to the placenta forfurther conversion to the sex hormones. While the significance ofC19 3β-hydroxy-5-ene steroid sulfates originating in FZFA forplacental estrogen formation is mostly recognized, the question“Which maternal and/or fetal functions may be served byexcessive production of PregS in the FZFA?“ - still remains open.Our hypothesis is that, besides the necessity to synthesize denovo all the maternal progesterone from cholesterol, it may bemore convenient to utilize the fetal PregS. The activities ofsulfatase and 3β-hydroxysteroid dehydrogenase (3β-HSD) aresubstantially higher than the activity of cytochrome P450scc,which is rate-limiting for the placental progesterone synthesisfrom LDL-cholesterol. However, as in the case of progesteronesynthesis from maternal LDL-cholesterol, the relativeindependence of progesterone levels on FZFA activity may be aconsequence of substrate saturation of enzymes convertingPregS to progesterone. Some of the literature along with ourcurrent data (showing no correlation between fetal and maternalprogesterone but significant partial correlations between fetaland maternal 20α-dihydroprogesterone (Prog20α) and betweenProg20α and progesterone within the maternal blood) indicatethat the localization of individual types of 17β-hydroxysteroiddehydrogenase is responsible for a higher proportion of estroneand progesterone in the fetus, but also a higher proportion ofestradiol and Prog20α in maternal blood. Type 217β-hydroxysteroid dehydrogenase (17HSD2), which oxidizesestradiol to estrone and Prog20α to progesterone, is highlyexpressed in placental endothelial cells lining the fetalcompartment. Alternatively, syncytium, which is directly incontact with maternal blood, produces high amounts of estradioland Prog20α due to the effects of type 1, 5 and 717β-hydroxysteroid dehydrogenases (17HSD1, 17HSD5, and17HSD7, respectively). The proposed mechanisms may serve thefollowing functions: 1) providing substances which may influencethe placental production of progesterone and synthesis ofneuroprotective steroids in the fetus; and 2) creating hormonalmilieu enabling control of the onset of labor.