Is Maternal Progesterone Actually Independent of the Fetal Steroids?
Authors: Hill M , Pařízek A , Jirásek J E , Jirkovská M , Velíková M , Dušková M , Klímková M , Pašková A , Žižka Z , Germanová A , Koucký M , Kalousová M , Stárka L 
Published: January 2021

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 3β-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 3β-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 3β-hydroxysteroid dehydrogenase (3β-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 20α-dihydroprogesterone (Prog20α) and between
Prog20α and progesterone within the maternal blood) indicate
that the localization of individual types of 17β-hydroxysteroid
dehydrogenase is responsible for a higher proportion of estrone
and progesterone in the fetus, but also a higher proportion of
estradiol and Prog20α in maternal blood. Type 2
17β-hydroxysteroid dehydrogenase (17HSD2), which oxidizes
estradiol to estrone and Prog20α 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 Prog20α due to the effects of type 1, 5 and 7
17β-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.