Why Is Raised Maternal Serum Prostaglandin E2 Not Associated With An Increased Incidence Of Miscarriage?

Why Is Raised Maternal Serum Prostaglandin E2 Not Associated With An Increased  Incidence Of Miscarriage?

Both anti-progesterones such as Mifepristone (RU 486), and Prostaglandins have achieved
considerable success in their ability to induce abortion.  The most effective treatment has been the
administration of a primary dose of anti-progesterone and the subsequent treatment with a small
dose of synthetic prostaglandin, eg. Misoprostol (1).  Only a small dose of PGE2 needs to be used,
a considerable advantage due to the side effects of NV (nausea and vomiting) it causes.
 
If a raised maternal serum PGE2 is associated with increased NVP (nausea and vomiting of
pregnancy) as we suggest (2), why is this raised maternal serum PGE2 not associated with an
increased incidence of miscarriage?
 
Prostaglandin dehydrogenase (PGDH) is the primary inactivating enzyme for prostaglandins and,
therefore, controls local levels of prostaglandins.  PGDH is under the control of progesterone, as
we have described in this paper.  As progesterone synthesis increases in pregnancy, so PGDH will
also increase and inactivate PGE2.  Cheng et al (3) wrote, in early pregnancy at 55 days of gestation
PGDH staining in the cells of the decidual mucosa taken from a patient who had undergone
surgical termination of pregnancy with no prior treatment, showed intense staining for PGDH in
decidual stroma cells, in decidual glands and in the endothelial lining of cells of small blood
vessels, both veins and arteries, of the decidua.  In the small arteries the cells of the muscle layer
were also PGDH positive, and intensely positive decidual stroma cells were arranged around the
circumference of the vessel.  In contrast in RU 486 treated tissue, the endothelial cell lining of
small blood vessels was commonly immunonegative for PGDH or with only weak and focal
reactivity, and with reduced immunoassaying for PGDH of the surrounding muscle and
decidualised stroma cells.  Thus, PGDH in decidual tissues would normally protect the uterine
myometrium from the side effects of maternal PGE2 (3).  Indeed, Bygdeman et al (4) have found
that within 24 hours of the administration of Mifepristone (RU 486 anti-progesterone which lowers
PGDH activity in cells) to women in early pregnancy, there is an increase in the contractility of the
uterus and the uterus becomes very sensitive to exogenous prostaglandins.
 
In contrast, the chorionic villi from a patient after surgical termination of pregnancy stained
intensely for PGDH in the cytotrophoblast cells, but with much less staining for PGDH in the
syncytiotrophoblast cells (3) suggesting the Prostaglandin E2 would still be synthesised by these
syncytiotrophoblast cells which bathe in maternal blood at the materno-fetal interface. This would
enable the maternal serum PGE2 to be raised at this stage of pregnancy.  In the natural state it is
PGDH in decidual cells and small blood vessels which prevents the PGE2 from causing an
abortion, although the maternal PGE2 produced by the syncytiotrophoblast cells of the chorionic
villi can still be the cause of NVP.


Cheng et al (5) investigating the effect of Mifepristone (RU 486) on the immunohistochemical
distribution of Prostaglandin E and its metabolite in decidual and chorionic tissue in early
pregnancy wrote, there was a clear distinction in the distribution of immunoreactive PGE2 among
the different cell types. The cytoplasm of syncytiotrophoblast cells stained positively for PGE2,
whereas, there was very little, if any, staining in the cytotrophoblast layer. There was no obvious
difference in staining between control villi from women who had a surgical termination of
pregnancy and villi from women treated with RU 486.  The intensity of PGE2 immunoassaying was
greater in decidual tissue after RU 486 treatment compared to that in controls. These changes were
most obvious in blood vessels (P<0.001) after only 12 hours of RU 486 treatment.  Overall, PGE2
staining of decidual stroma cells increased compared to that in controls, although changes were
less marked than the changes in corresponding blood vessels. Cheng continues, the early
appearance after RU 486 administration of a change in metabolism as indicated by the striking
increase in PGE2 in blood vessels, suggests that one of the main mechanisms by which
progesterone ensures a continuing successful pregnancy is the maintenance of low PG levels in the
vasculature (5).
 
In summary, the reason that raised maternal serum PGE2 which is associated with increased NVP
is not associated with an increased incidence of miscarriage, may be that the presence of PGDH in
decidual cells and decidual small arteries and veins results in a low level of PGE2 in the decidual
cells and small decidual blood vessels, thus protecting the uterine myometrium from PGE2. On the
other hand, PGE2 continues to be synthesised in syncytiotrophoblast cells of the chorionic villi,
where there is very little PGDH, and which bathe in maternal blood.  Released from these
syncytiotrophoblast cells of the chorionic villi, PGE2 can pass from the materno-fetal interface into
the uterine veins, thence to the cerebral chemoreceptor trigger zone causing nausea and vomiting of
pregnancy.

REFERENCES

1. BYGDEMAN M, VAN LOOK P F.

 Anti-progesterones for the interruption of pregnancy.

 Baillieres Clinical Obstetrics and Gynaecology. 1988;2(3):617-629.

2. GADSBY R, BARNIE-ADSHEAD A, GRAMMATOPOULOS D, GADSBY P.

Nausea and vomiting in pregnancy: an association between symptoms and maternal Prostaglandin E2.

 Gynecol Obstet Invest. 2000;50:149-152.

3. CHENG L, KELLY R W, THONG K J, HUME R, BAIRD D T.

The effects of Mifepristone (RU 486) on prostaglandin dehydrogenase in decidual and chorionic tissue in early pregnancy.

 Human Reprod. 1993;8(5):705-709.

4. BYGDEMAN M, SWAHN M-L.

 Progesterone receptor blockage. Effect on uterine contractility and early pregnancy.

 Contraception. 1985;32(1):45-51.

5. CHENG L, KELLY R W, THONG K J, HUME R, BAIRD D T.

 The effect of Mifepristone (RU 486) on the immunohistochemical distribution of Prostaglandin E2 and its metabolite in decidual and chorionic tissues in early pregnancy.

 J. Clin Endocrinol Metab. 1993;77:873-877.

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