Placental Aromatase Deficiency
by Jennifer Lynn Malto
Aromatase is an enzyme which is required for the making of estrogen by catalyzing
estrogen from androgen (Zhou 1990). The deficiency of this enzyme has diverse
consequences depending on the situation. A placental aromatase deficiency
produces a negative effect on both mother and child. Yet a lack of aromatase
in the breast tissue induces a positive result by preventing estrogen dependent
A rare condition called placental aromatase deficiency causes an expectant
mother to become deficient of aromatase in her placenta during her pregnancy
preventing the normal production and transfer of estrogen to the baby. This
affliction activates a temporary masculine appearance in the mother. This
symptom lasts as long as the pregnancy. In the child, the lack of aromatase
causes the child to look male but have the XX karyotype. Also, from DNA
testing, it is observed that the infant has two wild type alleles for the
autosomal recessive aromatase gene.
The affected child does not possess the genes for this anomaly. This effect
may be caused by the deficient amount of estrogen the child received as
a fetus. The placenta is the source of nutrients and is also the site where
endocrine and metabolic functions occur for the developing fetus (Hakkola
1996). Because the placenta of the effected mother lacks aromatase to produce
estrogen, it may be possible that the mother's system may attempt to compensate
for this insufficiency by delivering estrogen from other areas of the mother's
body which may explain the increased masculinity of the mother. And because
the child may not have received enough estrogen during development to cause
feminine development, the child became masculine. It may be possible that
the shortage of aromatase blocks the normal cascade of events to lead the
XX karyotype to a female phenotype.
In Drosophila, there is a Sxl gene which controls sex determination. There
is also a mle gene which allows for male differentiation. The Sxl turns
on a tra gene that causes female differentiation. Perhaps aromatase functions
in a similar manner. It may be possible that a similar Sxl gene regulates
the amount of estrogen needed for a normal XX female. However, without aromatase,
the estrogen is not produced, and the cascade is terminated allowing for
the cascade for male traits to continue (Klug 1994).
Studies have been conducted to learn more of this anomaly. Research has
shown that there had been an 87 base insert into the mother's mRNA allowing
for 29 new amino acids. This insert may be a result of a point mutation
at a splice junction permitting an intron of 87 bases to be translated adding
29 new amino acids. This would not cause a frameshift because a frameshift
in the reading frame would be adding a number of extra bases causing a change
in all the codons following the insert (Klug 1994). The induction of these
87 bases does not disrupt the typical amino acid translation from this region.
After the delivery of the child, this mRNA is no longer apparent. This is
strong evidence that this deficiency is only activated during pregnancy.
Other proof of the deactivation of this mutation after pregnancy is that
femininity of the mother returns.
Placental aromatase deficiency is a rare disorder, and research is still
being conducted to obtain a better understanding. Its rarity may be a result
of the gene's lethality. If a fetus were to have the homozygous recessive
autosomal genes, a spontaneous abortion may occur, assuming that having
wild type alleles for the aromatase gene indicates that the child produces
a normal functioning aromatase, and possessing the homozygous recessive
gene indicates that the child is deficient. Also, with the lack of aromatase,
the biochemical cascades requiring aromatase may be halted possibly creating
severe mutations. Because these mutations may be extreme spontaneous abortion
may result. It may be possible that those that are born with this condition
were able to retrieve enough aromatase from the mother's system to lessen
the severity of mutation. Another explanation as to why people with this
deficiency are very seldom seen is the quality of the testing. The testing
may not be specific or sensitive enough. There are males born with XX karoytype
because the Sry gene became attached to an X chromosome (Klug 1994). Conceivably
the Sry gene joined to the X chromosome because of the lack of estrogen
the child received during fetal development. Women who exhibit placental
aromatase deficiency should be tested for estrogen levels before, during
and after pregnancy and the child can be monitored as fetus to observe development.
After birth, the child can be tested for estrogen levels and to see if there
is an Sry gene on an X chromosome.
Scientists may not fully understand placental aromatase deficiency, but
they do know that aromatase is necessary to produce estrogen. With this
information, researchers are trying to use aromatase inhibitor medication
for women who have estrogen dependent breast cancer. It is the hope to eliminate
or lower estrogen to prevent the formation and growth of the tumors. To
inhibit aromatase from functioning, a mutation should be made at either
the regulatory or activation site of the aromatase enzyme. At the regulatory
site, a mutation may be inserted to signal the enzyme that a sufficient
amount of estrogen is present within its surroundings even though estrogen
levels are low. To effect the active site, a competitive inhibitor could
be added to compete for the binding site where the signal attaches. By adding
competition, not all the active sites will have the necessary substrate
to activate estrogen production lowering the levels of estrogen in the zone.
In order for this treatment to work, the target zone must be understood.
Aromatase behaves differently in different tissues. Because of its tissue
specificity, it may be that the aromatase in different regions has unlike
binding sites (Toda 1995). If this is true, then a general aromatase inhibitor
can not be given. If a general aromatase inhibitor is administered, negative
effects can result. It can cause a lack in estrogen in other areas of the
body which may effect other processes in the body other than preventing
Aromatase does play a major role in normal development of the body. It is
needed for normal fetal development and for maintenance of certain processes
within the body. Yet, research is showing that the lack of aromatase not
only causes unfavorable mutations as seen in placental aromatase deficiency,
but also desired changes in the case of estrogen dependent breast cancer.
More work needs to be done to understand aromatase in order to prohibit
placental aromatase deficiency and to help in the fight against breast cancer.
Hakkola, J. Pasanen, M. Hukkanen, J. Pelkonen, O. Maepaa, J, Edwards, RJ.
Boobis, AR, Raunio, H. February23, 1996. "Expression of Xenobiotic-metabolizing
Cytochrome P450 Forms in Human Full-term Placenta." Biochemical Pharmacology.
Klug, William S. Cummings, Michael R. Concepts of Genetics. Prentice Hall
Inc., New Jersey. p169, 176, 350.
Toda, K. Yang, LX. Shizuta, Y. June, 1995. "Transcriptional Regulation
of the Human Aromatase Cytochrome P450 Gene Expression in Human Placental
Cells." Journal of Steroid Biochemical Molecular Biology. 53:181-90.
Zhou, DJ. Pompon, D. Chen, SA. November 1, 1990. "Stable Expression
of Human Aromatase Complementary DNA in Mammalian Cells: A Useful System
for Aromatase Inhibitor Screening." Cancer Research. 50: 6949-54.
Return Case Studies in Virtual Genetics