estrogen dominance as a risk of prostate cancer

19.12.15: health/hormonics/cancer#prostate/estrogen:
. Dr.Lee 2002 noted that prostate cancer is
one of the many diseases that can be
associated with estrogen dominance,
where there is too much estrogen
relative to progesterone.
. this is supported by a 2011 study
[ Expert Rev Endocrinol Metab. 2011:
Estrogen action and prostate cancer.]

. estradiol-17β has been classified as a carcinogen
by the International Agency for Research on Cancer [9–11],
primarily based on its association with
endometrial and breast carcinoma in women [12–15].

. young men have low estrogen,
moderate progesterone,
and 4 times as much testosterone (T);
but when aging they get more estrogenic activity
and the combination of T and estrogen
is what dramatically increases the risk
of prostate cancer.
At least in rats, testosterone alone
is necessary, but not sufficient,
for the development of prostate cancer.
It is only with the addition of estrogen
that cancer can be reliably induced.

. studies have failed to show a correlation
between estrogen levels in blood
and the risk of prostate cancer;
eg, the Physician’s Health Study
suggested the opposite finding,
with an increasing prostate cancer risk
associated with decreasing estradiol levels
after adjusting for SHBG effects[18];
but the prostate can make its own estrogen
(intracrine steroid synthesis);
and, it's likely that local estrogen metabolites
produced by the CYP1B1 pathway (e.g., 4-OH-estradiol)
may play an important role in prostate carcinogenesis.

. certain polymorphisms in genes related to
estrogen metabolism (CYP1B1 and CYP19)
can increase prostate cancer risk [26].

African–American men have had
a two-fold higher rate of prostate cancer
than Caucasian–American men;
and coincidentally, also had significantly
higher serum estradiol levels.
. also, African–American women have
higher circulating estrogen concentrations
during pregnancy than Caucasian women [30,31],
so that the fetus prostate gets more estrogens.
. aromatase (CYP19), the enzyme that turns T into estradiol;
is altered in prostate cancer tissues [23]
and CYP19A1 expression is elevated 30-fold
in prostate cancer metastatic tissue,
as compared with primary tumors [24].

. and there are a lot of pollutants
that are not identical to estrogen;
so the Physician’s Health Study
would not have included them as estrogens,
but they contributed to estrogenic activity.

ways estrogenic activity can influence cancer:

DNA damage can happen in 3 ways:
directly from estrogen;
from inducing inflammation;
from causing hormonal dysregulation
(prostatic ER-mediated changes).

estrogen causes inflammation in 3 ways:
directly from estrogen;
from causing hyperprolactemia;
(that enhances estrogen function)
from causing hormonal dysregulation.

estrogen causes epigenotoxicity in 2 ways:
directly from estrogen;
from causing hormonal dysregulation.

hormonal dysregulation:

. types of estrogen-specific receptors (ER)
may have possibly opposing functions,
and the prostate has multiple ERs.
. direct estrogen signaling
plays an important role in the
development of the prostate gland
and possibly in the development of cancer [130–135].
Most hormonally regulated effects of estrogens
[as opposed to, eg, epigenetic effects]
have been attributed to the
nuclear steroid receptors ERα and ERβ [136];
eg, by initiating downstream kinase cascades
[Levin ER. 2009:
Estrogen receptors (ER) have been
localized to the plasma membrane
where both ERα and ERβ function in a
wide variety of cells and organs.
ERs have also been found in
discrete cytoplasmic organelles
including mitochondria
and the endoplasmic reticulum.
. roles of membrane ER signaling
include fluid resorption in the colon
pain perception, osteoblast survival,
and prevention of vascular injury
or cardiac hypertrophy.
]

Conclusion:

. estrogenic activity has been shown
to affect potential carcinogenesis,
by epigenotoxicity, hyperprolactinemia,
chronic inflammation, direct genotoxicity,
and prostatic ER-mediated changes.
Our understanding of estrogen’s function in
prostate cancer is still evolving.
Although androgens are clearly involved
in the progression of prostate cancer
and anti-androgen therapy will probably remain
the treatment of choice for metastastic disease,
it is equally clear that androgens are only
one side of the story;
and that the key to prevention of cancer
will be maintaining proper estrogen function,
[including the prevention of estrogen dominance].

refs.