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THE ROLES OF ESTROGENS IN MEN
Shippen, E.
Shillington Diagnostic Center, Shillington, Pennsylvania, USA
Testosterone is a pro-hormone that is metabolised into dihydrotestosterone,
DHT, or estradiol, the primary active form of estrogen
in both sexes. There are many roles of estrogen in
every tissue throughout the body through the action
of two different types of receptors, ERa and ERb,
and through activation of both nuclear and non-nuclear
mechanisms. In fact, there may be more estrogen receptors
and known activities as primary effects of testosterone
than there are for DHT and androgen receptors. It
is a sad day for the non-British men in the room to
learn that we are controlled and directed to a large
extent by a "queen", but to the female attendees,
it comes as no shock! We live in a sea of estrogens
from all phyla of plants and animals, to bacteria,
fungi and other micro-organisms. Estrogens are the
most common link between all life forms than any other
known substance, except, perhaps DNA and RNA. Additionally,
estrogens from man-made sources have become an ever
increasing source and problem for men and women, being
linked to disruptive activities that have now been
associated with diseases, such as endometriosis to
carcinogenic activities leading to cancers of the
breast and possibly the prostate. In men and women,
all estrogens arise from androgen precursors, almost
a Biblical metaphor. In both sexes, the enzyme that
converts C19 androgen precursors into estrone and
estradiol is aromatase. The vast majority of conversion
of androgens in men occurs in the intracrine pathways
within the tissues, rather than, as previously thought,
through testicular production. Still, circulating
estrogens somewhat parallels the rise and fall of
testosterone. The activity of this conversion may
be controlled either genetically or altered as the
result of aging changes, inflammatory disease, obesity,
drug effects and alcohol intake. The ingestion of
highly active xeno-estrogens from plastics, pesticides
or other chemicals contaminated in the environment,
such as dioxins or PCBs adds to the complexity. This
diverse impact can be the source of many of the chronic
changes and diseases associated with aging. The endocrine
disruptive effects of altered estrogen receptors and
pathways of metabolism may account for many of the
observed changes associated with endocrine deficiency.
Obviously, this area of endocrinology is extremely
complex. The importance of estrogen effects are at
the core of critical health mechanisms. Neural growth
and regeneration, cardiovascular functions of vasodilation,
smooth muscle and angiogenic changes needed to maintain
normal vascular tone and regenerative capacity, insulinotropic
effects, collagen synthesis and control of inflammatory
cytokines and immuno-regulatory peptides are only
a few of the well documented effects. We know from
the studies of genetic aromatase deficiency, how widespread
and diverse the changes from normal function occur:
increased cardiovascular lesions, osteopenia or osteoporosis,
altered sexuality and higher mortality rates. Conversely,
estrogen excess either genetically through testicular
over-production or local tissue over-production, may
result in widespread pathologic changes as well. The
observation that estrogens decline with aging and
declining testosterone levels is not always the case.
Men can become estrogen deficient due to lack of adequate
precursors from both testicular production of testosterone
or deficient adrenal gland androgens, particularly
DHEA. These men present with "classic" testosterone
deficiency symptoms and physical changes, such as
osteoporosis, sexual decline and dysfunction, and
cardiovascular disease among others. At the same time,
some men develop increased aromatase enzymes through
acquired obesity or from inflammatory disease which
may present as decreased testosterone with some of
the typical symptoms, but in which replacement may
not result in full clinical response, particularly
in the area of sexuality. This is seen frequently
in Syndrome X or the "metabolic syndrome", an increasing
problem in clinical medicine today. The growing interest
in the use of aromatase inhibitors to increase hypothalamic
activity and release of FSH and LH to increase production
of testosterone has resulted in mixed responses, particularly
in the area of sexuality. The problems in the "fine
tuning" of estrogen and androgen balance between individuals
come from the lack of knowledge of the individual's
innate optimal ratios and in failure to measure the
ratios before and after treatment. In cases where
both estrogen and testosterone are deficient due to
testicular dysfunction, the results may be disappointing
from further reduction in estrogen generation. In
fact, given the important beneficial effects on bone
maintenance, the neural and cardiovascular systems,
the long term treatment with aromatase inhibition
may be quite negative, even if some of the benefits
of androgen increase result in improved energy and
mood. An entirely different response may be seen in
"Syndrome X" individuals where excess estrogen production
is suppressive or antagonistic to testosterone production
and effects. In these men, there may be an initial
response to testosterone therapy followed by disappointing
return of symptoms, particularly in libido and sexual
function, as estrogen levels increase even further.
However, in these men the use of aromatase inhibitors
in carefully monitored doses that do not suppress
estrogens too much, may result in excellent clinical
improvement in all areas and possibly improved health
status. This group of men may be better treated with
DHT replacement, since lack of aromatization of DHT
will not increase estradiol. Interestingly, in men
who have been obese all their lives and have long-term
estrogen increase, there may be a "tolerance" for
the increased estrogen levels that may not suppress
sexuality. These are some of the "normal" low testosterone
individuals without significant symptoms. The roles
of excess xeno-estrogens may be far more pervasive
than previously thought, but, clearly, may be one
of the key factors in sexual dysfunction and disease
than has been recognized in the past. This area deserves
much more research. The critical principle in all
cases of testosterone deficiency comes from careful
clinical assessment of each individual's total hormonal
status and a keen knowledge of the effects of estrogens
and androgens in the pathophysiology of aging males.
Correct diagnosis of these dynamic factors leads to
proper treatment modalities.
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