In females, synthesis of estrogens starts
in theca interna cells
in the ovary, by the synthesis of androstenedione from cholesterol.
Androstenedione is a substance of weak
androgenic activity which serves
predominantly as a precursor for more potent androgens such as
testosterone as well as estrogen. This
compound crosses the basal
membrane into the surrounding
granulosa cells, where it is converted
either immediately into estrone, or into
testosterone and then estradiol in an
additional step. The conversion of
androstenedione to testosterone is catalyzed
by 17β-hydroxysteroid
dehydrogenase (17β-HSD), whereas the
conversion of androstenedione and
testosterone into estrone and estradiol,
respectively is catalyzed by aromatase,
enzymes which are both expressed in
granulosa cells. In contrast, granulosa
cells lack 17α-hydroxylase and 17,20-lyase,
where as theca cells express these enzymes
and 17β-HSD but lack aromatase. Hence, both
granulosa and theca cells are essential for
the production of estrogen in the ovaries.
Estrogen levels vary through the menstrual
cycle, with levels highest near
the end of the follicular
phase just before ovulation.
Estrogen levels vary through the menstrual cycle, with levels highest near
the end of the follicular phase just before ovulation.
Function
|
Here we look at the common and
significant functions of estrogens
as it both concerns normal body
regulatory functions and others.... |
The
actions of estrogen are mediated by the estrogen receptor (ER),
a dimeric nuclear protein that binds to DNA
and controls gene expression. Like other
steroid hormones, estrogen enters passively
into the cell where it binds to and
activates the estrogen receptor. The
estrogen:ER complex binds to specific DNA
sequences called a hormone response
element to activate the
transcription of target genes (in a study
using an estrogen-dependent breast cancer
cell line as model, 89 such genes were
identified). Since estrogen enters all
cells, its actions are dependent on the
presence of the ER in the cell. The ER is
expressed in specific tissues including the
ovary, uterus and breast. The metabolic
effects of estrogen in postmenopausal women
has been linked to the genetic polymorphism
of the ER.
While
estrogens are present in both men and women, they
are usually present at significantly higher
levels in women of reproductive age. They
promote the development of female secondary sexual
characteristics, such as breasts, and are also
involved in the thickening of the endometrium and
other aspects of regulating the menstrual
cycle. In males, estrogen regulates certain
functions of the reproductive system important
to the maturation of sperm and may be
necessary for a healthy libido.[13] Furthermore,
there are several other structural changes
induced by estrogen in addition to other
functions.
-
Structural functions
-
Promote formation of female secondary sex
characteristics
-
Accelerate metabolism
-
Increase fat stores
-
Stimulate endometrial growth
-
Increase uterine growth
-
Increase vaginal
lubrication
-
Thicken the vaginal wall
-
Maintenance of vessel and skin
-
Reduce bone
resorption, increase bone
formation
-
Effects on Protein synthesis
-
Increase hepatic
production of binding
proteins
-
Coagulation functions
-
Increase circulating level of factors 2, 7, 9, 10, plasminogen
-
Decrease antithrombin III
-
Increase platelet adhesiveness
-
Workings on the Lipids
-
Increase HDL, triglyceride
-
Decrease LDL,
fat deposition
-
Effect on Fluid balance
-
Salt (sodium) and water retention
-
Increase cortisol, SHBG
-
Gastrointestinal tract
-
Reduce bowel motility
-
Increase cholesterol in bile
-
Effects on Melanin
-
Increase pheomelanin,
reduce eumelanin
-
Business with Cancer
-
Support hormone-sensitive breast
cancers (see section below)
-
Lung function
-
Promotes lung function by
supporting alveoli (in
rodents but probably in humans).
-
Uterus lining
-
Estrogen together with progesterone promotes and
maintains the uterus lining in
preparation for implantation of
fertilized egg and maintenance of
uterus function during gestation
period, also upregulates oxytocin receptor in myometrium
-
Ovulation
-
Surge in estrogen level induces the
release of luteinizing
hormone, which then triggers
ovulation by releasing the egg from
the Graafian follicle in the ovary.
-
Sexual receptivity in estrus
-
Promotes sexual
receptivity, and induces lordosis
behavior. In non-human
mammals, it also induces estrus (in
heat) prior to ovulation, which also
induces lordosis
behavior. Female non-human
mammals are not sexually receptive
without the estrogen surge, i.e.,
they have no mating desire when not
inestrus.
-
Lordosis behavior
-
Regulates the stereotypical sexual
receptivity behavior; this lordosis
behavior is estrogen-dependent,
which is regulated by the ventromedial
nucleus of the hypothalamus.
-
Sexual desire
-
Sex drive is dependent on androgen levels only
in the presence of estrogen, but
without estrogen, free testosterone
level actually decreases sexual
desire (instead of increases sex
drive), as demonstrated for those
women who have hypoactive
sexual desire disorder, and
the sexual desire in these women can
be restored by administration of
estrogen (using oral
contraceptive). In non-human
mammals, mating desire is triggered
by estrogen surge in estrus.
Fetal
development
In
rodents, estrogens (which are locally
aromatized from androgens in the brain) play
an important role in psychosexual
differentiation, for example, by
masculinizing territorial behavior; the same
is not true in humans. In humans, the
masculinizing effects of prenatal androgens
on behavior (and other tissues, with the
possible exception of effects on bone)
appear to act exclusively through the
androgen receptor. Consequently, the utility
of rodent models for studying human
psychosexual differentiation has been
questioned.
Estrogen
and heart disease
Women
suffer less from heart disease due to
vasculo-protective action of oestrogen which
helps in preventing atherosclerosis. It also
helps in maintaining the delicate balance
between fighting infections and protecting
arteries from damage thus lowering the risk
of cardiovascular disease.
Immunological role
Oestrogen
has anti-inflammatory properties and helps
in mobilization of polymorphonuclear white
blood cells or neutrophils.
Mental
health
Estrogen
is considered to play a significant role in
women’s mental health.
Sudden estrogen withdrawal, fluctuating estrogen,
and periods of sustained estrogen low levels
correlate with significant mood lowering.
Clinical recovery from postpartum, perimenopause,
and postmenopause depression has been shown to be
effective after levels of estrogen were
stabilized and/or restored.
Compulsions in male lab mice, such as those
in obsessive-compulsive disorder (OCD), may
be caused by low estrogen levels. When
estrogen levels were raised through the
increased activity of the enzyme aromatase in male lab
mice, OCD rituals were dramatically
decreased. Hypothalamic protein
levels in the gene COMTare enhanced by increasing estrogen levels
which is believed to return mice that
displayed OCD rituals to normal activity.
Aromatase deficiency is ultimately suspected
which is involved in the synthesis of
estrogen in humans and has therapeutic
implications in humans having
obsessive-compulsive disorder.
Local
application of estrogen in the rat
hippocampus has been shown to inhibit the
re-uptake of serotonin. Contrarily, local
application of estrogen has been shown to
block the ability of fluvoxamine to slow serotonin clearance,
suggesting that the same pathways which are
involved in SSRI efficacy may also be
affected by components of local estrogen
signaling pathways.
Medical application
Oral
contraceptives
Since
estrogen circulating in the blood can negatively feed-back to
reduce circulating levels of FSH and LH,
most oral contraceptives contain a synthetic
estrogen, along with a synthetic progestin. Even in
men, the major hormone involved in LH
feedback is estradiol,
not testosterone.[citation
needed]
Hormone
replacement therapy
Estrogen
and other hormones are given to
postmenopausal women in order to prevent osteoporosis as
well as treat the symptoms of menopause such
as hot flushes, vaginal dryness, urinary
stress incontinence, chilly sensations,
dizziness, fatigue, irritability, and
sweating. Fractures of the spine, wrist, and
hips decrease by 50–70% and spinal bone
density increases by ~5% in those women
treated with estrogen within 3 years of the
onset of menopause and for 5–10 years
thereafter.
Before the
specific dangers of conjugated equine
estrogens were well understood, standard
therapy was 0.625 mg/day of conjugated
equine estrogens (such as Premarin). There
are, however, risks associated with
conjugated equine estrogen therapy. Among
the older postmenopausal women studied as
part of the Women's
Health Initiative (WHI), an orally
administered conjugated equine estrogen
supplement was found to be associated with
an increased risk of dangerous blood
clotting. The WHI studies used one
type of estrogen supplement, a high oral
dose of conjugated equine estrogens (Premarin alone
and with medroxyprogesterone acetate asPremPro).
In a study
by the NIH, esterified estrogens were not
proven to pose the same risks to health as
conjugated equine estrogens. Hormone replacement therapy has
favorable effects on serum cholesterol
levels, and when initiated immediately upon
menopause may reduce the incidence of
cardiovascular disease, although this
hypothesis has yet to be tested in
randomized trials. Estrogen appears to have
a protector effect on atherosclerosis: it
lowers LDL and triglycerides, it raises HDL
levels and has endothelial vasodilatation
properties plus an anti-inflammatory
component.
Research
is underway to determine if risks of
estrogen supplement use are the same for all
methods of delivery. In particular, estrogen
applied topically may
have a different spectrum of side-effects
than when administered orally, and
transdermal estrogens do not affect clotting
as they are absorbed directly into the
systemic circulation, avoiding first-pass
metabolism in the liver. This route of
administration is thus preferred in women
with a history of thrombo-embolic disease.
Estrogen
is also used in the therapy of vaginal
atrophy, hypoestrogenism (as a result of
hypogonadism, castration, or primary ovarian
failure), amenorrhea, dysmenorrhea, and
oligomenorrhea. Estrogens can also be used
to suppress lactation after
child birth.
Breast
cancer
About 80%
of breast cancers, once established, rely on
supplies of the hormone estrogen to grow:
they are known as hormone-sensitive or
hormone-receptor-positive cancers.
Suppression of production of estrogen in the
body is a treatment for these cancers.
Recently
researchers have discovered that the common table mushroom has
anti-aromatase properties and therefore possible
anti-estrogen activity. Clinical trials have
begun in the United States looking into
whether the table mushroom can
prevent breast cancer in people. A recent
study has highlighted the importance of this
research. In 2009, a case-control study of
the eating habits of 2,018 women revealed
that women who consumed mushrooms had an
approximately 50% lower incidence of breast
cancer. It has been found that Chinese women
who consumed mushrooms and green tea had a 90%
lower incidence of breast cancer.
Hormone-receptor-positive breast
cancers are treated with drugs which
suppress production of estrogen in the
body. This technique, in the context of
treatment of breast cancer, is known
variously as hormonal therapy, hormone therapy, or anti-estrogen
therapy (not to be confused with
hormone replacement therapy). Certain foods
such as soy may also suppress the
proliferative effects of estrogen and are
used as an alternative to hormone therapy.
Prostate
Cancer
Under
certain circumstances, estrogen may also be
used in males for treatment of prostate
cancer.
Miscellaneous
In humans
and mice, estrogen promotes wound healing.
At one
time, estrogen was used to induce growth attenuation in tall girls. Recently,
estrogen-induced growth attenuation was used
as part of the controversialAshley Treatment to keep a developmentally
disabled girl from growing to adult
size.
Most
recently, estrogen has been used in
experimental research as a way to treat
patients suffering from bulimia nervosa, in addition to cognitive
behavioral therapy, which is the
established standard for treatment in
bulimia cases. The estrogen research
hypothesizes that the disease may be linked
to a hormonal imbalance in the brain.
Estrogen
has also been used in studies which indicate
that it may be an effective drug for use in
the treatment of traumatic liver injury.
Health
risks and warning labels
Hyperestrogenemia (elevated levels of
estrogen) may be a result of exogenous
administration of estrogen or estrogen-like
substances, or may be a result of
physiologic conditions such as pregnancy.
Any of these causes is linked with an
increase in the risk of thrombosis.
The
estrogen-alone substudy of the WHI reported
an increased risk of stroke and deep
vein thrombosis (DVT) in
postmenopausal women 50 years of age or
older and an increased risk of dementia in
postmenopausal women 65 years of age or
older using 0.625 mg of Premarin conjugated
equine estrogens (CEE). The
estrogen-plus-progestin substudy of the WHI
reported an increased risk of myocardial infarction,
stroke, invasive breast cancer, pulmonary emboli and
DVT in postmenopausal women 50 years of age
or older and an increased risk of dementia
in postmenopausal women 65 years of age or
older using PremPro, which is 0.625 mg of
CEE with 2.5 mg of the progestin medroxyprogesterone
acetate (MPA).
The
labeling of estrogen-only products in the
U.S. includes a boxed warning that
unopposed estrogen (without progestogen) therapy
increases the risk ofendometrial cancer. Based on a review of data
from the WHI, on January 8, 2003 the FDA
changed the labeling of all estrogen and
estrogen with progestin products for use by
postmenopausal women to include a new boxed
warning about cardiovascular and other
risks.
Cosmetics
Some hair shampoos on
the market include estrogens and placental
extracts; others contain phytoestrogens.
There are case reports of young children
developing breasts after exposure to these
shampoos. In 1993, the FDA determined that
not all topically applied hormone-containing
drug products for OTC human use
aregenerally recognized as safe and effective and
are misbranded. An accompanying proposed
rule deals with cosmetics, concluding that
any use of natural estrogens in a cosmetic
product makes the product an unapproved new
drug and that any cosmetic using the term
"hormone" in the text of its labeling or in
its ingredient statement makes an implied
drug claim, subjecting such a product to
regulatory action.
In
addition to being considered misbranded
drugs, products claiming to contain
placental extract may also be deemed to be
misbranded cosmetics if the extract has been
prepared from placentas from which the
hormones and other biologically active
substances have been removed and the
extracted substance consists principally of
protein. The FDA recommends that this
substance be identified by a name other than
"placental extract" and describing its
composition more accurately because
consumers associate the name "placental
extract" with a therapeutic use of some
biological activity.
Historical Analysis on Estrogen
In 1929 Adolf
Butenandt and Edward Adelbert Doisy independently
isolated and determined the structure of
estrogen. Thereafter, the pace of hormonal
drug research accelerated.
The "first
orally effective estrogen", Emmenin, derived
from the late-pregnancy urine of Canadian
women, was introduced in 1930 by Collip and
Ayerst Laboratories. Estrogens are not
water-soluble and cannot be given orally,
but the urine was found to contain estriol glucuronide which is
water soluble and becomes active in the body
after hydrolysis.
Scientists
continued to search for new sources of
estrogen because of concerns associated with
the practicality of introducing the drug
into the market. At the same time, a German
pharmaceutical drug company, formulated a
similar product as Emmenin that was
introduced to German women to treat
menopausal symptoms.
In 1938,
British scientists obtained a patent on a
newly formulated nonsteroidal estrogen, diethylstilbestrol (DES),
that was cheaper and more powerful than the
previously manufactured estrogens. Soon
after, concerns over the side effects of DES
were raised in scientific journals while the
drug manufacturers came together to lobby
for governmental approval of DES. It was
only until 1941 when estrogen therapy was
finally approved by the Food and Drug
Administration (FDA) for the treatment of
menopausal symptoms.
Environmental effects
Estrogens
are among the wide range
of endocrine-disrupting compounds (a.k.a
EDCs) because they have high estrogenic
potency. When an EDC makes its way into the
environment, it may cause male reproductive
dysfunction to wildlife (a must look-into
research program on the effect of this
hormone on the feminization of males). The
estrogen excreted from farm animals makes
its way into fresh water systems. During the
germination period of reproduction the fish
are exposed to low levels of estrogen which
may cause reproductive dysfunction to male
fish.