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Endocrine system
In physiology, the endocrine system is a system of glands, each of which secretes
a type of hormone directly into the bloodstream to regulate the body. The
endocrine system is in contrast to exocrine system, which secretes its chemicals
using ducts. It words endo meaning inside, within, and crinis for secrete. The
endocrine system is an information signal system like the nervous system, yet its
effects and mechanism are classifiably different. The endocrine systems effects
are slow to initiate, and prolonged in their response, lasting for hours to weeks.
The nervous system sends information very quickly, and responses are generally
short lived. Hormones are substances (chemical mediators) released from
endocrine tissue into the bloodstream where they travel to target tissue and
generate a response. Hormones regulate various human functions, including
Metabolism, growth and development, tissue function, and mood. The field of
study dealing with the endocrine system and its disorders is endocrinology, a
branch of internal medicine.
Features of endocrine glands are, in general, their ductless nature, their
vascularity, and usually the presence of intracellular vacuoles or granules storing
their hormones. In contrast, exocrine glands, such as salivary glands, sweat
glands, and glands within the gastrointestinal tract, tend to be much less
vascular and have ducts or a hollow lumen.
In addition to the specialised endocrine organs mentioned above, many other
organs that are part of other body systems, such as the kidney, liver, heart and
gonads, have secondary endocrine functions. For example the kidney secretes
endocrine hormones such as erythropoietin and renin.
The endocrine system is made up of a series of glands that produce chemicals
called hormones. A number of glands that signal each other in sequence is
usually referred to as an axis, for example, the hypothalamic-pituitary-adrenal
axis.
Hormone
Epinephrine (adrenaline), a catecholamine-type hormone
A hormone is a chemical released by a cell or a gland in one part of the body
that sends out messages that affect cells in other parts of the organism. Only a
small amount of hormone is required to alter cell metabolism. In essence, it is a
chemical messenger that transports a signal from one cell to another. All
multicellular organisms produce hormones; plant hormones are also called
phytohormones. Hormones in animals are often transported in the blood. Cells
respond to a hormone when they express a specific receptor for that hormone.
The hormone binds to the receptor protein, resulting in the activation of a signal
transduction mechanism that ultimately leads to cell type-specific responses.
Endocrine hormone molecules are secreted (released) directly into the
bloodstream, whereas exocrine hormones (or ectohormones) are secreted
directly into a duct, and, from the duct, they flow either into the bloodstream or
from cell to cell by diffusion in a process known as paracrine signalling.
Recently it has been found that a variety of exogenous modern chemical
compounds have hormone-like effects on both humans and wildlife. Their
interference with the synthesis, secretion, transport, binding, action, or
elimination of natural hormones in the body are responsible of homeostasis,
reproduction, development, and/or behavioural changes sameway as the
endogenous produced hormones
Hormones as a signal
Hormonal signaling involves the following:[
1.
2.
3.
4.
Biosynthesis of a particular hormone in a particular tissue
Storage and secretion of the hormone
Transport of the hormone to the target cell(s)
Recognition of the hormone by an associated cell membrane or
intracellular receptor protein
5. Relay and amplification of the received hormonal signal via a signal
transduction process: This then leads to a cellular response. The reaction
of the target cells may then be recognized by the original hormoneproducing cells, leading to a down-regulation in hormone production.
This is an example of a homeostatic negative feedback loop.
6. Degradation of the hormone.
Hormone cells are typically of a specialized cell type, residing within a particular
endocrine gland, such as thyroid gland, ovaries, and testes. Hormones exit their
cell of origin via exocytosis or another means of membrane transport. The
hierarchical model is an oversimplification of the hormonal signaling process.
Cellular recipients of a particular hormonal signal may be one of several cell
types that reside within a number of different tissues, as is the case for insulin,
which triggers a diverse range of systemic physiological effects. Different tissue
types may also respond differently to the same hormonal signal. Because of this,
hormonal signaling is elaborate and hard to dissect]
Interactions with receptors
Most hormones initiate a cellular response by initially combining with either a
specific intracellular or cell membrane associated receptor protein. A cell may
have several different receptors that recognize the same hormone and activate
different signal transduction pathways, or a cell may have several different
receptors that recognize different hormones and activate the same biochemical
pathway.
For many hormones, including most protein hormones, the receptor is
membrane-associated and embedded in the plasma membrane at the surface of
the cell. The interaction of hormone and receptor typically triggers a cascade of
secondary effects within the cytoplasm of the cell, often involving
phosphorylation or dephosphorylation of various other cytoplasmic proteins,
changes in ion channel permeability, or increased concentrations of intracellular
molecules that may act as secondary messengers (e.g., cyclic AMP). Some protein
hormones also interact with intracellular receptors located in the cytoplasm or
nucleus by an intracrine mechanism.
For hormones such as steroid or thyroid hormones, their receptors are located
intracellularly within the cytoplasm of their target cell. To bind their receptors,
these hormones must cross the cell membrane. They can do so because they are
lipid-soluble. The combined hormone-receptor complex then moves across the
nuclear membrane into the nucleus of the cell, where it binds to specific DNA
sequences, effectively amplifying or suppressing the action of certain genes, and
affecting protein synthesis However, it has been shown that not all steroid
receptors are located intracellularly. some are associated with the plasma
membrane
An important consideration, dictating the level at which cellular signal
transduction pathways are activated in response to a hormonal signal, is the
effective concentration of hormone-receptor complexes that are formed.
Hormone-receptor complex concentrations are effectively determined by three
factors:
1. The number of hormone molecules available for complex formation
2. The number of receptor molecules available for complex formation
3. The binding affinity between hormone and receptor.
The number of hormone molecules available for complex formation is usually
the key factor in determining the level at which signal transduction pathways are
activated, the number of hormone molecules available being determined by the
concentration of circulating hormone, which is in turn influenced by the level
and rate at which they are secreted by biosynthetic cells. The number of
receptors at the cell surface of the receiving cell can also be varied, as can the
affinity between the hormone and its receptor.
Physiology of hormones
Most cells are capable of producing one or more molecules, which act as
signaling molecules to other cells, altering their growth, function, or metabolism.
The classical hormones produced by cells in the endocrine glands mentioned so
far in this article are cellular products, specialized to serve as regulators at the
overall organism level. However, they may also exert their effects solely within
the tissue in which they are produced and originally released.
The rate of hormone biosynthesis and secretion is often regulated by a
homeostatic negative feedback control mechanism. Such a mechanism depends
on factors that influence the metabolism and excretion of hormones. Thus,
higher hormone concentration alone cannot trigger the negative feedback
mechanism. Negative feedback must be triggered by overproduction of an
"effect" of the hormone.
Hormone secretion can be stimulated and inhibited by:
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Other hormones (stimulating- or releasing -hormones)
Plasma concentrations of ions or nutrients, as well as binding globulins
Neurons and mental activity
Environmental changes, e.g., of light or temperature
One special group of hormones is the tropic hormones that stimulate the
hormone production of other endocrine glands. For example, thyroidstimulating hormone (TSH) causes growth and increased activity of another
endocrine gland, the thyroid, which increases output of thyroid hormones.
A recently identified class of hormones is that of the "hunger hormones" ghrelin, orexin, and PYY 3-36 - and "satiety hormones" - e.g., cholecystokinin,
leptin, nesfatin-1, obestatin.
To release active hormones quickly into the circulation, hormone biosynthetic
cells may produce and store biologically inactive hormones in the form of pre- or
prohormones. These can then be quickly converted into their active hormone
form in response to a particular stimulus.
Effects of hormones
Hormones have the following effects on the body:
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stimulation or inhibition of growth
mood swings
induction or suppression of apoptosis (programmed cell death)
activation or inhibition of the immune system
regulation of metabolism
preparation of the body for mating, fighting, fleeing, and other activity
preparation of the body for a new phase of life, such as puberty,
parenting, and menopause
control of the reproductive cycle
hunger cravings
A hormone may also regulate the production and release of other hormones.
Hormone signals control the internal environment of the body through
homeostasis.
Chemical classes of hormones
Vertebrate hormones fall into three chemical classes:

Peptide hormones consist of chains of amino acids. Examples of small
peptide hormones are TRH and vasopressin. Peptides composed of scores
or hundreds of amino acids are referred to as proteins. Examples of
protein hormones include insulin and growth hormone. More complex
protein hormones bear carbohydrate side-chains and are called
glycoprotein hormones. Luteinizing hormone, follicle-stimulating
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hormone and thyroid-stimulating hormone are glycoprotein hormones.
There's also another type of hydrophilics hormones. They are called
nonpeptide hormones. Although they don't have peptide connections, they
are assimilated as peptide hormones.
Lipid and phospholipid-derived hormones derive from lipids such as
linoleic acid and arachidonic acid and phospholipids. The main classes
are the steroid hormones that derive from cholesterol and the eicosanoids.
Examples of steroid hormones are testosterone and cortisol. Sterol
hormones such as calcitriol are a homologous system. The adrenal cortex
and the gonads are primary sources of steroid hormones. Examples of
eicosanoids are the widely studied prostaglandins.
Monoamines derived from aromatic amino acids like phenylalanine,
tyrosine, tryptophan by the action of aromatic amino acid decarboxylase
enzymes. Examples of monoamines are thyroxine and adrenaline.
Pharmacology
Many hormones and their analogues are used as medication. The most
commonly prescribed hormones are estrogens and progestagens (as methods of
hormonal contraception and as HRT), thyroxine (as levothyroxine, for
hypothyroidism) and steroids (for autoimmune diseases and several respiratory
disorders). Insulin is used by many diabetics. Local preparations for use in
otolaryngology often contain pharmacologic equivalents of adrenaline, while
steroid and vitamin D creams are used extensively in dermatological practice.
A "pharmacologic dose" of a hormone is a medical usage referring to an amount
of a hormone far greater than naturally occurs in a healthy body. The effects of
pharmacologic doses of hormones may be different from responses to naturally
occurring amounts and may be therapeutically useful. An example is the ability
of pharmacologic doses of glucocorticoid to suppress inflammation.
A major organ of the endocrine system, the anterior pituitary, also called the
adenohypophysis, is the glandular, anterior lobe of the pituitary gland. The
anterior pituitary regulates several physiological processes including stress,
growth, and reproduction.
Its regulatory functions are achieved through the secretion of various peptide
hormones that act on target organs including the adrenal gland, liver, bone,
thyroid gland, and gonads. The anterior pituitary itself is regulated by the
hypothalamus and by negative feedback from these target organs.
Disorders of the anterior pituitary are generally classified by the presence of
over- or underproduction of pituitary hormones. For example, a prolactinoma is
a pituitary adenoma that overproduces prolactin. In Sheehan's syndrome of
postpartum hypopituitarism, the anterior pituitary uniformly malfunctions and
underproduces all hormones. Proper function of the anterior pituitary and of the
organs it regulates can often be ascertained via blood tests that measure
hormone levels.
Anatomy
The pituitary gland is a pea-sized gland that sits in a protective bony enclosure
called the sella turcica. It is composed of three lobes: anterior, intermediate, and
posterior. In many animals, these three lobes are distinct. However, in humans,
the intermediate lobe is but a few cell layers thick and indistinct; as a result, it is
often considered part of the anterior pituitary. In all animals, the fleshy,
glandular anterior pituitary is distinct from the neural composition of the
posterior pituitary.
The anterior pituitary is composed of multiple parts:
The pars distalis, or "distal part", comprises the majority of the anterior
pituitary and is where the bulk of pituitary hormone production occurs.
Occasionally, "pars distalis" is incorrectly used as a synonym for the
anterior pituitary.[
Pars tuberalis
The pars tuberalis, or "tubular part", forms a sheath extending up from
the pars distalis and wrapping around the pituitary stalk. Its function is
poorly understood.
Pars intermedia
The pars intermedia, or "intermediate part", sits between the pars
distalis and the posterior pituitary and is often very small in humans.
Hormone secretion
The posterior pituitary as a down growth of the brain, is a neurosecretory
organThe secretion of hormones from the posterior pituitary is controlled
directly by neurons in the hypothalamus. The connecting stalk between the
hypothalamus and the lobes of the pituitary gland, the infundibulum, carries the
hormones of the posterior pituitary from nuclei in the hypothalamus. The
hypothalmic supraoptic nuclei manufacture anti-diruetic hormone and the
hypothalmic paraventricular nuclei manufacture oxytocin. These hormones are
then stored in pituitary axons until their release is triggered .
The anterior pituitary is a glandular secretory organ. The secretion of hormones
from the anterior pituitary is controlled by inhibiting and releasing factors
secreted by neurons in the hypothalamus. These inhibiting and releasing factors
are released into a primary capillary plexus where they travel, via portal veins,
to a secondary capillary plexus where they stimulate the glandular tissue of the
anterior pituitary to release its hormones.
Embryology
The anterior pituitary arises from an invagination of the oral ectoderm and
forms Rathke's pouch. This contrasts with the posterior pituitary, which
originates from neuroectoderm.
Major hormones secreted
Symb Structur Secretory Staini
Target
Effect
ol(s)
e
cells
ng
Adrenocortic
Adren
Corticot ACT Polypep Corticotr Basop
Secretion of
otropic
al
ropin
H
tide
ophs
hil
glucocorticoids
hormone
gland
Opioi
Inhibit
BetaPolypep Corticotr Basop d
perception of
endorphin
tide
ophs
hil
recept
pain
or
ThyroidThyro Secretion of
Thyrotr
Glycopr Thyrotro Basop
stimulating
TSH
id
thyroid
opin
otein
phs
hil
hormone
gland hormones
FollicleGrowth of
Glycopr Gonadotr Basop Gonad
stimulating FSH
reproductive
otein
ophs
hil
s
hormone
system
Luteinizing
LH, Glycopr Gonadotr Basop Gonad Sex hormone
Lutropin
hormone
ICSH otein
ophs
hil
s
production
Promotes
Liver,
growth; lipid
Growth
Somatot GH, Polypep Somatotr Acido adipos
and
hormone
ropin
STH tide
ophs
phil e
carbohydrate
tissue
metabolism
Ovari
Lactotro
Secretion of
Lactoge
es,
Polypep phs and Acido
estrogens/proge
Prolactin
nic
PRL
mam
tide
Mammot phil
sterone; milk
hormone
mary
rophs
production
glands
Hormone
Other
names
The acidophilic cells (GH and PRL) have extensive rough endoplasmic reticulum
and produce single chain polypeptides without any glycosylation or
phosphorylation. Basophilic staining results from lysosome action modifying the
hormones (or prohormones in the case of corticotrophs) by glycosylation.
Regulation
Hormone secretion from the anterior pituitary gland is regulated by hormones
secreted by the hypothalamus. Neuroendocrine neurons in the hypothalamus
project axons to the median eminence, at the base of the brain. At this site, these
neurons can release substances into small blood vessels that travel directly to the
anterior pituitary gland (the hypothalamo-hypophysial portal vessels).
Tropic hormone
Tropic hormones are hormones which have other endocrine glands as their
target. Most tropic hormones are produced and secreted by the anterior
pituitary. The hypothalamus secretes tropic hormones that target the anterior
pituitary, and the thyroid gland secretes thyroxine, which targets the
hypothalamus and therefore can be considered a tropic hormone
Tropic hormones from the anterior pituitary include:
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Thyroid-stimulating hormone (TSH or thyrotropin) – stimulates the
thyroid gland to make and release thyroid hormone.
Adrenocorticotropic hormone (ACTH or corticotropin) – stimulates the
adrenal cortex to release glucocorticoids.
Luteinizing hormone (LH) – stimulates the release of steroid hormones in
gonads—the ovary and testes. Follicle-stimulating hormone (FSH) –
stimulates the maturation of eggs and production of sperm.
Growth hormone (GH)has both tropic and non-tropic effects. Growth
hormone's major tropic effect is it releases insulin-like growth factors
(IGFs) from the liver which causes bone growth. The hypothalamus
controls the release of hormones from the anterior pituitary by secreting
a class of hypothalamic neurohormones called releasing and releaseinhibiting hormones—which are released to the hypothalamohypophyseal portal system and act on the anterior pituitary.
Non-tropic hormone
Non-tropic hormones are hormones that directly stimulate target cells to induce
effects. This differs from the tropic hormones which act on another endocrine
gland.
Most endocrine glands, such as the gonads, pancreas, and adrenal glands ,
produce non-tropic hormones. Those released from the pituitary gland in the
brain include:
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Oxytocin (posterior lobe)- stimulates milk letdown in females.
Prolactin (PRL) (anterior lobe) - is remarkable for the diversity of its
effects among vertebrate species. The varied roles suggest that prolactin is
an ancient hormone with functions that have diversified during the
evolution of vertebrate groups.
Melanocyte-stimulating hormone (MSH) (intermediate lobe) - regulates
the activity of pigment-containing cells in the skins of some amphibians.
In mammals, MSH act on neurons in the brain, inhibiting hunger and
make skin colour dark it also can protect body form uv-ray
Growth hormone (GH)has both tropic and non-tropic effects. GH directly
stimulates muscle growth, a non-tropic effect. [1]
Estrogen
Estriol. Note two hydroxyl (-OH) groups attached to the D ring (rightmost ring)
Estradiol. Note one hydroxyl group attached to the D ring. The 'di' refers both to
this hydroxyl and the one on the A ring (leftmost).
Estrone. Note the ketone (=O) group attached to the D ring.
Estrogens (AmE), oestrogens (BE), or œstrogens, are a group of compounds
named for their importance in the estrous cycle of humans and other animals,
and functioning as the primary female sex hormones. Natural estrogens are
steroid hormones, while some synthetic ones are non-steroidal. Their name
comes from the Greek words estrus/οίστρος = sexual desire + gen/γόνο = to
generate.
Estrogens are synthesized in all vertebratesas well as some insects. Their
presence in both vertebrates and insects suggests that estrogenic sex hormones
have an ancient history.
Estrogens are used as part of some oral contraceptives, in estrogen replacement
therapy for postmenopausal women, and in hormone replacement therapy for
trans women.
Like all steroid hormones, estrogens readily diffuse across the cell membrane.
Once inside the cell, they bind to and activate estrogen receptors which in turn
modulate the expression of many genes.[3] Additionally, estrogens have been
shown to activate a G protein-coupled receptor, GPR30.[4]
Types
Steroidal
The three major naturally occurring oestrogens in women are estrone (E1),
estradiol (E2), and estriol (E3). Oestradiol (E2) is the predominant form in
nonpregnant females, estrone is produced during menopause, and estriol is the
primary oestrogen of pregnancy. In the body these are all produced from
androgens through actions of enzymes.
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From menarche to menopause the primary oestrogen is 17β-estradiol. In
postmenopausal women more estrone is present than oestradiol.
Oestradiol is produced from testosterone and estrone from
androstenedione by aromatase.
Oestrone is weaker than estradiol.
Premarin, a commonly prescribed estrogenic drug, contains the steroidal
oestrogens equilin and equilenin. There are oestradiol skin patches such as
Estraderm (the original brand, introduced in the late 1980s) that offer a
completely natural alternative. (A skin patch rather than pill also has the
advantage of direct transmission into the blood stream without going through
the liver.)
Reference ranges for the blood content of estradiol, the primary type of estrogen,
during the menstrual cycle.[5]
Nonsteroidal
A range of synthetic and natural substances have been identified that also
possess estrogenic activity.[6]
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Synthetic substances of this kind are known as xenoestrogens.
Plant products with estrogenic activity are called phytoestrogens.
Those produced by fungi are known as mycoestrogens.
Unlike estrogens produced by mammals, these substances are not necessarily
steroids.
Biosynthesis
Steroidogenesis, showing estrogens at bottom right as in pink triangle.
Oestrogens are produced primarily by developing follicles in the ovaries, the
corpus luteum, and the placenta. Luteinizing hormone (LH) stimulates the
production of estrogen in the ovaries. Some oestrogens are also produced in
smaller amounts by other tissues such as the liver, adrenal glands, and the
breasts. These secondary sources of oestrogens are especially important in
postmenopausal women. Fat cells also produce oestrogen, potentially being the
reason why underweight or overweight are risk factors for infertility. In females,
synthesis of oestrogens starts in theca interna cells in the ovary, by the synthesis
of androstenedione from cholesterol. Androstenedione is a substance of moderate
androgenic activity. This compound crosses the basal membrane into the
surrounding granulosa cells, where it is converted to oestrone or oestradiol,
either immediately or through testosterone. The conversion of testosterone to
oestradiol, and of androstenedione to oestrone, is catalyzed by the enzyme
aromatase.
Oestradiol levels vary through the menstrual cycle, with levels highest just before
ovulation.
Function
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
some 137 ER-regulated genes, of which 89 are direct target genes Since estrogen
enters all cells, its action are dependent on the presence of the ER in the cell. The
ER is expressed in specific tissues including the ovary, uterus and breast.
While oestrogens 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, oestrogen regulates certain functions of
the reproductive system important to the maturation of sperm and may be
necessary for a healthy libido.[13][14] Furthermore, there are several other
structural changes induced by oestrogen in addition to other functions.
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Structural
o promote formation of female secondary sex characteristics
o accelerate metabolism
o reduce muscle mass
o increase fat stores
o stimulate endometrial growth
o increase uterine growth
o increase vaginal lubrication
o thicken the vaginal wall
o maintenance of vessel and skin
o reduce bone resorption, increase bone formation
o morphic change (endomorphic -> mesomorphic -> ectomorphic)
protein synthesis
o increase hepatic production of binding proteins
coagulation
o increase circulating level of factors 2, 7, 9, 10, plasminogen
o decrease antithrombin III
o increase platelet adhesiveness
Lipid
o increase HDL, triglyceride
o decrease LDL, fat deposition
Fluid balance
o salt (sodium) and water retention
o increase cortisol, SHBG
Gastrointestinal tract
o reduce bowel motility
o increase cholesterol in bile
Melanin
o increase pheomelanin, reduce eumelanin
Cancer
o support hormone-sensitive breast cancers (see section below)
Lung function
o promotes lung function by supporting alveoli (in rodents but
probably in humans). Sexual desire is dependent on androgen
levels rather than estrogen levels Fetal development
In mice, oestrogens (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 As a result, the utility of rodent models for studying
human psychosexual differentiation has been questioned
Mental health
Oestrogen is considered to play a significant role in women’s mental health.
Sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained
oestrogen low levels correlates with significant mood lowering. Clinical recovery
from postpartum, perimenopause, and postmenopause depression has been
shown to be effective after levels of oestrogen were stabilized and/or
restored.[21][22]
Low oestrogen levels in male lab mice may be one cause of obsessive–compulsive
disorder (OCD). When oestrogen 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 COMT are
enhanced by increasing oestrogen 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 oestrogen in humans and has
therapeutic implications in humans having obsessive-compulsive disorder.[23]
Medical applications
Oral contraceptives
Since oestrogen circulating in the blood can negatively feed-back to reduce
circulating levels of FSH and LH, most oral contraceptives contain a synthetic
oestrogen, along with a synthetic progestin. Even in men, the major hormone
involved in LH feedback is estradiol, not testosterone.
Hormone replacement therapy
As more fully discussed in the article on Hormone replacement therapy,
oestrogen 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 oestrogens were well
understood, standard therapy was 0.625 mg/day of conjugated equine oestrogens
(such as Premarin). There are, however, risks associated with conjugated equine
oestrogen therapy. Among the older postmenopausal women studied as part of
the Women's Health Initiative (WHI), an orally administered conjugated equine
oestrogen supplement was found to be associated with an increased risk of
dangerous blood clotting. The WHI studies used one type of oestrogen
supplement, a high oral dose of conjugated equine oestrogens (Premarin alone
and with medroxyprogesterone acetate as PremPro).
In a study by the NIH, esterified oestrogens were not proven to pose the same
risks to health as conjugated equine oestrogens. 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 antiinflammatory component.
Research is underway to determine if risks of oestrogen 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.
Oestrogen is also used in the therapy of vaginal atrophy, hypoestrogenism (as a
result of hypogonadism, castration, or primary ovarian failure), amenorrhea,
dysmenorrhea, and oligomenorrhea. Oestrogens 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-receptorpositive 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 antiaromatase] 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. 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 controversial Ashley 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
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 progestagen) therapy increases the risk of
endometrial 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 cardiovascul and other risk
Progesterone
Progesterone also known as P4 (pregn-4-ene-3,20-dione) is a C-21 steroid
hormone involved in the female menstrual cycle, pregnancy (supports gestation)
and embryogenesis of humans and other species. Progesterone belongs to a class
of hormones called progestogens, and is the major naturally occurring human
progestogen.
Progesterone is commonly manufactured from the yam family, Dioscorea.
Dioscorea produces large amounts of a steroid called diosgenin, which can be
converted into progesterone in the laboratory.
Chemistry
Progesterone was independently discovered by four research groups.
Willard Myron Allen co-discovered progesterone with his anatomy professor
George Washington Corner at the University of Rochester Medical School in
1933. Allen first determined its melting point, molecular weight, and partial
molecular structure. He also gave it the name Progesterone derived from
Progestational Steroidal ketone
Like other steroids, progesterone consists of four interconnected cyclic
hydrocarbons. Progesterone contains ketone and oxygenated functional groups,
as well as two methyl branches. Like all steroid hormones, it is hydrophobic.
Sources
[
Progesterone is produced in the ovaries (to be specific, after ovulation in the
corpus luteum), the adrenal glands (near the kidney), and, during pregnancy, in
the placenta. Progesterone is also stored in adipose (fat) tissue.
In humans, increasing amounts of progesterone are produced during pregnancy:

At first, the source is the corpus luteum that has been "rescued" by the
presence of human chorionic gonadotropins (hCG) from the conceptus.

However, after the 8th week, production of progesterone shifts to the
placenta. The placenta utilizes maternal cholesterol as the initial
substrate, and most of the produced progesterone enters the maternal
circulation, but some is picked up by the fetal circulation and used as
substrate for fetal corticosteroids. At term the placenta produces about
250 mg progesterone per day.

An additional source of progesterone is milk products. They contain
much progesterone because on dairy farms cows are milked during
pregnancy, when the progesterone content of the milk is high. After
consumption of milk products the level of bioavailable progesterone goes
up
[edit] Plants
In at least one plant, Juglans regia, progesterone has been detected. In addition,
progesterone-like steroids are found in Dioscorea mexicana. Dioscorea mexicana
is a plant that is part of the yam family native to Mexico It contains a steroid
called diosgenin that is taken from the plant and is converted into progesterone
Diosgenin and progesterone are found in other Dioscorea species as well.
Another plant that contains substances readily convertible to progesterone is
Dioscorea pseudojaponica native to Taiwan. Research has shown that the
Taiwanese yam contains saponins — steroids that can be converted to diosgenin
and thence to progesterone. Many other Dioscorea species of the yam family
contain steroidal substances from which progesterone can be produced. Among
the more notable of these are Dioscorea villosa and Dioscorea polygonoides. One
study showed that the Dioscorea villosa contains 3.5% diosgenin.[11] Dioscorea
polygonoides has been found to contain 2.64% diosgenin as shown by gas
chromatography-mass spectrometry.[12] Many of the Dioscorea species that
originate from the yam family grow in countries that have tropical and
subtropical climates.[13]
BiosySynthesis
Top: Conversion of cholesterol (1) into pregnenolone (3) to progesterone (6).
Bottom: Progesterone is important for aldosterone (mineralocorticoid) synthesis,
as 17-hydroxyprogesterone is for cortisol (glucocorticoid), and androstenedione
for sex steroids.
In mammals, progesterone (6), like all other steroid hormones, is synthesized
from pregnenolone (3), which in turn is derived from cholesterol (1) (see the
upper half of the figure to the right).
Cholesterol (1) undergoes double oxidation to produce 20,22dihydroxycholesterol (2). This vicinal diol is then further oxidized with loss of the
side chain starting at position C-22 to produce pregnenolone (3). This reaction is
catalyzed by cytochrome P450scc. The conversion of pregnenolone to
progesterone takes place in two steps. First, the 3-hydroxyl group is oxidized to a
keto group (4) and second, the double bond is moved to C-4, from C-5 through a
keto/enol tautomerization reaction This reaction is catalyzed by 3betahydroxysteroid dehydrogenase/delta(5)-delta(4)isomerase.
Progesterone in turn (see lower half of figure to the right) is the precursor of the
mineralocorticoid aldosterone, and after conversion to 17-hydroxyprogesterone
(another natural progestogen) of cortisol and androstenedione. Androstenedione
can be converted to testosterone, estrone and estradiol.
Pregenolone and progesterone can also be synthesized by yeast
Laboratory
The Marker semisynthesis of progesterone from diosgenin.
An economical semisynthesis of progesterone from the plant steroid diosgenin
isolated from yams was developed by Russell Marker in 1940 for the ParkeDavis pharmaceutical company (see figure to the right).[16] This synthesis is
known as the Marker degradation. Additional semisyntheses of progesterone
have also been reported starting from a variety of steroids. For the example,
cortisone can be simultaneously deoxygenated at the C-17 and C-21 position by
treatment with iodotrimethylsilane in chloroform to produce 11-ketoprogesterone (ketogestin), which in turn can be reduced at position-11 to yield
progesterone
Levels
In women, progesterone levels are relatively low during the preovulatory phase
of the menstrual cycle, rise after ovulation, and are elevated during the luteal
phase. Progesterone levels tend to be < 2 ng/ml prior to ovulation, and > 5 ng/ml
after ovulation. If pregnancy occurs, progesterone levels are initially maintained
at luteal levels. With the onset of the luteal-placental shift in progesterone
support of the pregnancy, levels start to rise further and may reach 100200 ng/ml at term. Whether a decrease in progesterone levels is critical for the
initiation of labor has been argued and may be species-specific. After delivery of
the placenta and during lactation, progesterone levels are very low.
Progesterone levels are relatively low in children and postmenopausal women.
Adult males have levels similar to those in women during the follicular phase of
the menstrual cycle.
Progesterone levels during the menstrual cycle
- The ranges denoted By biological stage may be used in closely monitored
menstrual cycles in regard to other markers of its biological progression, with
the time scale being compressed or stretched to how much faster or slower,
respectively, the cycle progresses compared to an average cycle.
- The ranges denoted Inter-cycle variability are more appropriate to use in nonmonitored cycles with only the beginning of menstruation known, but where the
woman accurately knows her average cycle lengths and time of ovulation, and
that they are somewhat averagely regular, with the time scale being compressed
or stretched to how much a woman's average cycle length is shorter or longer,
respectively, than the average of the population.
- The ranges denoted Inter-woman variability are more appropriate to use when
the average cycle lengths and time of ovulation are unknown, but only the
beginning of menstruation is given.
Effects
showing changes to the endometrium due to progesterone Micrograph
(decidualization) H&E stain.
Progesterone exerts its primary action through the intracellular progesterone
receptor although a distinct, membrane bound progesterone receptor has also
been postulated In addition, progesterone is a highly potent antagonist of the
mineralocorticoid receptor (MR, the receptor for aldosterone and other
mineralocorticosteroids). It prevents MR activation by binding to this receptor
with an affinity exceeding even those of aldosterone and other corticosteroids
such as cortisol and corticosterone.
Progesterone has a number of physiological effects that are amplified in the
presence of estrogen. Estrogen through estrogen receptors upregulates the
expression of progesterone receptors Also, elevated levels of progesterone
potently reduce the sodium-retaining activity of aldosterone, resulting in
natriuresis and a reduction in extracellular fluid volume. Progesterone
withdrawal, on the other hand, is associated with a temporary increase in
sodium retention (reduced natriuresis, with an increase in extracellular fluid
volume) due to the compensatory increase in aldosterone production, which
combats the blockade of the mineralocorticoid receptor by the previously
elevated level of progesterone.
Reproductive system
Progesterone has key effects via non-genomic signalling on human sperm as they
migrate through the female tract before fertilization occurs, though the
receptor(s) as yet remain unidentified. Detailed characterisation of the events
occurring in sperm in response to progesterone has elucidated certain events
including intracellular calcium transients and maintained changes, slow calcium
oscillations,] now thought to possibly regulate motility. Interestingly
progesterone has also been shown to demonstrate effects on octopus spermatozoa
Progesterone modulates the activity of CatSper (cation channels of sperm)
voltage-gated Ca2+ channels. Since eggs release progesterone, sperm may use
progesterone as a homing signal to swim toward eggs (chemotaxis). Hence
substances that block the progesterone binding site on CatSper channels could
potentially be used in male contraception.
Progesterone is sometimes called the "hormone of pregnancy and it has many
roles relating to the development of the fetus:





Progesterone converts the endometrium to its secretory stage to prepare
the uterus for implantation. At the same time progesterone affects the
vaginal epithelium and cervical mucus, making it thick and impenetrable
to sperm. If pregnancy does not occur, progesterone levels will decrease,
leading, in the human, to menstruation. Normal menstrual bleeding is
progesterone-withdrawal bleeding. If ovulation does not occur and the
corpus luteum does not develop, levels of progesterone may be low,
leading to anovulatory dysfunctional uterine bleeding.
During implantation and gestation, progesterone appears to decrease the
maternal immune response to allow for the acceptance of the pregnancy.
Progesterone decreases contractility of the uterine smooth muscle
In addition progesterone inhibits lactation during pregnancy. The fall in
progesterone levels following delivery is one of the triggers for milk
production.
A drop in progesterone levels is possibly one step that facilitates the onset
of labor.
The fetus metabolizes placental progesterone in the production of adrenal
steroids.t] Nervous system
Progesterone, like pregnenolone and dehydroepiandrosterone, belongs to the
group of neurosteroids. It can be synthesized within the central nervous system
and also serves as a precursor to another major neurosteroid, allopregnanolone.
Neurosteroids affect synaptic functioning, are neuroprotective, and affect
myelination.[34] They are investigated for their potential to improve memory and
cognitive ability. Progesterone affects regulation of apoptotic genes.
Its effect as a neurosteroid works predominantly through the GSK-3 beta
pathway, as an inhibitor. (Other GSK-3 beta inhibitors include bipolar mood
stabilizers, lithium and valproic acid.)
Other syndromes








It raises epidermal growth factor-1 levels, a factor often used to induce
proliferation, and used to sustain cultures, of stem cells.
It increases core temperature (thermogenic function) during ovulation.
It reduces spasm and relaxes smooth muscle. Bronchi are widened and
mucus regulated. (Progesterone receptors are widely present in
submucosal tissue.)
It acts as an antiinflammatory agent and regulates the immune response.
It reduces gall-bladder activity
It normalizes blood clotting and vascular tone, zinc and copper levels, cell
oxygen levels, and use of fat stores for energy.
It may affect gum health, increasing risk of gingivitis (gum inflammation)
and tooth decay.
It appears to prevent endometrial cancer (involving the uterine lining) by
regulating the effects of estrogen.
Adverse effects
Pill form of progesterone (actually a synthetic version such as Progestogen)
taken at 400 mg as cited by the following patent can cause increased fluid
retention, which may result in epilepsy, migraine, asthma, cardiac or renal
dysfunction. Blood clots that can result in strokes and heart attacks, which may
lead to death or long-term disability, may develop; pulmonary embolus or breast
cancer can also develop as a result of progesterone therapy. Progesterone is
associated with an increased risk of thrombotic disorders such as
thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal
thrombosis
Common adverse effects include cramps, abdominal pain, skeletal pain, perineal
pain, headache, arthralgia, constipation, dyspareunia, nocturia, diarrhea,
nausea, vomiting, breast enlargement, joint pain, flatulence, hot flushes,
decreased libido, thirst, increased appetite, nervousness, drowsiness, excessive
urination at night. Psychiatric effects including depression, mood swings,
emotional instability, aggression, abnormal crying, insomnia, forgetfulness, sleep
disorders. Less frequent adverse effects that may occur include allergy, anemia,
bloating, fatigue, tremor, urticaria, pain, conjunctivitis, dizziness, vomiting,
myalgia, back pain, breast pain, genital itching, genital yeast infection, upper
respiratory tract infection, cystitis, dysuria, asthenia, xerophthalmia, syncope,
dysmenorrhea, premenstrual tension, gastritis, urinary tract infection, vaginal
discharge, pharyngitis, sweating, hyperventilation, vaginal dryness, dyspnea,
fever, edema, flu-like symptoms, dry mouth, rhinitis, leg pain, skin discoloration,
skin disorders, seborrhea, sinusitis, acne.
Current research suggests that progesterone plays an important role in the
signaling of insulin release and pancreatic function, and may affect the
susceptibility to diabetes It has been shown that women with high levels of
progesterone during pregnancy are more likely to develop glucose abnormalities.
Medical applications
The use of progesterone and its analogues have many medical applications, both
to address acute situations and to address the long-term decline of natural
progesterone levels. Because of the poor bioavailability of progesterone when
taken orally, many synthetic progestins have been designed with improved oral
bioavailability.[40] Progesteone was approved by the United States Food and
Drug Administration as vaginal gel on July 31, 1997 an oral capsule on May 14,
1998] in an injection form on April 25, 2001[] and as a vaginal insert on June 21,
2007. In Italy and Span, Progesterone is sold under the trademarkProgeffik.
Bioavailability
The route of administration impacts the effect of the drug. Given orally,
progesterone has a wide person-to-person variability in absorption and
bioavailability while synthetic progestins are rapidly absorbed with a longer
half-life than progesterone and maintain stable levels in the blood.
Progesterone does not dissolve in water and is poorly absorbed when taken
orally unless micronized in oil. Products are often sold as capsules containing
micronised progesterone in oil. Progesterone can also be administered through
vaginal or rectal suppositories or pessaries, transdermally through a gel or
cream, or via injection (though the latter has a short half-life requiring daily
administration).
"Natural progesterone" products derived from yams, do not require a
prescription but there is no evidence the human body can convert its active
ingredient (diosgenin, the plant steroid that is chemically converted to produce
progesterone industrially[16]) into progesterone.
Specific uses

Progesterone is used to support pregnancy in Assisted Reproductive
Technology (ART) cycles such as In-vitro Fertilization (IVF). While daily
intramuscular injections of progesterone-in-oil (PIO) have been the
standard route of administration, PIO injections are not FDA-approved
for use in pregnancy. A recent meta-analysis showed that the intravaginal
route with an appropriate dose and dosing frequency is equivalent to
daily intramuscular injections In addition, a recent case-matched study
comparing vaginal progesterone with PIO injections showed that live
birth rates were nearly identical with both methods.

Progesterone is used to control anovulatory bleeding. It is also used to
prepare uterine lining in infertility therapy and to support early
pregnancy. Patients with recurrent pregnancy loss due to inadequate
progesterone production may receive progesterone.
Progesterone is being investigated as potentially beneficial in treating
multiple sclerosis, since the characteristic deterioration of nerve myelin
insulation halts during pregnancy, when progesterone levels are raised;
deterioration commences again when the levels drop.
Vaginally dosed progesterone is being investigated as potentially
beneficial in preventing preterm birth in women at risk for preterm birth.
The initial study by Fonseca suggested that vaginal progesterone could
prevent preterm birth in women with a history of preterm birth.


A subsequent and larger study showed that vaginal progesterone was no better
than placebo in preventing recurrent preterm birth in women with a history of a
previous preterm birth but a planned secondary analysis of the data in this trial
showed that women with a short cervix at baseline in the trial had benefit in two
ways: a reduction in births less than 32 weeks and a reduction in both the
frequency and the time their babies were in intensive care.] In another trial,
vaginal progesterone was shown to be better than placebo in reducing preterm
birth prior to 34 weeks in women with an extremely short cervix at baseline. An
editorial by Roberto Romero discusses the role of sonographic cervical length in
identifying patients who may benefit from progesterone treatment. Progesterone
is used in hormone therapy for male-to-female transsexuals and other women
with intersex conditions - especially when synthetic progestins have been
ineffective or caused side-effects - since normal breast tissue cannot develop
except in the presence of both progestogen and estrogen. Mammary glandular
tissue is otherwise fibrotic, the breast shape conical and the areola immature].
Progesterone can correct those even after years of inadequate hormonal
treatment[d]. Research usually cited against such value was conducted using
Provera, a synthetic progestin[citation needed]. Progesterone also has a role in skin
elasticity and bone strength, in respiration, in nerve tissue and in female
sexuality, and the presence of progesterone receptors in certain muscle and fat
tissue may hint at a role in sexually-dimorphic proportions of those.

Progesterone receptor antagonists, or selective progesterone receptor
modulators (SPRM)s, such as RU-486 (Mifepristone), can be used to
prevent conception or induce medical abortions.
Note that methods of hormonal contraception do not contain progesterone but a
progestin.
Progesterone may affect male behavior. Progesterone is starting to be used in the
treatment of the skin condition hidradenitis suppurativa.[citation needed]
Aging
Since most progesterone in males is created during testicular production of
testosterone, and most in females by the ovaries, the shutting down (whether by
natural or chemical means), or removal, of those inevitably causes a considerable
reduction in progesterone levels. Previous concentration upon the role of
progestagens (progesterone and molecules with similar effects) in female
reproduction, when progesterone was simply considered a "female hormone",
obscured the significance of progesterone elsewhere in both sexes.
The tendency for progesterone to have a regulatory effect, the presence of
progesterone receptors in many types of body tissue, and the pattern of
deterioration (or tumor formation) in many of those increasing in later years
when progesterone levels have dropped, is prompting widespread research into
the potential value of maintaining progesterone levels in both males and females.
Brain damage
Previous studies have shown that progesterone supports the normal development
of neurons in the brain, and that the hormone has a protective effect on damaged
brain tissue. It has been observed in animal models that females have reduced
susceptibility to traumatic brain injury and this protective effect has been
hypothesized to be caused by increased circulating levels of estrogen and
progesterone in females.] A number of additional animal studies have confirmed
that progesterone has neuroprotective effects when administered shortly after
traumatic brain injury. Encouraging results have also been reported in human
clinical trials.
The mechanism of progesterone protective effects may be the reduction of
inflammation that follows brain trauma