Investigation of molecular –
cellular mechanisms of adrenal and sex glands hormones. Tissue hormones.
Hormones of adrenal cortex
Adrenal
glands consist of two parts: external - cortex, internal - medulla.
Each part secrets specific hormones.
Hormones
synthesized in adrenal cortex are named corticosteroids.
Mechanism of steroid hormones action (permeating into the cells):
http://www.youtube.com/watch?v=oOj04WsU9ko
In
difference to hormones of protein and peptide nature, receptors for steroid
hormones are located within the cells - in the cytoplasm. From cytoplasm the
hormone-receptor complexes is translocated
into the nucleus where they interact with DNA of nuclear chromatin
causing the activation of genes for respective enzyme proteins. So, if hormones
of the first group cause the activation of existing enzyme molecules, the
acting on the target cells of steroids and thyroid hormones results in the
biosynthesis of new enzyme molecules.
http://www.youtube.com/watch?v=0ss8YIoKw0g
Receptors for
steroid and thyroid hormones are located inside target cells, in the cytoplasm
or nucleus, and function as ligand-dependent
transcription factors. That is to say, the hormone-receptor complex binds to promoter regions of responsive genes and stimulate
or sometimes inhibit transcription from those genes.
Thus, the mechanism
of action of steroid hormones is to modulate gene expression in target cells.
By selectively affecting transcription from a battery of genes, the
concentration of those respective proteins are altered, which clearly can
change the phenotype of the cell.
Steroid and
thyroid hormone receptors are members of a large group
("superfamily") of transcription factors. In some cases, multiple
forms of a given receptor are expressed in cells, adding to the complexity of the
response. All of these receptors are composed of a single polypeptide chain
that has, in the simplist analysis, three distinct domains:
In addition
to these three core domains, two other important regions of the receptor
protein are a nuclear localization sequence, which targets the the protein to
nucleus, and a dimerization domain, which is responsible for latching two
receptors together in a form capable of binding DNA.
Being lipids,
steroid hormones enter the cell by simple diffusion across the plasma membrane.
Thyroid hormones enter the cell by facilitated diffusion. The receptors exist
either in the cytoplasm or nucleus, which is where they meet the hormone. When
hormone binds to receptor, a characteristic series of events occurs:
As
might be expected, there are a number of variations on the themes described
above, depending on the specific receptor in question. For example, in the
absense of hormone, some intracellular receptors do bind their hormone response
elements loosely and silence transcription, but, when complexed to hormone,
become activated and strongly stimulate transcription. Some receptors bind DNA
not with another of their kind, but with different intracellular receptor.
Corticosteroids have potent regulatory effect
on all kinds of metabolism. Cholesterol is the precursor of corticosteroids.
According to the biological effect corticosteroids are divided on two groups: glucocorticoids and mineralocorticoids. Glucocorticoids regulate the protein,
lipid and carbohydrate metabolism, mineralocorticoids - metabolism of water and
mineral salt.
The most important glucocorticoids: corticosterone,
hydrocortisone, cortisol. The
most important mineralocorticoid: aldosterone.
All biological active hormones of
adrenal cortex consist of 21 carbon atom and can be reviewed as derivatives of
carbohydrate pregnane.
The
synthesis of corticosteroids is regulated by ACTH.
In the blood corticosteroids are
connected with proteins and transported to different organs.
Time half-life for corticosteroids is
about 1 hour.
These
forms of hormones are lipids. They can enter the cell membrane quite easily and
enter right into the nuclei. Steroid hormones are generally carried in the
blood bound to specific carrier proteins
such as sex hormone binding globulin or corticosteroid binding globulin. Further
conversions and catabolism occurs in the liver, other "peripheral"
tissues, and in the target tissues.
Ways
of metabolism of corticosteroids:
1. Reduction.
Corticosteroids accept 4 or 6 hydrogen atoms and form couple compounds with
glucuronic acid. These compounds ere excreted by kidneys.
2. Oxidation
of 21-st carbon atom.
3. Reduction
of ring and decomposition of side chain. As result 17-ketosteroids are formed that are
excreted with urine. The determination of 17-ketosteroids in
urine - important diagnostic indicator. This is the indicator of adrenal
cortex function. In men 17-ketosteroids are also the terminal products of sex
hormones metabolism giving important information about testicles function.
4. Corticosteroids can be excreted by kidneys in
native structure.
Synthesis of steroid hormons
The name "glucocorticoid" derives from early
observations that these hormones were involved in glucose
metabolism. In the fasted state, cortisol stimulates
several processes that collectively serve to increase and maintain normal
concentrations of glucose in blood.
Metabolic effects:
Excessive glucocorticoid levels resulting from
administration as a drug or hyperadrenocorticism have effects on many systems.
Some examples include inhibition of bone formation, suppression of calcium
absorption (both of which can lead to osteoporosis), delayed
wound healing, muscle weakness, and increased risk of infection. These
observations suggest a multitude of less-dramatic physiologic roles for
glucocorticoids.
http://www.youtube.com/watch?v=0ss8YIoKw0g
The effect of glucocorticoids on protein
metabolism:
1. stimulate
the catabolic processes (protein decomposition) in connective, lymphoid and
muscle tissues and activate the processes of protein synthesis in liver;
2. stimulate
the activity of aminotransferases;
3. activate the
synthesis of urea.
The effect of glucocorticoids on
carbohydrate metabolism:
1. activate the
gluconeogenesis;
2. inhibit the activity
of hexokinase;
3. activate the glycogen
synthesis in liver.
Glucocorticoids causes the hyperglycemia.
The effect of glucocorticoids on
lipid metabolism:
1. promote the
absorption of lipids in intestine;
2. activate lipolisis;
3. activate the
conversion of fatty acids in carbohydrates.
Hyperfunction of adrenal cortex causes
Icenko-Kushing syndrome. This state
is called steroid diabetes. Symptoms:
hyperglycemia, glucosuria, hypercholesterolemia, hypernatriemia,
hyperchloremia, hypokaliemia.
http://www.youtube.com/watch?v=ku-QJyQ0j7M&feature=related
Hypercholesterolemia
Adrenal cortex hormones and their
artificial analogs are often used in clinic: for treatment of allergic and
autoimmune diseases, in hard shock states.
Blood and urine
cortisol, together with the determination of adrenocorticotropic hormone
(ACTH), are the three most important tests in the investigation of Cushing's
syndrome (caused by an overproduction of cortisol) and Addison's disease
(caused by the underproduction of cortisol).
Cushing's syndrome
Reference
ranges for cortisol vary from laboratory to laboratory but are usually within
the following ranges for blood:
·
adults (
·
child one to six
years (
·
newborn: 1/24 mg/dL.
Reference
ranges for cortisol vary from laboratory to laboratory, but are usually within
the following ranges for 24-hour urine collection:
·
adult: 10-100 mg/24 hours
·
adolescent: 5-55 mg/24 hours
·
Child: 2-27 mg/24 hours.
Abnormal
results
Increased levels
of cortisol are found in Cushing's syndrome, excess thyroid (hyperthyroidism),
obesity, ACTH-producing tumors, and high levels of stress.
Decreased
levels of cortisol are found in Addison's disease, conditions of low thyroid,
and hypopituitarism, in which pituitary activity is diminished.
Cushing's
syndrome
A hormonal
disorder caused by an abnormally high level of corticosteroid hormones.
Symptoms include high blood sugar levels, a moon face, weight gain, and
increased blood pressure
In
Since cortisol production by the
adrenal glands is normally under the control of the pituitary (like the thyroid gland), overproduction can be
caused by a tumor in the pituitary or within the adrenal glands themselves. When a pituitary tumor secretes too much ACTH
(Adrenal Cortical Tropic Hormone), it simply causes the otherwise normal
adrenal glands to produce too much cortisol. This type of Cushings
syndrome is termed "Cushings Disease" and it is diagnosed like other
endocrine disorders by measuring the appropriateness of hormone production. In
this case, serum cortisol will be elevated, and, serum ACTH will be elevated at
the same time. When the adrenal glands develop
a tumor, like any other endocrine gland, they usually produce excess amounts of
the hormone normally produced by these cells. If the adrenal tumor is composed
of cortisol producing cells, excess cortisol will be produced which can be
measured in the blood. Under these conditions, the normal pituitary will sense
the excess cortisol and will stop making ACTH in an attempt to slow the adrenal
down. In this manner, physicians can readily distinguish whether excess
cortisol is the result of a pituitary tumor, or an adrenal tumor.
Even more rare (but placed here for completion sake)
is when excess ACTH is produced somewhere other than the pituitary. This is
extremely uncommon, but certain lung cancers can make ACTH (we don't know why)
and the patients develop Cushings Syndrome in the same way they do as if the
ACTH was coming from the pituitary.
Causes
of Cushings Syndrome
ACTH
Dependent (80%)
Pituitary
Tumors (60%)
Lung
Cancers (5%)
ACTH
Independent (20%)
Benign
Adrenal Tumors (adenoma) (25%)
Malignant
Adrenal Tumors (adrenal cell carcinoma) (10%)
Testing
for Cushings Syndrome
The
most sensitive test to check for the possibility of this disease is to measure
the amount of cortisol
excreted in the
during during a 24 hour time period. Cortisol is normally secreted in different
amounts during the day and night, so this test usually will be repeated once or
twice to eliminate the variability which is normally seen. This normal
variability is why simply checking the amount of cortisol in the blood is not a
very reliable test. A 24 hour free cortisol level greater than 100 ug is
diagnostic of Cushings syndrome. The second test which
helps confirms this diagnosis is the suppression test which measures the
cortisol secretion following the administration of a powerful synthetic steroid
which will shut down steroid production in everybody with a normal adrenal gland.
Subsequent tests will distinguish whether the disease is due to an ACTH
dependent or independent cause.
Invariably,
once the diagnosis is made, patients will undergo a CT scan (or possibly an MRI
or Ultrasound) of the adrenal glands to look for tumors in one or both of them
(more information on adrenal x-ray tests on another page).
If the laboratory test suggest a pituitary origin, a CT or MRI of the brain
(and possibly of the chest as well) will be performed.
Treatment of Cushings Syndrome
Obviously,
the treatment of this disease depends upon the cause. Pituitary tumors are
usually removed surgically and often treated with radiation therapy.
Neurosurgeons and some ENT surgeons specialize in these tumors. If the cause is
determined to be within a single adrenal gland, this is treated by surgical
removal. If the tumor has characteristics of cancer on any of the x-ray tests,
then a larger, conventional operation is in order. If a single adrenal gland
possesses a small, well defined tumor, it can usually be removed by the new
technique of laparoscopic adrenalectomy.
Functions of mineralocorticoids.
Secretion of
mineralocorticoids is regulated by renin-angiotensine system
-
activates the
reabsorption of Na+, Cl- and water in kidney
canaliculuses;
-
promote the excretion of K+ by kidneys, skin and saliva.
Deficiency of corticosteroids
causes Addison's disease.
For this disease the hyperpigmentation
is typical because the deficiency of corticosteroids results in the excessive
synthesis of ACTH.
http://www.youtube.com/watch?v=FK1pPqWMXjM
Addison's disease
A rare
disorder in which symptoms are caused by a deficiency of hydrocortisone
(cortisol) and aldosterone, two corticosteroid hormones normally produced by a
part of the adrenal glands called the adrenal cortex. Symptoms include
weakness, tiredness, vague abdominal pain, weight loss, skin pigmentation and
low blood pressure.
Primary hyperaldosteronism has many causes,
including adrenal hyperplasia and adrenal carcinoma.[2]
The syndrome is due to:
· Bilateral
(micronodular) adrenal hyperplasia, 60%
· Adrenal
(Conn's) adenoma, 40%
· Glucocorticoid-remediable
hyperaldosteronism (dexamethasone-suppressible
hyperaldosteronism), <1%
· rare
forms, including disorders of the renin-angiotensin
system, <1%
Aldosterone enhances exchange of
sodium for potassium in the kidney, so increased aldosteronism will lead to hypernatremia (elevated
sodium level) and hypokalemia (low blood
potassium). Once the potassium has been significantly reduced by aldosterone, a
sodium/hydrogen pump in the nephron becomes more
active, leading to increased excretion of hydrogen ions and further
exacerbating the elevated sodium level resulting in a further increase in hypernatremia.
The hydrogen ions exchanged for sodium are generated by carbonic anhydrase in the renal
tubule epithelium, causing increased production of bicarbonate.
The increased bicarbonate and the excreted hydrogen combine to generate a metabolic
alkalosis.
The high pH of the blood
makes calcium less
available to the tissues and causes symptoms of hypocalcemia (low calcium
levels).
The sodium retention leads to plasma
volume expansion and elevated blood pressure. The increased blood pressure will
lead to an increased glomerular
filtration rate and
cause a decrease inrenin release from
the granular cells of the juxtaglomerular
apparatus in
the kidney. If a patient is thought to suffer from primary hyperaldosteronism,
the aldosterone:renin activity ratio is used to assess
this. The decreased renin levels and in turn the reactive down-regulation of angiotensin II are thought
to be unable to down-regulate the constitutively formed aldosterone, thus
leading to an elevated [plasma aldosterone:plasma renin activity] ratio
(lending the assay to be a clinical tool for diagnostic purposes).
Aside from hypertension, other
manifesting problems include myalgias, weakness, and chronic headaches. The muscle cramps are due to
neuron hyperexcitability seen in the setting of hypocalcemia, muscle weakness secondary to
hypoexcitability of skeletal muscles in the setting of low blood potassium
(hypokalemia), and headaches which are
thought to be due to both electrolyte imbalance (hypokalemia) and
hypertension.
Secondary hyperaldosteronism is often
related to decreased cardiac output, which is
associated with elevated renin levels.
Measuring aldosterone alone is not
considered adequate to diagnose primary hyperaldosteronism. The screening test
of choice for diagnosis is the plasma aldosterone:plasma
renin activity ratio. Renin activity, not simply plasma renin level, is
assayed. Both renin and
aldosterone are measured, and a ratio greater than 30 is indicative of primary
hyperaldosteronism.
In the absence of proper treatment,
individuals with hyperaldosteronism often suffer from poorly controlled high
blood pressure, which may be associated with increased rates of stroke, heart
disease, and kidney failure. With appropriate treatment, the prognosis is
excellent.
Sex hormones.
Sex hormones are synthesized
in testes, ovaries. Smaller amount of sex hormones are produced in adrenal
cortex and placenta. Small amount of male sex hormones are produced in ovaries
and female sex hormones - in testes.
Male sex hormones are called androgens and female - estrogens.
Chemical structure - steroids.
Synthesis and secretion of the
sex hormones are controlled by the pituitary honadotropic hormones. Sex hormones
act by means of the activation of gene apparatus of cells. Catabolism of sex
hormones takes place in liver. The time half-life is 70-90 min.
The main estrogens: estradiol,
estrole, estriole (are produced by follicles) and progesterone (is produced
by yellow body and placenta). The main biological role of
estrogens - conditioning for the reproductive female function (possibility of
ovum fertilization). Estradiol results in the proliferation of
endometrium and progesterone stimulates the conversion of endometrium in
decidual tissue which is ready for ovum implantation. Estrogens also cause the
development of secondary sexual features.
Estrogens
originate in the adrenal cortex and gonads and primarily affect maturation and
function of secondary sex organs (female sexual determination).
Estrogens, in
females, are produced primarily by the ovaries, and during
pregnancy, the placenta. Follicle-stimulating
hormone(FSH)
stimulates the ovarian production of estrogens by the granulosa cells of the ovarian follicles and corpora lutea.
Some estrogens are also produced in smaller amounts by other tissues such as
the liver, adrenal glands,
and the breasts. These
secondary sources of estrogens are especially important in postmenopausal
women.Fat cells produce
estrogen as well.
In females,
synthesis of estrogens starts in theca interna cells in the
ovary, by the synthesis of androstenedionefrom cholesterol.
Androstenedione is a substance of weak androgenic activity which serves
predominantly as aprecursor for more
potent androgens such as testosterone as well as estrogen. This compound
crosses thebasal 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,
whereas 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.
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 a
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.
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. Furthermore, there are several other
structural changes induced by estrogen in addition to other functions.
Structural
·
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
Protein synthesis
·
Increase hepatic production of binding proteins
·
Increase
circulating level of factors 2, 7, 9, 10, plasminogen
·
Decrease antithrombin III
·
Increase platelet adhesiveness
·
Increase HDL, triglyceride
·
Decrease LDL, fat deposition
Fluid
balance
·
Salt (sodium) and water
retention
·
Reduce
bowel motility
·
Increase cholesterol in bile
·
Increase pheomelanin, reduce eumelanin
Cancer
·
Support hormone-sensitive breast
cancers (see section below)
·
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
·
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.
Progestins
Progestins
originate from both ovaries and placenta, and mediate menstrual cycle and
maintain pregnancy.
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.
Androgens
originate in the adrenal cortex and gonads and primarily affect maturation and function
of secondary sex organs (male sexual determination).
http://www.youtube.com/watch?v=nLmg4wSHdxQ&feature=fvwrel
The
main androgen is testosterone. Its
synthesis is regulated by the luteinizing hormone. Testosterone forms the
secondary sexual features in males.
A subset of androgens, adrenal androgens, includes any
of the 19-carbon steroids synthesized by the adrenal cortex, the
inner-most layer of the adrenal cortex (zonula reticularis—innermost
region of the adrenal cortex), that function as weak steroids or steroid
precursors, including dehydroepiandrosterone (DHEA),
dehydroepiandrosterone sulfate (DHEA-S), and androstenedione.
Besides testosterone, other androgens include:
·
Dehydroepiandrosterone (DHEA) is a
steroid hormone produced in the adrenal cortex from cholesterol.
It is the primary precursor of natural estrogens. DHEA is
also called dehydroisoandrosterone ordehydroandrosterone.
·
Androstenedione (Andro) is an
androgenic steroid produced by the testes, adrenal cortex,
and ovaries. While androstenediones
are converted metabolically to testosterone and other
androgens, they are also the parent structure of estrone. Androstenediol is the
steroid metabolite thought to
act as the main regulator of gonadotropin secretion.
·
Androsterone is a chemical
byproduct created during the breakdown of androgens, or derived fromprogesterone, that also
exerts minor masculinising effects, but with one-seventh the intensity of
testosterone. It is found in approximately equal amounts in the plasma and urine of both males
and females.
·
Dihydrotestosterone (DHT) is a metabolite of
testosterone, and a more potent androgen than testosterone in that it binds
more strongly to androgen receptors. It is
produced in the adrenal cortex.
Testosterone
is the primary androgenic hormone. It instills its effects on the body both
directly, and through its conversion to metabolites (DHT, estradiol etc).
Androgens and other steroid hormones primarily exert their direct activities
through binding to specific receptors present in the cytosol of cells. Upon
binding to the receptor, the hormone forms a complex that then travels to the
nucleus of cells where it interacts with DNA to promote the formation of
specific proteins that then direct the actual biological changes.
Within the central nervous system (CNS), androgen
receptors are heavily located in specific places. Androgens and other steroid
hormones are able to penetrate the blood brain barrier and interact with their
appropriate CNS cytosolic receptors. The hypothalamus and anterior pituitary
gland are particularly dense in androgen receptors, and here they help regulate
the secretion of androgens as well as other hormones that control a wide
variety of biological functions. Androgen receptors are also located in parts
of the cerebral cortex, medulla, and amygdala. Here their specific functions
are not as well characterized.
The processes of androgen action that involve receptor
binding and DNA translation are known as receptor mediated, or “genomic”,
hormone actions. However, there are also lesser known actions of steroid
hormones that are non-genomic in mechanism. Non-genomic activities are particularly
key in the central nervous system where they combine
with genomic activities to produce specific effects.
Non-genomic actions of steroid hormones differ in a
very important way from genomic actions. Genomic effects are manifested over a
relatively long period of time (days) because they require a complex cascade of
events (binding, translation, transcription, accumulation of active enzyme
products) before the actual physiology of the target organ is altered. On the
other hand, genomic actions are extremely rapid (<1 minute). They are rapid
because their effects involve an immediate modulation of the membranes of cells
(particularly neural cells). These modulations may include changes to the
permeability of the membrane, as well as effects on the opening of vital ligand
gated ion channels. The end result is a quick and significant influence upon
the activities of key areas of the brain, and the relevance of this to the
medicinal use of androgenic hormones or prohormones should not be overlooked.
Effect
of sex hormones on protein metabolism:
1.
stimulate the
processes of protein, DNA, RNA synthesis;
2.
cause the positive
nitrogenous equilibrium.
Effect
of sex hormones on carbohydrate metabolism:
1. activate the Krebs
cycle;
2. activate the
synthesis of glycogen in liver.
Effect
of sex hormones on lipid metabolism:
1. enhance the
oxidation of lipids;
2. inhibit the
synthesis of cholesterol.
Effect
of sex hormones on energy metabolism:
-
stimulate the Krebs cycle, tissue respiration and ATP production.
Sex hormones are used for
treatment of variety diseases. For example, testosterone and its analogs are
used as anabolic remedies; male sex hormones are used for the treatment of
malignant tumor of female sex organs and vice versa.
Tissue hormones.
Prostaglandins.
The precursor of prostaglandins is arachidonic acid. Time
half-life - 30 s. There are different prostaglandins and they have a lot of physiological and pharmacological effects and
different prostaglandins have different effects.
Prostaglandins were first discovered
and isolated from human semen in the 1930s by Ulf von Euler of
Prostaglandins,
are like hormones in that they act as chemical messengers, but do not move to
other sites, but work right within the cells where they are synthesized.
Prostaglandins are unsaturated
carboxylic acids, consisting of of a 20 carbon skeleton that also contains a
five member ring. They are biochemically synthesized from the fatty acid,
arachidonic acid.
The unique shape of the arachidonic
acid caused by a series of cis double bonds helps to put it into position to
make the five member ring. See the prostaglandin in the next panel.
Functions of Prostaglandins:
There are a variety of physiological effects
including:
-
1. Activation of the inflammatory response, production
of pain, and fever. When tissues are damaged, white blood cells flood to
the site to try to minimize tissue destruction. Prostaglandins are produced as
a result.
-
2. Blood clots form when a blood vessel is damaged. A type of
prostaglandin called thromboxane stimulates constriction and clotting of
platelets. Conversely, PGI2, is produced to have the
opposite effect on the walls of blood vessels where clots should not be
forming.
-
3. Certain prostaglandins are involved with the induction of labor and
other reproductive processes. PGE2 causes uterine contractions and has been
used to induce labor.
-
4. Prostaglandins are involved in several other organs such as the
gastrointestinal tract (inhibit acid synthesis and increase secretion of
protective mucus), increase blood flow in kidneys, and leukotriens promote
constriction of bronchi associated with asthma.
Effects
of Aspirin and other Pain Killers:
When
you see that prostaglandins induce inflammation, pain, and fever, what comes to
mind but aspirin. Aspirin blocks an enzyme called
cyclooxygenase, COX-1 and COX-2, which is involved with the ring closure and
addition of oxygen to arachidonic acid converting to prostaglandins. The acetyl
group on aspirin is hydrolzed and then bonded to the alcohol group of serine as
an ester. This has the effect of blocking the channel in the enzyme and
arachidonic can not enter the active site of the enzyme.
By
inhibiting or blocking this enzyme, the synthesis of prostaglandins is blocked,
which in turn relives some of the effects of pain and fever.
Aspirin
is also thought to inhibit the prostaglandin synthesis involved with unwanted
blood clotting in coronary heart disease. At the same time an injury while
taking aspirin may cause more extensive bleeding.
See
the following chime tutorial for the detailed molecular basis for the
inhibition of the COX enzyme by aspirin.
Kallicrein-kinin
system. Kinins -
group of peptides with similar structure and biological properties. The main kinins - bradykinin
and kallidine.
Kinins are formed from their precursors kininogens that
are synthesized in liver owing to acting of kallicreins. Kallicreins are also
formed from inactive precursors prekallicreins by
means of proteolysis.
Functions: - kinins relax the
smooth muscles of blood vessels and decrease the blood pressure;
-
increase the capillaries permeability;
-
takes part in the inflammatory processes.
Bradykinin
is a potent endothelium-dependent vasodilator,
causes contraction of non-vascular smooth muscle, increases
vascular permeability and also is
involved in the mechanism of pain. Bradykinin also causes natriuresis,
contributing to a drop in blood pressure.
Bradykinin
raises internal calcium levels in neocortical astrocytes causing them
to release glutamate.
Bradykinin
is also thought to be the cause of the dry cough in some patients on angiotensin
converting enzyme (ACE)
inhibitor drugs. It is thought that bradykinin is converted to inactive
metabolites by angiotensin
converting enzyme (ACE),
therefore inhibition of this enzyme leads to increased levels of bradykinin
which causes a dry cough. This refractory cough is a common cause for stopping ACE inhibitor therapy. In which case angiotensin
II receptor antagonists (ARBs)
are the next line of treatment.
Renin-angiotensin
system.
Renin - enzyme that is
synthesized in special cells located near the renal glomerules.
Hormonal peptide-340 AA,an enzyme
.
T½ -15 min,
prepared and stored in granular JG cells in kidney and also other tisuue–the main source of
plasma
Renin (active) and 90% in prorenin (inactive but immune
reactive ).
It is synthesized In both constitutive and rate limiting pathway. It catalyzes
the rate limiting step of RAS – attract active future target.
Stretch receptors(pressure sensor) in the afferent arteriole, local SNS
, Na content of the tubular fluid
reaching the macula
Renin acts on angiotensinogen. As result angiotensin-I is formed. Under the effect of peptidase angiotensin-I is converted to angiotensin-II. Angiotensin-II causes 2 effects:
-
narrows the vessels and increases the blood pressure;
-
stimulates the secretion of aldosterone.
The decrease of renal blood stream is the specific
stimulant for renin secretion.
THE MOST POTENT VASOCONSTRICTOR SYSTEM IN THE BODY
Renin-Angiotensin
mechanism
The renin–angiotensin system (RAS) or the renin–angiotensin–aldosterone
system (RAAS) is a hormone system that
regulates blood pressure and water (fluid) balance.
When blood
volume is low, juxtaglomerular cells in the kidneys
secrete renin directly
into circulation. Plasma renin then
carries out the conversion of angiotensinogen released
by the liver to angiotensin I. Angiotensin I is subsequently converted
to angiotensin II by the enzyme angiotensin converting enzyme found
in the lungs. Angiotensin II is a potent vaso-active peptide that causes blood
vessels to constrict, resulting in increased blood pressure. Angiotensin II
also stimulates the secretion of the hormone aldosterone from
the adrenal cortex. Aldosterone causes the tubules
of the kidneys to increase the reabsorption of sodium and water into the blood.
This increases the volume of fluid in the body, which also increases blood
pressure.
If the
renin–angiotensin–aldosterone system is abnormally active, blood pressure will
be too high. There are many drugs that interrupt different steps in this system
to lower blood pressure. These drugs are one of the main ways to control high
blood pressure (hypertension), heart failure,kidney failure,
and harmful effects of diabetes.
The
system can be activated when there is a loss of blood volume or a drop in blood
pressure (such as in hemorrhage).
This loss of pressure is interpreted by baroreceptors in
the carotid sinus. In alternative fashion, a
decrease in the filtrate NaCl concentration and/or decreased filtrate flow rate
will stimulate the macula densa to signal the juxtaglomerular cells to release
renin.
·
If the perfusion of the juxtaglomerular apparatus in the
kidney's macula densa decreases, then the
juxtaglomerular cells (granular cells, modified pericytes in the glomerular
capillary) release the enzyme renin.
·
Renin cleaves a zymogen,
an inactive peptide,
called angiotensinogen, converting it into angiotensin I.
·
Angiotensin I is then converted
to angiotensin
II by angiotensin-converting enzyme (ACE),[5] which
is thought to be found mainly in lung capillaries.
One study in 1992 found ACE in all blood vessel endothelial cells.[6]
·
Angiotensin II is the major bioactive
product of the renin-angiotensin system, binding to receptors on intraglomerular mesangial cells,
causing these cells to contract along with the blood vessels surrounding them
and causing the release of aldosterone from
the zona glomerulosa in the adrenal
cortex. Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrinehormone.
Cardiovascular
effects
It is believed that angiotensin I may have some minor
activity, but angiotensin II is the major bio-active product. Angiotensin II
has a variety of effects on the body:
·
Throughout the body, it is a potent vasoconstrictor of arterioles.
·
In the kidneys, it constricts glomerular arterioles,
having a greater effect on efferent arterioles than afferent. As with most other
capillary beds in the body, the constriction of afferent arterioles increases the arteriolar resistance,
raising systemic arterial blood pressure and decreasing the blood flow.
However, the kidneys must continue to filter enough blood despite this drop in
blood flow, necessitating mechanisms to keep glomerular blood pressure up. To
do this, angiotensin II constricts efferent arterioles, which forces blood to
build up in the glomerulus, increasing glomerular pressure. The glomerular
filtration rate(GFR) is thus maintained, and blood filtration can
continue despite lowered overall kidney blood flow. Because the filtration
fraction has increased, there is less plasma fluid in the downstream
peritubular capillaries. This in turn leads to a decreased hydrostatic pressure
and increased oncotic pressure (due to unfiltered plasma proteins) in the
peritubular capillaries. The effect of decreased hydrostatic pressure and
increased oncotic pressure in the peritubular capillaries will facilitate
increased reabsorption of tubular fluid.
·
Angiotensin II decreases medullary blood flow through the
vasa recta. This decreases the washout of NaCl and urea in the kidney medullary
space. Thus, higher concentrations of NaCl and urea in the medulla facilitate
increased absorption of tubular fluid. Furthermore, increased reabsorption of
fluid into the medulla will increase passive reabsorption of sodium along the
thick ascending limb of the loop of Henle.
·
Angiotensin II stimulates Na+/H+ exchangers located on the apical
membranes (faces the tubular lumen) of cells in the proximal tubule and thick
ascending limb of the loop of Henle in addition to Na+ channels in the collecting ducts. This
will ultimately lead to increased sodium reabsorption
·
Angiotensin II stimulates the hypertrophy of renal tubule
cells, leading to further sodium reabsorption.
·
In the adrenal
cortex, it acts to cause the release of aldosterone.
Aldosterone acts on the tubules (e.g., the distal convoluted tubules and the cortical collecting
ducts) in the kidneys, causing them to reabsorb more sodium and water from the urine. This
increases blood volume and, therefore, increases blood pressure. In exchange
for the reabsorbing of sodium to blood, potassiumis secreted into the tubules,
becomes part of urine and is excreted.
·
Release of anti-diuretic hormone (ADH), also called vasopressin – ADH is made in the hypothalamus and
released from the posterior pituitary
gland. As its name suggests, it also exhibits vaso-constrictive
properties, but its main course of action is to stimulate reabsorption of water
in the kidneys. ADH also acts on the central nervous system to increase an individual's appetite
for salt, and to stimulate the sensation of thirst.
These effects directly act in concert to increase
blood pressure.
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Examples of peptide hormones
Hormones
of hypothalamus (releasing and inhibitory factors),
structure, mechanism of action.
Hypothalamus has the wide anatomic links with
other parts of the brain. Therefore in different mental disorders there is the
change of secretion of hypothalamus hormones.
http://www.youtube.com/watch?v=hLeBNyB1qKU&feature=related
Two groups of hormones are produced by
hypothalamus corresponding to the anterior and posterior pituitary.
Hypothalamus and posterior
pituitary. 3 peptides are synthesized in the hypothalamus that pass to the posterior pituitary along
axons where they are accumulated: oxytocin, vasopressin (antidiuretic hormone)
and neurophysin. The later binds the oxytocin and vasopressin and promotes
their transportation to the pituitary.
Hypothalamus and anterior
pituitary. Hypothalamus is connected with the anterior pituitary
by the net of blood capillaries, so called hypothalamic portal system.
Hypothalamus produces very active peptide compounds that pass via this portal
system to anterior pituitary and stimulate or oppress the secretion of tropic
hormones. Compounds stimulating the secretion are called releasing factors. 7
releasing factors are known according to the amount of tropic hormones of
anterior pituitary:
- corticotropin-releasing factor
- thyrotropin-releasing factors
- somatotropin-releasing factors
- follicletropin-releasing factor
- luteotropin-releasing factor
- prolactotropin-releasing factor
- melanotropin-releasing factor.
Hypothalamus also secretes substances called inhibitory
factors or statins, which can inhibit release of the some pituitary hormones. 3
inhibitory factors are known today:
- somatostatin
- prolactostatin
- melanostatin.
Releasing and inhibitory factors are produced in
only minute amounts.
http://www.youtube.com/watch?v=-UaSfYKsFh0
Hormones
of pituitury, structure, mechanism of action.
Tropic hormones are produced by the anterior
pituitary. Usually tropic hormones not directly regulate the metabolism
but act on the peripheral endocrine glands.
|
Somatotropic
hormone (STH, growth hormone)
Chemical structure: simple protein
The intensity of secretion is regulated by the
relationship between the somatotropic-releasing factor and somatostatin.
The main function of
somatotropic hormone - stimulation of growth. Hormone is
necessary for the bone tissue formation, for the muscle tissue growth, for the
formation of peculiarities of men and women body.
Somatotropic hormone can act both directly on the
metabolism and indirectly stimulating the synthesis of somatomedines (specific
protein growth factors which are synthesized in liver).
The
effect of somatotropic hormone on:
- protein metabolism:
stimulates the passing of amino acids into the cells;
activates
the synthesis of proteins, DNA, RNA.
- carbohydrate metabolism:
activates the insulinase of liver;
inhibits
the conversion of lipids to carbohydrates;
activates
the exit of glucose from liver;
inhibits
the entry of glucose into the cells.
- lipid metabolism: stimulates lipolisis;
stimulates
the oxidation of fatty acids.
The deficiency of somatotropic hormone in
children age causes nanism. Nanism - proportional underdevelopment of all body.
The deficiency of somatotropic hormone in adult
persons hasn’t clinical symptoms. The excess of somatotropic hormone in
children age causes gigantism.
The excess of somatotropic hormone in adult
persons causes acromegalia (disproportional
development of the separate body parts).
http://www.youtube.com/watch?v=VX2wgM4kUfM
Thyrotropic
hormone (TTH).
Chemical structure: glicoprotein.
This hormone is necessary for the normal
functions of thyroid glands.
Thyrotropic hormone promotes:
- accumulation of iodine in thyroid;
- including
of iodine into the tyrosine;
- synthesis of thyroxine and triiodothyronine.
Adrenocorticotropic
hormone (ACTH).
Chemical structure: polipeptide.
This hormone is necessary for the normal
functions of adrenal cortex. It enhances the formation of steroid hormones and
their secretion into the blood.
ACTH has also the melanocyte-stimulating
activity.
Excessive secretion of ACTH causes the
Icenko-Kushing disease (symptoms of hypercorticism, hyperpigmentation).
As you know, Cushing’s is a rarely diagnosed endocrine disorder
characterized by hypercortisolism. Cortisol is a hormone produced by the
adrenal glands and is vital to regulate the body’s cardivoascular functions and
metabolism, to boost the immune system and to fight inflammation. But its most important job is to help the body to respond to
stress.
The adrenal glands release cortisol in response to stress, so atheletes,
women experiencing pregnancy, and those suffering from alcoholism, panic
disorders and malnutrition naturally have higher-than-normal levels of
cortisol.
People with Cushing’s Syndrome live life with
too much cortisol for their bodies as a result of a hormone-secreting tumor.
Mine is located in the pituitary gland. Endogenous hypercortisolism leaves the
body in a constant state of “fight or flight,” which ravages the body and tears
down the body’s major systems including cardivascular, musculo-skeletal,
endocrine, etc.
Symptoms vary, but the most common symptoms include rapid, unexplained
weight gain in the upper body with increased fat around the neck and face
(“moon facies”); buffalo hump; facial flushing/plethora; muscle wasting in the
arms and legs; purplish striae (stretch marks) on the abdomen, thighs,
buttocks, arms and breasts; poor wound healing and bruising; severe fatigue;
depression, anxiety disorders and emotional lability; cognitive difficulties;
sleep disorders due to abnormally high nighttime cortisol production; high
blood pressure and high blood sugar/diabetes; edema; vision problems; premature
osteoperosis; and, in women, signs of hyperandrogenism such as menstrual
irregularities, infertility, hirsutism, male-patterned balding and
steroid-induced acne.
Most people with Cushing’s long for the ability to do simple things, like
walk a flight of stairs without having to sit for half an hour afterwards, or
vacuum the house or even unload a dishwasher.
One of the worst parts about this disease is the
crushing fatigue and muscle wasting/weakness, which accompanies hypercortisolism.
Not only do we become socially isolated because of the virilzing effects of an
endocrine tumor, which drastically alters our appearance, but we no longer feel
like ourselves with regard to energy. We would love to take a long bike ride,
run three miles or go shopping like we used to — activities, which we took for
granted before the disease struck. Those activities are sadly impossible at
times for those with advanced stages of the disease.
Gonadotropic
hormones.
Follicle
stimulating hormone (FSH).
Chemical structure: glycoprotein.
Function: stimulates the function of follicles
(oogenesis) in women and spermatogenesis in men.
FSH (follicle stimulating hormone) regulates the
development, growth, pubertal maturation, and reproductive processes of the
body
In both males and females, FSH stimulates the
maturation of germ cells.
In males, FSH induces sertoli cells to secrete inhibin and stimulates the
formation of sertoli-sertoli tight junctions (zonula occludens).
In females, FSH initiates follicular growth, specifically affecting granulosa
cells. With the concomitant rise in inhibin B, FSH levels then decline in the
late follicular phase. This seems to be critical in selecting only the most
advanced follicle to proceed to ovulation. At the end of the luteal phase,
there is a slight rise in FSH that seems to be of importance to start the next
ovulatory cycle.
Luteinizing
hormone (LH).
Chemical structure: glycoprotein.
Function: stimulates the formation of yellow body
in women and testosterone secretion in men.
In both males and females, (LH) Luteinising
hormone is essential for reproduction.
In females, at the time of menstruation, FSH initiates follicular growth,
specifically affecting granulosa cells. With the rise in estrogens, LH
receptors are also expressed on the maturing follicle that produces an
increasing amount of estradiol. Eventually at the time of the maturation of the
follicle, the estrogen rise leads via the 48 hour period.
This 'LH surge' triggers ovulation thereby not
only releasing the egg, but also initiating the conversion of the residual
follicle into a corpus luteum that, in turn, produces progesterone to prepare
the endometrium for a possible implantation. LH is necessary to maintain luteal
function for the first two weeks. In case of a pregnancy luteal function will
be further maintained by the action of hCG (a hormone
very similar to LH) from the newly established pregnancy. LH supports thecal
cells in the ovary that provide androgens and hormonal precursors for estradiol
production.
In the male, LH acts upon the Leydig cells of the
testis and is responsible for the production of testosterone, an androgen that
exerts both endocrine activity and intratesticular activity on spermatogenesis.
Prolactin
(PRL).
Chemical structure: protein.
Functions: - stimulates lactation;
- stimulates
function of yellow body (secretion of progesterone);
- promotes
formation of mother instinct;
- stimulates
the formation of prostate glandular tissue in men.
Lipotropic
hormone.
Chemical structure: protein.
Functions: - stimulates the mobilization of
lipids from depot;
- decreases
the Ca amount in blood;
- has the
melanocyte-stimulating activity.