Investigation of
thyroid hormones in the regulation of metabolism. Hormonal regulation of calsium and phosphorus
homeostasis.
Tissue hormones.
Investigation of molecular – cellular mechanisms of adrenal and sex glands hormones.
Hormones of
thyroid and parathyroid glands
Thyroid
synthesizes two kinds of hormones: iodine containing hormones and calcitonin.
Iodine
containing hormones - thyroxine and triiodthyronine.
Thyroid hormone is produced by the thyroid gland, which
consists of follicles in which thyroid hormone is synthesized through
iodination of tyrosine residues in the glycoprotein thyroglobulin. Thyroid
stimulating hormone (TSH), secreted by the anterior pituitary in response to
feedback from circulating thyroid hormone, acts directly on the TSH receptor
(TSH-R) expressed on the thyroid follicular cell basolateral membrane. TSH
regulates iodide uptake mediated by the sodium/iodide symporter, followed by a
series of steps necessary for normal thyroid hormone synthesis and secretion.
Thyroid hormone is essential for normal development, growth, neural
differentiation, and metabolic regulation in mammals.
TH synthesis
and secretion is exquisitely regulated by a negative-feedback system that
involves the hypothalamus, pituitary, and thyroid gland
[hypothalamic/pituitary/thyroid (HPT) axis]. Thyrotropin releasing hormone
(TRH) is a tripeptide (PyroGlu-His-Pro) synthesized in the paraventricular
nucleus of the hypothalamus. It is transported via axons to the median eminence
and then to the anterior pituitary via the portal capillary plexus. TRH binds
to TRH receptors in pituitary thyrotropes, a subpopulation of pituitary cells
that secrete thyroid stimulating hormone (TSH). TRH receptors are members of
the seven-transmembrane spanning receptor family and are coupled to Gq11.
TRH stimulation leads to release and synthesis of new TSH in thyrotropes. TSH
is a 28-kDa glycoprotein composed of α- and β-subunits designated as glycoprotein
hormone α-
and TSH β-subunits.
The α-subunit
also is shared with other hormones such as luteinizing hormone, follicle
stimulating hormone, and chorionic gonadotropin. Both TRH and TSH secretion are
negatively regulated by TH. An important mechanism for the negative regulation
of TSH may be the intrapituitary conversion of circulating T4 to T3 by type II deiodinase. Additionally,
somatostatin and dopamine from the hypothalamus can negatively regulate TSH
secretion.
TSH is the
primary regulator of TH release and secretion. It also has a critical role in
thyroid growth and development. TSH binds to the TSH receptor (TSHr), which
also is a seven-transmembrane spanning receptor coupled to Gs.
Activation of TSHr by TSH or autoantibodies in Graves' disease leads to an
increase in intracellular cAMP and stimulation of protein kinase A-mediated
pathways. A number of thyroid genes, including Na+/I− symporter (
The THs, T4 and the more potent T3, are
synthesized in the thyroid gland. Iodide is actively transported and
concentrated into the thyroid by
The
secretion of THs requires endocytosis of the stored iodinated Tg from the
apical surface of the thyroid follicular cell. The internalized Tg is
incorporated in phagolysosomes and undergoes proteolytic digestion, recapture
of MIT and DIT, and release of T4 and
T3 into the
circulation via the basal surface. The majority of released TH is in the form
of T4, as total serum T4 is 40-fold higher than serum T3 (90 vs. 2 nM). Only 0.03% of the total
serum T4 is free
(unbound), with the remainder bound to carrier proteins such as thyroxine binding
globulin (TBG), albumin, and thyroid binding prealbumin. Approximately 0.3% of
the total serum T3 is
free, with the remainder bound to TBG and albumin. It is the free TH that
enters target cells and generates a biological response.
The
major pathway for the production of T3 is via 5′-deiodination of the
outer ring of T4 by
deiodinases and accounts for the majority of the circulating T3.
Type I deioidinase is found in peripheral tissues such as liver and kidney and
is responsible for the conversion of the majority of T4 to T3 in circulation. Type II deiodinase is
found in brain, pituitary, and brown adipose tissue and primarily converts T4 to T3for intracellular use.
These deiodinases recently have been cloned and demonstrated to be
selenoproteins. 5′-Deiodination by type I deiodinase and type III
deioidinase, which is found primarily in placenta, brain, and skin, leads to
the generation of rT3, the key step in the inactivation of TH. rT3 and T3 can be further deiodinated in the
liver and are sulfo- and glucuronide-conjugated before excretion in the bile.
There also is an enterohepatic circulation of TH as intestinal flora
deconjugates some of these compounds and promotes the reuptake of TH.
Although
THs may exert their effects on a number of intracellular loci, their primary
effect is on the transcriptional regulation of target genes. Early studies
showed that the effects of THs at the genomic level are mediated by nuclear
TRs, which are intimately associated with chromatin and bind TH with high
affinity and specificity. Similar to steroid hormones that also bind to nuclear
receptors, TH enters the cell and proceeds to the nucleus. It then binds to
TRs, which may already be prebound to TREs located in promoter regions of
target genes. The formation of ligand-bound TR complexes that are also bound to
TREs is the critical first step in the positive or negative regulation of
target genes and the subsequent regulation of protein synthesis. Given their
abilities to bind both ligand and DNA as well as their ability to regulate
transcription, TRs can be regarded as ligand-regulatable transcription factors.
General model for thyroid hormone action in the nucleus. TR, thyroid
hormone receptor; RXR, retinoid X receptor
Thyroid hormone
regulates a wide range of genes after its activation from the prohormone,
thyroxine (T4), to the active form, triiodothyronine (T3). The signaling
pathway is complex and highly regulated due to the expression of cell and
tissue-specific thyroid hormone transporters, multiple thyroid hormone receptor
(TR) isoforms, and interactions with corepressors and coactivators.
Furthermore, in many cases, thyroid signals are involved in cross-talk with a
range of other signaling pathways.
Receptors for
thyroid hormones are intracellular DNA-binding proteins that function as
hormone-responsive transcription factors, very similar conceptually to
the receptors for steroid hormones.
Thyroid hormones
enter cells through membrane transporter proteins. A number of plasma membrane
transporters have been identified, some of which require ATP hydrolysis; the
relative importance of different carrier systems is not yet clear and may
differ among tissues. Once inside the nucleus, the hormone binds its receptor,
and the hormone-receptor complex interacts with specific sequences of DNA in
the promoters of responsive genes. The effect of the hormone-receptor
complex binding to DNA is to modulate gene expression, either by stimulating or
inhibiting transcription of specific genes.
Nuclear
action of thyroid hormone.
For the purpose of illustration, consider one mechanism
by which thyroid hormones increase the strength of contraction of the heart.
Cardiac contractility depends, in part, on the relative ratio of different
types of myosin proteins in cardiac muscle. Transcription of some myosin genes
is stimulated by thyroid hormones, while transcription of others in inhibited.
The net effect is to alter the ratio toward increased contractility.
Metabolism: Thyroid hormones stimulate diverse metabolic
activities most tissues, leading to an increase in basal metabolic rate. One
consequence of this activity is to increase body heat production, which seems
to result, at least in part, from increased oxygen consumption and rates of ATP
hydrolysis. By way of analogy, the action of thyroid hormones is akin to
blowing on a smouldering fire. A few examples of specific metabolic effects of
thyroid hormones include:
Lipid
metabolism: Increased thyroid
hormone levels stimulate fat mobilization, leading to increased concentrations
of fatty acids in plasma. They also enhance oxidation of fatty acids in many
tissues. Finally, plasma concentrations of cholesterol and triglycerides are
inversely correlated with thyroid hormone levels - one diagnostic indiction of
hypothyroidism is increased blood cholesterol concentration.
Carbohydrate
metabolism: Thyroid hormones
stimulate almost all aspects of carbohydrate metabolism, including enhancement
of insulin-dependent entry of glucose into cells and increased gluconeogenesis
and glycogenolysis to generate free glucose.
Protein
metabolism: in normal
concentration stimulate the synthesis of proteins and nucleic acids; in
excessive concentration activate the catabolic processes.
Growth: Thyroid hormones are clearly necessary for
normal growth in children and young animals, as evidenced by the growth-retardation
observed in thyroid deficiency. Not surprisingly, the growth-promoting effect
of thyroid hormones is intimately intertwined with that of growth hormone, a clear indiction that complex physiologic processes like
growth depend upon multiple endocrine controls.
Development: Of critical importance in mammals is the fact
that normal levels of thyroid hormone are essential to the development of
the fetal and neonatal brain.
Other
Effects: As mentioned
above, there do not seem to be organs and tissues that are not affected by
thyroid hormones. A few additional, well-documented effects of thyroid hormones
include:
Cardiovascular
system: Thyroid hormones
increases heart rate, cardiac contractility and cardiac output. They also
promote vasodilation, which leads to enhanced blood flow to many organs.
Central
nervous system: Both decreased
and increased concentrations of thyroid hormones lead to alterations in mental
state. Too little thyroid hormone, and the individual tends to feel mentally
sluggish, while too much induces anxiety and nervousness.
Reproductive
system:
Thyroid
Disease States
Disease is associated with both inadequate production
and overproduction of thyroid hormones. Both types of disease are relatively
common afflictions of man and animals.
Hypothyroidism is the result from any condition that results in
thyroid hormone deficiency. Two well-known examples include:
Iodine deficiency: Iodide is absolutely necessary for
production of thyroid hormones; without adequate iodine intake, thyroid
hormones cannot be synthesized. Historically, this problem was seen
particularly in areas with iodine-deficient soils, and frank iodine deficiency
has been virtually eliminated by iodine supplementation of salt.
Primary thyroid disease: Inflammatory diseases of the
thyroid that destroy parts of the gland are clearly an important cause of
hypothyroidism.
Common symptoms
of hypothyroidism arising after early childhood include lethargy, fatigue,
cold-intolerance, weakness, hair loss and reproductive failure. If these signs
are severe, the clinical condition is called myxedema. In the case of iodide deficiency, the thyroid
becomes inordinantly large and is called a goiter.
About 95
percent of the active thyroid hormone is thyroxine, and most of the remaining 5
percent is triiodothyronine. Both of these require iodine for their synthesis.
Thyroid hormone secretion is regulated by a negative feedback mechanism that involves
the amount of circulating hormone, hypothalamus, and adenohypophysis.
If there is
an iodine deficiency, the thyroid cannot make sufficient hormone. This
stimulates the anterior pituitary to secrete thyroid-stimulating hormone, which
causes the thyroid gland to increase in size in a vain attempt to produce more
hormones. But it cannot produce more hormones because it does not have the
necessary raw material, iodine. This type of thyroid enlargement is called
simple goiter or iodine
deficiency goiter.
Calcitonin is
secreted by the parafollicular cells of the thyroid gland. This hormone opposes
the action of the parathyroid glands by reducing the calcium level in the
blood. If blood calcium becomes too high, calcitonin is secreted until calcium
ion levels decrease to normal.
The most severe and devestating form of
hypothyroidism is seen in young children with congenital thyroid deficiency. If that condition is not corrected by supplemental therapy soon after
birth, the child will suffer from cretinism,
a form of irreversible growth and mental retardation.
Congenital
hypothyroidism can be endemic, genetic, or
sporadic. If untreated, it results in mild to severe impairment of both
physical and mental growth and development.
Poor length growth is apparent as early as the first
year of life. Adult stature without treatment ranges from 1 to
Sporadic and genetic cretinism results from abnormal development or
function of the foetal thyroid gland. This type of cretinism has been almost
completely eliminated in developed countries by early diagnosis by newborn screening schemes followed by lifelong treatment with thyroxine (T4).
Thyroxine must be dosed as tablets only, even to newborns, as the liquid oral
suspensions and compounded forms cannot be depended on for reliable dosing. In
the case of dosing infants, the T4 tablets are generally crushed and mixed with
breast milk, formula milk or water. If the medication is mixed with formulas
containing iron or soya products, larger doses may be required, as these
substances may alter the absorption of thyroid hormone from the gut. Frequent monitoring (every 2–3 weeks
during the first months of life) is recommended to ensure that infants with
congenital hypothyroidism remain within the high end of normal range, or euthyroid.
Cretinism arises from a diet deficient in iodine. It has affected many people worldwide and continues
to be a major public health problem in many countries. Iodine is
an essential trace element, necessary primarily for the synthesis of thyroid
hormones. Iodine deficiency is the most common preventable cause of brain
damage worldwide. Although iodine is found in many
foods, it is not universally present in all soils in adequate amounts. Most
iodine, in iodide form, is in the oceans where the iodide ions oxidize to
elemental iodine, which then enters the atmosphere and falls to earth as rain,
introducing iodine to soils. Earth deficient in iodine is most common inland
and in mountainous areas and areas of frequent flooding, but can also occur in
coastal regions owing to past glaciation, and leaching by snow, water and heavy
rainfall, which removes iodine from the soil.[8] Plants
and animals grown in iodine deficient soils are correspondingly deficient.
Populations living in those areas without outside food sources are most at risk
ofiodine
deficiency diseases.
Most cases of hypothyroidism are readily treated by oral administration
of synthetic thyroid hormone. In times past, consumption of dessicated animal
thyroid gland was used for the same purpose.
Hyperthyroidism results from
secretion of thyroid hormones. In most species, this condition is less common
than hypothyroidism. In humans the most common form of hyperthyroidism is Graves disease, an immune
disease in which autoantibodies bind to and activate the thyroid-stimulating
hormone receptor, leading to continual stimulation of thyroid hormone
synthesis. Another interesting, but rare cause of hyperthyroidism is so-called hamburger thyrotoxicosis.
exophthalmic goiter
Common signs of hyperthyroidism are basically the opposite of those seen
in hypothyroidism, and include nervousness, insomnia, high heart rate, eye
disease and anxiety.
Calcitonin.
Calcitonin is synthesized by the parafollicle cells of
thyroid.
Chemical structure: peptide.
Functions: - promotes the transition of calcium from
blood in bones;
-
inhibits the reabsorption of phosphorus in
kidneys.
Thus, calcitonin decreases the Ca and P contents in
blood.
Parathyroid glands.
Parathyroid
Gland
Four small
masses of epithelial tissue are embedded in the connective tissue capsule on
the posterior surface of the thyroid glands. These are parathyroid glands, and they
secrete parathyroid hormone or parathormone. Parathyroid hormone is the most
important regulator of blood calcium levels. The hormone is secreted in
response to low blood calcium levels, and its effect is to increase those
levels.
Parathyroid
hormone. Chemical
structure: protein.
Functions:
1.
promotes the transition of calcium from bones to blood;
2.
promotes the absorption of Ca in the intestine;
3.
inhibits the reabsorption of phosphorus in kidneys.
Thus,
parathyroid hormone increases the Ca amount in blood and decreases the P amount in blood.
Body Distribution
of Calcium and Phosphate
There are three major pools of
calcium in the body:
Intracellular
calcium:
·
A large majority of calcium within cells is sequestered in mitochondria
and endoplasmic reticulum. Intracellular free calcium concentrations fluctuate
greatly, from roughly 100 nM to greater than 1 uM, due to release from cellular
stores or influx from extracellular fluid. These fluctuations are integral to
calcium's role in intracellular signaling, enzyme activation and muscle
contractions.
Calcium in
blood and extracellular fluid:
Roughly half
of the calcium in blood is bound to proteins. The concentration of ionized
calcium in this compartment is normally almost invariant at approximately
Bone calcium:
A vast
majority of body calcium is in bone. Within bone, 99% of the calcium is tied up
in the mineral phase, but the remaining 1% is in a pool that can rapidly
exchange with extracellular calcium.
As with
calcium, the majority of body phosphate (approximately 85%) is present in the
mineral phase of bone. The remainder of body phosphate is present in a variety
of inorganic and organic compounds distributed within both intracellular and
extracellular compartments. Normal blood concentrations of phosphate are very
similar to calcium.
Fluxes of
Calcium and Phosphate
Maintaining
constant concentrations of calcium in blood requires frequent adjustments,
which can be described as fluxes of calcium between blood and other body
compartments. Three organs participate in supplying calcium to blood and
removing it from blood when necessary:
·
The small intestine is the site where dietary calcium is absorbed.
Importantly, efficient absorption of calcium in the small intestine is
dependent on expression of a calcium-binding protein in epithelial cells.
·
Bone serves as a vast reservoir of calcium.
Stimulating net resorption of bone mineral releases calcium and phosphate into
blood, and suppressing this effect allows calcium to be deposited in bone.
The
kidney is critcally important in calcium homeostasis. Under normal blood
calcium concentrations, almost all of the calcium that enters glomerular
filtrate is reabsorbed from the tubular system back into blood, which preserves
blood calcium levels. If tubular reabsorption of calcium decreases, calcium is
lost by excretion into urine.
Hormonal
Control Systems
Maintaining
normal blood calcium and phosphorus concentrations is managed through the
concerted action of three hormones that control fluxes of calcium in and out of
blood and extracellular fluid:
Calcitonin
is a hormone that functions to reduce blood calcium levels. It is secreted in
response to hypercalcemia and has at least two effects:
·
Suppression of renal tubular reabsorption of calcium. In other words,
calcitonin enhances excretion of calcium into urine.
·
Inhibition of bone resorption, which would minimize fluxes of calcium
from bone into blood.
Although
calcitonin has significant calcium-lowing effects in some species, it appears
to have a minimal influence on blood calcium levels in humans.
Vitamin D
acts also to increase blood concentrations of calcium.
It is generated through the activity of parathyroid hormone within the kidney.
Far and away the most important effect of vitamin D is to facilitate absorption
of calcium from the small intestine. In concert with parathyroid hormone,
vitamin D also enhances fluxes of calcium out of bone.
http://www.youtube.com/watch?v=JwPVibQ6_3Y&feature=related
http://www.youtube.com/watch?v=n7vybcT9_F4
Parathyroid
hormone serves to increase blood
concentrations of calcium. Mechanistically, parathyroid hormone
preserves blood calcium by several major effects:
·
Stimulates production of the biologically-active form of vitamin D
within the kidney.
·
Facilitates mobilization of calcium and phosphate from bone. To prevent
detrimental increases in phosphate, parathyroid hormone also has a potent
effect on the kidney to eliminate phosphate (phosphaturic effect).
·
Maximizes tubular reabsorption of calcium within the kidney. This
activity results in minimal losses of calcium in urine.
Hypoparathyroidism, or insufficient secretion of
parathyroid hormone, leads to increased nerve excitability. The low blood
calcium levels trigger spontaneous and continuous nerve impulses, which then
stimulate muscle contraction.
Since
parathyroid gland disease (hyperparathyroidism) was first described in 1925,
the symptoms have become known as "moans, groans, stones, and bones...with
psychic overtones". Although about 5-7% of people with
parathyroid disease (hyperparathyroidism) claim they don't have symptoms and to
feel fine when the diagnosis of hyperparathyroidism is made, almost 100% of
parathyroid patients will actually say they feel better after the parathyroid
problem has been cured--proving they had symptoms. The bottom line: Nearly ALL
patients with parathyroid problems have symptoms. Sometimes the symptoms are
real obvious, like kidney stones, frequent headaches, and depression. Sometimes
the symptoms are not so obvious, like high blood pressure and the inability to
concentrate. If you have symptoms, you are almost guaranteed to feel remarkably
better once the parathyroid tumor has been removed. As we often tell our
parathyroid patients: "you will be amazed at how a 16 minute
mini-procedure will change your life!"
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
Sweden. Thinking they had come from the prostate gland, he named them
prostaglandins. It has since been determined that they exist and are synthesized
in virtually every cell of the body.
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.
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.