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, structure, mechanism of action.
Thyroid synthesizes two kinds of hormones: iodine containing hormones and calcitonin.
Iodine containing hormones - thyroxine and triiodthyronine.
Thyroxine and triiodthyronine are iodinated derivatives of amino acid tyrosine.
Functions: these hormones are necessary for growth of organism, mental, physical and sex development, they regulate the rate of basal metabolism.
Effect of thyroxine and triiodthyronine on the protein metabolism:
1. in normal concentration stimulate the synthesis of proteins and nucleic acids;
2. in excessive concentration activate the catabolic processes.
Effect of thyroxine and triiodthyronine on the carbohydrate metabolism:
1. promote the absorption of carbohydrates in the intestine;
2. activates the decomposition of glycogen.
Effect of thyroxine and triiodthyronine on the lipid metabolism:
- activate the lipid oxidation and mobilization.
Effect of thyroxine and triiodthyronine on the energy metabolism:
1. activates dehydrogenases of mitochondria;
2. in excessive amount of these hormones the disconnection of tissue respirstion and oxidative phosphorylation takes place. As result the formation of ATP is decreased and the temperature of the organism is increased.
Excessive secretion of thyroid hormones, called hyperthyroidism,
is responsible for Graves' disease,
or exophthalmic goiter
while deficiency in thyroid hormones, hypothyroidism
is characteristic of the disease myxedema.
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 hormone. Chemical structure: protein.
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:
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 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:
Parathyroid hormone serves to increase blood concentrations of calcium. Mechanistically, parathyroid hormone preserves blood calcium by several major effects:
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.
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!"
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.
Calcitonin is a hormone that functions to reduce blood calcium levels. It is secreted in response to hypercalcemia and has at least two effects:
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.
Mechanism of steroid hormones action (permeating into the cells):
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.
• Receptors for thyroid hormones are members of a large family of nuclear receptors that include those of the steroid hormones. They function as hormone-activated transcription factors and thereby act by modulating gene expression. In contrast to steroid hormone receptors, thyroid hormone receptors bind DNA in the absence of hormone, usually leading to transcriptional repression. Hormone binding is associated with a conformational change in the receptor that causes it to function as a transcriptional activator.
• Currently, four different thyroid hormone receptors are recognized: alpha-1, alpha-2, beta-1 and beta-2.
• The presence of multiple forms of the thyroid hormone receptor, with tissue and stage-dependent differences in their expression, suggests an extraordinary level of complexity in the physiologic effects of thyroid hormone.
• Thyroid hormone receptors bind to short, repeated sequences of DNA called thyroid or T3 response elements (TREs), a type of hormone response element. A TRE is composed of two AGGTCA "half sites" separated by four nucleotides. The half sites of a TRE can be arranged as direct repeats, pallindromes or inverted repeats.
• The DNA-binding domain of the receptor contains two sets of four cysteine residues, and each set chelates a zinc ion, forming loops known as "zinc fingers". A part of the first zinc finger interacts directly with nucleotides in the major groove of TRE DNA, while residues in the second finger interact with nucleotides in the minor groove of the TRE. Thus, the zinc fingers mediate specificity in binding to TREs.
• Thyroid hormone receptors can bind to a TRE as monomers, as homodimers or as heterodimers with the retinoid X receptor (RXR), another member of the nuclear receptor superfamily that binds 9-cis retinoic acid. The heterodimer affords the highest affinity binding, and is thought to represent the major functional form of the receptor.
• Thyroid hormone receptors bind to TRE DNA regardless of whether they are occupied by T3. However, the biological effects of TRE binding by the unoccupied versus the occupied receptor are dramatically different. In general, binding of thyroid hormone receptor alone to DNA leads to repression of transcription, whereas binding of the thyroid hormone-receptor complex activates transcription.
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.
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.
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.
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.
Because steroids and sterols are lipid soluble, they can diffuse fairly freely from the blood through the cell membrane and into the cytoplasm of target cells. In the cytoplasm the steroid may or may not undergo an enzyme-mediated alteration such as reduction, hydroxylation, or aromatization. In the cytoplasm, the steroid binds to the specific receptor, a large metalloprotein. Upon steroid binding, many kinds of steroid receptor dimerizes, two receptor subunits join together to form one functional DNA-binding unit that can enter the cell nucleus. In some of the hormone systems known, the receptor is associated with a heat shock protein which is released on the binding of the ligand, the hormone. Once in the nucleus, the steroid-receptor ligand complex binds to specific DNA sequences and induces transcription of its target genes.
It discussing steroid hormones, one is required to talk about cholesterol; cholesterol is know as a sterol, which is a natural product from the steroid nucleus. Cholesterol is very important, as we learned, in the production of steroid hormones, in fact they are the precursor for bile acids (bile acids aid in fat digestion), steroid hormones, and provitamin D (When irradiated by sunlight it changes to vitamin D3.
Cholesterol, if we recall, is incorporated into the cell membrane by lipoproteins.There it plays a role in the regulation of membrane fluidity. It has been stated that cholesterol is probably responsible for permitting steroid hormones to enter the cell.
Synthesis of steroid hormons
Functions of glucocorticoids.
Glucocorticoids have antiinflammatory, antiallergic, antiimmune effect. They support the blood pressure and constancy of the extracellular liquids.
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.
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.
Hyperfunction of adrenal cortex causes Icenko-Kushing syndrome. This state is called steroid diabetes. Symptoms: hyperglycemia, glucosuria, hypercholesterolemia, hypernatriemia, hyperchloremia, hypokaliemia.
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).
Reference ranges for cortisol vary from laboratory to laboratory but are usually within the following ranges for blood:
Reference ranges for cortisol vary from laboratory to laboratory, but are usually within the following ranges for 24-hour urine collection:
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.
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.
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
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
Glucocorticoids originate in the adrenal cortex and affect mainly metabolism in diverse ways; decrease inflammation and increase resistance to stress.
Mineralocorticoids originate in adrenal cortex and maintain salt and water balance.
Estrogens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs (female sexual determination).
Androgens originate in the adrenal cortex and gonads and primarily affect maturation and function of secondary sex organs (male sexual determination).
Progestins originate from both ovaries and placenta, and mediate menstrual cycle and maintain pregnancy.
Androgens and estrogens play a major role in the development of both sexes secondary characteristics. Androgens, or testosterone and androsterone give the male its sex characteristics during puberty and for promoting tissue and muscle growth. Estrogens, or estrone and estradiol are forms of testosterone synthesized in the ovaries, which control female secondary characteristics and regulation of the menstrual cycle. Another sex hormone is needed for preparing the uterus for implantation of the ovum, this hormone is progesterone.
Hormones are needed throughout the body for various functions, however, just as important as these function is the regulation and control of these steroids.
Sex hormones are synthesized in testicles, 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 testicles.
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.
The main androgen is testosterone. Its synthesis is regulated by the luteinizing hormone. Testosterone forms the secondary sexual features in males.
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.
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: - decrease the activity of lipid tissue lipase;
- regulate the calcium metabolism in muscle tissue and as result effect on the contraction and relaxation of muscles;
- inhibit the gastric secretion;
- stimulate the formation of steroids.
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.
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.
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