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.

Structure of Intracellular Receptors

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:

• The amino-terminus: In most cases, this region is involved in activating or stimulating transcription by interacting with other components of the transcriptional machinery. The sequence is highly variable among different receptors.
• DNA binding domain: Amino acids in this region are responsible for binding of the receptor to specific sequences of DNA.
• The carboxy-terminus or ligand-binding domain: This is the region that binds hormone.

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.

Hormone-Receptor Binding and Interactions with 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:

• Receptor activation is the term used to describe conformational changes in the receptor induced by binding hormone. The major consequence of activation is that the receptor becomes competent to bind DNA.
• Activated receptors bind to "hormone response elements", which are short specific sequences of DNA which are located in promoters of hormone-responsive genes. In most cases, hormone-receptor complexes bind DNA in pairs, as shown in the figure below.
• Transcription from those genes to which the receptor is bound is affected. Most commonly, receptor binding stimulates transcription. The hormone-receptor complex thus functions as a transcription factor.

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

Glucocorticoids

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:

• Stimulation of gluconeogenesis, particularly in the liver: This pathway results in the synthesis of glucose from non- hexose substrates such as amino acids and glycerol from triglyceride breakdown, and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best-known metabolic function of glucocorticoids.

• Mobilization of amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis.

• Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose.

• Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis.

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 (8 A.M.): 6-28 mg/dL; adults (4 P.M.): 2-12 mg/dL

· child one to six years (8 A.M.): 3-21 mg/dL; child one to six years (4 P.M.): 3-10 mg/dL

· 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 1932, a physician by the name of Harvey Cushing described eight patients with central body obesity, glucose intolerance, hypertension, excess hair growth, osteoporosis, kidney stones, menstrual irregularity, and emotional liability. It is now known that these symptoms are the result of excess production of cortisol by the adrenal glands. Cortisol is a powerful steroid hormone, and excess cortisol has detrimental effects on many cells throughout the body. Although some of these symptoms are common by themselves, the combination of these suggests that a workup for this disease may be in order. Keep in mind that Cushings syndrome is rare, occurring in only about 10 patients per one million population. On the other hand, simple obesity can be associated with some of these symptoms in the absence of an adrenal tumor--this is related to the slightly different mechanism by which normally produced steroids are metabolized by individuals who are obese.

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.

. Mineralocorticoids 

Primary aldosteronism

Conn's syndrome is an aldosterone-producing adenoma. Conn's syndrome is named after Jerome W. Conn (1907–1994), the Americanendocrinologist who first described the condition at the University of Michigan in 1955.

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

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

Coagulation

· Increase circulating level of factors 2, 7, 9, 10, plasminogen

· Decrease antithrombin III

· Increase platelet adhesiveness

Lipid

· Increase HDL, triglyceride

· Decrease LDL, fat deposition

Fluid balance

· Salt (sodium) and water retention

· Increase cortisol, SHBG

Gastrointestinal tract

· Reduce bowel motility

· Increase cholesterol in bile

Melanin

· Increase pheomelanin, reduce eumelanin

Cancer

· Support hormone-sensitive breast cancers (see section below)

Lung function

· Promotes lung function by supporting alveoli (in rodents but probably in humans).

Uterus lining

· Estrogen together with progesterone promotes and maintains the uterus lining in preparation for implantation of fertilized egg and maintenance of uterus function during gestation period, also upregulates oxytocin receptor in myometrium

Ovulation

· Surge in estrogen level induces the release of luteinizing hormone, which then triggers ovulation by releasing the egg from the Graafian follicle in the ovary.

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

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.

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 Desna cell - release around JGA→Renin .

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.

Local renin-angiotensin systems

Locally expressed renin-angiotensin systems have been found in a number of tissues, including the kidneys, adrenal glands, the heart, vasculature and nervous system, and have a variety of functions, including local cardiovascular regulation, in association or independently of the systemic renin-angiotensin system, as well as non-cardiovascular functions. Outside the kidneys, renin is predominantly picked up from the circulation but may be secreted locally in some tissues; its precursor prorenin is highly expressed in tissues and more than half of circulating prorenin is of extrarenal origin, but its physiological role besides serving as precursor to renin is still unclear.Outside the liver, angiotensinogen is picked up from the circulation or expressed locally in some tissues; with renin they form angiotensin I, and locally expressed angiotensin converting enzyme, chymase or other enzymes can transform it into angiotensin II. This process can be intracellular or interstitial.

In the adrenal glands, it is likely involved in the paracrine regulation of aldosterone secretion, in the heart and vasculature, it may be involved in remodeling or vascular tone, and in the brain where it is largely independent of the circulatory RAS, it may be involved in local blood pressure regulation. In addition, both the central and peripheral nervous systems can use angiotensin for sympathetic neurotransmision. Other places of expression include the reproductive system, the skin and digestive organs. Medications aimed at the systemic system may affect the expression of those local systems, beneficially or adversely.

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.