Investigation of thyroid hormones in the regulation of metabolism. Hormonal regulation of calsium and phosphorus homeostasis.
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.
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. 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
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.
Common signs of hyperthyroidism are basically the opposite of those seen in hypothyroidism, and include nervousness, insomnia, high heart rate, eye disease and anxiety. Graves disease is commonly treated with anti-thyroid drugs (e.g. propylthiourea, methimazole), which suppress synthesis of thyroid hormones primarily by interfering with iodination of thyroglobulin by thyroid peroxidase.
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.
· 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.
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 1 mM, or 10,000 times the basal concentration of free calcium within cells. Also, the concentration of phosphorus in blood is essentially identical to that of 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.
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.
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.
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.
· 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).
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!"
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 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.
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.
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.
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.
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.
Hyperfunction of adrenal cortex causes Icenko-Kushing syndrome. This state is called steroid diabetes. Symptoms: hyperglycemia, glucosuria, hypercholesterolemia, hypernatriemia, hyperchloremia, hypokaliemia.
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).
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.
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.
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.
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.
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.
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 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.
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 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.
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, 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.
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.
· 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
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 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.
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.
· 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.
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.
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 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.
- 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.
- 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.
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.
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.
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.
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 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.