Clinical Chemistry - 17 Hormones

CLINICAL CHEMISTRY HORMONES PRODUCES BY ENDOCRINE GLANDS OUTLINE • Hormones Produced by Endocrine Glands o Hypothalamus o Anterior Pituitary Gland o Posterior Pituitary Gland o Thyroid Gland o Parathyroid Gland o Adrenal Gland o Adrenal Cortex o Adrenal Medulla o Pancreas o Testes o Ovary o Miscellaneous Hormones HORMONES PRODUCED BY ENDOCRINE GLANDS HORMONES PRODUCED BY THE HYPOTHALAMUS GONADOTROPHIN-RELEASING HORMONE (GnRH) • Also known as Luteinizing-hormone releasing hormone (LHRH) • It is a tropic peptide hormone responsible for the release of FSH and LH from the anterior pituitary. • GnRH is synthesized and released from neurons within the hypothalamus. • Control of FSH and LH o At the pituitary, GNRH stimulates the synthesis and secretion of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These processes are controlled by the size and frequency of GNRH pulses, as well as by feedback from androgens and estrogens. Low frequency GNRH pulses lead to FSH release, whereas high frequency GNRH pulses stimulate LH release. • Activity o GNRH activity is very low during childhood, and is activated at puberty. During the reproductive years, pulse activity is critical for successful reproductive function as controlled by feedback loops. However, once a pregnancy is established, GNRH activity is not required. o Elevated prolactin levels decrease GNRH activity. In contrast, hyperinsulinemia increases pulse activity leading to disorderly LH and FSH activity. GNRH formation is congenitally absent in Kallmann syndrome. THYROTROPIN-RELEASING HORMONE (TRH) • Also called thyrotropin-releasing factor (TRF), thyroliberin or protirelin • It is a tropic tripeptide hormone that stimulates the release of thyroid-stimulating hormone and prolactin by the anterior pituitary. • Clinical significance o It is used in pharmacology (brand name Relefact TRH) to test the response of the anterior pituitary gland. o Medical preparations of TRH are used in diagnostic tests of thyroid disorders and in acromegaly DOPAMINE • It is a neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. • Dopamine is also a neurohormone released by the hypothalamus. Its main function as a hormone is to inhibit the release of prolactin from the anterior lobe of the pituitary. • Dopamine can be supplied as a medication that acts on the sympathetic nervous system, producing effects such as increased heart rate and blood pressure. • However, because dopamine cannot cross the blood-brain barrier, dopamine given as a drug does not directly affect the central nervous system. To increase the amount of dopamine in the brains of patients with diseases such as Parkinson's disease and dopa-responsive dystonia, L-DOPA (levodopa), which is the precursor of dopamine, can be given because it can cross the blood-brain barrier • Functions in the brain o Dopamine has many functions in the brain, including important roles in behavior and cognition, voluntary movement, motivation and reward, inhibition of prolactin production (involved in lactation), sleep, mood, attention, and learning CORTICOTROPIN-RELEASING HORMONE (CRH) • Originally named corticotropin-releasing factor (CRF), and also called corticoliberin, is a polypeptidehormone and neurotransmitter involved in the stress response. • Marked reduction in CRH has been observed in association with Alzheimer's disease, andautosomal recessive hypothalamic corticotropin deficiency has multiple and potentially-fatal metabolicconsequences including hypoglycemia and hepatitis. • In addition to being produced in the hypothalamus, CRH is also synthesized in peripheral tissues, suchas T lymphocytes, and is highly expressed in the placenta. In the placenta, CRH is a marker thatdetermines the length of gestation and the timing of parturition and delivery. GROWTH HORMONE-RELEASING HORMONE (GHRH) • Also known as Growth-hormone-releasing factor (GRF or GHRF) or somatocrinin, is a releasing hormone for growth hormone. • GHRH first appears in the human hypothalamus between 18 and 29 weeks of gestation, which corresponds to the start of production of growth hormone and other somatotropes in fetuses. • Effect o GHRH stimulates GH production and release by binding to the GHRH Receptor (GHRHR) on cells in the anterior pituitary. HORMONES PRODUCED BY THE ANTERIOR PITUITARY GLAND (ADENOHYPOPHYSIS) ANTERIOR PITUITARY GLAND • “True Endocrine Gland” • The hormones secreted are either peptides or glycoproteins • ACTH, TSH, FSH and LH = Tropic hormones

• 5 Types of cells by Immunochemical Tests : o Somatotropes – secrete GH o Lactotropes – secrete prolactin o Thyrotropes – secrete TSH o Gonadotropes – secrete LH and FSH o Corticotropes – secrete ACTH GROWTH HORMONE (GH) OR SOMATOTROPIN • Growth hormone (GH) is a Protein Poly-peptide hormone. • Most abundant of all pituitary hormones • It stimulates growth and cell reproduction and regeneration in humans and other animals. • Controlled by GHRH and Somatostatin • Structurally similar to prolactin and human placental lactogen • Markedly elevated during sleep (deep sleep) • The overall metabolic effect is to metabolize fat stores while conserving glucose • Growth hormone is used clinically to treat children's growth disorders and adult growth hormone deficiency. In recent years, replacement therapies with human growth hormones (HGH) have become popular in the battle against aging and weight management. • Reported effects include decreased body fat, increased muscle mass, increased bone density, increased energy levels, improved skin tone and texture, increased sexual function and improved immune system function. • At this time HGH is still considered a very complex hormone and many of its functions are still unknown. • Specimen requirement: fasting serum, complete rest for 30 minutes before collection • Reference Interval: below 1 ng/ml (<1g/L) • Stimulators of GH secretion include : o peptide hormones o Growth hormone releasing hormone (GHRH also known as somatocrinin) through binding to the growth hormone releasing hormone receptor (GHRHR) o sex hormones o increased androgen secretion during puberty (in males from testis and in females from adrenal cortex) o estrogen o clonidine and L-DOPA by stimulating GHRH release o hypoglycaemia, arginine and propranolol by inhibiting somatostatin release o deep sleep o fasting o vigorous exercise • Inhibitors of GH secretion include : o somatostatin from the periventricular nucleus o hyperglycemia o glucocorticoids • Growth hormone has many other effects on the body: o Increases calcium retention, and strengthens and increases the mineralization of bone o Increases muscle mass through sarcomere hyperplasia o Promotes lipolysis o Increases protein synthesis o Stimulates the growth of all internal organs excluding the brain o Plays a role in fuel homeostasis o Reduces liver uptake of glucose o Promotes gluconeogenesis in the liver o Contributes to the maintenance and function of pancreatic islets o Stimulates the immune system • Excesses o Prolonged GH excess thickens the bones of the jaw, fingers and toes. Resulting heaviness of the jaw and increased thickness of digits is referred to as acromegaly (>50 ng/ml). Accompanying problems can include pressure on nerves, muscle weakness, insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function. o The excessive GH can cause excessive growth, traditionally referred to as pituitary gigantism. o Exercise and fasting (burst of GH secretion occur) o Liver disease o Renal disease o Anorexia nervosa • Deficiencies o The effects of growth hormone deficiency vary depending on the age at which they occur. o In children, growth failure and short stature are the major manifestations of GH deficiency, with common causes including genetic conditions and congenital malformations. o It can also cause delayed sexual maturity. o In adults, deficiency is rare o Adults with GHD present with non-specific problems including truncal obesity with a relative decrease in muscle mass and, in many instances, decreased energy and quality of life. FOLLICLE-STIMULATING HORMONE (FSH) • Synthesized and secreted by gonadotropes • FSH regulates the development, growth, pubertal maturation, and reproductive processes of the human body. FSH and Luteinizing hormone (LH) act synergistically in reproduction. • Important markers in diagnosing fertility and menstrual cycle disorders • Structure o FSH is a glycoprotein. o Its structure is similar to those of LH, TSH, and hCG o The sugar part of the hormone is composed of fucose, galactose, mannose, galactosamine, glucosamine, and sialic acid • Activity o FSH regulates the development, growth, pubertal maturation, & reproductive processes of human body. o In both males and females, FSH stimulates the maturation of germ cells. o Like its partner, LH, FSH release at the pituitary gland is controlled by pulses of gonadotropin-releasing hormone (GnRH). • Disease states o FSH levels are normally low during childhood and, in females, high after menopause o High FSH levels ▪ High levels of Follicle-Stimulating Hormone are indicative of situations where the normal restricting feedback from the gonad is absent, leading to an unrestricted pituitary FSH production. Whereas this is normal in females leading up to and during postmenopause, it is abnormal during the reproductive years.

▪ If the FSH level is high during the reproductive years, this may be a sign of: o Premature menopause also known as Premature Ovarian Failure o Poor ovarian reserve also known as Premature Ovarian Aging o Gonadal dysgenesis, Turner syndrome o Castration o Swyer syndrome o Testicular failure. o Low FSH levels ▪ Diminished secretion of FSH can result in failure of gonadal function (hypogonadism). This condition is typically manifested in males as failure in production of normal numbers of sperm. ▪ In females, cessation of reproductive cycles is commonly observed. Conditions with very low FSH secretions are: • Polycystic Ovarian Syndrome • Polycystic Ovarian Syndrome + Obesity + Hirsutism + Infertility • Kallmann syndrome • Hypothalamic suppression • Hypopituitarism • Hyperprolactinemia • Gonadotropin deficiency LUTEINIZING HORMONE (LH) • Also known as lutropin is a hormone produced by the anterior pituitary gland. • In the female, an acute rise of LH – the LH surge – triggers ovulation. • In the male, where LH had also been called Interstitial Cell Stimulating Hormone (ICSH), it stimulates Leydig cell production of testosterone. • Important markers in diagnosing fertility and menstrual cycle disorders • The release of LH at the pituitary gland is controlled by pulses of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Those pulses, in turn, are subject to the estrogen feedback from the gonads. • Normal levels o LH levels are normally low during childhood and, in women, high after menopause. • High LH levels o Persistently high LH levels are indicative of situations where the normal restricting feedback from the gonad is absent, leading to a pituitary production of both LH and FSH. While this is typical in the menopause, it is abnormal in the reproductive years. There it may be a sign of: ▪ Premature menopause ▪ Gonadal dysgenesis, Turner syndrome ▪ Castration ▪ Swyer syndrome ▪ Polycystic Ovary Syndrome ▪ Testicular failure • Deficient LH activity o Diminished secretion of LH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. o In females, amenorrhea is commonly observed. Conditions with very low LH secretions are: ▪ Kallmann syndrome ▪ Hypothalamic suppression ▪ Hypopituitarism ▪ Eating disorder ▪ Hyperprolactinemia ▪ Gonadotropin deficiency THYROID-STIMULATING HORMONE (TSH) • Also known as thyrotropin is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland which regulates the endocrine function of the thyroid gland • Controlling the rate of release o TSH stimulates the thyroid gland to secrete the hormones thyroxine (T4) and triiodothyronine (T3). o TSH production is controlled by a Thyrotropin Releasing Hormone, (TRH), which is manufactured in the hypothalamus and transported to the anterior pituitary gland, where it increases TSH production and release. Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release. • Diagnostic use o TSH levels are tested in the blood of patients suspected of suffering from excess (hyperthyroidism), or deficiency (hypothyroidism) of thyroid hormone. o Generally, a standard reference range for TSH for adults is between 0.4 and 5.0 uIU/mL (equivalent to mIU/L), but values vary slightly among labs ADRENOCORTICOTROPIC HORMONE (ACTH) • Also known as corticotropin is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. • It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress (along with corticotropin-releasing hormone from the hypothalamus). • Its principal effects are increased production of androgens and, as its name suggests, cortisol from the adrenal cortex. • Highest level is between 6-8AM; lowest level is bet. 6-11PM • Specimen for testing should not be allowed to have contact with glass because ACTH adheres to glass surface causing a decreased level, instead it should be placed in a prechilled polysterene tubes • ACTH acts at several key steps to influence adrenal cortex: o ACTH stimulates lipoprotein uptake into cortical cells. This increases the bio-availability of cholesterol in the cells of the adrenal cortex. o ACTH increases the transport of cholesterol into the mitochondria and activates its hydrolysis. • Associated conditions (increased) o Addison's disease o Small cell carcinoma (a common cause of ACTH secreted ectopically) o Adrenoleukodystrophy o Congenital adrenal hyperplasia o Cushing's syndrome o Nelson's syndrome

PROLACTIN • Also known as Luteotropic hormone (LTH) is a peptide hormone primarily associated with lactation. • In breastfeeding, the act of an infant suckling the nipple stimulates the production of prolactin, which fills the breast with milk via a process called lactogenesis, in preparation for the next feed. Oxytocin, another hormone, is also released, which triggers milk let-down. • Pituitary lactogenic hormone, a stress hormone, a direct effector hormone • Structurally similar to GH • It also acts in conjunction with estrogen and progesterone to promote breast tissue development • Dopamine is its main inhibitory factor • Specimen requirement: blood should be collected 3-4 hours after the individual has awakened; fasting sample • Effects o Prolactin has many effects including regulating lactation, orgasms, and stimulating proliferation of oligodendrocyte precursor cells. o It stimulates the mammary glands to produce milk (lactation): Increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands of the breasts and increases the production of milk. o Prolactin provides the body with sexual gratification after sexual acts: The hormone counteracts the effect of dopamine, which is responsible for sexual arousal. This is thought to cause the sexual refractory period. The amount of prolactin can be an indicator for the amount of sexual satisfaction and relaxation. o Unusually high amounts are suspected to be responsible for impotence and loss of libido. o Prolactin also has a number of other effects including contributing to surfactant synthesis of the fetal lungs at the end of the pregnancy and immune tolerance of the fetus by the maternal organism during pregnancy; it also decreases normal levels of sex hormones — estrogen in women and testosterone in men. • Diagnostic use o Prolactin levels may be checked as part of a sex hormone workup, as elevated prolactin secretion can suppress the secretion of FSH and GnRH, leading to hypogonadism, and sometimes causing erectile dysfunction in men. o Prolactin levels may be of some use in distinguishing epileptic seizures from psychogenic non-epileptic seizures. The serum prolactin level usually rises following an epileptic seizure • Conditions associated with elevated prolactin secretion o Hyperprolactinaemia is the term given to having too-high levels of prolactin in the blood. o Prolactinoma o Excess thyrotropin-releasing hormone (TRH), usually in primary hypothyroidism o Many anti-psychotic medications o Emotional stress o Pregnancy and Lactation. • Conditions associated with decreased prolactin o Bulimia o Excess dopamine MELANOCYTE-STIMULATING HORMONE (MSH) • The melanocyte-stimulating hormones (collectively referred to as MSH or intermedins) are a class of peptide hormones that in nature are produced by cells in the intermediate lobe of the pituitary gland. • They stimulate the production and release of melanin (melanogenesis) by melanocytes in skin and hair. • MSH is produced in the anterior pituitary. MSH released into the brain has effects on appetite and sexual arousal. • Melanocyte-stimulating hormone increases in humans during pregnancy. This, along with increased estrogens, causes increased pigmentation in pregnant women. • In Cushing's disease high levels of adrenocorticotropic hormone (ACTH) production also leads to high MSH levels, which cause an abnormal darkening. ENDORPHIN • Endorphins are endogenous opioid polypeptide compounds. They are produced by the pituitary gland and the hypothalamus in vertebrates during strenuous exercise, excitement, pain and orgasm, and they resemble the opiates in their abilities to produce analgesia and a sense of well-being. • Endorphins work as "natural pain relievers", whose effects may be enhanced by other medications. • The term endorphin rush has been adopted in popular speech to refer to feelings of exhilaration brought on by pain, danger, or other forms of stress, supposedly due to the influence of endorphins. • When a nerve impulse reaches the spinal cord, endorphins are released which prevent nerve cells from releasing more pain signals. Immediately after injury, endorphins allow humans to feel a sense of power and control over themselves that allows them to persist with activity for an extended time LIPOTROPIN • Lipotropin is a hormone produced by the cleavage of pro-opiomelanocortin (POMC). The anterior pituitary gland produces the pro-hormone POMC, which undergoes cleavage to adrenocorticotropin (ACTH) and β-lipotropin (β-LPH). • Beta-lipotropin o Fragment of POMC. o It stimulates melanocytes to produce melanin, and can also be cleaved into smaller peptides. HORMONES PRODUCED BY THE POSTERIOR PITUITARY GLAND (NEUROHYPOPHYSIS) POSTERIOR PITUITARY GLAND • Capable of releasing hormone but not capable of producing it. • The hormones released are synthesized in the supraoptic (ADH) and paraventricular nuclei (oxytocin) of the hypothalamus • The release of these hormones occurs in response to serum osmolality or by suckling • Hormones produces are controlled by the CNS

VASOPRESSIN • Arginine vasopressin (AVP), also known as vasopressin, argipressin or antidiuretic hormone (ADH) • Vasopressin is a peptide hormone. It is derived from a preprohormone precursor that is synthesized in the hypothalamus and stored in vesicles at the posterior pituitary. Most of it is stored in the posterior pituitary to be released into the blood stream; however, some of it is also released directly into the brain. • It is a nonapeptide that acts on the DCT and collecting tubule of the nephron • It decreases production of urine by promoting reabsorption of water by the renal tubules (maintains water homeostasis) • Osmolality of blood is principal regulator of ADH secretion • A decreased in blood volume or blood pressure will stimulate ADH release • It is a potent pressor agent and affects blood clotting by promoting Factor VII release from the hepatocytes and vWF release from the endothelium • Function o One of the most important roles of AVP is to regulate the body's retention of water; it is released when the body is dehydrated and causes the kidneys to conserve water, thus concentrating the urine, and reducing urine volume. o In high concentrations, it also raises blood pressure by inducing moderate vasoconstriction. • Kidney o Vasopressin has three effects by which it contributes to increased urine osmolarity (increased concentration), and decreased urine excretion. These are: o It increases the permeability to water of the distal convoluted tubules and collecting tubules in the nephrons of kidneys and thus allows water reabsorption and excretion of a smaller volume of concentrated urine - antidiuresis. o ADH's second effect on the kidney is to increase the permeability of the papillary portion of the collecting duct to urea, allowing increased reabsorption of urea into the medullary interstitium, down the concentration gradient created from the removal of water in the cortical collecting duct. o The third effect that AVP has on the kidney is that it stimulates sodium reabsorption in the thickascending loop of Henle by increasing the activity of the Na+-K+-2Cl--cotransporter. • Cardiovascular system o Vasopressin increases peripheral vascular resistance and thus increases arterial blood pressure. This effect appears small in healthy individuals; however it becomes an important compensatory mechanism for restoring blood pressure in hypovolemic shock such as occurs during hemorrhage. • Central nervous system (CNS) o Vasopressin released within the brain has many actions: o It has been implicated in memory formation, including delayed reflexes, image, short- and long-term memory, though the mechanism remains unknown, and these findings are controversial. o Vasopressin released from centrally-projecting hypothalamic neurons is involved in aggression, blood pressure regulation and temperature regulation. • Control o Vasopressin is secreted from the posterior pituitary gland in response to reductions in plasma volume, in response to increases in the plasma osmolality, and in response to cholecystokinin by the small intestine: ▪ Secretion in response to reduced plasma volume is activated by pressure receptors in the veins, atria, and carotids. ▪ Secretion in response to increases in plasma osmotic pressure is mediated by osmoreceptors in the hypothalamus ▪ Secretion in response to increases in plasma Cholecystokinin is mediated by an unknown pathway. o Many factors influence the secretion of vasopressin: ▪ Ethanol (alcohol) acts as an antagonist for AVP in the collecting ducts of the kidneys, which prevents aquaporins from binding to the collecting ducts, and prevents water reabsorption. ▪ Angiotensin II may stimulate secretion of AVP. • Secretion o The main stimulus for secretion of vasopressin is increased osmolality of plasma. Reduced volume of extracellular fluid also has this effect, but is a less sensitive mechanism. • Role in disease o Decreased vasopressin release or decreased renal sensitivity to AVP leads to diabetes insipidus, a condition featuring hypernatremia (increased blood sodium concentration), polyuria (excess urine production), and polydypsia (thirst). o Diabetes Insipidus o True Diabetes insipidus ((Hypothalamic/Neurogenic/Cranial/Central Diabetes Insipidus) ▪ Deficiency of ADH with normal ADH receptor ▪ Failure of the pituitary gland to secrete ADH ▪ Large volume of urine excreted (3-20 L/day) o Nephrogenic Diabetes insipidus ▪ Normal ADH but abnormal ADH receptor ▪ Failure of the kidney to respond to normal or elevated ADH levels ▪ High levels of AVP secretion ▪ Syndrome of inappropriate antidiuretic hormone (SIADH) and resultant hyponatremia (low blood sodium levels) occurs in brain diseases and conditions of the lungs (Small cell lung carcinoma). o Medications such as carbamazipine, clofibrate, vinca alkaloids o Physiologic stimuli such as nausea, pregnancy, hypoglycemia and hypoxia • Analytical Methods o Direct measurement of ADH ▪ Urine immunoassay ▪ Serum immunoassay (RIA) + extraction prodecure ▪ Serum/urine osmolality o Test for SIADH secretion ▪ Serum electrolyte determination ▪ Water load test to evaluate patient’s ability to suppress ADH secretion o Test for Diabetes Insipidus ▪ Dehydration test – restricting water intake to test the ability to concentrate the urine and to respond to ADH

OXYTOCIN • It is a mammalian hormone that also acts as a neurotransmitter in the brain. • It is best known for its roles in female reproduction: it is released in large amounts after distension of the cervix and vagina during labor, and after stimulation of the nipples, facilitating birth and breastfeeding, respectively. • Recent studies have begun to investigate oxytocin's role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, trust, love, and maternal behaviors. • Synthesis, storage and release o Oxytocin is made in magnocellular neurosecretory cells of the supraoptic and paraventricular nuclei of the hypothalamus and is stored in Herring bodies at the axon terminals in the posterior pituitary. o It is then released into the blood from the posterior lobe (neurohypophysis) of the pituitary gland. o Oxytocin is also made by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord. • Actions o Letdown reflex – in lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be 'let down' into a collecting chamber, from where it can be extracted by compressing the areola and sucking at the nipple. Sucking by the infant at the nipple is relayed by spinal nerves to the hypothalamus. o Uterine contraction – important for cervical dilation before birth and causes contractions during the second and third stages of labor. Oxytocin release during breastfeeding causes mild but often painful uterine contractions during the first few weeks of lactation. This also serves to assist the uterus in clotting the placental attachment point postpartum. o Due to its similarity to vasopressin, it can reduce the excretion of urine slightly. More importantly, in several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and in humans, high doses of oxytocin can result in hyponatremia. o Modulation of hypothalamic-pituitary-adrenal axis activity. Oxytocin, under certain circumstances, indirectly inhibits release of adrenocorticotropic hormone and cortisol and, in those situations, may be considered an antagonist of vasopressin. • Potential adverse reactions o Oxytocin is relatively safe when used at recommended doses. Potential side effects include: o Central nervous system : Subarachnoid hemorrhage, seizures. o Cardiovascular : Increased heart rate, decreased blood pressure, systemic venous return, cardiac output, and arrhythmias. o Genitourinary : Impaired uterine blood flow, pelvic hematoma, tetanic uterine contractions, uterine rupture, postpartum hemorrhage. HORMONES PRODUCED BY THE THYROID GLAND THYROID GLAND • Butterfly-shaped gland • It is consists of two lobes (one on either side of the trachea) located in the lower part of the neck just below the larynx (voicebox) • The lobes are connected by a narrow band called isthmus • By 11 weeks of gestation, the gland begins to produce measurable amounts of hormone • Follicle – is the fundamental structural unit of the thyroid gland o Follicular cells (T3 and T4) o Parafolllicular cells or C cells (Calcitonin) • Functions of Thyroid Hormones o For tissue growth o Form development of the CNS o Elevated heat production o Increased oxygen consumption • The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are tyrosine-based hormones produced by the thyroid gland. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half life than T3. The ratio of T4 to T3 released in the blood is roughly 20 to 1. Thyroxine is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5'-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). TRIIODOTHYRONINE (T3) • Also known as the 3,5,3’ triiodothyronine • It has the most active throid hormonal activity • Almost 80% is produced from the tissue deiodination of T4 • The principal application of this hormone is in diagnosing T3 thyrotoxicosis • Better indicator of recovery from hyperthyroidism as well as the recognition of recurrence of hyperthyroidism • An increase in the concentration of T3 is the first abnormally seen in cases of hyperthyroidism TETRAIODOTHYRONINE (T4) • Also known as 3,5,3’5’ tetraiodothyronine • Principal secretory product • A prohormone for T3 production • All circulating T4 originates in the thyroid gland • The amount of serum T4 is a good indicator of the thyroid secretory rate CIRCULATION • Most of the thyroid hormone circulating in the blood is bound to transport proteins. Only a very small fraction of the circulating hormone is free (unbound) and biologically active, hence measuring concentrations of free thyroid hormones is of great diagnostic value. • When thyroid hormone is bound, it is not active, so the amount of free T3/T4 is what is important. For this reason, measuring total thyroxine in the blood can be misleading

THYROID HORMONE BINDING PROTEINS • Thyroxine-Binding Globin (TBG) o Transports 70-75% of total T4 o Affinity for T3 is lower than T4 • Thyroxine-Binding Prealbumin (Transthyetin) o Transports 15-20% of total T4 o T3 has no affinity for prealbumin • Thyroxine-Binding Albumin o Transports most of the T3 o Transports 10% of total T4 RELATED DISEASES: HYPERTHYROIDISM • Thyrotoxicosis o Is applied to a group of syndromes caused by high levels of free thyroid hormones in the circulation o TSH is low, FT4 is normal but increased FT3-T3 thyrotoxicosis or Plummer’s disease • Grave’s disease (diffuse toxic goiter) o The most common cause of thyrotoxicosis; autoimmune disease o It occurs 6x more commonly in women than in men o Caused by circulating antibodies to TSH receptor o Features: exophthalmos (bulging eye), pritibial myxedema • Riedel’s thyroiditis o The thyroid turns into a woody or stony-hard mass • Subclinical hyperthyroidism o Showing no clinical symptoms but TSH is low and FT3 and FT4 are normal • Secondary (pituitary) hyperthyroidism o Increased TSH and FT4 • Subacute granulomatous/Subacute nonsuppurative thyroiditis/De Quervain’s thyroiditis (painful thyroiditis) o Associated with neck pain, low grade fever and swings in thyroid function tests o Thyroidal peroxidaxe (TPO) antibodies are absent, ESR and thyroblobulin levels are elevated RELATED DISEASES: HYPOTHYROIDISM • Primary hypothyroidism o Primarily due to deficiency of elemental iodine o It is also caused by destruction or ablation of the thyroid gland o Other causes: surgical removal of the gland; used of radioactive iodine for hyperthyroidism treatment; radiation exposure; drugs such as lithium o Hashimoto’s disease ▪ Chronic autoimmune thryroiditis ▪ Most common cause of primary hypothyroidism ▪ Associated with enlargement of the thyroid gland (goiter) ▪ Method for testing: TPO antibody test = (+) result o Myxedema ▪ Describes peculiar nonpitting swelling of the skin ▪ The skin becomes infiltrated by mucopolysaccharides ▪ Clinical features: puffy face, weight gain, slow speech, eyebrows thinned, dry and yellow skin, anemia ▪ Myxedema coma – severe form of primary thyroidism • Secondary hypothyroidism o Due to pituitary destruction of pituitary adenoma o T3 and T4 low levels, TSH is also decreased • Tertiary hypothyroidsm o Due to hypothalamic disease, T3 and T4 low levels, TSH is also decreased • Congenital hypothyroidism/Cretinism o Defects in the development of function of the gland o Screening test: TT4 (decreased) o Confirmatory test: TSH (increased) • Effect of iodine deficiency on thyroid hormone synthesis o If there is a deficiency of dietary iodine, the thyroid will not be able to make thyroid hormone. The lack of thyroid hormone will lead to decreased negative feedback on the pituitary, leading to increased production of thyroid stimulating hormone, which causes the thyroid to enlarge (goiter) endemic colloid goiter. This has the effect of increasing the thyroid's ability to trap more iodide, compensating for the iodine deficiency and allowing it to produce adequate amounts of thyroid hormone. EFFECTS OF THYROXINE • Increases cardiac output • Increases heart rate • Increases ventilation rate • Increases basal metabolic rate • Potentiates the effects of catecholamines (i.e increases sympathetic activity) • Potentiates brain development • Thickens endometrium in females CALCITONIN • Hormone that is produced in humans primarily by the parafollicular cells (also known as C-cells) of the thyroid, and in many other animals in the ultimobranchial body. • It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH). • It has been found in fish, reptiles, birds, and mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant to regulation of normal calcium homeostasis. • Physiology o The hormone participates in calcium (Ca2+) and phosphorus metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH). o To be specific, calcitonin affects blood Ca2+ levels in three ways: ▪ Inhibits Ca2+ absorption by the intestines ▪ Inhibits osteoclast activity in bones ▪ Inhibits phosphate reabsorption by the kidney tubules ▪ Increases absolute Ca2+ and Mg+ reabsorption by the kidney tubules, calcitonin is a renal Caconserving hormone. o Secretion of calcitonin is stimulated by: ▪ an increase in serum [Ca2+] ▪ gastrin and pentagastrin

HORMONES PRODUCED BY THE PARATHYROID GLAND PARATHYROID GLAND • It is located on or near the thyroid capsule (region of the thyroid gland) sometimes within the thyroid gland • It may also be found outside their normal anatomic site – between the hyoid bone in the neck and mediastinum • Most people have 4 parathyroid glands but some have 8 or as few as 2 • Smallest endocrine gland in the body PARATHYROID HORMONE • Parathyroid hormone (PTH), parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84amino acids. • It acts to increase the concentration of calcium (Ca2+) in the blood, whereas calcitonin (a hormone produced by the parafollicular cells (C cells) of the thyroid gland) acts to decrease calcium concentration. (hypercalcemic hormone) – if calcium levels decrease, PTH is released • Preserves calcium and phosphate within normal range • PTH acts to increase the concentration of calcium in the blood by acting upon parathyroid hormone receptor in three parts of the body • Promotes bone resorption • Stimulates conversion of inactive vitamin D to activated vitamin D3 • Indirectly stimulates intestinal absorption of calcium • PTH half-life is approximately 4 minutes. It has a molecular mass of 9.4 kDa. • Functions o Regulation of serum calcium : Parathyroid hormone regulates serum calcium through its effects on the following tissues: ▪ Bone - It enhances the release of calcium from the large reservoir contained in the bones. Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their expression of Osteoprotegerin(OPG). OPG binds to RANKL and blocks it from interacting with RANK, a receptor for RANKL (Receptor activator of nuclear factor kappa-B ligand). The binding of RANKL to RANK (facilitated by the decreased amount of OPG) stimulates these osteoclast precursors to fuse, forming new osteoclasts which ultimately enhances bone resorption ▪ Kidney - It enhances active reabsorption of calcium and magnesium from distal tubules and the thick ascending limb. As bone is degraded both calcium and phosphate are released. It also greatly increases the excretion of phosphate, with a net loss in plasma phosphate concentration. By increasing the calcium:phosphate ratio more calcium is therefore free in the circulation ▪ Intestine via kidney - It enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D. Vitamin D activation occurs in the kidney. PTH up-regulates 25-hydroxyvitamin D3 1-alpha-hydroxylase, the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to its active form (1,25-dihydroxy vitamin D). This activated form of vitamin D increases the absorption of calcium (as Ca2+ ions) by the intestine via calbindin o Regulation of serum phosphate ▪ PTH reduces the reabsorption of phosphate from the proximal tubule of the kidney which means more phosphate is excreted through the urine. ▪ However, PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, which is mediated by an increase in activated vitamin D, the absorption of phosphate is not as dependent on vitamin D as is that of calcium. The end result is a small net drop in the serum concentration of phosphate o Vitamin D synthesis ▪ PTH increases the activity of 1- α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol to 1,25dihydroxycholecalciferol, the active form of vitamin D. • Stimulators o Decreased serum [Ca2+]. o Mild decreases in serum [Mg2+]. o An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense Calcium phosphate, triggering an increase in PTH) Inhibitors o Increased serum [Ca2+]. o Severe decreases in serum [Mg2+], which also produces symptoms of hypoparathyroidism (such as hypocalcemia) • Clinical Disorders: Hyperparathyroidism o Primary Hyperparathyroidism (physiologic effect lies with the PT gland) ▪ Most common cause of hypercalcemia ▪ Due to the presence of a functioning parathyroid adenoma ▪ Accompanied with phosphaturia ▪ If it is undetected, severe demineralization may occur o Secondary Hyperparathyroidism ▪ Develops in response to serum calcium ▪ There is diffuse hyperplasia of all 4 glands ▪ The patient develops severe bone disease ▪ Causes: vitamin D deficiency and chronic renal failure o Tertiary Hyperparathyroidism ▪ It occurs when patients with secondary hyperparathyroidism ▪ Develop autonomous function of the hyperplastic parathyroid glands or of a parathyroid adenoma ▪ The phosphate levels are normal to high; calcium phosphates in soft tissue

• Clinical Disorders: Hypoparathyroidism o Due to accidental injury to the PT glands during thyroid or neck surgery, removal of the glands with thyroid glands, or idiopathic atrophy o Other cause: autoimmune parathyroid destruction o Individuals are unable to maintain calcium concentration in blood without calcium supplementation HORMONES PRODUCED BY THE ADRENAL GLAND ADRENAL GLAND • Also known as suprarenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped • It is composed of distinct but conjoined glands, the outer adrenal cortex (yellow) and the inner adrenal medulla (dark mahogany) • They are chiefly responsible for releasing hormones in response to stress through the synthesis of corticosteroids such as cortisol and catecholamines such as epinephrine. • The adrenal glands affect kidney function through the secretion of aldosterone, a hormone involved in regulating the osmolarity of blood plasma. ADRENAL CORTEX • Outer region of the adrenal gland secreting the steroid hormone • Major site of steroid hormone production Layer Name Primary Product Most superficial cortical layer Zona glomerulosa Mineralocorticoids (aldosterone) Middle cortical layer Zona fasciculate Glucocorticoids (cortisol) Deepest cortical layer Zona reticularis Weak androgens MINERALOCORTICOIDS • They are produced in the zona glomerulosa. • The primary mineralocorticoid is aldosterone (most potent – electro regulating hormone). • Its secretion is regulated by the oligopeptide angiotensin II (angiotensin II is regulated by angiotensin I, which in turn is regulated by renin). • Aldosterone is secreted in response to high extracellular potassium levels, low extracellular sodium levels, and low fluid levels and blood volume. • Aldosterone affects metabolism in different ways: o It increases urinary excretion of potassium ions o It increases interstitial levels of sodium ions o It increases water retention and blood volume • Clinical Disorders : o Primar y hyperaldosteronism (Conn’s disease) ▪ Caused by Aldosterone-secreting adrenal adenoma ▪ Symptoms: HPN, hypokalemia, mild hypernatremia and metabolic alkalosis o Secondary hyperaldosteronism ▪ Occurs as a result of excessive production of rennin ▪ Liddle’s syndrome (pseudohyperaldosteronism) – resembles primary aldosteronism clinically but aldosterone level is low and absence of HPN ▪ Bartter’s syndrome (Bumetanide-sensitive chloride channel mutation) – elevated concentrations of Aldosterone and rennin ▪ Gitelman’s syndrome (Thiazide-sensitive transporter mutation) – increased aldosterone o Hypoaldosteronism ▪ Due to destruction of the adrenal glands and deficiency of glucocorticoid ▪ It is also associated with enzyme 21-hydroxylase deficiency ▪ Symptoms: hyperkalemia and metabolic acidosis GLUCOCORTICOIDS • They are produced in the zona fasciculata. • The primary glucocorticoid released by the adrenal gland in the human is cortisol and corticosterone in many other animals. • Its secretion is regulated by the hormone ACTH from the anterior pituitary. • Secretion is diurnal and is associated with a person’s sleep-wake cycle o High level in the early morning (6-8AM) and lowest at night (10PM-12AM) • Upon binding to its target, cortisol enhances metabolism in several ways: o It stimulates the release of amino acids from the body o It stimulates lipolysis, the breakdown of fat o It stimulates gluconeogenesis, the production of glucose from newly-released amino acids and lipids – resulting in hyperglycemia (anti-insulin effect) o It increases blood glucose levels in response to stress, by inhibiting glucose uptake into muscle and fat cells o It strengthens cardiac muscle contractions o It increases water retention o It has anti-inflammatory and anti-allergic effects • Clinical Disorders : o Hypercorticolism (Cushing’s syndrome) ▪ Is cause primarily by excessive production of cortisol and ACTH ▪ S/S: weight gain but with thin extremities (buffalo hump), hyperglycemia, thinning of the skin, poor wound healing, HPN, decreased WBC o Hypocorticolism ▪ Primary Hypocorticolism (Primary Adrenal Insufficiency) • Due to decreased cortisol production – 90% destruction of the adrenal cortex, Aldosterone deficiency, excess ACTH release • Disorders: Addison’s disease – hypotension, Hyponatremia, hyperkalemia, hyperpigmentation and darkening of the skin ▪ Secondary and Tertiary Hypocorticolism • Due to hypothalamic-pituitary insufficiency with loss of ACTH • No problem with mineralocorticoid secretion; absence of hyperpigmentation

ANDROGENS • They are produced in the zona reticularis. • Produce as by-product of cortical synthesis that are regulated by ACTH • Circulate bound to steroid hormone binding globulin (SHBG) • The most important androgens include: o Testosterone : a hormone with a wide variety of effects, ranging from enhancing muscle mass and stimulation of cell growth to the development of the secondary sex characteristics. o Dihydrotestosterone (DHT): a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors. o Androstenedione (Andro): 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. o Dehydroepiandrosterone (DHEA): It is the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or dehydroandrosterone. The reticularis also produces DHEAsulfatedue to the actions of a sulfotransferase, SULT2A1 HORMONES PRODUCED BY ADRENAL MEDULLA • The adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. • It is innermost part of adrenal gland, consisting of cells that secrete epinephrine (adrenaline), norepinephrine (noradrenaline), and a small amount of dopamine in response to stimulation by sympathetic preganglionic neurons. • Composed mainly of hormone-producing chromaffin cells, the adrenal medulla is the principal site of the conversion of the amino acid tyrosine into the catecholamines epinephrine, norepinephrine, and dopamine. EPINEPHRINE (ADRENALINE / SECONDARY AMINE) • Is a hormone and a neurotransmitter. • Most abundant medullary hormone • Called the “flight and fright hormone” because it is released in response to physiologic (injuries) or psychological (stress, anxiety) threats • Any form of stress that increases cortisol levels stimulates its production • It increases glucose concentration (glycogenolysis) • Functions : o increases heart rate o constricts blood vessels o dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system • Chemically, epinephrine is a catecholamine, a monoamine produced only by the adrenal glands from the amino acids phenylalanine and tyrosine • The term adrenaline is derived from the Latin roots ad- and renes and literally means "on the kidney", in reference to the adrenal gland's anatomic location on the kidney. • The Greek roots epi and nephros have similar meanings and give rise to epinephrine. The term epinephrine is often shortened to epi NOREPINEPHRINE (NORADRENALINE / PRIMARY AMINE) • Is a catecholamine with multiple roles including as a hormone and a neurotransmitter. • Areas of the body that produce or are affected by norepinephrine are described as noradrenergic. • One of the most important functions of norepinephrine is its role as the neurotransmitter released from the sympathetic neurons affecting the heart. An increase in norepinephrine from the sympathetic nervous system increases the rate of contractions • As a stress hormone, norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are controlled • Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. It increases the brain's oxygen supply • Norepinephrine can also suppress neuroinflammation when released diffusely in the brain from the locus coeruleus • When norepinephrine acts as a drug it increases blood pressure by increasing vascular tone through αadrenergic receptor activation. The resulting increase in vascular resistance triggers a compensatory reflex that overcomes its direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called reflex bradycardia. • Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase • It is released from the adrenal medulla into the blood as a hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous system where it is released from noradrenergic neurons in the locus coeruleus. • The actions of norepinephrine are carried out via the binding to adrenergic receptors DOPAMINE • A cathecolamine produced in the body by the decarboxylation of 3,4-dihydroxyphenylalanine (DOPA) • Present in highest concentration in the regions of the brain ENKEPHALIN • Produced by the chromaffin cells • Regulates pain • Clinical Disorders: o Pheochromocytoma ▪ Tumors of the adrenal medulla or sympathetic ganglia ▪ Commonly seen in 3rd to 5th decades of life ▪ Due to overproduction of cathecolamines ▪ Tachycardia, headache, tightness of chess, sweating and pallor o Neuroblastoma ▪ A fatal malignant condition in children resulting to excessive production of norepinephrine

HORMONES PRODUCED BY THE PANCREAS PANCREAS • Most important digestive gland in the Gastrointestinal system • Functions: o Exocrine ▪ Responsible for the synthesis of digestive enzyme o Endocrine ▪ Responsible for the synthesis of hormones INSULIN • A hormone central to regulating carbohydrate and fat metabolism in the body. • Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle. • Insulin stops the use of fat as an energy source by inhibiting the release of glucagon. With the exception of the metabolic disorder diabetes mellitus and Metabolic syndrome, insulin is provided within the body in a constant proportion to remove excess glucose from the blood, which otherwise would be toxic. When blood glucose levels fall below a certain level, the body begins to use fat as an energy source through glycogenolysis. • When control of insulin levels fails, diabetes mellitus will result. As a consequence, insulin is used medically to treat some forms of diabetes mellitus. Patients with type 1 diabetes depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. • Patients with type 2 diabetes are often insulin resistant and, because of such resistance, may suffer from a "relative" insulin deficiency. Some patients with type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately. Over 40% of those with Type 2 diabetes require insulin as part of their diabetes management plan. • Insulin also influences other body functions, such as vascular compliance and cognition. Once insulin enters the human brain, it enhances learning and memory and benefits verbal memory in particular. • It is produced in the islets of Langerhans in the pancreas. The name comes from the Latin insula for "island". Insulin's structure varies slightly between species of animals. Insulin from animal sources differs somewhat in "strength" (in carbohydrate metabolism control effects) in humans because of those variations. Porcine insulin is especially close to the human version. • Physiological Effects o The actions of insulin on the global human metabolism level include: ▪ Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about two-thirds of body cells) ▪ Increase of DNA replication and protein synthesis via control of amino acid uptake ▪ Modification of the activity of numerous enzymes o The actions of insulin (indirect and direct) on cells include: ▪ Increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin, which is directly useful in reducing high blood glucose levels as in diabetes. ▪ Increased lipid synthesis – insulin forces fat cells to take in blood lipids, which are converted to triglycerides; lack of insulin causes the reverse. ▪ Increased esterification of fatty acids – forces adipose tissue to make fats (i.e., triglycerides) from fatty acid esters; lack of insulin causes the reverse. ▪ Decreased proteolysis – decreasing the breakdown of protein ▪ Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse. ▪ Decreased gluconeogenesis – decreases production of glucose from nonsugar substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); lack of insulin causes glucose production from assorted substrates in the liver and elsewhere. ▪ Decreased autophagy - decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely ▪ Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption. ▪ Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood. This possible occurs via insulin-induced translocation of the Na+/K+-ATPase to the surface of skeletal muscle cells. ▪ Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in microarteries; lack of insulin reduces flow by allowing these muscles to contract. ▪ Increase in the secretion of hydrochloric acid by parietal cells in the stomach ▪ Decreased renal sodium excretion • Diseases and Syndromes o There are several conditions in which insulin disturbance is pathologic: o Diabetes mellitus – general term referring to all states characterized by hyperglycemia ▪ Type 1 – autoimmune-mediated destruction of insulin- producing β-cells in the pancreas, resulting in absolute insulin deficiency ▪ Type 2 – multifactoral syndrome with combined influence of genetic susceptibility and influence of environmental factors, the best known being obesity, age, and physical inactivity, resulting ininsulin resistance in cells requiring insulin for glucose absorption. This form of diabetes is strongly inherited.

o Other types of impaired glucose tolerance ▪ Insulinoma - a tumor of pancreatic β-cells producing excess insulin or reactive hypoglycemia. ▪ Polycystic ovary syndrome – a complex syndrome in women in the reproductive years where an ovulation and androgen excess are commonly displayed as hirsutism. In many cases of PCOS, insulin resistance is present. GLUCAGON • A hormone secreted by the pancreas, raises blood glucose levels. • Its effect is opposite that of insulin, which lowers blood glucose levels. • The pancreas releases glucagon when blood sugar (glucose) levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. Glucagon raises blood glucose levels. High blood glucose levels stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels at a stable level. • The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas • Regulatory mechanism o Increased secretion of glucagon is caused by: ▪ Decreased plasma glucose (indirectly) ▪ Increased catecholamines - norepinephrine and epinephrine ▪ Increased plasma amino acids (to protect from hypoglycemia if an all-protein meal is consumed) ▪ Sympathetic nervous system ▪ Acetylcholine ▪ Cholecystokinin o Decreased secretion (inhibition) of glucagon is caused by: ▪ Somatostatin ▪ Insulin ▪ Increased free fatty acids and keto acids into the blood ▪ Increased urea production SOMATOSTATIN • Secreted by the delta cells of pancreas • Inhibits release of insulin • Inhibits release of glucagon HORMONES PRODUCED BY THE REPRODUCTIVE GLANDS: TESTES TESTOSTERONE • Is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. • In mammals, testosterone is primarily secreted in the Leydig cells of the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands. • It is the principal male sex hormone and an anabolic steroid. • In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass and the growth of body-hair. • In addition, testosterone is essential for health and well-being as well as the prevention of osteoporosis. • On average, an adult human male body produces about ten times more testosterone than an adult human female body, but females are more sensitive to the hormone. • Levels demonstrate circadian pattern and peak at the time of awakening (7AM); fall to their lowest level at 8PM • Physiological Effects o Testosterone effects can be classified as virilizing and anabolic, although the distinction is somewhat artificial, as many of the effects can be considered both. Testosterone is anabolic, meaning it builds up bone and muscle mass. o Anabolic effects include growth of muscle mass and strength, increased bone density and strength, and stimulation of linear growth and bone maturation. o Androgenic effects include maturation of the sex organs, particularly the penis and the formation of the scrotum in the fetus, and after birth (usually at puberty) a deepening of the voice, growth of the beard and axillary hair. Many of these fall into the category of male secondary sex characteristics. o Testosterone effects can also be classified by the age of usual occurrence. For postnatal effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone. • Prenatal o The prenatal androgen effects occur between 4 and 6 weeks of the gestation. o Genital virilization o Development of prostate and seminal vesicles o Gender identity • Early infancy o Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4 –6 months of age. o The function of this rise in humans is unknown. It has been speculated that "brain masculinization" is occurring since no significant changes have been identified in other parts of the body. Surprisingly, the male brain is masculinized by testosterone being aromatized into estrogen, which crosses the blood-brain barrier and enters the male brain, whereas female fetuses have alpha-fetoprotein which binds up the estrogen so that female brains are not affected. • Pre-peripubertal o Pre- Peripubertal effects are the first observable effects of rising androgen levels at the end of childhood, occurring in both boys and girls. o Adult-type body odour o Increased oiliness of skin and hair, acne o Pubarche (appearance of pubic hair) o Axillary hair o Growth spurt, accelerated bone maturation o Hair on upper lip and sideburns.

• Pubertal o Pubertal effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males, these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the blood. o Enlargement of sebaceous glands. This might cause acne. o Phallic enlargement or clitoromegaly o Increased libido and frequency of erection or clitoral engorgement o Pubic hair extends to thighs and up toward umbilicus o Facial hair (sideburns, beard, moustache) o Loss of scalp hair (Androgenetic alopecia) o Chest hair, periareolar hair, perianal hair o Leg hair o Axillary hair o Subcutaneous fat in face decreases o Increased muscle strength and mass o Deepening of voice o Growth of the Adam's apple o Growth of spermatogenic tissue in testicles, male fertility o Growth of jaw, brow, chin, nose, and remodeling of facial bone contours o Shoulders become broader and rib cage expands o Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women • Adult o Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels decrease in the later decades of adult life. o Testosterone is necessary for normal sperm development. It activates genes in Sertoli cells, which promote differentiation of spermatogonia. o Regulates acute HPA (Hypothalamic –pituitary– adrenal axis) response under dominance challenge o Mental and physical energy o Maintenance of muscle trophism o Testosterone regulates the population of thromboxane A2 receptors on megakaryocytes and platelets and hence platelet aggregation in humans o Libido as evinced in clitoral engorgement/penile erection frequency o Testosterone does not cause or produce deleterious effects on prostate cancer. In people who have undergone testosterone deprivation therapy, testosterone increases beyond the castrate level have been shown to increase the rate of spread of an existing prostate cancer. o Recent studies have shown conflicting results concerning importance of testosterone in maintaining cardiovascular health. Nevertheless, maintaining normal testosterone levels in elderly men has been shown to improve many parameters which are thought to reduce cardiovascular disease risk, such as increased lean body mass, decreased visceral fat mass, decreased total cholesterol, and glycemic control. o Under dominance challenge, may play a role in the regulation of the fight-or-flight response o Falling in love decreases men's testosterone levels while increasing women's testosterone levels. It is speculated that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes. It has been found that when the testosterone and endorphins in the ejaculated semen meet the cervical wall after sexual intercourse, females receive a spike in testosterone, endorphin, and oxytocin levels, and males after orgasm during copulation experience an increase in endorphins and a marked increase in oxytocin levels. This adds to the hospitable physiological environment in the female internal reproductive tract for conceiving, and later for nurturing the conceptus in the pre-embryonic stages, and stimulates feelings of love, desire, and paternal care in the male (this is the only time male oxytocin levels rival a female's). o Recent studies suggest that testosterone levels play a major role in risk-taking during financial decisions. o The administration of testosterone makes men selfish and more likely to punish others for being selfish towards them. o Fatherhood also decreases testosterone levels in men, suggesting that the resulting emotional and behavioral changes promote paternal care. o In animals (grouse and sand lizards), higher testosterone levels have been linked to a reduced immune system activity. Testosterone seems to have become part of the honest signaling system between potential mates in the course of evolution. • Infertility o Pretesticular Infertility (Secondary hypogonadism) ▪ Due to hypothalamic or pituitary lesions ▪ Testosterone, FSH, LH levels = normal /decreased o Testicular Infertility (Primary hypogonadism) ▪ Maybe congenital or acquired ▪ Decreased testosterone levels and increased FSH and LH levels o Post-testicular Infertility ▪ Due to disorders of sperm transport and function ▪ Testosterone, FSH and LH levels are normal HORMONES PRODUCED BY THE REPRODUCTIVE GLANDS: OVARY ESTROGEN • Estrogens are produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta. • Luteinizing hormone (LH) stimulates the production of estrogen in the ovaries. • 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 also produce estrogen, potentially the reason why being underweight or overweight are risk factors for infertility. • In females, synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. • Androstenedione is a substance of moderate androgenic activity. This compound crosses basal membrane into surrounding granulosa cells, where it is converted to estrone or estradiol, either immediately or through testosterone.

• The conversion of testosterone to estradiol, and of androstenedione to estrone, is catalyzed by the enzyme aromatase. • Estradiol levels vary through the menstrual cycle, with levels highest just before ovulation • Function o Structural ▪ promote formation of female secondary sex characteristics ▪ accelerate metabolism ▪ reduce muscle mass ▪ 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 ▪ morphic change (endomorphic -> mesomorphic -> ectomorphic) o Protein Synthesis ▪ increase hepatic production of binding proteins o Coagulation ▪ increase circulating level of factors 2, 7, 9, 10, plasminogen ▪ decrease antithrombin III ▪ increase platelet adhesiveness o Lipid ▪ increase HDL, triglyceride ▪ decrease LDL, fat deposition o Fluid Balance ▪ salt (sodium) and water retention ▪ increase cortisol, SHBG – sex hormone binding globulin o Gastrointestinal Tract ▪ reduce bowel motility ▪ increase cholesterol in bile o Melanin ▪ increase pheomelanin, reduce eumelanin o Cancer ▪ support hormone-sensitive breast cancers (see section below) o Lung Function ▪ promotes lung function by supporting alveoli (in rodents but probably in humans). • Estrone (E1) o most abundant estrogen in post menopausal women • Estradiol (E2) o most potent estrogen secreted by the ovary o most abundant estrogen in the pre menaopausal women o serves a negative feedback for FSH o it us used in assessing ovarian function o Estriol (E3) ▪ metabolite of estradiol ▪ the estrogen found in the maternal urine ▪ major estrogen secreted in the placenta ▪ used to assess the fetoplacental unit, post date gestations and intra uterine retardation ▪ used as marker for Down Syndrome (together with AFP and hCG) PROGESTERONE • Progesterone is produced in the ovaries (to be specific, after ovulation in the corpus luteum), the adrenal glands (near the kidney), and, during pregnancy, in the placenta. • Progesterone is also stored in adipose (fat) tissue. • Used primarily for the evaluation of fertility in female • Deficiency results in failure of implantation of embryo • Single best hormone to determine whether ovulation has occured • In humans, increasing amounts of progesterone are produced during pregnancy: o At first, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropins (hCG) from the conceptus. o However, after the 8th week, production of progesterone shifts to the placenta. The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetalcorticosteroids. At term the placenta produces about 250 mg progesterone per day. o An additional source of progesterone is milk products. They contain much progesterone because on dairy farms cows are milked during pregnancy, when the progesterone content of the milk is high. After consumption of milk products the level of bio available progesterone goes up. RELAXIN • In the female, it is produced by the corpus luteum of the ovary, the breast and, during pregnancy, also by the placenta, chorion, and decidua. • In the male, it is produced in the prostate and is present in human semen. • In males, relaxin enhances motility of sperm in semen. • In females relaxin is produced mainly by the corpus luteum, in both pregnant and nonpregnant females; it rises to a peak within approximately 14 days of ovulation, and then declines in the absence of pregnancy, resulting in menstruation. During the first trimester of pregnancy, levels rise and additional relaxin is produced by the decidua. • Relaxin's role or necessity in human pregnancy remains under investigation, as in humans its peak is reached during the 14 weeks of the first trimester and at delivery. It is believed to soften the pubic symphysis. MISCELLANEOUS HORMONES GASTRIC HORMONES • Gastrin o Hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. o It is released by G cells in the stomach, duodenum, and the pancreas. o Its release is stimulated by peptides in the lumen of the stomach.

o Release ▪ Gastrin is released in response to certain stimuli. These include: • stomach distension • vagal stimulation (mediated by the neurocrine bombesin, or GRP in humans) • the presence of partially digested proteins especially amino acids • hypercalcemia ▪ Gastrin release is inhibited by • The presence of acid (primarily the secreted HCl) in the stomach (a case of negative feedback). • Somatostatin also inhibits the release of gastrin, along with secretin, GIP (gastro inhibitory peptide), VIP, glucagon and calcitonin. • Incretin o Group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated. o They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. o As expected, they also inhibit glucagon release from the alpha cells of the Islets of Langerhans LIVER HORMONES • Androsterone o Is a steroid hormone with weak androgenic activity. It is made in the liver from the metabolism of testosterone • Medullipin o Is a hormone created by the interstitial cells of renal papilla, which is converted to medullipin II in the liver. This, in turn, results in vasodilation and decreased blood pressure. INTESTINAL HORMONES • N-Acylphosphatidylethanolamines (NAPEs) o Are hormones released by the small intestine into the bloodstream when it processes fat. NAPEs travels to the hypothalamus in the brain and suppress appetite. This mechanism could be relevant for treating obesity. • Cholecystokinin o Is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. o Previously called pancreozymin • Gastric inhibitory polypeptide (GIP) or glucose-dependent insulinotropic peptide o It has traditionally been called gastrointestinal inhibitory peptide or gastric inhibitory peptide and was believed to neutralize stomach acid, to protect the small intestine from acid damage, reduce the rate at which food is transferred through the stomach, and inhibit the GI motility and secretion of acid. • Motilin o The main function of motilin is to increase the migrating myoelectric complex component of gastrointestinal motility and stimulate the production of pepsin. o Motilin is also called "Housekeeper of the gut" because it improves peristalsis in the small intestine and clears out the gut to prepare for the next meal o A high level of motilin secreted between meals into the blood stimulates the contraction of the fundus and antrum and accelerates gastric emptying. It then contracts the gallbladder and increases the squeeze pressure of the lower esophageal sphincter. o Other functions of motilin include increasing the release of pancreatic polypeptide and somatostatin • Secretin o Is a hormone that controls the secretions into the duodenum, and also separately, water homeostasis throughout the body. o It is produced in the S cells of the duodenum in the crypts of Lieberkühn. o Its effect is to regulate the pH of the duodenal contents via the control of gastric acid secretion and buffering with bicarbonate from the centro acinar cells of the pancreas as well as intercalated ducts. o It is notable for being the first hormone to be identified. HORMONE OF THE HEART • Atrial natriuretic peptide (ANP), atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), or atriopeptin , o Is a powerful vasodilator, and a protein (polypeptide) hormone secreted by heart muscle cells. o It is involved in the homeostatic control of body water, sodium, potassium and fat (adipose tissue). o It is released by muscle cells in the upper chambers (atria) of the heart (atrial myocytes), in response to high blood pressure. o ANP acts to reduce the water, sodium and adipose loads on the circulatory system, thereby reducing blood pressure. HORMONE OF THE BONE • Osteocalcin o Is secreted solely by osteoblasts and thought to play a role in the body's metabolic regulation and is pro-osteoblastic, or bone-building, by nature. o It is also implicated in bone mineralization and calcium ion homeostasis. o Osteocalcin acts as a hormone in the body, causing beta cells in the pancreas to release more insulin, and at the same time directing fat cells to release hormone adiponectin, which increases sensitivity to insulin HORMONE OF THE BLOOD • Leukocyte-promoting Factor o Is a cytokine/hormone that is produced by neutrophils when they encounter a foreign antigen. It stimulates the bone marrow to increase the rate of leukopoiesis, in order to replace the neutrophils that will inevitably be lost when they begin to phagocytose the foreign antigens

HORMONES OF THE KIDNEYS • Erythropoietin o Is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine for erythrocyte (red blood cell) precursors in the bone marrow. • Urodilarin o Is a hormone that causes diuresis through increasing renal blood flow o It is secreted in response to increased mean arterial pressure and increased blood volume from the cells of the distal tubule and collecting duct. o It is important in oliguric patients (such as those with acute renal failure andchronic renal failure) as it lowers serum creatinine and increases urine output. o