pituitary gland is Master Gland


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pituitary gland is Master Gland

  1. 1. pituitary gland is Master Gland
  2. 3. anterior pituitary (adenohypophysis) classical gland composed predominantly of cells that secrete protein hormones. posterior pituitary (neurohypophysis) -not really an organ, but an extension of the hypothalamus. composed largely of the axons of hypothalamic neurons which extend downward as a large bundle behind the anterior pituitary. It also forms the so-called pituitary stalk , which appears to suspend the anterior gland from the hypothalamus.
  3. 6. Hormones of the Pituitary pituitary gland - pea-sized structure located at the base of the brain. In humans-two lobes: Anterior Lobe Posterior Lobe
  4. 7. The Anterior Lobe Anterior lobe contains 6 types of secretory cells, all but one of which are specialized to secrete only one of the anterior lobe hormones. All of them secrete their hormone in response to hormones reaching them from the hypothalamus of the brain
  5. 8. Thyroid Stimulating Hormone (TSH) TSH (also known as thyrotropin) –glycoportein consisting of: a  chain of 112 amino acids and an  chain of 89 amino acids.  chain is identical to that found in 2 other pituitary hormones, FSH and LH as well as in hCG.
  6. 9. The secretion of TSH is - stimulated by the arrival of thyrotropin releasing hormone (TRH) from the hypothalamus. - inhibited by the arrival of somatostatin from the hypothalamus. As name suggests, TSH stimulates the thyroid gland to secrete THs
  7. 10. Thyroid-Stimulating Hormone (Thyrotropin) TSH (thyrotropin)- is secreted from thyrotrophs TSH receptors (GPCR) on epithelial cells in the thyroid gland, and stimulates that gland to synthesize and release thyroid hormones. TSH is a glycoprotein hormone 2 subunits which are non-covalently bound to one another.
  8. 11. Thyroid-Stimulating Hormone (Thyrotropin) Found in pituitaries of all vertebrates Most important role is control of thyroid gland to liberate thyroid hormones Also induces metamorphism in amphibians Important role in thermogenesis in mammals
  9. 12. The most important controller of TSH secretion is thyroid-releasing hormone. TRH is secreted by hypothalamic neurons into hypothalamic-hypophyseal portal blood, finds its receptors on thyrotrophs in the anterior pituitary and stimulates secretion of TSH. One interesting aspect of TRH is that it is only 3 amino acids long. Its basic sequence is glutamic acid-histidine-proline, although both ends of the peptide are modified .
  10. 14. Some people develop antibodies against their own TSH receptors. When these bind the receptors, they "fool" the cell into making more T4 causing hyperthyroidism. The condition is called thyrotoxicosis or Graves' disease .
  11. 15. A deficiency of TSH causes hypothyroidism: inadequate levels of T4 (and thus of T3 ). Recombinant human TSH has recently become available to treat patients with TSH deficiency. Some people inherit mutant TSH receptors. This can result in hypothyroidism. A deficiency of TSH, or mutant TSH receptors, have also been implicated as a cause of osteoporosis. Mice, whose TSH receptors have been knocked out, develop increased numbers of bone-reabsorbing osteoclasts.
  12. 16. Follicle-Stimulating Hormone (FSH) FSH is a heterodimeric glycoprotien consisting of - same  chain found in TSH (and LH) -  chain of 115 amino acids (gives it its unique properties) Synthesis and release of FSH is triggered by the arrival from the hypothalamus of gonadotropin releasing hormone GnRH
  13. 17. Effect of FSH depends on one's sex FSH in females In sexually-mature females, FSH (assisted by LH) acts on the follicle to stimulate it to release estrogens FSH in males In sexually-mature males, FSH acts on spermatogonia (with the aid of testosterone) stimulating the production of sperm.
  14. 18. Luteinizing Hormone (LH) LH is synthesized within the same pituitary cells as FSH and under the same stimulus (GnRH). Heterodimeric glycoprotein -same 89 aa  subunit found in FSH & TSH -  chain of 115 aa that is responsible for its properties.
  15. 19. Effects of LH also depend on sex LH in females In sexually-mature females, LH stimulates the follicle to secrete estrogen in the first ½ of the menstrual cycle a surge of LH triggers the completion of meiosis I of the egg and its release (ovulation) in the middle of the cycle stimulates the now-empty follicle to develop into the corpus luteum , which secretes progesterone during the latter ½ of the menstrual cycle.
  16. 20. LH in males LH acts on the interstitial cells (also known as Leydig cells) of the testes stimulating them to synthesize and secrete the male sex hormone, testosterone. LH in males is also known as interstitial cell stimulating hormone (ICSH).
  17. 21. Gonadotropins: Luteinizing and Follicle Stimulating Hormones LH and FSH are called gonadotropins because stimulate the gonads in males-the testes in females-the ovaries. **Not necessary for life*** Essential for reproduction. Both hormones are secreted from gonadotrophs in the anterior pituitary. Most gonadotrophs secrete only LH or FSH, but some appear to secrete both hormones.
  18. 22. Physiologic Effects of Gonadotropins Physiologic effects of the gonadotrophins are known only in the ovaries and testes. Together, then regulate many aspects of gonadal function in both males and females.
  19. 23. Luteinizing Hormone In both sexes, LH stimulates secretion of sex steroids from the gonads. In the testes, LH binds to receptors on Leydig cells, stimulating synthesis and secretion of testosterone. Theca cells in the ovary respond to LH stimulation by secretion of testosterone, which is converted into estrogen by adjacent granulosa cells.
  20. 24. Control of Gonadotropin Secretion principle regulator of LH and FSH secretion is GnRH. GnRH is a 10 aa peptide that is synthesized and secreted from hypothalamic neurons and binds to receptors on gonadotrophs.
  21. 25. Control of Gonadotropin Secretion In a classical negative feedback loop, sex steroids inhibit secretion of GnRH and also have direct negative effects on gonadotrophs. This regulatory loop leads to pulsatile secretion of LH and, to a much lesser extent, FSH. The number of pulses of GnRH and LH varies from a few per day to one or more per hour. In females, pulse frequency is clearly related to stage of the cycle.
  22. 27. Disease States Diminished secretion of LH or FSH can result in failure of gonadal function (hypogonadism). This condition is typically manifest in males as failure in production of normal numbers of sperm. In females, cessation of reproductive cycles is commonly observed. Elevated blood levels of gonadotropins usually reflect lack of steroid negative feedback .
  23. 29. Prolactin (PRL) 198 aa During pregnancy it helps in the preparation of the breasts for future milk production. After birth- promotes the synthesis of milk. Prolactin secretion is stimulated by TRH repressed by estrogens and dopamine In pregnant mice, prolactin stimulates the growth of new neurons in the olfactory center of the of the brain.
  24. 30. Growth Hormone (GH) also called somatotropin 191 aa GH-secreting cells are stimulated to synthesize and release GH by the intermittent arrival of growth hormone releasing hormone (GHRH) from the hypothalamus.
  25. 31. GH promotes body growth by: binding to receptors on the surface of liver cells this stimulates them to release insulin-like growth factor-1 (IGF-1; also known as somatomedin) IGF-1 acts directly on the ends of the long bones promoting their growth
  26. 32. Things that can go wrong In childhood-hyposecretion of GH produces the stunted (but normally well-proportioned) growth of a midget. Growth retardation can also result from an inability to respond to GH. This can result from inheriting mutant genes encoding the receptors for GHRH or GH or a defect in STAT 5B.
  27. 33. <ul><ul><li>Hypersecretion leads to gigantism </li></ul></ul><ul><li>In adults, a hypersecretion of GH leads to acromegaly. </li></ul>
  28. 34. Hormone-replacement therapy GH from domestic mammals like cows and pigs does not work in humans. So for many years, the only source of GH for therapy was that extracted from the glands of human cadavers. This supply was shut off when several patients died from a rare neurological disease attributed to contaminated glands. Now, with recombinant DNA methods, recombinant human GH (rHGH) is available .
  29. 35. While a great benefit to patients suffering from GH deficiency, there has also been pressure to use it to stimulate growth in youngsters who have no deficiency but whose parents want them to grow up tall. Summer of 2003, the U.S. FDA approved the use of human growth hormone (HGH) for boys predicted to grow no taller than 5′3″ and for girls, 4′11″ even though otherwise perfectly healthy.
  30. 36. ACTH — the adrenocorticotropic hormone ACTH of 39 aa peptide. Produced from a larger precursor proopiomelanocortin (POMC). ACTH acts on the cells of the adrental cortex stimulating them to produce glucocortiocoids, like cortisol mineralcortiocoids, like aldosterone Androgens (male sex hormones, like testosterone
  31. 37. in the fetus, ACTH stimulates the adrenal cortex to synthesize a precursor of estrogen called dehydroepiandrosterone sulfate (DHEA-S) which helps prepare the mother for giving birth
  32. 38. Production of ACTH depends on the intermittent arrival of corticotropin-releasing hormone (CRH) from the hypothalamus. Hypersecretion of ACTH is a frequent cause of Cushing's disease .
  33. 39. Alpha Melanocyte-Stimulating Hormone (α-MSH) another cleavage product POMC In fact, α-MSH is identical to the first 13 amino acids at the amino terminal of ACTH.
  34. 40. Pituitary cell types of Rathke's pouch Corticotropes , produce (POMC) and cleave it into adrenocorticotropic hormone (ACTH) needed for glucocorticoid synthesis in the adrenal gland Melanotropes , which produce POMC, but cleave it into αMSH (for pigment formation, feeding regulation) Somatotropes , which produce growth hormone
  35. 41. Pituitary cell types of Rathke's pouch Lactotropes , which make prolactin (for milk production, uterine contractions) Gonadotropes , which synthesize lutenizing hormone and follicle stimulating hormone (for gonad growth and development)
  36. 43. Anterior pituitary cells Somatotropes Lactotropes Thyrotropes Gonadotropes Corticotropes Intermediate pituitary cell, secreting melanocyte-stimulating hormone Magnocellular neurosecretory cells secreting oxytocin secreting vasopressin
  37. 44. The Posterior Lobe The posterior lobe of the pituitary releases 2 hormones, both synthesized in the hypothalamus, into the circulation. Antidiuretic Hormone (ADH). ADH is a peptide of 9 amino acids. It is also known as arginine vasopressin. ADH acts on the collecting ducts of the kidney to facilitate the reabsorption of water into the blood. This it acts to reduce the volume of urine formed (giving it its name of antidiuretic hormone).
  38. 45. <ul><ul><li>A deficiency of ADH or </li></ul></ul><ul><ul><li>inheritance of mutant genes for its receptor (called V2) </li></ul></ul><ul><li>leads to excessive loss of urine, a condition known as diabetes insipidus. The most severely-afflicted patients may urinate as much as 30 liters (almost 8 gallons!) of urine each day. The disease is accompanied by terrible thirst, and patients must continually drink water to avoid dangerous dehydration. </li></ul>
  39. 46. Oxytocin peptide of 9 aa Acts on certain smooth muscles: stimulating contractions of the uterus at the time of birth stimulating release of milk when the baby begins to suckle. Oxytocin is often given to prospective mothers to hasten birth.
  40. 47. Oxytocin also acts in the brain where it enhances: bonding between males and females after they have mated; bonding between a mother and her newborn; and, in humans, increases the level of one's trust in other people .
  41. 48. Hormone Major target organ Major Physiologic effect Anterior GH Liver, adipose tissue Promotes growth (indirectly) and control of protein, lipid and carbohydrate metabolism TSH Thyroid gland Stimulates secretion of thyroid hormones ACTH Adrenal gland (cortex) Stimulates secretion of glucocorticoids PRL Mammary gland Milk production LH Ovary and testis Control of reproductive function FSH Ovary and testis Control of reproductive function
  42. 49. Hormone Major target organ Major Physiologic effect Posterior ADH Kidney Conservation of body water OXY Ovary and testis Stimulates milk ejection and uterine contractions
  43. 50. Physiologic Effects of Growth Hormone A critical concept in understanding growth hormone activity is that it has 2 distinct types of effects: Direct effects –due to GH binding its receptor on target cells. Fat cells (adipocytes), for example, have growth hormone receptors (GHR), and growth hormone stimulates them to break down triglyceride and suppresses their ability to take up and accumulate circulating lipids.
  44. 51. Physiologic Effects of Growth Hormone A critical concept in understanding growth hormone activity is that it has 2 distinct types of effects: Indirect effects are mediated primarily by a IGF-1 a hormone that is secreted from the liver and other tissues in response to growth hormone. A majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells.
  45. 53. Effects on Growth Growth is a very complex process and requires the coordinated action of several hormones. Major role of GH in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-I. IGF-I stimulates proliferation of chondrocytes (cartilage cells), resulting in bone growth. IGF-I also appears to be the key player in muscle growth. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates aa uptake and protein synthesis in muscle and other tissues .
  46. 54. Metabolic Effects GH has important effects on protein, lipid and carbohydrate metabolism. Protein metabolism : GH stimulates protein anabolism in many tissues. This effect reflects increased amino acid uptake, increased protein synthesis and decreased oxidation of proteins. Fat metabolism: GH enhances the utilization of fat by stimulating triglyceride breakdown and oxidation in adipocytes. Carbohydrate metabolism : GH is one of many hormones that serves to maintain blood glucose within a normal range.
  47. 55. Control of Growth Hormone Secretion Production of GH is modulated by many factors, including stress, exercise, nutrition, sleep and GH itself. primary controllers are 2 hypothalamic hormones and one hormone from the stomach:
  48. 56. GHRH is a hypothalamic peptide that stimulates both the synthesis and secretion of growth hormone. Somatostatin (SS) is a peptide produced by several tissues in the body, including the hypothalamus. SS inhibits growth hormone release in response to GHRH and to other stimulatory factors such as low blood glucose concentration. Ghrelin is a peptide hormone secreted from the stomach. It binds to receptors on somatotrophs and potently stimulates secretion of growth hormone.
  49. 58. Growth hormone secretion part of a negative feedback loop involving IGF-I . High blood levels of IGF-I lead to decreased secretion of growth hormone by -directly suppressing the somatotroph -stimulating release of somatostatin from the hypothalamus.
  50. 59. GH also feeds back to inhibit GHRH secretion and probably has a direct (autocrine) inhibitory effect on secretion from the somatotroph. Integration of all the factors that affect GH synthesis and secretion lead to a pulsatile pattern of release.
  51. 60. Basal concentrations of GH in blood are low. In children and young adults, the most intense period of growth hormone release is shortly after the onset of deep sleep.
  52. 61. Existence of GH? 1922 Hypophoysectomized rats failed to grow Rescued with pituitary extract treatment Human GH effective in promoting linear growth of children with congenital GH deficiency. GH circulates bound to binding proteins (GHBP) Circulating levels decrease 2-3 week after birth to basal adult levels Most secreted 90 minutes after sleep Secretion ALSO induced by intense exercise
  53. 62. GH - Anabolic hormone Made by acidophils (somatotrophs) Derived from a prohormone Rapidly converted by proteolysis 191 aa 2 S-S bonds Very similar in structure to PRL
  54. 63. Disease States States of GH deficiency and excess provide evidence to the role of this hormone in normal physiology. Such disorders can reflect lesions in either the hypothalamus , the pituitary or in target cells .
  55. 64. A deficiency state can result not only from a deficiency in production of the hormone, but in the target cell's response to the hormone. Clinically, deficiency in GH or GH receptor defects are recogonized as growth retardation or dwarfism.
  56. 65. DWARF MICE
  57. 66. The manifestation of GH deficiency depends upon the age of onset of the disorder and can result from either heritable or acquired disease.
  58. 67. Excessive secretion of GH is also very dependent on the age of onset and is seen as 2 distinctive disorders: Gigantism is the result of excessive GH secretion that begins in young children or adolescents. It is a very rare disorder, usually resulting from a tumor of somatotropes.
  59. 68. Acromegaly results from excessive secretion of GH in adults. Insideous onset Clinically, an overgrowth of bone and connective tissue leads to a change in appearance that might be described as having &quot;coarse features&quot;. Excessive GH and IGF-I also lead to metabolic derangements, including glucose intolerance.
  60. 69. Acromegaly is a hormonal disorder that results when the pituitary gland produces excess GH Most commonly affects middle-aged adults can result in serious illness and premature death. Once recognized, acromegaly is treatable in most patients, but because of its slow and often insidious onset, it frequently is not diagnosed
  61. 70. acromegaly comes from the Greek words for &quot;extremities&quot; and &quot;enlargement&quot; and reflects one of its most common symptoms, the abnormal growth of the hands and feet .
  62. 71. Soft tissue swelling of the hands and feet- often an early feature- patients noticing a change in ring or shoe size.
  63. 72. Gradually, bony changes alter the patient's facial features: the brow and lower jaw protrude, the nasal bone enlarges, spacing of the teeth increases. Overgrowth of bone and cartilage often leads to arthritis. When tissue thickens- may trap nerves, causing carpal tunnel syndrome, characterized by numbness and weakness of the hands.
  64. 73. Other symptoms of acromegaly include thick, coarse, oily skin; skin tags; enlarged lips, nose and tongue; deepening of the voice due to enlarged sinuses and vocal cords; snoring due to upper airway obstruction; excessive sweating and skin odor; fatigue and weakness; headaches; impaired vision; abnormalities of the menstrual cycle and sometimes breast discharge in women; and impotence in men. There may be enlargement of body organs- liver, spleen, kidneys and heart.
  65. 74. The most serious health consequences of acromegaly
  66. 75. Summary When GH-producing tumors occur in childhood, the disease that results is called gigantism rather than acromegaly. Fusion of the growth plates of the long bones occurs after puberty so that development of excessive GH production in adults does not result in increased height. Prolonged exposure to excess GH before fusion of the growth plates causes increased growth of the long bones and increased height.
  67. 76. What Causes Acromegaly? prolonged overproduction of GH by the pituitary gland. GHRH stimulates the pituitary gland to produce GH. Another hypothalamic hormone, somatostatin, inhibits GH production and release.
  68. 77. What Causes Acromegaly? Secretion of GH by the pituitary into the bloodstream causes the production of another hormone, called insulin-like growth factor 1 (IGF-1), in the liver. IGF-1 is the factor that actually causes the growth of bones and other tissues of the body. IGF-1, in turn, signals the pituitary to reduce GH production.
  69. 78. What Causes Acromegaly? GHRH, somatostatin, GH, and IGF-1 levels in the body are tightly regulated by each other and by sleep, exercise, stress, food intake and blood sugar levels. If the pituitary continues to make GH independent of the normal regulatory mechanisms, the level of IGF-1 continues to rise, leading to bone growth and organ enlargement. The excess GH also causes changes in sugar and lipid metabolism and can cause diabetes .
  70. 79. <ul><li>What Causes Acromegaly? </li></ul><ul><li>Pituitary Tumors </li></ul><ul><li>90 % of acromegaly patients- overproduction of GH is caused by a benign tumor of the pituitary gland, called an adenoma. </li></ul><ul><li>These tumors produce excess GH and, as they expand, compress surrounding brain tissues, such as the optic nerves. </li></ul><ul><li>expansion causes the headaches and visual disturbances </li></ul><ul><li>compression of the surrounding normal pituitary tissue can alter production of other hormones, leading to changes in menstruation and breast discharge in women and impotence in men </li></ul>
  71. 80. <ul><li>What Causes Acromegaly? </li></ul><ul><li>Pituitary Tumors </li></ul><ul><li>marked variation in rates of GH production and the aggressiveness of the tumor. Some adenomas grow slowly and symptoms of GH excess are often not noticed for many years. Other adenomas grow rapidly and invade surrounding brain areas or the sinuses, which are located near the pituitary. </li></ul>
  72. 81. What Causes Acromegaly? Pituitary Tumors In general, younger patients tend to have more aggressive tumors. Most pituitary tumors arise spontaneously and are not genetically inherited. Many pituitary tumors arise from a genetic alteration in a single pituitary cell which leads to increased cell division and tumor formation. This genetic change, or mutation, is not present at birth, but is acquired during life.
  73. 82. Causes of Acromegaly? Non-pituitary Tumors In a few patients, acromegaly is not caused by pit. tumors but by tumors of the pancreas, lungs, and adrenal glands. These tumors also lead to an excess of GH, either because they produce GH themselves or, more frequently, because they produce GHRH , the hormone that stimulates the pituitary to make GH. In these patients, the excess GHRH can be measured in the blood and establishes that the cause of the acromegaly is not due to a pituitary defect.
  74. 83. When these non-pituitary tumors are surgically removed, GH levels fall and the symptoms of acromegaly improve. In patients with GHRH-producing, non-pituitary tumors, the pituitary still may be enlarged and may be mistaken for a tumor. Therefore, it is important that physicians carefully analyze all &quot;pituitary tumors&quot; removed from patients with acromegaly in order not to overlook the possibility that a tumor elsewhere in the body is causing the disorder.
  75. 84. How Common is Acromegaly? Small pituitary adenomas are common. During autopsies, they are found in up to 25 % of the U.S. population. However, these tumors rarely cause symptoms or produce excessive GH or other pituitary hormones. Scientists estimate that about 3 out of every million people develop acromegaly each year and that 40 to 60 out of every million people suffer from the disease at any time. However, because the clinical diagnosis of acromegaly often is missed, these numbers probably underestimate the frequency of the disease.
  76. 85. How is Acromegaly Diagnosed? If a doctor suspects acromegaly, he or she can measure the GH level in the blood after a patient has fasted overnight to determine if it is elevated. However, a single measurement of an elevated blood GH level is not enough to diagnose acromegaly, because GH is secreted by the pituitary in spurts and its concentration in the blood can vary widely from minute to minute.
  77. 86. How is Acromegaly Diagnosed? Because of these problems, more accurate information can be obtained when GH is measured under conditions in which GH secretion is normally suppressed. Physicians often use the oral glucose tolerance test (OGTT) to diagnose acromegaly, because ingestion of 75 g of glucose lowers blood GH levels less than 2 ng/ml in healthy people. In patients with GH overproduction, this reduction does not occur .
  78. 87. How is Acromegaly Diagnosed? Physicians also can measure IGF-1 levels in patients with suspected acromegaly. Elevated GH levels increase IGF-1 blood levels. Because IGF-1 levels are much more stable over the course of the day, they are often a more practical and reliable measure than GH levels. Elevated IGF-1 levels almost always indicate acromegaly . However, a pregnant woman's IGF-1 levels are two to three times higher than normal. In addition, physicians must be aware that IGF-1 levels decline in aging people and may be abnormally low in patients with poorly controlled diabetes mellitus.
  79. 88. How is Acromegaly Diagnosed? After acromegaly has been diagnosed by measuring GH or IGF-1, imaging techniques, such as computed tomography (CT) scans or magnetic resonance imaging (MRI) scans of the pituitary are used to locate the tumor that causes the GH overproduction. Both techniques are excellent tools to visualize a tumor without surgery. If scans fail to detect a pituitary tumor, the physician should look for non-pituitary tumors in the chest, abdomen, or pelvis as the cause for excess GH. The presence of such tumors usually can be diagnosed by measuring GHRH in the blood and by a CT scan of possible tumor sites.
  80. 89. How is Acromegaly Treated? The goals of treatment are to reduce GH production to normal levels, to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, to preserve normal pituitary function, and to reverse or ameliorate the symptoms of acromegaly. Currently, treatment options include surgical removal of the tumor, drug therapy , and radiation therapy of the pituitary.
  81. 90. How is Acromegaly Treated? Surgery Surgery - rapid and effective treatment. surgeon reaches the pituitary through an incision in the nose and, with special tools, removes the tumor tissue in a procedure called transsphenoidal surgery.
  82. 91. How is Acromegaly Treated? Surgery This procedure promptly relieves the pressure on the surrounding brain regions and leads to a lowering of GH levels. If the surgery is successful, facial appearance and soft tissue swelling improve within a few days. Surgery is most successful in patients with blood GH levels below 40 ng/ml before the operation and with pituitary tumors no larger than 10 mm in diameter.
  83. 92. How is Acromegaly Treated? Surgery Complications of surgery may include cerebrospinal fluid leaks, meningitis, or damage to the surrounding normal pituitary tissue, requiring lifelong pituitary hormone replacement.
  84. 93. How is Acromegaly Treated? Surgery Even when surgery is successful and hormone levels return to normal, patients must be carefully monitored for years for possible recurrence. More commonly, hormone levels may improve, but not return completely to normal. These patients may then require additional treatment, usually with medications.
  85. 94. How is Acromegaly Treated? Drug Therapy 2 medications currently are used to treat acromegaly. These drugs reduce both GH secretion and tumor size. drug therapy is sometimes used to shrink large tumors before surgery.
  86. 95. Drug Therapy Bromocriptine (Parlodel®) reduces GH secretion from some pituitary tumors. Side effects include GI upset, nausea, vomiting, light-headedness when standing, and nasal congestion. These side effects can be reduced or eliminated if medication is started at a very low dose at bedtime, taken with food, and gradually increased to the full therapeutic dose.
  87. 96. How is Acromegaly Treated? Drug Therapy Because bromocriptine can be taken orally, it is an attractive choice as primary drug or in combination with other treatments. However, bromocriptine lowers GH and IGF-1 levels and reduces tumor size in less than half of patients with acromegaly. Some patients report improvement in their symptoms although their GH and IGF-1 levels still are elevated.
  88. 97. How is Acromegaly Treated? Drug Therapy octreotide (Sandostatin®). Octreotide is a synthetic form of a brain hormone, somatostatin, that stops GH production. This drug must be injected under the skin every 8 hours for effective treatment.
  89. 98. How is Acromegaly Treated? Drug Therapy Most patients with acromegaly respond to this medication. In many patients, GH levels fall within 1 hour and headaches improve within minutes after the injection. Several studies have shown that octreotide is effective for long-term treatment. Octreotide also has been used successfully to treat patients with acromegaly caused by non-pituitary tumors.
  90. 99. How is Acromegaly Treated? Because octreotide inhibits GI and pancreatic function-long-term use causes digestive problems such as loose stools, nausea, and gas in one third of patients. In addition, approximately 25% of patients develop gallstones , which are usually asymptomatic. In rare cases, octreotide treatment can cause diabetes. On the other hand, scientists have found that in some acromegaly patients who already have diabetes, octreotide can reduce the need for insulin and improve blood sugar control.
  91. 100. How is Acromegaly Treated? Radiation Therapy Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. usually reserved for patients who have tumor remaining after surgery. These patients often also receive medication to lower GH levels.
  92. 101. How is Acromegaly Treated? Radiation Therapy Radiation therapy is given in divided doses over 4-6 weeks. This treatment lowers GH levels by about 50% over 2 - 5 years. Patients monitored for more than 5 years show significant further improvement. Radiation therapy causes a gradual loss of production of other pituitary hormones with time. Loss of vision and brain injury, which have been reported, are very rare complications of radiation treatments.
  93. 102. How is Acromegaly Treated? Radiation Therapy generally used for patients whose tumors are not completely removed by surgery; for patients who are not good candidates for surgery because of other health problems or patients who do not respond adequately to surgery and medication.
  94. 103. How is Acromegaly Treated? No single treatment is effective for all patients. Treatment should be individualized depending on patient characteristics, such as age and tumor size. If the tumor has not yet invaded surrounding brain tissues, removal of the pituitary adenoma by an experienced neurosurgeon is usually the first choice.
  95. 104. How is Acromegaly Treated? After surgery, a patient must be monitored for a long time for increasing GH levels. If surgery does not normalize hormone levels or a relapse occurs, a doctor will usually begin additional drug therapy. The first choice should be bromocriptine because it is easy to administer; octreotide is the second alternative. With both drugs, long-term therapy is necessary because their withdrawal can lead to rising GH levels and tumor re-expansion.
  96. 110. Teeth not aligned properly
  97. 112. PROLACTIN Mammary growth and Dev’t Lactogenesis Diverse Roles in Vertebrates Role in non pregnant females and males 1928-shown pit extract could stimulate milk production in rabbits Estrogens stimulate PRL directly Hyperprolactinemia and PRL secreting pit tumors are common in women of reproductive age Serum PRL increase at puberty (FSH and LH)
  98. 113. PROLACTIN Effects growth and differentiation of integumental structures Hair and sebaceous glands in mammals Brood patch/feather Devt in birds Evidence to suggest a role in testicular function Hypophosectomy of adult rats causes a loss of testicular LH receptors and loss of testes response to LH PRL needed for LH receptor
  99. 114. PROLACTIN Plasma levels only a bit higher in women Overlap of conc. ranges in sexes Secreted episodically Half life in blood of 15-20 min Night time surge (like GH) Not identical to GH surge
  100. 115. PROLACTIN Found glycosylated in pit. and plasma CHO groups vary among species- this heterogeneity accounts for differences in activity Similar to GH, but different actions Breast feeding women-normal GH Acromegaly only occasionally have gallactorrhea
  101. 116. PROLACTIN All cells express PRL receptors although the anterior pituitary is the major source of prolactin, the hormone is synthesized and secreted in many other tissues . Overall, several hundred different actions have been reported for prolactin in various species.
  102. 117. PRL critical role of prolactin in lactation has been confirmed in mice with targeted deletions in the prolactin gene. Female mice that are heterozygous for the deleted prolactin gene (and produce roughly half the normal amount of prolactin) show failure to lactate after their first pregnancy.
  103. 118. PROLACTIN Prolactin also appears important in several non-lactational aspects of reproduction. In some species (rodents, dogs, skunks), prolactin is necessary for maintenance of corpora lutea (ovarian structures that secrete progesterone).
  104. 119. PROLACTIN Mice that are homozygous for an inactivated prolactin gene and thus incapable of secreting prolactin are infertile due to defects in ovulation, fertilization, preimplantation development and implantation.
  105. 120. PROLACTIN Effects on Immune Function The PRL receptor is widely expressed by immune cells, and some types of lymphocytes synthesize and secrete PRL. These observations suggest that PRL may act as an autocrine or paracrine modulator of immune activity. Interestingly, mice with homozygous deletions of the PRL gene fail to show significant abnormalities in immune responses.
  106. 121. PROLACTIN Effects on Immune Function A considerable amount of research is in progress to delineate the role of PRL in normal and pathologic immune responses. It appears that prolactin has a modulatory role in several aspects of immune function, but is not strictly required for these responses.
  107. 122. PROLACTIN Control of Prolactin Secretion In contrast to what is seen with all the other pituitary hormones, hypothalamus tonically suppresses prolactin secretion from the pituitary. There is usually a hypothalamic &quot;brake&quot; set on the lactotroph, and prolactin is secreted only when the brake is released.
  108. 123. PROLACTIN Control of Prolactin Secretion If the pituitary stalk is cut, prolactin secretion increases, while secretion of all the other pituitary hormones fall dramatically due to loss of hypothalamic releasing hormones.
  109. 124. PROLACTIN Control of Prolactin Secretion Dopamine serves as the major prolactin-inhibiting factor or brake on prolactin secretion. Dopamine is secreted into portal blood by hypothalamic neurons, binds to receptors on lactotrophs, and inhibits both the synthesis and secretion of prolactin.
  110. 125. PROLACTIN Control of Prolactin Secretion Agents and drugs that interfere with dopamine secretion or receptor binding lead to enhanced secretion of prolactin.
  111. 126. PROLACTIN In addition to tonic inhibition by dopamine, PRL secretion is positively regulated by several hormones, including TRH and GnRH. Stimulation of the nipples and mammary gland, as occurs during nursing, leads to prolactin release.
  112. 127. PROLACTIN Estrogens provide a well-studied positive control over prolactin synthesis and secretion. The increasing blood concentrations of estrogen during late pregnancy appear responsible for the elevated levels of prolactin that are necessary to prepare the mammary gland for lactation at the end of gestation.
  113. 129. What Is a Prolactinoma? benign tumor of the pituitary gland that produces PRL MOST common type of pituitary tumor. Symptoms of prolactinoma are caused by too much prolactin in the blood (hyperprolactinemia) or by pressure of the tumor on surrounding tissues.
  114. 130. How Common Is Prolactinoma? Autopsy studies indicate that 25 % of the U.S. population have small pituitary tumors. Forty percent of these pituitary tumors produce prolactin, but most are not considered clinically significant. Clinically significant pituitary tumors affect the health of approximately 14 out of 100,000 people.
  115. 132. What Causes Prolactinoma? Although research continues to unravel the mysteries of disordered cell growth-the cause of pituitary tumors remains unknown . Most pituitary tumors are sporadic—they are not genetically passed from parents to offspring.
  116. 133. What Are the Symptoms? In women, high blood levels of PRL often cause infertility and changes in menstruation. In some women, periods may disappear altogether. In others, periods may become irregular or menstrual flow may change. Women who are not pregnant or nursing may begin producing breast milk. Some women may experience a loss of libido (interest in sex). Intercourse may become painful because of vaginal dryness.
  117. 134. What Are the Symptoms? In men, the most common symptom of prolactinoma is impotence . Because men have no reliable indicator such as menstruation to signal a problem, many men delay going to the doctor until they have headaches or eye problems caused by the enlarged pituitary pressing against nearby eye nerves. They may not recognize a gradual loss of sexual function or libido . Only after treatment do some men realize they had a problem with sexual function.
  118. 135. What Else Causes Prolactin To Rise? In some people, high blood levels of prolactin can be traced to causes other than a pituitary tumor. Prescription Drugs -PRL secretion in the pituitary is normally suppressed by dopamine. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete prolactin.
  119. 136. What Else Causes Prolactin To Rise? In some people, high blood levels of prolactin can be traced to causes other than a pituitary tumor. These drugs include the major tranquilizers trifluoperazine (Stelazine) and haloperidol (Haldol); metoclopramide (Reglan), used to treat gastroesophageal reflux and the nausea caused by certain cancer drugs; and less often, alpha methyldopa and reserpine, used to control hypertension
  120. 137. What Else Causes Prolactin To Rise? In some people, high blood levels of prolactin can be traced to causes other than a pituitary tumor. Other Pituitary Tumors Other tumors arising in or near the pituitary—such as those that cause acromegaly or Cushing's syndrome—may block the flow of dopamine from the brain to the prolactin-secreting cells.
  121. 138. What Else Causes Prolactin To Rise? In some people, high blood levels of prolactin can be traced to causes other than a pituitary tumor. Hypothyroidism. Increased prolactin levels are often seen in people with hypothyroidism, and doctors routinely test people with hyperprolactinemia for hypothyroidism. Breast Stimulation also can cause a modest increase in the amount of prolactin in the blood.
  122. 139. How is Prolactinoma Diagnosed? A doctor will test for prolactin blood levels in women with unexplained milk secretion (galactorrhea) or irregular menses or infertility, and in men with impaired sexual function and, in rare cases, milk secretion.
  123. 140. How is Prolactinoma Diagnosed? If prolactin is high, a doctor will test thyroid function and ask first about other conditions and medications known to raise prolactin secretion. The doctor will also request a MRI which is the most sensitive test for detecting pituitary tumors and determining their size. MRI scans may be repeated periodically to assess tumor progression and the effects of therapy.
  124. 141. How is Prolactinoma Diagnosed? Computer Tomography (CT scan) also gives an image of the pituitary, but it is less sensitive than the MRI. In addition to assessing the size of the pituitary tumor, doctors also look for damage to surrounding tissues, and perform tests to assess whether production of other pituitary hormones is normal. Depending on the size of the tumor, the doctor may request an eye exam with measurement of visual fields.
  125. 142. How Is Prolactinoma Treated? Medical Treatment goal of treatment is to return PRL secretion to normal, reduce tumor size, correct any visual abnormalities, and restore normal pituitary function. In the case of very large tumors, only partial achievement of this goal may be possible.
  126. 143. How Is Prolactinoma Treated? Medical Treatment Because dopamine is the chemical that normally inhibits prolactin secretion, doctors may treat prolactinoma with bromocriptine or cabergoline, drugs that act like dopamine.
  127. 144. How Is Prolactinoma Treated? Medical Treatment This type of drug is called a dopamine agonist . These drugs shrink the tumor and return prolactin levels to normal in approximately 80 % of patients. Both have been approved by the FDA for the treatment of hyperprolactinemia. Bromocriptine is the only dopamine agonist approved for the treatment of infertility. Another dopamine agonist, pergolide, is available in the U.S., but is not approved for treating conditions that cause high blood levels of prolactin.
  128. 145. How Is Prolactinoma Treated? Medical Treatment Bromocriptine treatment should not be interrupted without consulting a qualified endocrinologist. Prolactin levels often rise again in most people when the drug is discontinued. In some, however, prolactin levels remain normal, so the doctor may suggest reducing or discontinuing treatment every two years on a trial basis.
  129. 146. How Is Prolactinoma Treated? Medical Treatment Cabergoline is also associated with side effects such as nausea and dizziness, but less common and less severe than with bromocriptine. As with bromocriptine therapy, side effects may be avoided if treatment is started slowly.
  130. 147. How Is Prolactinoma Treated? Surgery Surgery should be considered if medical therapy cannot be tolerated or if it fails to reduce PRL levels, restore normal reproduction and pituitary function, and reduce tumor size. If medical therapy is only partially successful, this therapy should continue, possibly combined with surgery or radiation. The results of surgery depend a great deal on tumor size and PRL level as well as the skill and experience of the neurosurgeon.
  131. 148. How Is Prolactinoma Treated? Surgery The higher the prolactin level, the lower the chance of normalizing serum prolactin. In the best medical centers, surgery corrects prolactin levels in 80% of patients with a serum PRL less than 250 ng/ml. Even in patients with large tumors that cannot be completely removed, drug therapy may be able to return serum prolactin to the normal range after surgery. Depending on the size of the tumor and how much is removed, studies show that 20-50 % will recur, usually within 5 years.
  132. 149. How do I choose a skilled neurosurgeon? Because the results of surgery are so dependent on the skill and knowledge of the neurosurgeon, a patient should ask the surgeon about the number of operations he or she has performed to remove pituitary tumors, and for success and complication rates in comparison to major medical centers . The best results come from surgeons who have performed many hundreds or even thousands of such operations.
  133. 150. How Does Prolactinoma Affect Pregnancy and Oral Contraceptives? If a woman has a small prolactinoma, there is no reason that she cannot conceive/have a normal pregnancy after successful medical therapy. The pituitary enlarges and prolactin production increases during normal pregnancy in women without pituitary disorders.
  134. 151. How Does Prolactinoma Affect Pregnancy and Oral Contraceptives? Women with PRL-secreting tumors may experience further pituitary enlargement and must be closely monitored during pregnancy. However, damage to the pituitary or eye nerves occurs in less than 1% of pregnant women with prolactinoma. In women with large tumors, the risk of damage to the pituitary or eye nerves is greater, and some doctors consider it around 25%
  135. 152. Antidiuretic Hormone (Vasopressin) 9 aa peptide secreted from the posterior pituitary. Within hypothalamic neurons, the hormone is packaged in secretory vesicles with a carrier protein called neurophysin , and both hormone and carrier are released upon hormone secretion.
  136. 153. Antidiuretic Hormone (Vasopressin) Roughly 60% of the mass of the body is water despite wide variation in the amount of water taken in each day, body water content remains incredibly stable. Such precise control of body water and solute concentrations is a function of several hormones acting on both the kidneys and vascular system, but there is no doubt that ADH is a key player in this process.
  137. 154. Effects on the Kidney single most important effect of ADH is to conserve body water by reducing urine output A diuretic is an agent that increases the rate of urine formation. Injection of small amounts of ADH into a person or animal results in antidiuresis or decreased formation of urine, and the hormone was named for this effect.
  138. 155. ADH hormone binds to receptors in the distal or collecting tubules of the kidney and promotes reabsorbtion of water back into the circulation. In the absence of ADH, the kidney tubules are virtually impermeable to water, and it flows out as urine.
  139. 156. ADH stimulates water reabsorbtion by stimulating insertion of &quot;water channels&quot; or aquaporins into the membranes of kidney tubules. These channels transport solute-free water through tubular cells and back into blood, leading to a decrease in plasma osmolarity and an increased osmolarity of urine.
  140. 157. Effects on the Vascular System In many species, high concentrations of ADH cause widespread constriction of arterioles, which leads to increased arterial pressure. It was for this effect that the name vasopressin was coined. In healthy humans, ADH has minimal pressor effects .
  141. 158. Control of ADH Secretion Most important variable regulating ADH secretion is plasma osmolarity , or the concentration of solutes in blood. Osmolarity is sensed in the hypothalamus by neurons known as an osmoreceptors, and those neurons, in turn, simulate secretion from the neurons that produce ADH
  142. 159. Control of ADH Secretion When plasma osmolarity is below a certain threshold, the osmoreceptors are not activated and ADH secretion is suppressed. When osmolarity increases above the threshold, the ever-alert osmoreceptors recognize this a the cue to stimulate the neurons that secrete ADH. ADH concentrations rise steeply and linearly with increasing plasma osmolarity.
  143. 160. There is an interesting parallel between ADH secretion and thirst. Both stimulated by hypothalamic osmoreceptors, although probably not the same ones. The osmotic threshold for ADH secretion is considerably lower than for thirst, as if the hypothalamus is saying &quot;Let's not bother by invoking thirst unless the situation is bad enough that ADH cannot handle it alone.&quot;
  144. 161. Secretion of ADH is also stimulated by decreases in blood pressure and volume, conditions sensed by stretch receptors in the heart and large arteries. Changes in blood pressure and volume are not nearly as sensitive a stimulator as increased osmolarity, but are nonetheless potent in severe conditions.
  145. 162. For example, Loss of 15 or 20% of blood volume by hemorrhage results in massive secretion of ADH Another potent stimulus of ADH is
  146. 163. Disease States Most common disease of man and animals related to ADH is diabetes insipidus. This condition can arise from either of two situations: Hypothalamic (&quot;central&quot;) diabetes insipidus results from a deficiency in secretion of ADH from the posterior pituitary. Causes of this disease include head trauma, and infections or tumors involving the hypothalamus.
  147. 164. Disease States Nephrogenic diabetes insipidus occurs when the kidney is unable to respond to ADH. Most commonly, this results from some type of renal disease, but mutations in the ADH receptor gene or in the gene encoding aquaporin-2 have also been demonstrated in affected humans.
  148. 165. Disease States major sign of either type of diabetes insipidus is excessive urine production. Some human patients produce as much as 16 liters of urine per day! If adequate water is available for consumption, the disease is rarely life-threatening, but withholding water can be very dangerous. Hypothalamic diabetes insipidus can be treated with exogenous ADH
  149. 166. Biology of a Hangover: ADH Inhibition When alcohol is consumed, it enters the blood-causes the pituitary gland to block the synthesis of ADH . Hence, the kidneys send water directly to the bladder instead of reabsorbing it into the body. This is why drinkers have to make frequent trips to the bathroom after urinating for the first time after drinking.
  150. 167. Biology of a Hangover: ADH Inhibition According to studies, drinking about 250 mls of an alcoholic beverage causes the body to expel 800 to 1,000 mls of water This diuretic effect decreases as the alcohol in the bloodstream decreases, but the after effects help create a hangover.
  151. 168. Aquaporins: Water Channels Water crosses cell membranes by two routes: -diffusion through the lipid bilayer (NOT MUCH) -through water channels called aquaporins. Functional characterization of the first aquaporin was reported in 1992 Water channels were suspected to exist well before that time, because the osmotic permeability of some types of cells was much too large to be accounted for by simple diffusion across PM
  152. 169. Aquaporins: Water Channels The classical aquaporins transport solute-free water across cell membranes; they appear to be exclusive water channels and do not permeate membranes to ions or other small molecules.
  153. 170. The Aquaporin Family (6TMD) More than 10 different mammalian aquaporins have been identified to date (likely more) . Closely related water channel proteins have been isolated from plants, insects and bacteria. Aquaporin-1 from human red blood cells was the first to be discovered and is probably the best studied.
  154. 171. Based on studies with aquaporin-1, it appears that aquaporins exist in the plasma membrane as homotetramers. Each aquaporin monomer contains two hemi-pores, which fold together to form a water channel.
  155. 172. Patterns of Aquaporin Expression Each of the aquaporins has an essentially unique pattern of expression among tissues and during development. summary of these attributes and some of the important potential or known functions is presented below: Major Sites of Expression Comments Aquaporin-0 Eye: lens fiber cells Fluid balance within lens Aquaporin-1 RBC Osmotic protection Aquaporin-2 Kidney: collecting ducts Mediates ADH activity Aquaporin-3 Kidney (collecting ducts) Reabsorbtion of H2O into blood Aquaporin-5 Salivary glands Production of saliva Lacrimal glands Production of tears Aquaporin-7 * Testis and sperm Aquaporin-8 Testis, pancreas, liver, others Aquaporin-9 Leukocytes
  156. 173. Several interesting and important features of aquaporin-mediated water transport are illustrated in the principal cells that line collecting ducts in the kidney. Water flowing through these ducts can either continue on and be voided in urine or be reabsorbed across the epithelium and back into blood. Reabsorption is essentially nil unless the epithelial cells see ADH, which strongly stimulates reabsorption of water. Collecting duct cells express at least two aquaporins:
  157. 174. Aquaporin-2 is synthesized and present Yet, in the absence of ADH hormone, resides in a pool of membrane vesicles within the cytoplasm. Binding of ADH to its receptor in the cell not only stimulates transcription of the aquaporin-2 gene, but causes the intracellular pool of aquaporin-2 to be inserted into the apical membrane. The cell is now able to efficiently take up water from the lumen of the duct. Aquaporin-3 is constitutively expressed in the basolateral membrane of the cell. When water floods into the cell through aquaporin-2 channels, it can rapidly exit the cell through the aquaporin-3 channels and flow into blood.
  158. 175. (AP2) Take up water from lumen, AP3 faciliate its movement into the blood
  159. 176. ADH bind receptor this activates a G protein and Adenylate cyclase to increase cAMP which cause Aquaporin 2 vesicles to fuse with the PM to move water into the cells. Water comes in via A2 and goes out into the blood via A3, hence preventing loss via urine. Make sure you understand how ADH results in water movement into the blood.
  160. 177. Aquaporins and Disease Considering the importance of water transport in a myriad of physiologic processes, it is to be expected that lesions in aquaporin genes or acquired dysfunction in aquaporins may cause or contribute to several disease states. The search for such connections is still early, but 2 clear examples of disease have been identified as resulting from deficiency in aquaporins: Mutations in the aquaporin-2 gene cause hereditary nephrogenic diabetes insipidus in humans . Mice homozygous for inactivating mutations in the aquaporin-0 gene develop congenital cataracts.
  161. 179. Oxytocin in a 9 aa peptide synthesized in hypothalamic neurons and transported down axons of the posterior pituitary for secretion into blood.
  162. 180. Oxytocin is also secreted within the brain and from a few other tissues, including the ovaries and testes. Oxytocin differs from ADH in 2 of the 9 amino acids. Both hormones are packaged into granules and secreted along with carrier proteins called neurophysins.
  163. 181. Physiologic Effects of Oxytocin In years past, oxytocin had the reputation of being an &quot;uncomplicated&quot; hormone , with only a few well-defined activities related to birth and lactation. As has been the case with so many hormones, further research has demonstrated many subtle but profound influences of this little peptide. Nevertheless, it has been best studied in females where it clearly mediates 3 major effects :
  164. 182. Physiologic Effects of Oxytocin 3 major effects : Stimulation of milk ejection (milk letdown): Milk is initially secreted into small sacs within the mammary gland called alveoli, from which it must be ejected for consumption or harvesting. Mammary alveoli are surrounded by smooth muscle (myoepithelial) cells which are a prominent target cell for oxytocin. Oxytocin stimulates contraction of myoepithelial cells, causing milk to be ejected into the ducts and cisterns.
  165. 183. Physiologic Effects of Oxytocin 3 major effects : Stimulation of uterine smooth muscle contraction at birth: At the end of gestation, the uterus must contract vigorously and for a prolonged period of time in order to deliver the fetus. During the later stages of gestation, there is an increase in abundance of oxytocin receptors on uterine smooth muscle cells, which is associated with increased &quot;irritability&quot; of the uterus (and sometimes the mother as well).
  166. 184. Physiologic Effects of Oxytocin 3 major effects : Stimulation of uterine smooth muscle contraction at birth: Oxytocin is released during labor when the fetus stimulates the cervix and vagina, and it enhances contraction of uterine smooth muscle to facilitate parturition or birth.
  167. 185. Physiologic Effects of Oxytocin 3 major effects : Establishment of maternal behavior: Successful reproduction in mammals demands that mothers become attached to and nourish their offspring immediately after birth. It is also important that non-lactating females do not manifest such nurturing behavior. The same events that affect the uterus and mammary gland at the time of birth also affect the brain. During parturition, there is an increase in concentration of oxytocin in cerebrospinal fluid, and oxytocin acting within the brain plays a major role in establishing maternal behavior.
  168. 186. <ul><li>Physiologic Effects of Oxytocin </li></ul><ul><li>3 major effects : </li></ul><ul><li>Evidence for this role of oxytocin come from 2 types of experiments. </li></ul><ul><li>infusion of oxytocin into the ventricles of the brain of virgin rats or non-pregnant sheep rapidly induces maternal behavior. </li></ul><ul><li>administration into the brain of antibodies that neutralize oxytocin or of oxytocin antagonists will prevent mother rats from accepting their pups. </li></ul><ul><li>Other studies support the contention that this behavioral effect of oxytocin is broadly applicable among mammals. </li></ul>
  169. 187. Mice that are unable to secrete oxytocin due to targeted disruptions of the oxytocin gene will mate, deliver their pups without apparent difficulty and display normal maternal behavior. However, they do show deficits in milk ejection and have subtle derangements in social behavior. It may be best to view oxytocin as a major facilitator of parturition and maternal behavior rather than a necessary component of these processes.
  170. 188. Both sexes secrete oxytocin - what about its role in males? Males synthesize oxytocin in the same regions of the hypothalamus as in females, and also within the testes and perhaps other reproductive tissues. Pulses of oxytocin can be detected during ejaculation. Current evidence suggests that oxytocin is involved in facilitating sperm transport within the male reproductive system and perhaps also in the female, due to its presence in seminal fluid. It may also have effects on some aspects of male sexual behavior.
  171. 189. It may also have effects on some aspects of male sexual behavior. Intracerebroventricular (ICV) injection of oxytocin (300 ng) produced an immediate cessation in sexual behavior in sexually active male prairie voles ... Other studies in guinea pigs show a role of OXY in cohabitiation in males and females
  172. 190. Control of Oxytocin Secretion The most important stimulus for release of hypothalamic oxytocin is initiated by physical stimulation of the nipples or teats. The act of nursing or suckling is relayed within a few milliseconds to the brain via a spinal reflex arc. These signals impinge on oxytocin-secreting neurons, leading to release of oxytocin.
  173. 191. A number of factors can inhibit oxytocin release, among them acute stress. For example, oxytocin neurons are repressed by catecholamines, which are released from the adrenal glands in response to many types of stress, including fright. So, don’t scare the cows in the milking parlor or set off firecrackers around a mother nursing her baby.
  174. 192. Both the production of oxytocin and response to oxytocin are modulated by circulating levels of sex steroids. The burst of oxytocin released at birth seems to be triggered in part by cervical and vaginal stimulation by the fetus, but also because of abruptly declining concentrations of progesterone . Another well-studied effect of steroid hormones is the marked increase in synthesis of uterine oxytocin receptors late in gestation, resulting from increasing concentrations of circulating estrogen.
  175. 193. Number of enzymes in a variety of tissues that can degrade the neurohypophysial hormones in a specific manner One example- oxytocinase -appears in human blood in pregnancy, made in placenta Kidney also has peptidases which break down these hormones
  176. 194. Hormone Other names Symbol(s) Target Effect Oxytocin - - Target= Uterus , mammary glands Effect= Uterine contractions ; lactation Vasopressin Arginine vasopressin, argipressin, antidiuretic hormone AVP, ADH Target= Kidneys or Arterioles Effect=stimulates water retention; raises blood pressure by contracting arterioles
  177. 195. Lots of other neurohypophysial hormones Hydrins -hydroosmotic peptides have role in osmoregulatory adaptation in amphibians Urophysis-gland in FISH Urotensins- t eleost hormones . A family of small peptides isolated from urophyses of bony fishes . They have many different physiological effects , including long -lasting hypotensive activity and have been proposed as antihypertensives . There are at least four different compounds : urotensin I, urotensin II, urotensin III, and urotensin IV .
  178. 196. Vasotocin (AVT) rather than vasopressin is present in the pituitary of non mammal vertebrates Important in sexual behavior and muscle contraction Non -mammalian vertebrates (fish, amphibians, reptiles and birds)
  179. 197. POMC and the melanocortins ACTH made in pars distalis in corticotrophs  MSH in pars intermedia Both come from cleaved POMC  MSH and ACTH have similar sequences within their structure
  180. 198. Adrenocorticotropic hormone, as its name implies, stimulates the adrenal cortex. More specifically, it stimulates secretion of glucocorticoids such as cortisol, and has little control over secretion of aldosterone, the other major steroid hormone from the adrenal cortex. Another name for ACTH is corticotropin .
  181. 199. ACTH is secreted from the anterior pituitary in response to corticotrophin-releasing hormone (CRH) from the hypothalamus. CRH is secreted in response to many types of stress, which makes sense in view of the &quot;stress management&quot; functions of glucocorticoids. CRH itself is inhibited by glucocorticoids, making it part of a classical negative feedback loop
  182. 201. Within the pituitary gland, ACTH is produced in a process that also generates several other hormones. A large precursor protein named proopiomelanocortin (POMC) is synthesized and proteolytically chopped into several fragments. Not all of the cleavages occur in all species and some occur only in the intermediate lobe of the pituitary.
  183. 203. The major attributes of the hormones other than ACTH that are produced in this process are summarized as follows: Lipotropin: Originally described as having weak lipolytic effects, its major importance is as the precursor to beta-endorphin. Beta-endorphin and Met-enkephalin: Opioid peptides with pain-alleviation and euphoric effects. Melanocyte-stimulating hormone (MSH): Known to control melanin pigmentation in the skin of most vertebrates. 
  184. 204. ACTH acts on steriodogenic tissue of the adrenal glands secrete a number of steriod hormones that profoundly effect carbohydrate and mineral metabolism. Steroid tissue surrounds the adrenal medulla to form the adrenal cortex . 
  185. 205. The Adrenal Gland: When you think about the adrenal glands, you should think about stress . Stress can take many forms: taking an examination, recovering from a broken bone, running away from an invading army, or maintaining proper levels of energy substrates in the face of even mild starvation. For human males, there is even considerable stress associated with shopping . 
  186. 206. The adrenal produces 3 major classes of hormones, each of which aid in dealing with the multitude of small and large stresses faced by animals and people almost daily. There is no doubt that at least 2 of these groups - glucocorticoids and mineralocorticoids - are necessary for life.
  187. 207. The adrenal cortex is a factory for steroid hormones. In total, at least 2-3 dozen different steroids are synthesized and secreted from this tissue, but two classes are of particular importance: Class of Steroid Major Representative Physiologic Effects Mineralocorticoids Aldosterone Na+, K+ and water homeostasis Glucocorticoids Cortisol Glucose homeostasis and many others Additionally, the adrenal cortex produces some sex steroids, particularly androgens.
  188. 208. caused by prolonged exposure of the body's tissues to high levels of the cortisol . Sometimes called &quot;hypercortisolism,&quot; relatively rare and most commonly affects adults aged 20 -50. An estimated 10-15 of every million people are affected each year.
  189. 209. What Are the Symptoms ? Symptoms vary most people have upper body obesity, rounded face, increased fat around the neck, and thinning arms and legs. Children tend to be obese with slowed growth rates.
  190. 210. Symptoms vary most people have upper body obesity , rounded face, increased fat around the neck , and thinning arms and legs . Children tend to be obese with slowed growth rates.
  191. 211. What Are the Symptoms ? Other symptoms appear in the skin, which becomes fragile and thin. It bruises easily and heals poorly. Purplish pink stretch marks may appear on the abdomen, thighs, buttocks, arms and breasts. bones are weakened, and routine activities such as bending, lifting or rising from a chair may lead to backaches, rib and spinal column fractures.
  192. 212. Most people have severe fatigue, weak muscles, high blood pressure and high blood sugar . Irritability, anxiety and depression are common. Women usually have excess hair growth on their faces, necks, chests, abdomens, and thighs. Their menstrual periods may become irregular or stop. Men have decreased fertility with diminished or absent desire for sex.
  193. 213. What Causes Cushing's Syndrome? Cushing's syndrome occurs when the body's tissues are exposed to excessive levels of cortisol for long periods of time. Many people suffer the symptoms of Cushing's syndrome because they take glucocorticoid hormones such as prednisone for asthma, rheumatoid arthritis, lupus and other inflammatory diseases, or for immunosuppression after transplantation.
  194. 214. REMINDER Effects on Inflammation and Immune Function Glucocorticoids have potent anti-inflammatory and immunosuppressive properties. This is particularly evident when they administered at pharmacologic doses, but also is important in normal immune responses. As a consequence, glucocorticoids are widely used as drugs to treat inflammatory conditions such as arthritis or dermatitis, and as adjunction therapy for conditions such as autoimmune diseases.
  195. 215. What Causes Cushing's Syndrome? Others develop Cushing's syndrome because of overproduction of cortisol by the body. Normally, the production of cortisol follows a precise chain of events. CRH-ACTH-cortisol
  196. 216. Cortisol performs vital tasks in the body. helps maintain blood pressure and cardiovascular function, reduces the immune system's inflammatory response, balances the effects of insulin in breaking down sugar for energy, regulates the metabolism of proteins, carbohydrates, and fats.
  197. 217. One of cortisol's most important jobs is to help the body respond to stress. For this reason, women in their last 3 months of pregnancy and highly trained athletes normally have high levels of the hormone. People suffering from depression, alcoholism, malnutrition and panic disorders also have increased cortisol levels.
  198. 218. What Causes Cushing's Syndrome? Pituitary adenomas -&quot; Cushing's disease “ Ectopic ACTH Syndrome Adrenal Tumors Familial Cushing's Syndrome
  199. 219. What Causes Cushing's Syndrome? Pituitary adenomas cause most cases of Cushing's syndrome. secrete increased amounts of ACTH. Most patients have a single adenoma. This form of the syndrome, known as &quot; Cushing's disease ,&quot; affects women 5X more frequently than men.
  200. 220. What Causes Cushing's Syndrome? Ectopic ACTH Syndrome Some benign or malignant (cancerous) tumors that arise outside the pituitary can produce ACTH. Lung tumors cause over 50% of these cases. Men are affected 3X more frequently than women. The most common forms of ACTH-producing tumors are oat cell, or small cell lung cancer, which accounts for about 25% of all lung cancer cases Other less common types of tumors that can produce ACTH are thymomas, pancreatic islet cell tumors, and medullary carcinomas of the thyroid.
  201. 221. What Causes Cushing's Syndrome? Adrenal Tumors Sometimes, an abnormality of the adrenal glands, most often an adrenal tumor, causes Cushing's syndrome. average age of onset is about 40 years. Most cases involve non-cancerous tumors of adrenal tissue which release excess cortisol into the blood. Adrenocortical carcinomas, or adrenal cancers, are the least common cause of Cushing's syndrome. Cancer cells secrete excess levels of several adrenal cortical hormones, including cortisol and adrenal androgens. Adrenocortical carcinomas usually cause very high hormone levels and rapid development of symptoms.
  202. 222. What Causes Cushing's Syndrome? Familial Cushing's Syndrome Most cases of Cushing's syndrome are not inherited. Rarely, however, some individuals have special causes of Cushing's syndrome due to an inherited tendency to develop tumors of one or more endocrine glands. In Primary Pigmented Micronodular Adrenal Disease, children or young adults develop small cortisol-producing tumors of the adrenal glands. In Multiple Endocrine Neoplasia Type I (MEN I), hormone secreting tumors of the parathyroid glands, pancreas and pituitary occur. Cushing's syndrome in MEN I may be due to pituitary, ectopic or adrenal tumors.
  203. 223. How Is Cushing's Syndrome Diagnosed? Often x-ray exams of the adrenal or pituitary glands are useful for locating tumors. 24-Hour Urinary Free Cortisol Level This is the most specific diagnostic test. The patient's urine is collected over a 24-hour period and tested for the amount of cortisol. Levels higher than 50–100 micrograms a day for an adult suggest Cushing's syndrome. The normal upper limit varies in different laboratories, depending on which measurement technique is used.
  204. 224. How Is Cushing's Syndrome Diagnosed? Once Cushing's syndrome has been diagnosed, other tests are used to find the exact location of the abnormality that leads to excess cortisol production. The choice of test depends, in part, on the preference of the endocrinologist or the center where the test is performed.
  205. 225. How Is Cushing's Syndrome Diagnosed? Dexamethasone Suppression Test This test helps to distinguish patients with excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumors. Patients are given dexamethasone, a synthetic glucocorticoid, by mouth every 6 hours for 4 days. For the first 2 days, low doses of dexamethasone are given, and for the last 2 days, higher doses are given. Twenty-four hour urine collections are made before dexamethasone is administered and on each day of the test.
  206. 226. Dexamethasone Suppression Test Since cortisol and other glucocorticoids signal the pituitary to lower secretion of ACTH, the normal response after taking dexamethasone is a drop in blood and urine cortisol levels. Different responses of cortisol to dexamethasone are obtained depending on whether the cause of Cushing's syndrome is a pituitary adenoma or an ectopic ACTH-producing tumor.
  207. 227. How Is Cushing's Syndrome Diagnosed? CRH Stimulation Test This test helps to distinguish between patients with pituitary adenomas and those with ectopic ACTH syndrome or cortisol-secreting adrenal tumors. Patients are given an injection of CRH, which causes the pituitary to secrete ACTH. Patients with pituitary adenomas usually experience a rise in blood levels of ACTH and cortisol. This response is rarely seen in patients with ectopic ACTH syndrome and practically never in patients with cortisol-secreting adrenal tumors.
  208. 228. How Is Cushing's Syndrome Diagnosed? Direct Visualization of the Endocrine Glands (Radiologic Imaging) Imaging tests reveal the size and shape of the pituitary and adrenal glands and help determine if a tumor is present. most common are the CT (computerized tomography) scan and MRI (magnetic resonance imaging). A CT scan produces a series of x-ray pictures giving a cross-sectional image of a body part. MRI also produces images of the internal organs of the body but without exposing the patient to ionizing radiation.
  209. 229. How Is Cushing's Syndrome Diagnosed? Petrosal Sinus Sampling This test is not always required, but in many cases, it is the best way to separate pituitary from ectopic causes of Cushing's syndrome. Samples of blood are drawn from the petrosal sinuses, veins which drain the pituitary, by introducing catheters through a vein in the upper thigh/groin region, with local anesthesia and mild sedation. X-rays are used to confirm the correct position of the catheters.
  210. 230. X-rays are used to confirm the correct position of the catheters.
  211. 231. How Is Cushing's Syndrome Diagnosed? Petrosal Sinus Sampling ACTH levels are measured in each of the blood samples obtained during the procedure. The ratios between the petrosal sinus sampling and the peripheral vein samples are compared. The results are used to determine whether ACTH production is due to either a pituitary or a non-pituitary source.
  212. 232. How Is Cushing's Syndrome Diagnosed? Petrosal Sinus Sampling Usually CRH, the hormone which causes the pituitary to secrete ACTH, is given during this test to improve diagnostic accuracy. Levels of ACTH in the petrosal sinuses are measured and compared with ACTH levels in a forearm vein. ACTH levels higher in the petrosal sinuses than in the forearm vein indicate the presence of a pituitary adenoma; similar levels suggest ectopic ACTH syndrome.
  213. 233. How Is Cushing's Syndrome Diagnosed? Imaging procedures are used to find a tumor after a diagnosis has been established. Imaging is not used to make the diagnosis of Cushing's syndrome because benign tumors, sometimes called &quot;incidentalomas,&quot; are commonly found in the pituitary and adrenal glands. These tumors do not produce hormones detrimental to health and are not removed unless blood tests show they are a cause of symptoms or they are unusually large. Conversely, pituitary tumors are not detected by imaging in almost 50 % of patients who ultimately require pituitary surgery for Cushing's syndrome.
  214. 234. How Is Cushing's Syndrome Treated? Pituitary Adenomas Several therapies are available to treat the ACTH-secreting pituitary adenomas of Cushing's disease. The most widely used treatment is surgical removal of the tumor.
  215. 235. How Is Cushing's Syndrome Treated? Pituitary Adenomas If surgery has failed or person not suitable candidates for surgery, radiotherapy is another possible treatment. Radiation to the pituitary gland is given over a 6-week period, with improvement occurring in 40-50 % of adults and up to 80% of children. It may take several months or years before patients feel better from radiation treatment alone. However, the combination of radiation and the drug mitotane (Lysodren®) can help speed recovery.
  216. 236. How Is Cushing's Syndrome Treated? Pituitary Adenomas Mitotane suppresses cortisol production and lowers plasma and urine hormone levels . Treatment with mitotane alone can be successful in 30- 40 % of patients. Other drugs used alone or in combination to control the production of excess cortisol: Aminoglutethimide metyrapone trilostane and ketoconazole ,
  217. 237. MITOTANE As a chemical, mitotane resembles the insecticides DDD and DDT, although mitotane does not harm people as these do. Scientists do not understand why, but the drug causes damage to the adrenocortex in such a way as to be helpful for some patients with adrenal disease including tumors. In addition, mitotane restricts the ability of the gland to produce chemicals.
  218. 238. How Is Cushing's Syndrome Treated? Ectopic ACTH Syndrome To cure the overproduction of cortisol caused by ectopic ACTH syndrome, it is necessary to eliminate all of the cancerous tissue that is secreting ACTH. The choice of cancer treatment—surgery, radiotherapy, chemotherapy, immunotherapy, or a combination of these treatments—depends on the type of cancer and how far it has spread. Since ACTH-secreting tumors (for example, small cell lung cancer) may be very small or widespread at the time of diagnosis, cortisol-inhibiting drugs, like mitotane, are an important part of treatment.
  219. 239. How Is Cushing's Syndrome Treated? Ectopic ACTH Syndrome In some cases, if pituitary surgery is not successful, surgical removal of the adrenal glands (bilateral adrenalectomy) may take the place of drug therapy.
  220. 240. How Is Cushing's Syndrome Treated? Adrenal Tumors Surgery is the mainstay of treatment for benign as well as cancerous tumors of the adrenal glands.
  221. 241. Addison's disease occurs when the adrenal glands do not produce enough of the hormone cortisol and, in some cases, the hormone aldosterone. The disease is also called adrenal insufficiency, or hypocortisolism .
  222. 242. Multiple functions of cortisol Aldosterone Aldosterone belongs to a class of hormones called mineralocorticoids, also produced by the adrenal glands. It helps maintain blood pressure and water and salt balance in the body by helping the kidney retain sodium and excrete potassium.
  223. 243. Symptoms of ADDISON’S Disease The symptoms of adrenal insufficiency usually begin gradually. Characteristics of the disease are chronic, worsening fatigue muscle weakness loss of appetite weight loss About 50 % of the time, one will notice nausea vomiting diarrhea
  224. 244. Other Symptoms low blood pressure that falls further when standing, causing dizziness or fainting skin changes in Addison's disease, with areas of hyper-pigmentation, or dark tanning, covering exposed and nonexposed parts of the body; this darkening of the skin is most visible on scars; skin folds; pressure points such as the elbows, knees, knuckles, and toes; lips; and mucous membranes Addison's disease can cause irritability and depression. Because of salt loss, a craving for salty foods also is common. Hypoglycemia, or low blood glucose, is more severe in children than in adults. In women, menstrual periods may become irregular or stop.
  225. 245. Because the symptoms progress slowly, they are usually ignored until a stressful event like an illness or an accident causes them to become worse. This is called an addisonian crisis , or acute adrenal insufficiency. In most cases, symptoms are severe enough that patients seek medical treatment before a crisis occurs. However, in about 25% of patients, symptoms first appear during an addisonian crisis. Symptoms of an addisonian crisis include sudden penetrating pain in the lower back, abdomen, or legs severe vomiting and diarrhea dehydration low blood pressure loss of consciousness
  226. 246. Diagnosis In its early stages, adrenal insufficiency can be difficult to diagnose. A review of a patient's medical history based on the symptoms, especially the dark tanning of the skin , will lead a doctor to suspect Addison's disease. A diagnosis of Addison's disease is made by laboratory tests. The aim of these tests is first to determine whether levels of cortisol are insufficient and then to establish the cause. X-ray exams of the adrenal and pituitary glands may be useful in helping to establish the cause.
  227. 247. Diagnosis ACTH Stimulation Test This is the most specific test for diagnosing Addison's disease. In this test, blood cortisol, urine cortisol, or both are measured before and after a synthetic form of ACTH is given by injection. In the so-called short, or rapid, ACTH test, measurement of cortisol in blood is repeated 30 to 60 minutes after an intravenous ACTH injection. The normal response after an injection of ACTH is a rise in blood and urine cortisol levels. Patients with either form of adrenal insufficiency respond poorly or do not respond at all.
  228. 248. Diagnosis CRH Stimulation Test When the response to the short ACTH test is abnormal, a &quot;long&quot; CRH stimulation test is required to determine the cause of adrenal insufficiency. In this test, synthetic CRH is injected intravenously and blood cortisol is measured before and 30, 60, 90, and 120 minutes after the injection. Patients with primary adrenal insufficiency have high ACTHs but do not produce cortisol. Patients with secondary adrenal insufficiency have deficient cortisol responses but absent or delayed ACTH responses. Absent ACTH response points to the pituitary as the cause; a delayed ACTH response points to the hypothalamus as the cause.
  229. 249. Diagnosis CRH Stimulation Test In patients suspected of having an addisonian crisis, the doctor must begin treatment with injections of salt, fluids, and glucocorticoid hormones immediately. Although a reliable diagnosis is not possible while the patient is being treated for the crisis, measurement of blood ACTH and cortisol during the crisis and before glucocorticoids are given is enough to make the diagnosis. Once the crisis is controlled and medication has been stopped, the doctor will delay further testing for up to 1 month to obtain an accurate diagnosis.
  230. 250. Causes Failure to produce adequate levels of cortisol can occur for different reasons. The problem may be due to a disorder of the adrenal glands themselves (primary adrenal insufficiency) or to inadequate secretion of ACTH by the pituitary gland (secondary adrenal insufficiency).
  231. 251. Primary Adrenal Insufficiency- Addison's disease affects about 1 in 100,000 people. Most cases are caused by the gradual destruction of the adrenal cortex by the body's own immune system. About 70% of reported cases of Addison's disease are caused by autoimmune disorders, in which the immune system makes antibodies that attack the body's own tissues or organs and slowly destroy them.
  232. 252. Primary Adrenal Insufficiency- Addison's disease cause Adrenal insufficiency occurs when at least 90% of the adrenal cortex has been destroyed. As a result, often both glucocorticoid (cortisol) and mineralocorticoid (aldostertone) hormones are lacking. Sometimes only the adrenal gland is affected, as in idiopathic adrenal insufficiency; sometimes other glands also are affected, as in the polyendocrine deficiency syndrome.
  233. 253. Causes Tuberculosis TB an infection which can destroy the adrenal glands , accounts for about 20% of cases of primary adrenal insufficiency in developed countries. When adrenal insufficiency was first identified by Dr. Thomas Addison in 1849, TB was found at autopsy in 70 -90% of cases. As the treatment for TB improved, however, the incidence of adrenal insufficiency due to TB of the adrenal glands has greatly decreased.
  234. 254. Other Causes Less common causes of primary adrenal insufficiency are chronic infection, mainly fungal infections cancer cells spreading from other parts of the body to the adrenal glands surgical removal of the adrenal glands
  235. 255. Secondary Adrenal Insufficiency This form of adrenal insufficiency is much more common than primary adrenal insufficiency and can be traced to a lack of ACTH. Without ACTH to stimulate the adrenals, the adrenal glands' production of cortisol drops, but not aldosterone. A temporary form of secondary adrenal insufficiency may occur when a person who has been receiving a glucocorticoid hormone such as prednisone for a long time abruptly stops or interrupts taking the medication. WHY??? Glucocorticoid hormones block the release of both CRH and ACTH.
  236. 256. Treatment Treatment of Addison's disease involves replacing, or substituting, the hormones that the adrenal glands are not making. Cortisol is replaced orally with hydrocortisone tablets, a synthetic glucocorticoid, taken once or twice a day. If aldosterone is also deficient, it is replaced with oral doses of a mineralocorticoid called fludrocortisone acetate (Florinef), which is taken once a day. Patients receiving aldosterone replacement therapy are usually advised by a doctor to increase their salt intake. Because patients with secondary adrenal insufficiency normally maintain aldosterone production, they do not require aldosterone replacement therapy.
  237. 257. Treatment During an addisonian crisis, low blood pressure, low blood glucose, and high levels of potassium can be life threatening. Standard therapy involves intravenous injections of hydrocortisone, saline (salt water), and dextrose (sugar). This treatment usually brings rapid improvement.