Nu Patho Study Guide 3

41. Know how protein hormones are transmitted in the blood.

(p. 691, 7th ed) Protein hormones (peptide hormones) are water soluble and circulate in free (unbound) forms throughout the body. Most water soluble hormones activate G protein-linked receptors. Water soluble hormones act as first messengers, binding to receptors on the cell's plasma membrane. The signals initiated by hormone-receptor binding are then transmitted into the cell by the action of the second messenger. Water soluble hormones generally have a short half-life because they are catabolized by circulating enzymes.

25. What is aldosterone and why do we need it?

(p. 101-102, 717-718; 6th ed) (p. 108-109, 708-709, 7th ed) Aldosterone is the most potent of the naturally occurring mineralocortocoids and acts to conserve sodium by increasing the activity of the sodium pump of the epithelial cells. It is synthesized and secreted in the adrenal cortex. In the kidney, aldosterone primarily acts to increase sodium ion reabsorption (thus promoting water reabsorption), and increase K+ and hydrogen ion excretion. High aldosterone levels may lead to alkalosis and hypokalemia. Aldosterone secretion is influenced by plasma levels of Na+, K+, and circulating blood volume (aldosterone is secreted when Na+ levels are low, K+ levels are high, or renal perfusion is decreased.) Aldosterone increases reabsorption of Na+ (and H2O) and secretion of K+ by the distal tubule of the kidney. Thus, ECF concentration of Na+ increases and K+ is excreted in the urine. This is a vital component of the renin-angiotensisn-aldosterone system, a mechanism by which Na+ and H20 levels are regulated by the body. Stimulation of aldosterone secretion is influenced by Angiotensin II. Pathologically elevated levels of aldosterone have been implicated in the myocardial changes associated with heart failure. Aldosterone conserves sodium, blood volume, and blood pressure. Functions: Conserves sodium, blood volume, and blood pressure. Maintains extracellular volume by acting on distal nephron epithelial cells to increase sodium reabsorption and potassium and hydrogen excretion. Other effects of aldosterone include: enhancement of cardiac muscle contraction, stimulation of ectopic ventricular activity through secondary cardiac pacemakers in the ventricles, stiffening of the blood vessels with increased vascular resistance, decreased fibroinolysis. Pathologically elevated levels of aldosterone have been implicated in the myocardial changes associated with heart failure.

43. Know the relationship between calcium and phosphorus.

(p. 111-112, 711; 6th ed) (p. 119, 733; 7th ed) Calcium and phosphate balance is rigidly controlled; if the concentration of one ion increases, that of the other decreases. Their relationship is inverse. Calcium and phosphate balance is regulated by three hormones: parathyroid hormone (PTH), vitamin D, and calcitonin. Acting together, these substances determine the amount of dietary calcium and phosphate absorbed from the intestine, the deposition and absorption of calcium and phosphate from the bone, and the renal reabsorption and excretion of calcium and phosphate by the kidney. The parathyroid glands are sensitive to calcium concentrations, and the PTH controlled ionized calcium in the blood and extracellular fluids. Parathyroid glands secrete PTH in response to low serum calcium. The renal regulation of calcium and phosphate balance requires PTH. A lack of circulating PTH causes depressed serum calcium levels and increased serum phosphate levels. In the absence of PTH, resorption of calcium from bone and regulation of calcium reabsorption from the renal tubules are impaired. Calcium also increases intraparathyroid destruction of PTH but does not affect the rate of PTH synthesis. Magnesium and phosphate levels also affect PTH secretion. Hyperphosphatemia leads to hypocalcemia because of calcium-phosphate precipitation in soft tissue and bone. Alterations in serum phosphate levels therefore may indirectly influence PTH secretion by affecting serum calcium levels. The overall effect of PTH is to increase serum calcium and to decrease serum phosphate concentration. ANSWER 2: Know the relationship between calcium and phosphorus: Calcium and phosphorus have an inverse relationship thus, if the concentration of one ion increases or decreases, that of the other increases or decreases. Calcium and phosphate balance is regulated by Parathyroid hormone (PTH), Vitamin D, and Calcitonin. PTH: Stimulates reabsorption of calcium along the distal tubule of the nephron and inhibits phosphate reabsorption by the proximal tubule of the nephron, resulting in increased in serum calcium and increased urinary excretion of phosphate. Hyperphosphatemia is associated with inhibition of the renal enzyme necessary for the conversion of vitamin D to its active form. This depressed serum calcium levels by reducing gastrointestinal absorption of calcium. Vitamin D: (Cholecalciferol) The renal activation of vitamin D begins when the serum calcium level decreases and stimulates secretion of PTH. PTH then acts to increase calcium reabsorption and enhance renal excretion of phosphate, producing decreased phosphate level. The combination of low calcium level and increased PTH secretion causes the renal activation of vitamin D. The activated vitamin D (D3 calcitriol) increases absorption of calcium and phosphate I the in the small intestine, enhance bone calcification, ad increase renal tubular reabsorption of calcium and phosphate. In renal failure, vit D is not activated; serum calcium level decreases, phosphate level increases. Calcitonin: (produced by C cells of the thyroid gland) primarily decreases calcium levels by inhibiting osteoclastic activity in bone.

28. Understand the role of insulin, how does insulin affect potassium.

(p. 114, 704-706, 7th ed) Role of insulin: Insulin is an anabolic hormone synthesized by the beta cells of the pancreas that circulates freely in the plasma. It promotes the synthesis of proteins, carbs, lipids, and nucleic acids in the liver, muscle, and adipose tissue (see table 20-8) with a net effect to stimulate cellular metabolism. The major consequence of insulin release is to decrease blood glucose as well as stimulate protein and fat synthesis. By binding to its tyrosine-kinase receptor subtype (initiating a series of events) insulin facilitates a 10-20 fold increase rate of glucose uptake into many cells within the body, particularly skeletal and cardiac muscle, liver, and adipose cells (figure 20-16). The sensitivity of the insulin receptor is a key component in maintaining normal cellular function. The brain and red blood cells do not require insulin for glucose transport. Insulin secretion is promoted by increased blood levels of glucose, amino acids (arginine and lysine), serum free fatty acids, and gastrointestinal hormones, and by parasympathetic stimulation of the beta cells. Insulin secretion is diminished in response to low blood glucose levels (hypoglycemia), high levels of insulin (negative feedback to the beta cells), and sympathetic stimulation of the alpha cells in the islets. Prostaglandin also inhibits insulin secretion. Insulin and Potassium: Insulin also facilitates the intracellular transport of potassium, phosphate, and magnesium. Insulin contributes to the regulation of plasma potassium levels by stimulating the sodium-potassium-APase pump, thereby promoting the movement of potassium into liver and muscle cells simultaneously with glucose transport. Insulin can also be used to treat hyperkalemia; however, dangerously low levels of plasma potassium can result from the administration of insulin when potassium levels are depressed. Insulin facilitates intracellular potassium transport; thus decreasing extra cellular potassium.

30. Understand the roles of epinephrine and norepinephrine.

(p. 340, 719; 6th ed) (p. 345-346, 710; 7th ed) The adrenal medulla, together with the sympathetic division of the autonomic nervous system, is embryonically derived from neural crest cells. The adrenal medulla functions as a sympathetic ganglion without postganglionic processes. Chromaffin cells (pheochromacytes) are the cells of the adrenal medulla. The major products stored and secreted by the chromaffin cells are the catecholamines epinephrine (adrenaline) and norepinephrine, which are synthesized from the amino acid phenylalanine. Only 30% of circulating epinephrine comes from the adrenal medulla; the other 70% of is released from nerve terminals. The medulla is only a minor source of norepinephrine. Adrenal catecholamines are stored in secretory granules within the chromaffin cells. Physiologic stress to the body (e.g. traumatic injury, hypoxia, hypoglycemia, and many others) triggers release of adrenal catecholamines through acetylcholine (from the preganglionic sympathetic fibers), which depolarizes the chromaffin cells. Depolarization causes exocytosis of the storage granules from the chromaffin cells with release of epinephrine and norepinephrine into the bloodstream; therefore, the catecholamines from the adrenal medulla are hormones and not neurotransmitters. Once released, the catecholamines remain in the plasma for only seconds to minutes. The catecholamines exert their biologic effects after binding to a plasma membrane receptor (alpha-1, alpha-2, beta-1, or beta-2) in target cells and activating the adenylyl cyclase system. Catecholamines have diverse effects on the entire body. Their release and the body's response have been characterized as the "fight or flight" response. The metabolic effects of catecholamines promote hyperglycemia through a variety of mechanisms and through interference with usual glucose regulatory feedback mechanisms. (p.710) Catecholamines circulate bound to the protein albumin once they are released from the adrenal medulla. Norepinephrine: Norepinephrine regulates blood pressure by constricting smooth muscle in all blood vessels. During stress, norepinephrine raises blood pressure by constricting peripheral vessels; it dilates the pupils of the eye, causes piloerection, and increases sweat gland action in the armpits and palms. Epinephrine: Epinephrine is rapidly transported to and acts on several organs, but it is metabolized quickly, making it short-acting. Metabolically, epinephrine causes transient hyperglycemia (high blood glucose level), decreases glucose uptake in the muscles and other organs, and decreases insulin release from the pancreas. This is accomplished by activating enzymes whose actions promote glucose formation (gluconeogenesis) and glycogen breakdown (glycogenolysis) in the liver, while inhibiting glycogen formation. This prevents glucose from being taken up by peripheral tissue and preserves it for the CNS. Further, very little adrenal norepinephrine reaches distal tissue; thus, the effects caused by norepinephrine during the stress response are primarily elicited from the SNS. Epinephrine has a greater influence on cardiac action and is the principal catecholamine involved in metabolic regulation. Epinephrine enhances myocardial contractility (inotropic effect), increases the heart rate (chronotropic effect), and increases venous return to the heart, all of which increases cardiac output and blood pressure. Epinephrine dilates blood vessels of skeletal muscle, allowing for greater oxygenation. Epinephrine also mobilizes free fatty acids and cholesterol by stimulating lipolysis, freeing triglycerides and fatty acids from fat stores, and by inhibiting degradation of circulating cholesterol to bile acids. The catecholamines, epinephrine and norepinephrine, stimulate two major classes of receptors: alpha-adrenergic receptors and beta-adrenergic receptors. Epinephrine binds to and activates both alpha and beta receptors. Norepinephrine binds primarily to an alpha-adrenergic at physiologic concentrations. Catecholamines can modify the numbers of cells of the immune system circulating in the blood. Injection of epinephrine into healthy human subjects is associated with a transient increase of the number of lymphocytes in the peripheral blood.

32. Where are the target cells for each hormone located?

(p. 689-693, 7th ed) The target cell hormone receptors have two main functions: (1) to recognize and bind with high affinity to their particular hormones and (2) to initiate a signal to appropriate intracellular effectors. Hormone receptors may be located in or on the plasma membrane or in the intracellular compartment of the target cell. Water-soluble hormones have a high molecular weight and cannot diffuse across the cell membrane. They interact or bind with receptors in or on the cell membrane and mediate short-acting responses. Lipid-soluble steroids, vitamin D, retinoic acid, and thyroid hormones diffuse freely across the plasma and nuclear membranes and bind with cytosolic or nuclear receptors.

29. What is the role of TSH? Where is it secreted? Know the negative feedback loop

(p. 690-691, 700-702, 7th ed) Role: The effects of TSH on the thyroid include; (1) an immediate increase in the release of stored thyroid hormones, (2) an increase in iodide uptake and oxidation, (3) an increase in thyroid hormone synthesis, and (4) an increase in the synthesis and secretion of prostaglandins by the thyroid. TSH is also important in stimulating the growth and maintenance of the thyroid gland by stimulating thyrocyte hypertrophy and hyperplasia and decreasing apoptosis. Secretion: Thyroid-stimulating hormone (TSH) is a glycoprotein hormone synthesized and stored within the anterior pituitary. TSH is secreted from cells in the anterior pituitary called thyrotrophs (thyrotropic). It circulates to bind with TSH receptor sites located on the outer side of the thyroid cell's plasma membrane. Negative-feedback loop: Negative-feedback is the most common type of feedback system. In Negative-feedback system, plasma levels of one type of hormone influence the level of other types of hormones. Increased anterior pituitary release of TSH stimulates the synthesis and secretion of TH. TSH is inhibited by thyroxin (T4) and to a lesser extent by triiodothyronine (T3). TSH secretion is regulated by TRH primarily in the hypothalamus and by the negative-feedback inhibition from TH. Negative-feedback maintains hormones within physiologic ranges. Lack of negative-feedback inhibition on hormonal release often results in pathologic conditions. The concentration of thyroid hormones (T3 and T4) in the blood regulates the pituitary release of TSH; when T3 and T4 concentrations are low, the production of TSH is increased, and, conversely, when T3 and T4 concentrations are high, TSH production is decreased.

34. Oxytocin-where is it secreted, what are its effects?

(p. 696, 699, 7th ed) Oxytocin is responsible for contraction of the uterus during labor and milk ejection in lactating women and may affect sperm motility in men. In women, oxytocin is secreted in response to suckling and mechanical distention of the female reproductive tract. Stimulated by sucking, oxytocin binds to its receptors on myoepithelial cells in the mammary tissues and causes contraction of those cells. This results in increased intramammary pressure and milk expression ("let down" reflex). In response to distention of the uterus, oxytocin stimulates contractions. Oxytocin functions near the end of labor to enhance the effectiveness of contractions, promote delivery of the placenta, and stimulate postpartum uterine contractions, thereby preventing excessive bleeding. Oxytocin has been implicated in behavior responses, especially in women. It has been suggested that oxytocin and its receptor play a role in the brain's responsiveness to stressful stimuli, especially in the pregnant and postpartum states.

27. What is oxytocin? How does it relate to the pituitary gland?

(p. 698-699, 7th ed) Oxytocin: Oxytocin is responsible for contraction of the uterus and milk ejection in women and may effect sperm motility in men. In women, oxytocin is secreted in response to sucking and distention of the female reproductive tract. Stimulated by sucking, this results in increased intramammary pressure and milk expression ('letdown" reflex). Oxytocin functions near the end of labor to enhance the effectiveness of contractions, promote delivery of the placenta, and stimulate postpartum uterine contractions. oxytocin has also been implicated in the behavioral response in the brains response to stress, especially in pregnant and postpartum states. Relationship to pituitary: Oxytocin is secreted by the posterior pituitary. The posterior pituitary can be seen as a storage and releasing site for hormones synthesized in the hypothalamus. The release of oxytocin is mediated by cholinergic and adrenergic neurotransmitters. The major stimulus to release is glutamate, whereas the major inhibitor is GABA.

42. Know ADH. Where is it secreted? Where does it act?

(p. 706, 6th ed) (p. 698, 7th ed) What is ADH? ADH is a polypeptide hormone. Also called arginine- vasopressin. It is synthesized in the supraoptic and periventricular nuclei of the hypothalamic neurons. It is packaged and moved in secretory vesicles down the axons of the pituitary stalk for storage in the pars nervosa. It is secreted by the posterior pituitary. ADH travel to posterior pituitary by way of the hypothalamohypophysial nerve tract. (MADE IN THE HYPOTHALAMUS, PACKAGED IN PITUITARY STALK, STORED IN PARS NERVOSA). The release of ADH is directed by cholinergic/ adrenergic neurotransmitters. The major stimulus to the release is GLUTAMATE, whereas its inhibition is directed by GABA. *Think of the Posterior Pituitary as the storage and releasing site for the hypothalamus' hormones (ADH and oxytocin)* *Posterior pituitary's major function is PLASMA OSMOLALITY CONTROL* Where is it secreted? The secretion of ADH is regulated primarily by the OSMORECEPTORS OF THE HYPOTHALAMUS (near/in in supraoptic nuclei- also where is is made). The osmoreceptors are stimulated by increasing plasma osmolality= H2O reabsorbed from the kidney which goes to blood = plasma dilution (Side note- ADH has NO effect on electrolytes, but you will see decreased serum electrolyte concentrations when this happens). Another stimulus to ADH secretion is CHANGES IN INTRAVASCULAR VOLUME (these changes are monitored by mechanoreceptors in the left atrium, carotid, and aortic arches). A volume loss of 7%-25% causes increased ADH secretion. Stress, nicotine, trauma, pain, exercise, nausea and heat exposure can also trigger increased ADH secretion. ADH secretion decreases with a decrease in plasma osmolality, increased intravascular volume (think: ADH holds onto H2O- don't want anything extra), hypertension, increased estrogen, progesterone, alcohol ingestion, and angiotensin II Where does it act? Plasma osmolality is regulated by ADH.: a.) At physiologic levels, ADH acts on VASOPRESSIN 2 of the renal tubules to increase the tubules' permeability. Increased permeability. Increased H2O reabsorption at the tubules in kidneys (Holds onto H2O) More H2O in blood and more concentrated urine This process can be inhibited: Prostglandin E, hypercalcemina, and hypokalemia b.) At pathophysiologically HIGH SERUM levels, ADH acts on VASOPRESSIN 1 and causes vasoconstriction Increased BP *This baroreceptor response is much more SENSITIVE than ADH response to changes in osmolality * ADH does not significantly affect vessel tone (vasoconstriction, vasodilation). Therefore, this needs to be achieved pharmacologically. High doses of ADH, or VASOPRESSIN, can be given to patients during hemorrhage, and shock to increase BP

26. What is the role of calcitonin?

(p. 709, 6th ed) (p. 702, 7th ed) Table 21-6, Pg. 701 Calcitonin (thyrocalcitonin) acts to lower serum calcium levels by inhibition of bone-resorbing osteoclasts. High levels of calcitonin are required for the bone-resorbing effect to take place yet deficiencies do not lead to hypocalcemia. Consequently, the metabolic effects of calcitonin deficiency or excess do not appear to be significant in humans. Calcitonin is used in the treatment of osteoporosis, osteoarthritis, Paget bone disease, hypercalcemia, osteogenesis imperfect, and metastatic cancer of the bone. The precursor molecule to calcitonin (procalcitonin) is a stress hormone that is elevated in infectious and inflammatory disorders and its measurement can aid in the diagnosis of these serious diseases. Lowers serum phosphate levels May also decrease calcium and phosphorus absorption in GI

31. What is parathyroid hormone? What are the effects of PTH?

(p. 711-712, 6th ed) (p. 702-703, 7th ed) The parathyroid glands produce parathyroid hormone (PTH), a regulator of serum calcium. PTH works in concert with vitamin D to increase serum calcium concentration. PTH is regulated primarily by the level of ionized plasma calcium, although how these regulatory mechanisms work is not precisely clear. Calcium also increase intraparathyroid destruction of PRH but apparently does not affect the rate of PRH synthesis. Magnesium and phosphate levels also affect PTH secretion. Hypomagnesemia in persons with normal calcium levels acts as a mild stimulant to PTH secretion. Hypomagnesemia decreases PTH secretion. Hyperphosphatemia leads to hypocalcemia because of calcuim-phosphate precipitation in soft tissue and bone. Alterations in serum phosphate levels therefor may indirectly influence PTH secretion by affection serum calcium levels. (Figure 20-13). The overall effect of PTH is to increase serum calcium and to decrease serum phosphate concentration. Once the parathyroid gland is stimulated, PTH is secreted. Once released, PTH enters the circulation in unbound form. The hormone attaches to plasma membrane receptors in target tissues, where the biologic effects of PTH are mediated primarily by activation of the adenylyl cyclase system. PTH is the single most important factor in the regulation of serum calcium levels. To achieve regulation of serum calcium, PTH acts directly on bone and kidneys. In bone, PTH has at least two effects. In acute hypocalcemia. PTH secretions stimulates osteoblast to release receptor activator for nuclear factor-kappa beta ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) which result s in osteoclast proliferation, maturation, and release of acidic enzymes, such as cathepsin. These enzymes mobilize calcium form bone which increase the serum calcium. In the kidneys, PTH acts on its plasma membrane receptor in the distal an proximal tubules of the nephron to increase reabsorption of calcium and to decrease reabsorption of phosphorus, respectively. PTH also decreases proemial tubule reabsorption of bicarbonate. In the kidney, PTH stimulates the synthesis of biologically active form of vitamin D (1,25-dihydroxy-vitamin D3) serves as a cofactor with PTH for osteoblast stimulation and, and as potent stimulator of calcium and phosphate absorption in the intestine. In this way PTH increases gastrointestinal absorption of calcium.

23. Know the pathophysiology, etiology, clinical manifestations, treatment and complications of syndrome of inappropriate antidiuretic hormone (SIADH)?

(p. 718-719, 7th ed) Diseases of the posterior pituitary gland and causes abnormal secretion of ADH. An excessive amount of ADH results in water retention and a hypoosmolar state (SIADH), whereas a deficiency in the amount or response to this hormone results in serum hyperosmolarity (Diabetes Insipidus). Syndrome of inappropriate antidiuretic hormone (SIADH) secretion is characterized by high levels of ADH in the absence of normal physiologic stimuli for its release. It can complicate: • Malignancies: SIADH is associated with ectopic secretion of ADH by several types of tumor cells. Tumors reported to have been associated with SIADH include: small cell carcinoma of the lung, duodenum, stomach, pancreas, bladder, prostate, endometrium, lymphomas, & sarcomas. • Pulmonary disorders associated with SIADH include: pneumonia, TB, asthma, cystic fibrosis, & resp. failure requiring mechanical ventilation. • CNS disorders that may cause SIADH include: encephalitis, meningitis, intracranial hemorrhage, tumors, & trauma. • Surgical procedures: Any surgery can result in post-op fluid volume shifts & transient SIADH for 5-7 days after surgery. The exact mechanism is unknown but SIADH is most likely related to fluid & volume changes, amount & type of IVF given, and the use of narcotic analgesics. It is especially common after surgery of the pituitary gland where store ADH is released in an unregulated fashion. • Use of certain medications: (especially in older adults) Antidepressants, antipsychotics, narcotics, general anesthetics, chemo agents, NSAIDS, quinolone antibiotics, & synthetic ADH analogs can all be important causes of SIADH. These drugs serve to either simulate ADH release, to enhance the physiologic effects of ADH, or to have a biologic action similar to ADH. • Neurogenic: In these individuals, mutations in arginine vasopressin (AVP) genes lead to chronic activation of tubular V2 receptor and resulting excessive free water reabsorption. Pathophysiology: Water retention results from the action ADH on renal collecting ducts, where it increases their permeability to water, thus increasing water reabsorption by the kidneys. This results in expansion of extracellular fluid volume that leads to dilutional hyponatremia, hypoosmolarity, & urine that is inappropriately concentrated with respect to serum osmolarity. Clinical Manifestations: The symptoms of SIADH result for hypotonic (dilutional) hyponatremia & are associated with hypervolemia & weight gain. The severity & rapidity of onset of the hyponatremia determine the extent of symptoms: • Sodium that decreases rapidly from 140-130meq/L Thirst, impaired taste, anorexia, dyspnea on exertion, fatigue, & dulled sensorium. • Sodium level between 130-120mEq/Lsevere GI symptoms such as vomiting & abdominal cramps. Peripheral edema is usually absent. • Sodium level below 115mEq/Lconfusion, lethargy, muscle twitching, & seizures may occur. • Sodium level below 110mEq/Leven slow decreases in sodium at this level will cause severe & sometimes irreversible neurologic damage. Symptoms resolve with correction of hyponatremia. Evaluation & Treatment: Diagnosis: (1) Serum hypoosmolarity (<280mOsm/kg) & hyponatremia (serum sodium level <135mEq/L) (2) Urine hyperosmolarity (the osmolarity of the urine is always higher than the concurrent serum osmolarity) (3) Urine sodium excretion that matches sodium intake. (4) Normal renal, adrenal, & thyroid function (5) Absence of conditions that can alter volume status (recent diuretic usage, HF, hypervolemia from any cause, or renal insufficiency). Individuals with neurologic injury may develop hyponatremia caused by cerebral salt wasting syndrome but it is easily differentiated from SIADH because it characterized by hypovolemia, weight loss, & urine sodium levels are elevated. Treatment: Involves correction of the underlying problem: emergency correction of severe hyponatremia by administration of hypertonic saline (ex. 3% NS) & MOST IMPORTANTLY, fluid restriction to 800-1000ml/day. Careful monitoring is important. Resolution occurs within 3 days, with a 2-3kg weight loss resulting from increased water clearance. If hyponatremia is corrected too quickly, a severe neurologic syndrome call central pontine myelinolysis can ensue. Although no drug therapy is available to suppress ectopically produced ADH, Demeclocycline, which causes renal tubules to develop resistance to ADH, may be used to treat chronic/resistant SIADH. Conivaptan, an ADH receptor agonist has been approved for the treatment of hospitalized patients with hyponatremia caused by ADH excess. An oral form of ADH receptor antagonists has been developed.

44. Know the pathophysiology, etiology, clinical manifestations, treatment and complications of diabetes insipidus. Neurogenic and nephrogenic

(p. 719-720, 7th ed) Diabetes insipidus (DI) is an insufficiency of ADH, leading to polyuria (frequent urination) and polydipsia (frequent drinking). There are three forms: Neurogenic (hypothalamic), nephrogenic (renal) and plydipsic (polydipsia-poluria syndrome). Neurogenic DI is the form encountered most often in clinical practice and is caused by insufficient amounts of ADH. It occurs when any organic lesion of the hypothalamus, or posterior pituitary interferes with ADH synthesis, transport or release. Causative lesions include primary or secondary brain tumors, aneurysms, thrombosis, infections, and immunologic disorders. DI is a well-recognized complication of closed-head trauma and of pituitary surgery in which DI can be transient or permanent. Neurogenic DI can be a complication of pregnancy. In rare cases, it also can be caused by hereditary disorders that affect ADH genes or result in structural changes in the pituitary gland, such as septo-optic dysplasia (absence of the septum pellucidum in the brain and underdevelopment of the optic nerve). Nephrogenic DI is associated with an insensitivity of the renal collecting tubules to ADH. The nephrogenic from of DI can be genetic of acquired. This from of DI is often idiopathic, although several genetic abnormalities that the affect the vasopressin receptor have been noted. One of the best described is a mutation in the gene that codes for aquaporin-2, which if one of four water transport channels in the renal tubule. Acquired nephrogenic DI is generally related to disorders and drugs that damage the renal tubules or inhibit the generation of cAMP in the tubules. These disorders include pyelonephritis, amyloidosis, destructive uropathies, polycystic disease, and intrinsic renal disease, all of which lead to irreversible DI. Dipsogenic: This form occurs when excessive fluid intake lowers the plasma osmolarity to the point that it falls below the threshold for ADH secretion Patho: Neurogenic, nephrogenic, and dipsogenic DI are all characterized by the inability of the kidney to increase permeability of water. This causes excretion of large volumes of dilute urine and an increase in plasma osmolality. In conscious individuals, the thirst mechanism is stimulate and induces polydipsia. For unknown reason the person usually craves cold drinks. The urine output is varied but can increase from the normal output of 1 to 2 L/day to as much as 8 to 12 L/day. The urine specific gravity is low, from 1.00 to 1.005, which is consistent with the failure to reabsorb water. Dehydration develops rapidly without ongoing fluid replacement. IF the individual with DI cannot maintain balance with the urinary loss of water, serum hypernatremia and hyperosmolality occur. Other serum electrolytes generally are not affected. Clinical manifestations: The signs and symptoms of DI include polyuria, nocturia, continuous thirst, and polydipsia. Untreated individuals with long-standing DI may develop a large bladder capacity and hydronephrosis. Idiopathic neurogenic DI usually has an abrupt onset, and many individuals can specifically recall the date of onset of their symptoms. Those with posttraumatic or postneurosurgical DI may develop a classic three-phase syndrome: (1) Diuresis (2) antidiruesis, and (3) polyuria/polydipsia. Nephrogenic DI usually has a more gradual onset. Evaluation and Treatment: DI must be distinguished from other polyuric states, including diabetes mellitus. The basic criteria for the diagnosis of DI include polyuria, polydipsia, low urine specific gravity (<1.010), low urine osomolality (<200 MOsm/kg), hypernatremia, high serum osomolality (300 mOsm or more depending on adequate water intake), and continued diuresis despite a serum sodium level of 145 mEq/L or greater. Treatment for neurogenic DI is based on the extent of the ADH deficiency and on individual variables such as age, endocrine and cardiovascular status, and lifestyle. Patients with a urine output over 9L/day and urine osmo less than 100 mOsm/kg after dehydration or water restriction test generally require ADH replacement. Replacement therapy for symptomatic neurogenic DI includes administration of the synthetic vasocpressin analog desmopressin acetate (DDAVP) given intranasally or orally. Treatment for nephrogenic DI requires treatment of any reversible underlying disorders, discontinuation of etiologic medications, and correction of associate electrolyte disorders. Although the use of thiazide diuretics has been implicated as a cause for DI, they improve salt and water absorption at the proximal tuble and may be helpful in moderate DI. New treatments for genetic abnormalities involving the V2 receptor are being evaluated.

22. What is the relationship between primary adenoma and thyroid and adrenal hypofunction?

(p. 722, 7th ed) Pituitary adenomas are usually benign slow-growing tumors that arise from cells of the anterior pituitary. The pressure produced by a pituitary adenoma is associated with decreased function of neighboring anterior pituitary cells, which results in hyposecretion of other anterior pituitary hormones. Example: As the tumor grows, if it exerts sufficient pressure, thyroid and adrenal hypofunction may occur because of lack of TSH and ACTH. These result in the symptoms of hypothyroidism and hypocortisolism.

21. What is acromegaly?

(p. 722-724, 7th ed) Acromegaly occurs in adults exposed to continuously excessive levels of GH and concomitant elevation of IGF-1(insulin-like growth factor). In children and adolescents whose epiphyseal plates have not yet closed, the effect of increased GH levels on long bone growth is termed gigantism. The most common cause is a primary autonomous GH-secreting pituitary adenoma. Acromegaly occurs more often in women than men and is diagnosed most often in adults in their forties and fifties, although the disease is usually present for years preceding the diagnosis. Acromegaly is a slowly progressive disease that, if untreated, is associated with a decreased life expectancy. The increased number of deaths associated with acromegaly are caused by cardiac hypertrophy, hypertension, atherosclerosis, and type 2 DM that lead to CAD. Malignancies, including colon, breast, and lung cancer are also more common. Patho: With a GH- secreting adenoma, the usual GH baseline secretion pattern and sleep-related GH peaks are lost, and an unpredictable secretory pattern ensues. With only slight elevations of GH, IGF-1 levels increase, stimulating growth. In children whose epiphyseal plates have not yet closed, the effect of increased GH levels causes excessive skeletal growth, with some growing to 8-9 feet tall. In the adult, epiphyseal closure has occurred and increased amounts of GH and IGF-1 cause connective tissue proliferation and increased cytoplasmic matrix, as well as bony proliferation that results in the characteristic appearance of acromegaly. GH also effects glucose, lipid, and protein metabolism. Hyperglycemia results from GH's inhibition of peripheral glucose uptake and increased hepatic glucose production, followed by compensatory hyperinsulinism and, finally, insulin resistance. Excessive levels of GH and IGF-1 also affect the cardiovascular system. It is not clearly understood, but hypertension and left heart failure are seen in 1/3 to ½ of people with acromegaly. Cardiomyopathy is also a factor. Hyperphosphatemia and hypopituitarism may occur. Clinical Manifestations: As a result of connective tissue proliferation, individuals with acromegaly have enlarged tongues, interstitial edema, increase in the size and function of sebaceous and sweat glands (body odor), and coarse skin and body hair. Bony proliferation cause arthropathy in large joints with swelling and decreased ROM and periosteal vertebral growth, which caused kyphosis. Enlargement of facial bones and bones of the hands and feet result in protrusion of the lower jaw and forehead. Because IGF-1 stimulates cartilaginous growth, elongation of ribs at the bone-cartilage junction is increased leading to a barrel-chested appearance, as well as increased proliferation of cartilage in the spine and joints. This causes backache, arthralgia, and arthritis (early manifestations). Continued bony and soft tissue over-growth leads to nerve entrapment and nerve damage resulting in weakness, muscular atrophy, foot drop, and sensory changes in the hands. Evaluation and Treatment: Diagnosis is accomplished by documenting elevated IGF-1 levels and GH suppression during oral glucose tolerance testing. Goals of treatment are to normalize GH and IGF-1 serum levels, restoring normal pituitary function or preventing complications related to tumor expansion. Treatment of choice is transsphenoidal surgery or endonasal endoscopic surgery for the adenoma. Radiation therapy is an option when GH control is not essential, when patient is not a surgical candidate, or when hyperfunction persists after subtotal resection. Somatostatin analogs (Octreotide and lanreotide), dopaminergic agonist (cabergoline), and Pegnisomant may be effective medications.

45. Know pituitary tumors and clinical manifestations of each.

(p. 733, 735-736; 6th ed) (p. 722, 724; 7th ed) Pituitary Adenomas (Hyperpituitarism): (722) usually benign, slow growing tumors that arise from cells of the anterior pituitary, most commonly those that secrete GH and prolactin. Very common in the population with prevalence rates estimated about 17%. The pathogenesis of pituitary adenomas includes hypothalamic and intrapituitary factors, which include altered expression of the pituitary cycle genes, activation of pituitary selective oncoprotiens, or loss of pituitary suppressor factors. The vast majority of pituitary tumors are microadenomas that are hormonally silent and do not pose significant hazards to the individual. These are usually found on high resolution MRI accidentally. Primary pituitary carcinomas are rare, representing 0.2% of all pituitary tumors. Pathophysiology: local expansions of pituitary adenomas may cause both neurological and secretory defects. Adenoma tissue secretes the hormone of the cell type from it arose, without regard to physiological needs and without benefit of regulatory feedback mechanisms. Clinical Manifestations: related to tumor growth and hormone hypersecretion or hyposecretion. Effects from tumor size increase include nonspecific complaints of headache and fatigue. Visual changes produced by pressure on the optic chiasm-visual field impairment and temporary blindness. If the tumor infiltrates to other cranial nerves, neurologic function is affected. Pituitary adenomas arise from hormone producing cells and are most often associated with increased secretion of GH and prolactin. Pressure produced by growing pituitary adenomas is also associated with decreased function of neighboring anterior pituitary hormones. GH hyposecretion will cause menstrual irregularities in woman, decreased libido, and receding secondary sex characteristics. If tumors excretes sufficient pressure, thyroid and adrenal hypofunction may occur because of lack of TSH and ACTH. These result in symptoms of hypothyroidism and hypocortisolism. Evaluation and Treatment: Diagnosis involves physical and laboratory evaluation including pertinent hormone assay and radiographic exams of the skull (CT or MRI w/contrast). Goal of Treatment is to protect from effects of tumor growth and to control hormone hypersecretion or hyposecretion while minimizing damage to appropriately secreting portions of the pituitary. Depending on tumor size/type- treatment may include medications to suppress tumor growth, transsphenoidal tumor resections, or radiation therapy. Prolactinoma: (724) Pituitary tumors that secrete prolactin are called prolactinomas, and are the most common of the hormonally active pituitary tumors encountered. Microprolactinomas (<1cm) are usually encapsulated and noninvasive, whereas Microprolactinomas (>1cm) commonly expand into the optic chasm and invade local structures. The physiologic actions of prolactin include breast development during pregnancy, postpartum milk production and suppression of ovarian function in nursing women. Pathophysiology: The hallmark of a Prolactinoma is sustained increase in serum prolactin. Due to the increasing size of the adenoma, hypopituitarism may occur because of compression of surrounding hormone secreting cells. CNS symptoms may develop because of growth and pressure of the adenoma within the sella turica. Clinical Manifestations: Pathologic elevations in prolactin in woman result in amenorrhea, nonpeurperal milk production (galactorrhea), hirsutism (excessive body hair in a masculine distribution pattern), and osteopenia caused by estrogen deficiency. Menstrual abnormalities and galactorrhea are alarming symptoms in woman and are early onset symptoms for microadenomas. Men are more likely to have larger tumors upon diagnosis with associated compressive impairments. High prolactin levels in men cause hypogonadism, erectile dysfunction, impaired libido, oligospermia, and diminished ejaculate volume. Evaluation and Treatment: A thorough history to exclude meds that cause elevations in prolactin; serum TSH level; search for nonpituitary causes if prolactin level less than 50 ng/ml. Prolactin levels more than 200 ng/ml are associated with prolactinomas and are indications for MRI of the pituitary. Treatment of choice includes dopaminergic agonists (bromocriptine, cabergoline, and pregolide) are associated with rapid reduction in the size of the tumor and a reversal of the gonadal effects of hyperprolactinemia. In individuals who are treatment resistant/intolerant to medications, transsphenoidal surgery, endonasal endoscopic surgery and radiotherapy are options.

19. What is hypoparathyroidism?

(p. 733, 7th ed) Hypoparathyroidism: Abnormally low PTH levels are most commonly caused by damage to the parathyroid glands during thyroid surgery. A low serum Ca+ level and a high phosphorous level in the absence of renal failure, intestinal disorders, or nutritional deficiencies suggest hypoparathyroidism. Hypoparathyroidism is also associated with genetic syndromes, including familial hypoparathyroidism and DiGeorge syndrome (velocaridofacial syndrome). Hypomagnesemia also can cause a decrease in PTH secretion and function. Pathophysiology: A lack of circulating PTH causes a depressed serum calcium level and an increased serum phosphate level. In the absence of PTH, the abilities to reabsorb calcium from bone and to regulate calcium reabsorption from the renal tubules is impaired. The phosphaturic effects of PTH are lost, resulting in hyperphosphatemia. The effects of hypomagnesemia are not clearly understood. Once serum magnesium levels return to normal, however, PTH secretion returns to normal, as does peripheral tissues' responsiveness to PTH. Clinical Manifestations: Symptoms associated with hypoparathyroidism are related to hypocalcemia. Hypocalcemia causes a lowering of the threshold for nerve and muscle excitation. This is manifested as muscle spasms, hyperreflexia, tonic-clonic convulsions, laryngeal spasms, and in severe cases, death from asphyxiation. Chvostek and Trousseau signs may be used to evaluate for neuromuscular irritability. Chvostek sign is elicited by tapping the cheek resulting in twitching of the upper lip. Trousseau sign is elicited by sustained inflation of a sphygmomanometer placed on the upper arm to a level above the systolic blood pressure with resultant painful carpal spasm. Other symptoms include dry skin, loss of body and scalp hair, hypoplasia of developing teeth, horizontal ridges on the nails, cataracts, basal ganglia calcifications (which may be associated with a parkinsonian syndrome), and bone deformities, including brachydactyly and bowing of the long bones. Phosphate retention caused by increased renal reabsorption of phosphate is associated also with hypoparathyroidism. Hyperphosphatemia is associated with inhibition of the renal 744745 enzyme necessary for the conversion of vitamin D to its most active form. This enzyme, 25-OH vitamin D 1α-hydroxylase also is required by PTH. This tends to depress serum calcium levels further by reducing gastrointestinal absorption of calcium. Evaluation and Treatment: A low serum calcium level and high phosphorus level in the absence of renal failure, intestinal disorders, or nutritional deficiencies suggest hypoparathyroidism. The treatment is directed toward the alleviation of hypocalcemia: parenteral administration of calcium. In acute cases, parenteral administration of calcium, which allows correction within minutes Maintenance of serum calcium is achieved with pharmacologic doses of an active form of vitamin D and oral calcium.

35. Know the pathophysiology, etiology, clinical manifestations, treatment and complications of DM I and DM II.

(p. 734-743, 7th ed) Diabetes Mellitus: A group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Type 1 DM: Type 1 DM is the most common form of diabetes in those under age 12. It is a slowly progressive autoimmune T cell-associated disease that occurs in genetically susceptible individuals. Pathophysiology: Two distinct types of DMI have been identifiedL autoimmune and non-immune. Autoimmune-mediated DM (type 1A) is caused by cell mediated destruction of the pancreas. Non-immune is far less common and occurs secondary to other diseases. Idiopathic diabetes occurs mostly in people of Asian or African descent. The exact nature of genetic susceptibility to type 1A diabetes is not clearly understood, but the strongest association is with major histocompatibility complex. Several types of viral infections have been implicated with autoimmune damage to beta cells, especially enteroviruses, although a cause and effect relationship has not been proven. Before hyperglycemia occurs, 80-90% of the function of the insulin-secreting beta cells in the islet of Langerhans must be lost. Beta cell abnormalities are present long before the acute clinical onset. Alpha-cell and beta-cell functions are abnormal. Lack of insulin and amylin and a relative excess of glucagon exist. The ratio of insulin to glucagon in the portal vein controls hepatic glucose and fat metabolism. The paracrine action of insulin and amylin normally suppress secretion of glucagon. High levels of glucagon relative to insulin levels contribute to the generation of hyperglycemia and hyperketonemia. Clinical Manifestations: DM1 affects the metabolism of fat, protein, and carbs. Glucose accumulates in the blood and appears in the urine as the renal threshold for glucose is exceeded, producing an osmotic diuresis and symptoms of polyuria and polydipsia. Wide fluctuations in blood glucose levels occur. Protein and fat breakdown occur because of the lack of insulin, resulting in weight loss. Lipolysis is enhanced and there is an increase in the amount of nonesterified fatty acids delivered to the liver which increases glyconeogenesis, contributing to hyperglycemia. In the absence of insulin, the release of free fatty acids from adipocytes increases production of ketone bodies by the mitochondria of the liver at a rate that exceeds peripheral use. Accumulation of ketone bodies causes a drop in pH and triggers the buffering system associated with metabolic acidosis. DKA, caused by increased levels of circulating ketones in the absence of the antilipolytic effect of insulin, may occur. Evaluation and Treatment: The diagnosis is not difficult when the symptoms of polyuria, polyphagia, weight loss, and hyperglycemia are present in fasting and postprandial states. Treatment regimens are designed to achieve optimal glucose control without causing significant hypoglycemia. All individuals with DM1 require some combination of insulin supplementation, meal planning, exercise program, and self-monitoring of blood glucose levels. Type 2 DM: Much more common than type 1 and has been rising in incidence since 1940. An environmental-genetic interaction appears to be responsible. The most well-recognized risk factors are age, obesity, hypertension, physical inactivity, and family history. The metabolic syndrome is a constellation of disorders (central obesity, dyslipidemia, prehypertension, and an elevated fasting blood glucose level) that together confer a high risk of developing type 2 diabetes and associated cardiovascular complications. Pathophysiology: The combination of genetic, epigenetic, and environmental influences results in the basic pathophysiologic mechanisms of type 2 diabetes: insulin resistance and decreased insulin secretion by beta cells. Insulin resistance is a suboptimal response of insulin-sensitive tissues to insulin. Obesity is present in 60-80% of those with type 2 DM and is a major contributor to insulin resistance through several important mechanisms. In most individuals with DMII, compensatory hyperinsulinemia prevents the clinical appearance of diabetes for many years. Eventually islet cell dysfunction develops and leads to a relative deficiency of insulin activity. Beta-cell dysfunction is caused in part by a decrease in beta cell mass. Pancreatic alpha cells in DMII are less responsive to glucose inhibition, resulting in increased glucagon secretion. These abnormally high levels of glucagon have long been known to pay a rose in the increased hepatic production of glucose and resultant hyperglycemia. Hyperinsulinemia and hyperleptinemia are associated with decreased levels of ghrelin in DMII.Amylin is another beta cell hormone that is decreased. Clinical Manifestations: Nonspecific. The affected individual is usually over weight, dyslipidemic, hyperinsulinemic, and hypertensive. Individuals will usually complain of nonspecific symptoms such as fatigue, pruritus, recurrent infections, visual changes, or symptoms of neuropathy. In those whose diabetes has progressed without treatment, symptoms related to coronary artery, peripheral artery, and cerebrovascular disease may develop. Evaluation and Treatment: Prevention of DM II hinges on diet and exercise to reduce weight. Pharmacologic therapy may be considered for those at highest risk. Oral hypoglycemic drugs may be used. Insulin therapy may be needed in the later stages because of loss of beta-cell function. Acute Complications of Diabetes: hypoglycemia, DKA, HHNS, Symogi Effect, Dawn Phenomenon Chronic Complications of Diabetes: oxidative stress, hyperglycemia and the polyol pathway, hyperglycemia and protein kinase C, hyperglycemia and glycation, hyperglycemia and the hexosamine pathway, microvascular disease, macrovascular disease.

20. What is Graves disease? Signs and symptoms? Labs?

(p. 736-738, 6th ed) (p. 726-728, 7th ed) Graves disease: Is an autoimmune disease that results in stimulation of the thyroid gland and resultant hyperthyroidism (50-80% of cases of hyperthyroidism). It is more common in women. Characterized as a multisystem syndrome consisting of one or more of the following: hyperthyroidism, diffuse thyroid enlargement (goiter), ophthalmopathy, and pretibial myxedema. Triggers for onset include: stressful life events, recent childbirth, and infection. Genetic and environmental factors play an important role in the development of Graves disease; however the exact cause is unknown. Pathophysiology: Normal regulatory mechanisms are overridden by abnormal immunologic mechanisms. T lymphocytes are sensitized to thyroid antigens and stimulate B cells to produce IgG antibodies that bind to TSH receptors in the thyroid gland and stimulate the synthesis and secretion of excess TH (autoantibodies called thyroid-stimulating immunoglobulins, which are found in 95% people with Graves disease). Hyperfunction of the thyroid gland is reflected in a dramatically increased iodide uptake and increased rate of hypervascularity and enlargement of the gland (goiter). Increased T3 production leads to long-term hyperstimulation of the thyroid gland. A small number of patients with Graves disease and very high levels of thyroid-stimulating immunoglobulins experience pretibial myxedema (Graves dermopathy), characterized by subcutaneous swelling on the anterior portions of the legs and by indurated and erythematous skin. Thyroid-associated dermopathy is associated with thyrotropin receptor antigens on fibroblasts and recruited T lymphocytes. Manifestations occasionally appear on hands leading to the appearance of clubbed fingers (thyroid acropachy). Clinical Manifestations: Manifestations include: goiter, bruit over thyroid, increased cortisol degradation, hypercalcemia, decreased PTH secretion, decreased sensitivity to insulin, oligomenorrhea/amenorrhea, erectile dysfunction, decreased libido, increased estradiol and estrone levels, weight loss, increased peristalsis, nausea, vomiting, anorexia, abdominal pain, decreased serum lipids, excessive sweating, flushing, warm skin, heat intolerance, fine hair, temporary hair loss, palmar erythema, exopthalmus, increased cardiac output, tacycardia, loud heart tones, supraventricular dysrhythmias, LV dilation, restlessness, short attention span, compulsive movement, fatigue, tremor, insomnia, increased appetite, emotional lability, dyspnea, and reduced vital capacity. Many patients with Graves disease experience one of two categories (or both) of ocular manifestations: functional abnormalities resulting from hyperactivity of the sympathetic division of the ANS; or infiltrative changes involving the orbital contents with enlargement of ocular muscles. Functional abnormalities include lag of the globe on upward gaze or lag of upper lid on downward gaze—caused by overactivity of Mueller (eyelid) muscles. Infiltrative ophthalmopathy is characterized by orbital fat accumulation and inflammation with edema of the orbital contents resulting in protrusion of the globe (exophthalmos); these changes lead to diplopia due to extraocular muscle weakness; pain, irritation, lacrimation, photophobia, and blurred vision; occasionally decreased visual acuity, papilledema, visual field impairment, exposure keratopathy, and corneal ulceration may occur. Labs: Diagnosis of thyrotoxicosis is based on symptoms of TH excess and documentation of increased circulating thyroid hormone levels. Elevated serum free thyroxine (T4) and triiodothyronine (T3) are found in all forms of thyrotoxicosis. TSH production by the pituitary is inhibited through the usual negative feedback loop. Therapy: Antithyroid drugs (propylthioruacil and methimazole), radioactive iodine, surgery. One major complication of radioactive iodine and surgical treatment is excessive ablation of the thyroid gland, leading to hypothyroidism. Treatment does not reverse infiltrative ophthalmopathy or pretibial myxedema. Progressive ophthalmopathy may be helped with glucocorticoids and an experienced oculoplastic surgeon. Skin lesions rarely require treatment, but may be treated with topical glucocorticoids if the patient is symptomatic. ***** Note - * Note: Thyrotoxic crisis (thyroid storm) is a rare, dangerous development/worsening of hyperthyroidism, particularly if the disease is either undiagnosed or under-treated. Death can occur within 48 hours if not treated. S/s include hyperthermia, tachycardia, agitation/delirium, & N/V/D (contributing to fluid volume depletion).

13. Understand hypo/hyperglycemia

(p. 743, 747; 7th ed) Hypoglycemia: a lowered plasma glucose level. Occurs when blood glucose levels are less than 35mg/dl in newborns for the first 48 hours of life and less than 45-60 mg/dl in children and adults. Individuals with Type 2 Diabetes are at less risk for hypoglycemia than those with Type 1 because they retain relatively intact glucose counter-regulatory mechanisms. Symptoms result from either their activation of the sympathetic nervous system (adrenergic symptoms) or from an abrupt cessation of glucose delivery to the brain (neuroglycemic symptoms) or both. Adrenergic reactions occur when the decrease in blood glucose is rapid with tachycardia, palpitations, diaphoresis, tremors, pallor, and arousal anxiety. This reaction is generated when the hypothalamus senses decreased glucose levels. Reduced substrate delivery to the brain (neuroglycopenia) causes changes in neuronal kinase activity and firing rates, thus producing further symptoms including headache, dizziness, irritability, fatigue, poor judgment, confusion, visual changes, hunger, seizures, and coma. When receiving beta-blocking medication, the autonomic symptoms may be blunted, and recovery from hypoglycemia may be delayed because of impaired glycogenesis and hampered delivery of gluconeogenic substrates to the liver. Treatment: When symptoms are nonspecific the safest treatment is to provide some form of glucose because failure to provide glucose may precipitate convulsions, coma, and death. Glucose (15-20g) to a conscious pt. Hyperglycemia: fasting blood glucose greater than or equal to 126mg/dl or 2 hour post load glucose greater than or equal to 200mg/dl. Five metabolic events are associated with tissue-damaging effects of chronic hyperglycemia. 1.)With hyperglycemia glucose is shunted to the polyol pathway (alternate metabolic pathway for glucose metabolism) and is converted to sorbitol by the enzyme aldose reductase. Sorbitol is then slowly converted to fructose by sorbitol dehydrogenase. This accumulation of sorbitol and fructose increases intracellular osmotic pressure and attracts water, leading to cellular injury. 2.) Protein kinase C (PKC) is an enzyme that is inappropriately activated in different tissues by hyperglycemia, particularly the diacyglycerol (DAG)-PKC pathway. Consequences- insulin resistance, production of extracellular matrix and cytokines, vascular cell proliferation, enhanced contractility, and increased permeability. These effects contribute to the macrovascular, microvascular, and neurologic complications of diabetes. 3.) induction of reactive oxygen species (oxidative stress). 4.) Production of advanced glycation end products. 5.) accumulation of hexosamines. Symptoms include: fatigue, pruritus, recurrent infections, visual changes, and symptoms of neuropathy (parathesias or weakness).

18. Know hyperglycemic hyperosmolar syndrome (HHS)? Know diabetic ketoacidosis? What's the difference?

(p. 744-746, 7th ed) Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS), or hyperglycemic Hyperosmolar state (HHS) is a life-threatening emergency. Precipitated by infections, meds, nonadherence to diabetic Tx, coexisting disease. More common with Type2 diabetes and with chronic pancreatitis. Pathophysiology: HHNKS differs from DKA in the degree of insulin deficiency (more profound in DKA) and the degree of fluid deficiency (more marked in HHNKS). HHNKS: characterized by lack of ketosis. Insulin levels are sufficient to prevent excessive lipolysis but not to use glucose properly. Glucose levels are higher than in DKA because of volume depletion. Clinical manifestations: Glycosuria and polyuria result from extreme glucose elevation. (19g of glucose/hr loss in diuresis). Severe volume depletion, increased serum osmolarity, intracellular dehydration, loss of electrolytes (K+). Neuro changes: stupor, seizure, coma (correlates with the degree of hyperosmolarity, common and sometimes called hyperosmolar hyperglycemic coma). Evaluation and Tx: HHNKS glucose as high as 600mg/dl, near normal bicarb and pH. Serum osmolarity greater than 320mOsm/L. Absent or low ketone levels. Dehydration far more severe than in DKA. (more rapid fluid replacement needed). Deficit in Potassium (extreme), phosphorus and sodium. High risk for infection, sepsis, venous thrombosis. High mortality. Diabetic Ketoacidosis (DKA) (p. 744) Complication of DM. Develops with absolute or relative deficiency of insulin and an increase in insulin counterregulatory hormones. Most common with Type 1 diabetes (can occur in type2). Also in ketosis-prone diabetes (KPD syndrome). Precipitating factors: intercurrent illness, infection, trauma, surgery, MI, interruption of insulin administration. Young or old. Low BMI. Pathophysiology: with relative insulin deficiency, increased counterregulatory hormones (catecholamines, cortisol, glucagon, GH). The hormones antagonize insulin. Increased fat mobilization, increased ketogenesis and glucogenesis (production). Hyperketonemia and metabolic acidosis occur. Clinical manifestations (p.745): Polyuria and dehydration (from osmotic diuresis and hyperglycemia). Plasma glucose level is higher than renal threshold, significant loss of glucose in urine. Deficit: Potassium (most signif.), Sodium, Phosphorus, Magnesium. Total body Potassium deficit even with normal or elevated serum levels (shift of K+ out of cells). Symptoms: Kussmaul respirations, postural dizziness, CNS depression, ketonuria, anorexia, nausea, abdominal pain, thirst, polyuria, vomiting, acetone (fruity) odor on the breath. Diagnosis: 1. serum glucose >250mg/dl 2. serum bicarb <18mg/dl 3. Serum pH<7.30. 4. Presence of an anion gap 5.presence of urine and serum ketones. Tx: insulin + fluids. Differences: HHNKS differs from DKA in the degree of insulin deficiency (which is more profound in DKA) and the degree of fluid deficiency (which is more marked in HHNKS). Levels of free fatty acids in HHNKS are consistently lower than those found in DKA. HHNKS is characterized also by a lack of ketosis. Because the amount of insulin required to inhibit fat breakdown is less than those that needed for effective glucose transport, insulin levels are sufficient to prevent excessive lipolysis but not to use glucose properly. Glucose levels are considerably higher in HHNKS than in DKA because of volume depletion. Neurologic changes, such as stupor, correlate with degree of hyperosmolarity and are more common in HHNKS than in DKA. An important distinction is that the dehydration in HHNKS is far more severe than that in DKA.

14. Why do diabetic pts usually develop hyperlipidemia?

(p. 746, 751, 7th ed) ******Per the Instructor, below is all you need to know for this question.****** HYPERLIPIDEMIA Chronic hyperglycemia, insulin resistance, hyperinsulinemia, and dyslipidemia contribute to the production of reactive oxygen species (ROS) and the detrimental effects of oxidative stress. Increased formation of AGEs, defects in the polyol pathway, uncoupling of nitric oxide synthase,xanthine oxidase, and nicotinamide adnine dinucleotide phosphate (NADPH) oxidase generate ROS, which damage large and small vessels and contrivute to atherogenesis and to micro- and macrovascular disease. Direct cellular injury, contributes to these late complications of diabetes mellitus.

16. Why do diabetics develop retinopathy? Know microvascular complications of DM.

(p. 747-750, 7th ed) Retina is most metabolically active structure per wt of tissue in body. Retina is vulnerable target. DR is leading cause of blindness worldwide and in US adults younger than 60. Seems to develop more rapidly in individuals with type 2 diabetes because of the likelihood of long-standing hyperglycemia before diagnosis. Most people with diabetes will eventually develop retinopathy and are also more likely to develop cataracts and glaucoma. DR is associated with increased risk of life-threatening systemic vascular complications, including stroke, coronary heart disease, and HF. Prevalence and severity is strongly related to age of person, duration of diabetes, and extent of glycemic control. Diabetic retinopathy results from relative hypoxemia, damage to retinal blood vessels and vasoconstriction, red blood cell and platelet aggregation, influence of vascular endothelial growth factors and growth hormone, and angiogenesis. The following 3 stages of retinopathy lead to loss of vision o 1. Nonproliferative: characterized by thickening of retinal capillary basement membrane and increase in retinal capillary permeability, vein dilation, microaneurysm formation, and superficial (flame-shaped) and deep (blot) hemorrhages. o 2. Preproliferative: progression of retinal ischemia with areas of poor perfusion that culminate in infarcts o 3. Proliferative: neovascularization (angiogenesis) and fibrous tissue formation within the retina or optic disc. Traction of the new vessels on the vitreous humor may cause retinal detachment or hemorrhage into the vitreous humor. Maculopathy is progressive process that may accompany the increased retinal capillary permeability, vessel occlusion, and ischemia. If formation of exudates, edema, or ischemia occurs near the forvea, serious loss of vision may result. Macular edema (fluid accumulation and retinal thickening near the center of the macula) is the leading cause of vision loss among persons with diabetes. Blurring of vision can also be a consequence of hyperglycemia and sorbitol accumulation in the lens. Dehydration of the lens, aqueous humor, and vitreous humor also reduces visual acuity. Cataracts, optic neuropathy, and defects in eye muscle function also are associated with the chronic complications of hyperglycemia and diabetes mellitus. Laser treatments are used to reduce rate of vision loss from diabetic macular edema and neovascularization. Vitrectomy is surgical procedure used to treat and intravitreal hemorrhage secondary to rupture of neovascular capillary tuft. Intravitreal delivery of steroids, antivascular endothelial growth factor preparations, and renin-angiotensin system (RAS) inhibitors are being evaluated. Micovascular complications of diabetes: Aka disease in capillaries. Leading cause of blindness, end-stage renal failure, and various neuropathies. Thickening of capillary basement membrane, endothelial cell hyperplasia, thrombosis, and pericyte degeneration are characteristic of diabetic microangiography and develop over 1-2 years. Thickening eventually results in decreased tissue perfusion. Hyperglycemia is prerequisite for these microvascular changes and may be related to glycation of structural proteins, which results in accumulation of AGEs. Frequency and severity of lesions appear to be proportional to duration of disease and blood glucose control. Hypoxia and ischemia accompany microangiography, particularly in the retina, kidney, and nerves. Many individuals with DM type 2 present with microvascular complications because of the long duration of asymptomatic hyperglycemia that generally precedes diagnosis. This underscores the need for diabetes screening. • Includes diabetic retinopathy and diabetic neuropathy (p.747) Diabetic Nephropathy: (p.747-749) Diabetes is most common cause of end stage kidney disease in Western world. Early phases of nephropathy are asymptomatic and begin to develop after 10 years with type 1 or after 5-8 years with type 2. There are some differences in renal lesions in type 1 and type 2, with glomerular changes and earlier microalbuminuria in type 1 being most prominent; however hyperglycemia is major initiating factor in both types. Exact process responsible for destruction of kidneys in diabetes is unknown. Multiple mechanisms contribute to nephropathy, including chronic hyperglycemia, systemic HTN, hyperperfusion, hyperfiltration, increased blood viscosity, increased glomerular pressure, albuminuria, protein kinase C, growth factors, advanced glycation end products, the polyol pathway, inflammatory cytokines, oxidative stress, the RAS, and hypercholesterolemia. Glomeruli injured by protein denaturation, hyperglycemia with high renal blood flow (hyperfiltration) and intraglomerular HTN exacerbated by systemic HTN. Renal glomerular filtration changes occur early in diabetes and occasionally may precede the overt manifestations of the disease. Diabetic Neuropathies: (749) Diabetic neuropathy most common complication of diabetes. Nerves do not require insulin for glucose transport and are particularly vulnerable to pathologic effects of chronic hyperglycemia. Underlying pathologic mechanism includes both metabolic and vascular factors related to chronic hyperglycemia. Inflammation, ischemia, oxidative stress, advanced glycation end products, and increased formation of polyols contribute todemyelination, nerve degeneration, and delayed conduction. Both somatic and peripheral nerve cells show diffuse or focal damage resulting in polyneuropathy. Sensory deficits generally precede motor involvement. Extremities involved first in "stocking and glove" pattern. (p.749-751) Diabetic neuropathy is form of "dying back neuropathy in which distal portions of neurons are intitially and eventually severely affected. Earliest morphologic change is axonal degeneration that preferentially involves sensory nerve fibers, particularly the smaller polymodal unmyelinated peripheral C fibers and the larger myelinated Aδ fibers. Metabolic activity of Schwann cells is disturbed, causing segmental loss of myelin and characteristic pattern of demyelination and remyelination observed in long term diabetic neuropathy. Location of the pathologic condition can include spinal cord, posterior root ganglia, or peripheral nerves. Changes may occur alone or in combination. Nerve degeneration begins in periphery. (p.750) Distal symmetric polyneuropathy (sensory, autonomic, and motor nerve involvement) is most common neuropathy with involvement of both large and small nerve fibers. Loss of small nerve fiber function includes neuropathic pain and loss of sensation, and carries high risk for development of foot ulceration with subsequent gangrene and amputation. Large nerve fiber involvement results in sensory loss of proprioception and vibration with ataxia, loss of coordination, and risk for falls and fractures. Motor involvement results in weakness and muscle atrophy, particularly in lower legs and feet. (p. 750)

17. Why does polyuria and polydipsia and weight loss occur with the onset of diabetes?

(p. 749, 6th ed) (p. 738, 7th ed) Table 22-7 Polyuria - In Type 1 Diabetes Mellitus polyuria is caused because hyperglycemia acts an osmotic diuretic; the amount of glucose filtered by the glomeruli of the kidneys exceeds the amount that can be reabsorbed by the renal tubules; glycosuria results, accompanied by large amounts of water lost in the urine. Polydipsia occurs because of the elevated blood glucose levels, water is osmotically attracted from body cells, resulting in intracellular dehydration and hypothalamus stimulation of thirst. Weight loss occurs because of the fluid loss in osmotic diuresis and the loss of body tissue as fat and proteins are used for energy as a result of the effects of insulin deficiency.

15. Why do diabetic pts have CVD?

(p. 751, 7th ed) DIABETES AND CARDIOVASCULAR DISEASE The premature atherosclerosis of diabetes has many contributing factors, including hyperinsulinemia (insulin resistance), hyperglycemia, hypertriglyceridemia, low levels of high-density lipoprotein (HDL), high levels of low-density proteins (LDL), lipoprotein oxidation, platelet abnormalities, and vascular consequences of AGEs Advanced glycosylated end products attach to their receptor (RAGE) in the walls of blood vessels, promoting oxidation stress, inflammation, and endothelial and vascular smooth muscle dysfunction (Figure 22-21). The process tends to be more severe and accelerated with the presence of other risk factors, including hyperlipidemia, hypertension, and smoking. Coronary artery disease (CAD) is the most common cause of morbidity and mortality (up to 75%) in both men and women with diabetes mellitus. In general, the prevalence of CAD increases with the duration but not the severity of diabetes. Risk factors contributing to the disease include hyperglycemia and insulin resistance, high levels of LDLs and triglycerides (lipotoxicity), low levels of HDLs, increased levels of apolipoprotein B, platelet abnormalities, and endothelial cell dysfunction. Myocardial infarction (death of heart muscle as result of coronary artery occlusion) is the cause of death in up to 75% of those diabetes. Individuals with DM have a higher mortality during the acute phase of myocardial infarctions than do non-diabetic individuals because they are often asymptomatic as a result of sensory and automatic neuropathy. Atherosclerotic CAD is accelerated in diabetes because of hyperglycemia-induced endothelial dysfunction, impaired fibrinolysis, increased platelet aggression, plaque instability, dysfunctional arterial remodeling, and fibrotic and calcified arteries. In addition, the incidence of remodeling (heart failure or myocardial dysfunction in the absence of CAD and HTN) is higher in individuals with diabetes. The reason is unclear but maybe related to metabolic remodeling of the myocardium with the presence of increased amounts of collagen in the ventricular wall, which reduces the mechanical compliance of the heart during filling, inflammation and changes in calcium management Diastolic dysfunction is the earliest symptom. Guidelines have been developed to reduce the risk and improve prevention, screen, and treatment of cardiovascular and coronary artery disease in individuals with diabetes.

24. Know the pathophysiology, etiology, clinical manifestations, treatment and complications of Cushing disease.

(p. 752-755, 7th ed) Etiology of Cushing Disease/Cushing Syndrome: Disorder of the adrenal cortex related to hyperfunction causing increased levels of circulating cortisol. Hyperfunction that causes increased secretion of adrenal androgens and estrogens leads to virilization or feminization, and hyperfunction that causes increased levels of aldosterone leads to hyperaldosteronism. Cushing syndrome refers to the complex of clinical manifestations resulting from chronic exposure to excess cortisol. Cushing disease is overproduction of pituitary ACTH by a pituitary adenoma (benign tumor). Ectopic secretion of ACTH by an ectopic-secreting non-pituitary tumor also can cause hypercortisolism. ACTH-independent hypercortisolism is caused by cortisol secretion from tumors of the adrenal glands. All disorders are rare. A Cushing-like syndrome may develop as a result of the exogenous administration of glucocorticoids. Pathophysiology: With "ACTH-dependent hypercortisolism", the excess ACTH stimulates excess production of cortisol and there is loss of feedback control of ACTH secretion. Individuals with Cushing syndrome: 1) do not have diurnal or circadian secretion patterns of ACTH and cortisol and, 2) they do not increase ACTH and cortisol secretion in response to a stressor. Secretion of both cortisol and adrenal androgens is increased, and corticotropin-releasing hormone (CRH) secretion is inhibited. With "ACTH-independent" secreting tumors generally secrete only cortisol. Elevated cortisol levels suppress CRH and ACTH secretion from the hypothalamus and anterior pituitary, which leads to low levels of ACTH causing atrophy of the adrenal cortex and altering the cortisol-secreting activity of normal cells. When the secretion of cortisol by the tumor exceeds normal cortisol levels, symptoms of hypercortisolism develop. Clinical Manifestations: Weight gain is the most common feature and results from the accumulation of adipose tissue in the trunk, face, and cervical areas, also called, "truncal obesity," "moon face", and "buffalo hump". Transient weight gain from sodium and water may be present. Glucose intolerance and diabetes mellitus may develop, with polyuria from hyperglycemia and glycosuria. Other symptoms include: vascular sensitivity (vasoconstriction, hypertension), protein and muscle wasting (thinning of the limbs), muscle weakness, osteoporosis (fractures, vertebral compression fractures, bone and back pain, kyphosis, reduced height), hypercalciuria (renal stones), thin skin (purple striae on truck, easy bruising, skin breaks and ulcerations), bronze or brownish hyperpigmentation of the skin, mucous membranes and hair), acne, facial flush, supraclavicular fat pad, metabolic syndrome (abdominal obesity/pendulous abdomen, hypertension, glucose intolerance and dyslipidemias), at risk for cardiovascular complications (CAD, heart failure and stroke), suppression of immune system (infections and poor wound healing), alterations in mental status (learning, memory, irritability, depression, schizophrenia). Females may experience symptoms of increased adrenal androgen levels such as increased body and facial hair, oligomenorrhea, voice changes, recession/thinning of scalp hair, clitoral hypertrophy and infertility. Evaluation and Treatment: Lab tests include urinary free cortisol concentration, abnormal dexamethasone suppressibility of urinary or serum cortisol, simultaneous measurement of ACTH and cortisol levels, and late evening salivary cortisol levels. Routine labs may reveal hyperglycemia, glycosuria, hypokalemia, and metabolic alkalosis. Tumors are diagnosed using imaging procedures. Treatment is specific for the cause of hypercorticoadrenalism, and includes medication, radiation and surgery. Differentiation among pituitary, ectopic, and adrenal causes is essential for treatment. Without treatment, approximately 50% of individuals with Cushing syndrome die within 5 years of onset as a result of overwhelming infection, suicide, complications from generalized arteriosclerosis, and hypertensive disease. Complications: Cushing syndrome, metabolic syndrome, hypertension, hyperglycemia, diabetes mellitus, dyslipidemia, immune suppression, poor wound healing, altered mental status, suicide, infertility, hypokalemia, metabolic alkalosis, elevated cortisol levels, glucose intolerance, and increased risk for cardiovascular complications

12. What occurs with the fetus at each week of gestation?

(p. 768-770 , 7th ed) WEEKS OF GESTATION During embryonic development, the initial reproductive structures of male and female embryos are homologous (the same) and consist of one pair of primary sex organs, or gonads, and two pairs of ducts, the mesonephric ducts (wolffian ducts) and the paramesonephric (mullerian ducts). Both pairs of ducts empty into the urogenital sinus. During the first 7-8 weeks of gestation, both male and female embryos develop an elevated structure called the genital tubercle, which develops into the external reproductive organs under hormonal influence of testosterone or lack there of in females. Male embryos: • 6-7 weeks gestation- the male embryo will differentiate under the influence of testes-determining factor (TDF, stimulating the gonadal development of testes, which in turn produces antimullerian hormone(AMH) and testosterone. Sertoli cells appear and aggregate to form testicular cords. When sertoli cells mature, they will produce inhibin and androgen-binding protein, which is important for spermatogenesis. • 8th week- Leydig cells differentiate and the secretion of testosterone begins. Under the influence of testosterone, the male gonads develop into two testes. The paramesonephric ducts degenerate and the mesonephric ducts develop (Wolffian system) into the vas deferens (tubes that carry sperm from the testes to the urethra.) • Testis (XY) differentiated by 9 weeks gestation. • 9 months gestation- testes have descended into the scrotum. Female embryos: • 6-8 weeks- In the absence of testosterone there is a loss of the Wolffian system and the two gonads develop into ovaries. • 16-20 weeks- There is rapid mitotic multiplication of germ cells, peak of 6-7 million oogonia. Oogonia are transformed into oocytes throughout the remainder of pregnancy. By birth, only 1-2 million oocytes remain. • Ovaries (XX) differentiated by 18 weeks gestation (Figure 22-1 pg 728) Hormones: • 4-5 weeks- anterior pituitary development starts. • 10 weeks- gonadotropin-releasing hormone (GnRH) is produced in the hypothalamus; this controls the production of the gonadotropins: LH (leutinizing hormone) and FSH (follicle stimulating hormone). This cycle is referred to as the hypothalamic-pituitary axis and stimulates production of estrogen and progesterone b the ovaries. LH ans FSH rise until 28 weeks gestation , until the production of estrogen and progesterone by the ovaries and placenta is high enough to result in the decline of gonadotropin production. • 12 weeks- The vascular connection between the hypothalamus and pituitary is established. • At term- a sensitive negative-feedback system (which includes gonadostat) is operative in the human fetus. Chronological Timeline: • 4-6 weeks: anterior pituitary gland development starts • 6-7 weeks: MALE embryo differentiates under influence of TDF, a protein expressed by gene on Y chromosome and male gonads develops into 2 testes • 6-8 weeks: FEMALE gonadal development occurs in presence of estrogen- causes regression of wolffian system- gonads develop into ovaries, which will produce ova. • 7-8 weeks: both male and female embryos develop an elevated structure called the genital tubercle (fig 23-2) • 8 weeks: MALE testosterone secretion begins • 10 weeks: FEMALE mullerian ducts join to become the uterus, fallopian tubes, cervix, and upper 2/3 of the vagina • 10 weeks: GnRH is produced in hypothalamus and controls the production of LH and FSH by the anterior pituitary • 12 weeks: vascular connection between the hypothalamus and pituitary is established • 18 weeks: FEMALE ovary is differentiated • 28 weeks: FEMALE- FSH and LH levels rise until weeks 28, when production of estrogen and progesterone by the ovaries and placenta is high enough to result in the decline of gonadotropin production • 40 weeks: MALE testes have descended into the scrotum • By the end of pregnancy a negative feedback system (gonadostat) is operative in the human fetus. The gonadostat responds to high placental estrogens by releasing low levels of GnRH. Soon after birth steroid hormone levels drop because of withdrawal of maternal placental hormones.

11. Know the different parts of the female GU system and the function of each.

(p. 771-776 ,7th ed) female anatomy The function of the female reproductive system is to produce mature ova and, when they are fertilized, protect and nourish them through embryonic and fetal life and expel them at birth. External Genitalia Mons pubis - is a fatty layer of tissue over the pubic symphysis. This cushion of tissue protects the pubic symphysis during sexual intercourse. Labia majora - the principal function is to protect the inner structures of the vulva. It has two folds of skin that arise at the mons pubis and extend back to the fourchette, forming a cleft. The labia majora contains an extensive network of nerve endings making the labia majora highly sensitive to temperature, touch, pressure, and pain. Labia minora - two smaller, thinner folds of skin lie within the labia majora. Anteriorly they form the clitoral hood and frenulum then split to enclose the vestibule and converge near the anus, forming the fourchette. Well supplied with nerves, blood vessels, and sebaceous glands. These glands secrete a bactericidal fluid that has a distinctive odor and lubricates and waterproofs the vulvar skin. Clitoris - a richly innervated, erectile organ that lies anterior between the labia minora. The clitoris is a major site of sexual stimulation and orgasm. It secretes a fluid called smegma, which has a unique odor and may be erotically stimulating to the male. Vestibule - an area protected by the labia minora and contains the external opening of the vagina (introitus). The hymen may cover the introitus. Also contains the urethra (urinary meatus). These structures are lubricated by two pairs of glands: Skene and Bartholin. Skene glands open on each side of the meatus, and Bartholin glands open on each side of the introitus. Secretions from both sets of glands facilitate coitus, and enhances the viability and motility of sperm. Perineum - the area between the vaginal orifice and anus. Varies in length from 2 to 5 cm and stretches remarkably. The length and elasticity of the perineal body influence tissue resistance and injury during childbirth. Internal Genitalia Vagina - elastic fibromuscular canal which extends up and back from the introitus to the lower portion of the uterus. Mucosal secretions from the upper genital organs, menstrual fluids, and products of conception leave the body through the vagina, which also receives the penis during coitus. The vaginal wall is composed of 4 layers: mucous membrane, fibrous connective tissue, smooth muscle, and connective tissue. Self-cleansing to defend it from infection (acid-base balance that discourages proliferation of bacteria and thickness of vaginal epithelium) pH is 7 before puberty and becomes acidic (4 or 5) until menopause, then is becomes more alkaline. Uterus - hollow, pear shaped organ. The functions are to anchor and protect the fertilized ovum, provide an optimal environment while it develops, and push the fetus out at birth. Plays important role in sexual response and conception by dilating slightly. During orgasm the rhythmic contractions facilitate movement of sperm through cervical os. Uterine wall compromised of 3 layers: perimetrium is the outer serous membrane that covers the uterus, myometrium is the thick muscular middle layer and facilitates birth, and endometrium which is responsive to sex hormones and regenerates functional layer after menstruation. Cervix acts as a mechanical barrier to infectious microorganisms that may be present in the vagina. Fallopian Tubes - enter the uterus bilaterally just beneath the fundus and functions to conduct the ova from the spaces around the ovaries to the uterus. The widened ends (infundibulum) are fringed or fimbriated and create a current that draws the ovum into the infundibulum. Once the ovum has entered the fallopian tube, cilia and peristalsis keep it moving toward the uterus. The ampulla (distal third) is the usual site of fertilization. Ovaries - female gonads are the primary female sex reproductive organs. The two main functions are secretion of female hormones and development and release of female gametes, or ova.

36. What hormone is linked to obesity and early puberty in females?

(p. 778, 803, 7th ed) (BOX: What's New? Precocious Puberty) OBESITY & EARLY PUBERTY Studies implicate obesity, leptin, ghrelin, and environmental endocrine disruptor chemicals (EDCs) as possible contributors to precocious puberty in girls. Obesity may affect the production and secretion of leptin and ghrelin, powerful communicators of satiety, hunger, metabolic rate, and in timing of puberty. Menarche appears to be related to body weight, especially percentage of body fat (ratio of fat to lean tissue), which may trigger a change in the metabolic rate and lead to hormonal changes associated with early menarche. There is an increased sensitivity to leptin (a regulatory hormone of appetite and energy metabolism) during puberty and, in theory, the adolescent consumes more calories to meet caloric needs of the pubertal growth spurt. The percent of body fat and leptin levels in girls continue to increase, whereas muscle mass increases in boy.

7. What does breast milk contain?

(p. 784, 7th ed) Physiologically, breast milk is the most appropriate nourishment for newborns. Not only does its composition change over time to meet the changing digestive capabilities and nutritional requirements of the infant but it also contains immune cells, specific immunoglobulins, especially IgA, and nonspecific antimicrobial factors, such as lysozymes and lactoferrin, that protect the infant against infection, allergies, and asthma. It reduces the incidence of adult obesity, atheroserotic disease, and type 1 & 2 diabetes.

9. Know the male GU anatomy and the function of the glands.

(p. 784-791, 7th ed) male anantomy In men the external genitalia perform the major functions of reproduction. Sperm, are produced in the testes and delivered to the vagina by the penis. The internal male genitalia have a more accessory function. They consist of conducting tubes and fluid-producing glands, all of which aid in the transport of sperm from the testes to the urethral opening of the penis. External Genitalia: Testes: are the essential organs of reproduction. They produce gametes (sperm) and produce sex hormones (androgens and testosterone). They are suspended in the scrotal sac outside of the pelvic cavity because sperm production requires an environment that is 1 or 2 degrees cooler than the body temperature. Its supply lines include the ducts, blood vessels, lymphatic vessels, and nerves of the spermatic cord. The seminiferous tubules constitute the bulk (80%) of testicular volume and are the site of sperm production. The two ends of the seminiferous tubule join through a straight section called the tubulus rectus. Sperm travels through these sections to the central portion of the testis, rete testis, then though the efferent tubules to the epididymis, where the sperm mature. Epididymis: comma shaped structure that curves over the posterior portion of each testis and consists of a single highly packed and markedly coiled duct whose structural function is to conduct sperm from the efferent tubules to the vas deferens. *The duct can become inflamed from infection by microorganisms, causing epididymitis. While sperm is contained in the epididymis (12 days or more), they receive nutrients and testosterone and some biochemical or physiologic mechanism to enhance their capacity for fertilization. The tail of the epididymis is continuous with the vas deferens, a duct with muscular layers capable of powerful peristalsis that transports sperm toward the urethra. Scrotum: encloses the testes, epididymides, and spermatic cord. It is a skin-covered fibro-muscular sac that is homologous to the female labia majora. The skin is thin and has rugae (wrinkles or folds) that enable is to enlarge or relax away from the body depending on temperature. The tunica dartos forms a septum that separates the two testes. Cold temperatures cause the tunica dartos to contract and pull the testes close to the body. Penis: has 2 main functions: delivery of sperm to the vagina and elimination of urine. Externally, the penis consists of a shaft with a tip, the glans, which contains the opening of the urethra. For protection, the skin of the glans folds over the tip of the penis, forming the prepuce or foreskin. Internally, the penis consists of the urethra and 3 compartments: 2 corpora cavernosa and the corpus spongiosum. Internal Genitalia: Ducts: consists of the two vasa deferentia, ejaculatory duct, and the urethra. They conduct sperm and glandular secretions from the testes to the urethral opening of the penis. The ejaculatory duct contracts rhythmically during emission and ejaculation. Glands: consists of the prostate gland, two seminal vesicles, and two Cowper (bulbourethral) glands. They secrete fluids that sever as a vehicle for sperm transport and create an alkaline, nutritious medium that promotes sperm motility and survival. The seminal vesicles are a pair of glands that provide fructose as a source of energy for ejaculated sperm, and secrete prostaglandins that promote smooth muscle contraction assisting with sperm transport. The prostate gland is regulated by androgens and the androgen receptor. Without them the prostate is at risk for hyperplastic and malignant growth. Prostate secretions contribute to the ejaculate and helps sperm survive in the acid environment of the female reproductive tract. Cowper glands are the last pair of glands to add fluid to the ejaculate.

6. What is the pathophysiology behind the signs and symptoms of menopause?

(p. 791-795, 7th ed) Table 23-6, pg. 794 Menopause is the cessation of ovulation due to loss of ovarian follicles resulting in reduced ovarian production of estradiol, increased FSH and LH, and decreased inhibin (inhibits release of FSH). 5-10 years before menopause, approx. 90% of women note mild-extreme variability in menstrual flow. Changes in hormones occur during this time including erratically higher estradiol levels, decreased progesterone levels, and a disturbed ovarian-pituitary-hypothalamic feedback causing premenopausal symptoms. Uterine changes occur primarily in the endometrium. The increase in anovulatory cycles allows proliferative growth of the endometrium. The physiology of vasomotor flushes (hot flashes) is poorly understood. One theory proposes that rapid changes in estrogen may result in loss of negative feedback over hypothalamic noradrenaline synthesis shows physiology, hormonal changes, and symptomatology.

4. What is the difference between primary and secondary amenorrhea and what is compartment II?

(p. 805-807, 7th ed) Amenorrhea is lack of menstruation. Primary amenorrhea is the failure of menarche and the absence of menstruation by age 13 years without the development of secondary sex characteristics or by age 15 regardless of the presence of of secondary sex characteristics. A thorough evaluation is needed. The major clinical manifestation is: absence of 1st menstrual period. The cause of amenorrhea determines whether secondary sex characteristics and height are affected. TX: correction of underlying disorder hormone replacement to induce secondary sex characteristics. (p.805-806) (See fiqure 24-2 on page 806.) Secondary amenorrhea is the absence of menstruation for a time equivalent to three or more cycles in women who have previously menstruated. Pregnancy is the most common condition to rule out prior to further evaluation. Can be caused by dramatic weight loss (malnutrition or excessive exercise). Common during early adolescence and the peri-menopausal period, pregnancy, and lactation. The most common cause is (after pregnancy) are thyroid disorders (hypothyroidism) hyperprolactinemia, HPO interruption secondary to excessive exercise , stress, weight loss, and polycystic ovary syndrome (PCOS). (p.806-807) See figure 24-3 on p. 807 Compartment II (etiology of primary amenorrhea) disorders involve the ovary and are often linked with genetic abnormalities. These include gonadal dysgenesis (Turner syndrome), androgen insensitivity syndrome (AIS) or male pseudo- hermaphroditism. (p.805) Turner Syndrome: lack of 2 functioning and complete X chromosomes, which results in the ovaries lacking gametes and ovarian failure. Without primitive gametes and follicles, follicular development and estrogen secretion can't occur. AIS : the individual is male genetically, but female morphologically. The gonads are usually found in the abdomen or inguinal canal.

2. Understand the different uterine tumor types.

(p. 821-822, 830-831; 7th ed) Uterine tumor Leiomyomas: p.821: Commonly called Myomas or Uterine Fibroids, are benign smooth muscle tumors in the myometrium. Cause is unknown but size of tumor is related to estrogen, progesterone, growth factor, angiogenesis, and apoptosis. Also possible genetic component. Classified as: Subserous, Submucous, and Intramural based on location within the various layers of the uterine wall. Unlike cancer, cannot proliferate blood flow. Risk Factors: nulliparity, obesity, PCOS, diabetes, black race, and hypertension. Endometrial carcinomas: p. 830: Arise from glandular epithelium of uterine lining. Primary risk factor is prolonged exposure to estrogen without presence of progesterone (known as unopposed estrogen). Other risk factors include obesity, diabetes, gallbladder disease, and hypertension. About 75% endometrial cancers are adenocarcinomas. Clinical manifestation: most common is abnormal vaginal bleeding. Uterine sarcomas: p.830: Rare and arise from mesenchymal tissues of and near uterus including myometrial smooth muscle, endometrial stroma, or adjacent connective tissues. Uterine sarcomas are rare. Can be divided into: endometrial stromal sarcoma, leiomyosarcoma, and adenosarcoma based on the involved tissue types. Lack of epidemiological and treatment data due to low occurrence. Risk factors may include chronic excess estrogen exposure, tamoxifen, and African American race. Symptoms: abnormal uterine bleeding, mass, pelvic pressure/pain, and foul and profuse vaginal discharge Treatment: Total hysterectomy which may include bilateral salpingo-oophorectomy and selective lymphadenectomy followed by radiation therapy or chemotherapy, or both. Two types of histology for uterine cancer: Type I tumors: most common result from estrogen exposure leading to endometrial hyperplasia Type II tumors: more invasive into the uterine muscle and can metastasize resulting in increase risk of death

40. Know pathophysiology, etiology, clinical manifestations, diagnostics, treatment and complications of endometriosis.

(p. 823-825, 7th ed) Endometriosis Etiology: Ectopic responds to the hormonal fluctuations of the menstrual cycle. i. Cause of endometriosis is not known but there are 3 theories 1. Sampson: caused by implantation of endometrial cells during retrograde menstruation in which menstrual fluids move through the fallopian tubes and into the pelvic cavity. It is known to happen in all women but not all women develop endometriosis. 2. Impaired cellular and humoral immunity, alterations in cytokines and growth factor signaling have been identified. 3. Possible autoimmune response is suspectedcausing body to tolerate ectopic implantation of endometrial cells ii. A genetic predisposition to endometriosis has been documented. Pathophysiology: can occur throughout the body but generally occur in the pelvic and abdominal cavities. iii. Most common sites of implantation: ovaries, uterine ligaments, rectovaginal septum, peritoneum. 1. Other sites: sigmoid colon, small intestines, rectum appendix, bladder, uterus, vulva, vagina lymph nodes, extremities, pleural cavity, lungs laparotomy scar, and hernia sacs. iv. Cyclic changes depend on the blood supply of the implants and the presence of glandular and stromal cells. 1. If sufficient blood supply, ectopic endometrium proliferates and breaks down, and bleeds with normal menstrual cycles causing inflammationtriggering cellular inflammatory mediators (cytokines/chemokines) leading to fibrosis, scarring, adhesions and pain. Clinical Manifestations: can mimic other disease processes(i.e., PID, IBS, ovarian cyst) v. Symptoms are variable in frequency and severity and include 1. Primarily infertility, pain 2. Dysmenorrhea-not related to the degree of endometriosis 3. Dyschezia(pain on defecation): occurs w/bleeding of ectopic endometrium in the rectosigmoid musculature and subsequent fibrosis 4. Dyspanreunia(pain on intercourse) a. Less common: constipation, abnormal vaginal bleeding vi. If implants are located within the pelvic they can cause asymptomatic pelvic mass having irregular, movable nodules and a fixed, retroinverted uterus. vii. Most symptoms are explained by proliferation, breakdown, and bleeding of the ectopic endometrial tissue w/subsequent formation of adhesions. viii. The degree of endometriosis is NOT related to the frequency or severity of symptoms in most instances. ix. Infertility:25-40% of women with infertility have endometriosis 1. Link b/w endometriosis and infertility is strong, yet the degree of disease and infertility is not as closely associated. 2. Women with untreated minimal to mild disease may have high pregnancy rates or may experience infertility. 3. The uterine endometrium in women w/ endometriosis appears to have an overactive response to estrogen and underactive response to progesteroneimpairing endometrial receptivity to blastocyst implantationdecreasing chance of successful pregnancy. 4. Exact mechanism for infertility in women with endometriosis is unknown. Diagnostics: presumptive diagnosis made based on clinical manifestations but laparoscopy is required for definitive diagnosis-classification system below includes extent and severity Stages Degree of Invasiveness I MINIMAL II MILD III MODERATE Treatment: aimed at preventing or decreasing progression and spread, alleviating pain, and restoring fertility x. Current therapies: suppression of ovulation w/noncyclic estrogen-progestin COCs, depomedroxyprogesteroe acetate(DMPA), danazol(diminshes midcycle LH surge),GnRH agonist/analogs(block menstrual cycle) gestrinone(antiprogestational steroid), mifepristone(antiprogestational/glucocoriticoide that inhibits ovulation and disrupts endometrial integrity), atrophy of endometrium w/ progestins, DMPA, LNG-IUD xi. Newer therapy: injectable GnRH antagonist-immediate inhibition of gonadotropin release BUT does not have a substantially improved success rate. xii. Conservation Surgical Treatment: laparscopic removal of endometrial implants w/conventional or laser techniques and presacral neurectomy for severe dysmenorrhea 1. Effectiveness increased when medical regimens are combined Complications: recurrent symptoms develop in majority of women within a few years, even with surgery. Endometrial carcinoma accounts for approximately 5.8% of all cancers, in women. Infertility and dysmenorrhea are common.

3. What is PCOS and what does it cause? Clinical manifestations? Treatment? Causes? Pathophysiology?

(p. 824-826, 6th ed) (p. 810-812, 7th ed) Polycstic Ovary Syndrome remains one of the most common endocrine disturbances affecting women, especially young women. And is a Leading cause of Infertility in the United States. Have to have at least two of the following conditions for diagnosis of PCOS: oligo-ovulation/anovulation, elevated levels of androgens, or clinical signs of hyperandrogenism and polycystic ovaries. Do not need to have polycystic ovaries for diagnosis, and having polycystic ovaries doesn't necessarily mean one has PCOS. Evidence of androgen excess, chronic anovulation, and inappropriate gonadotropin secretion along with a glucose tolerance test help with positive diagnosis of PCOS. Complications of PCOS : Leading Cause of Infertility ; Possible late outcomes of PCOS include: dyslipidemia, diabetes mellitus, cardiovascular disease, hypertension, endometrial hyperplasia and carcinoma. Women with PCOS are at an inncreased risk for gestational DM, pregnancy-induced HTN, preterm birth, and perinatal mortality. Clinical Manifestations: Usually appear within 2 years of puberty but may appear after a variable period of normal menstrual function and, possibl pregnancy. Symptoms are related to anovulation and hyper-androgenism and include; dysfunctional bleeding or amenorrhea, hirsutism, acne, and infertility. See Box 24-4 p.811 for a complete listing of signs and symptoms (with prevelance), summary of hormonal disturbances, and complications of PCOS. Cause: Underlying cause unknown but thought to have a genetic factor making ovaries more susceptible/sensitive to insulin's stimulation of androgen production. Pathophysiology: A Hyperandrogenic state is a cardinal feature in the pathogenesis of PCOS. Insulin stimulates androgen secretion by the ovarian stroma and reduces serum sex hormone-binding globulin (SHBG) directly and independently. The net effect is an increase in free testosterone levels. Excessive androgens affect follicular growth, and insulin affects follicular decline by suppressing apoptosis and enabling follicles, which would normally disintegrate, to survive. Weight gain tends to aggravate symptoms, whereas weightloss may ameliorate some of the endocrine and metabolic events thus decreasing symptoms. Treatment: Goals of treatment include; reversing signs and symptoms of androgen excess, instituting cyclic menstruation, restoring fertility, and ameliorating any associated metabolic or endocrine disturbances. Traditional treatment focused on correcting anovulation and effects of hyperandrogenism by combination theory of oral contraceptives, antiandrogens, and fertility agents. Now that we have a better understanding of the role insulin resistance (IR) and hyperinsulinemia play in the disease Insulin sensitizers such as metformin are used to decrease insulin, prevent diabetes and heart disease, and to help restore fertility. Progesterone therapy is recommended to oppose estrogen's effects on the endometrium and as a means to initiate monthly withdrawal bleeding. For infertile women Antiestrogens (such as clomiphene citrate) may be used to facilitate ovulation and works better when combined with an insulin sensitizer. Lifestyle changes to reduce weight improves insulin resistance.

37. Etiology of cervical intraepithelial carcinoma (CIN) and cervical Ca.

(p. 825-826, 7th ed) Cervical cancer is almost exclusively caused by human papillomavirus (HPV) infection. HPV causes both CIN and cervical cancer. Infection with high-risk oncogenic types of HPV (16 & 18) is a necessary precursor to development of the precancerous cell changes, known as dysplasia, of the cervix that leads to invasive cancer. Precancerous dysplasia, also called cervical intraepithelial carcinoma (CIN) and cervical carcinoma in situ (CIS), is a more advanced form of the cell changes. These cell changes can be detected non-invasively through examination of the cervical cells. The cells can be destroyed to prevent cancer development if dysplasia can be detected early. There are 2 main types of cells of the cervix: squamous epithelial cells and columnar epithelial cells. Squamous epithelial cells in older women cover the portions of the cervix that protrude into the vagina, and columnar epithelial cells line the inner portions of the cervical canal. The line where the two cells types meet, known as the transformation zone, is very vulnerable to the oncogenic effects of HPV. Certain gene polymorphisms on the genes that control epidermal growth factor increase the risk that HPV infection will lead to invasive cancer. Anything that affects the integrity of the immune system may affect the later risk of cervical cancer including poor nutrition and chronic stress. HIV infection greatly increases the risk that women infected with HPV will develop cervical cancer, and women with HIV should be screened for cervical cancer more frequently than women without HIV. Like other cancers, cervical cancer requires the accumulation of genetic alterations for carcinogenesis to occur. However, the discrete tumor suppressor gene locations have yet to be identified. Several chromosome regions with recurrent loss of heterozygosity (LOH) have been identified. In addition, other genes may influence a woman's receptivity to HPV. For instance, HPV may up-regulate the E6 oncoprotein in certain gene sequences, causing a greater production of vascular epidermal growth factor, which allows the tumor to promote blood vessel growth toward the proliferating cells, fueling growth.

8. What is the BRCA1 gene?

(p. 863-864, 7th ed) Box 24-16 A small total proportion of breast cancers are the result of highly penetrant dominant genes (i.e., hereditary breast cancers). BRCA1, located on chromosome 17, is a breast cancer susceptibility gene, which is one of the most important of the dominant genes. BRCA1 and BRCA2 (unmutated; normal) are tumor-suppressor genes. BRCA1 and BRCA2 function is a common pathway of genome protection. They work at different stages in the DNA damage response and in DNA repair. BRCA1 functions in both cell cycle check point activation and DNA repair, whereas BRCA2 is a mediator of the DNA repair mechanism-homologous recombination. A deleterious mutation in BRCA1 (or BRCA2) increases a woman's risk of developing breast cancer or ovarian cancer, or both. Harmful BRCA1 mutations may increase a woman's risk of developing cervical, uterine, pancreatic, and colon cancer. Harmful mutations in BRCA1 are highest in families with a history of both breast and ovarian cancer, family members with tumors that develop from different sites in the body, or a Jewish background. However, not every woman who has a harmful BRCA1 mutation will develop breast or ovarian cancer, or both. BUT they are 5x more likely. A woman with a BRCA1 mutation is about five times more likely to develop breast cancer than a woman without the mutation. Men with harmful BRCA1 mutations have an increased risk of breast cancer and possibly of pancreatic, testicular, and early-onset prostate cancer

38. Etiology of epididymitis. Complications?

(p. 897, 7th ed) Etiology: Epididymitis, or inflammation of the epididymis, generally occurs in sexually active young males (younger than 35 years) and is rare before puberty in young men the usual cause is a sexually transmitted microorganism, such as N. gonorrhoeae or C. trachomatis. Men who practice unprotected anal intercourse may acquire sexually transmitted epididymitis because of Escherichia coli, Haemophilus influenzae, tuberculosis (especially in regions where incidence of pulmonary tuberculosis is high), Cryptococcus, or Brucella. In men older than 35 years, enterobacteriaceae (intestinal bacteria) and Pseudomonas aeruginosa associated with urinary tract infections and prostatitis also may cause epididymitis. Besides an infectious etiology, epididymitis may result from a chemical inflammation caused by the reflux of sterile urine into the ejaculatory ducts. It is associated with urethral strictures, congenital posterior valves, and excessive physical straining in which increased abdominal pressure is transmitted to the bladder. Chemical epididymitis is usually self-limiting and does not require evaluation or intervention unless it persists. The pathogenic microorganism usually reaches the epididymis by ascending the vasa deferentia from an already infected urethra or bladder. The presence of bacteria initiates the inflammatory response, causing symptoms of bacterial epididymitis. Epididymitis caused by heavy lifting or straining results from reflux or urine from the bladder into the vas deferens and epididymis. Urine is extremely irritating to the epididymis and initiates an inflammatory response called chemical epididymitis. Acute, severe pain is typically the main symptom. Antibiotic therapy for the infection itself is necessary. Analgesics, ice and scrotal elevation can provide symptomatic relief. Bed rest and scrotal elevation are recommended until the scrotum is no longer tender. Complete resolution of swelling and pain may take several weeks to months. Complications: Include abscess formation, infarction of the testis, recurrent infection, and infertility. Infarction probably is caused by thrombosis (obstruction by blood clots) of the prostatic vessels secondary to severe inflammation. Recurrent epididymitis may result from inadequate initial treatment or failure to identify or treat predisposing factors. Chronic epididymitis can cause scarring of the epididymal endothelium. Once scarring has occurred, treatment with antibiotics is ineffective because adequate antibiotic levels cannot be achieved within the epididymis.

39. Sexually transmitted diseases in teenage girls-why are they more susceptible?

(p. 919, 7th ed) TEENAGE GIRLS Adolescents have the greatest risk for STI exposure and infection due to high risk-taking behavior (unprotected sex). Adolescent women may have a physiologically increased susceptibility to infection because of increased cervical immaturity and lack of immunity. Rates of gonorrhea, chlamydia, vaginitis, cervical condyloma, genital warts, and PID are highest in adolescents and young women and decline exponentially with increasing age .

1. Know all STDS: pathophysiology, etiology, clinical manifestations, diagnostic tests, treatment, and complications. How is each transmitted during pregnancy to the fetus? Know the different stages of syphilis; what organism causes each STD and is it viral, bacterial etc.? Do you treat both partners and why? What age group has the greatest risk of STDs and why? What causes cervical cancer?

See end

Gonorrhea?

BACTERIAL Gonorrhea Pathology: Local or systemic. Manifestations: Uncomplicated-urethral infections in men and urogenital infections in women. Men will have sudden onset of painful urination or purulent penile discharge or both within a week of infection. Women's symptoms will manifest within 10days or within 1 to 2 days after the next menstrual period. Initially asymptomatic, symptoms appear after spread to the upper reproductive tract. Symptoms include, dysuria, increased vaginal discharge, abnormal menses, dyspareunia, lower abd pain and fever. Complicated- prostatitis, epididymitis, lymphangitis, and urethral stricture in men and salpingitis, PID, and bartholinitis in women. Diagnosis: direct culture is preferred. Physical exam may disclose cervical friability and erythema and mucopurulent discharge from the cervical os. Abdominal palpation bilateral lower quadrant tenderness and rebound tenderness. Treatment: quickly becoming antibiotic resistant. Multidrug therapy is recommended. (Ceftriaxone IM and azithromycin or doxycycline po) Complications: PID, sterility and disseminated infection. Transmission to fetus: If passed to the fetus the infection usually manifests as an eye infection and develops 1-12 days after birth.

Bacterial vaginosis (929)

BACTERIAL Bacterial vaginosis (929) Pathology: sexually associated condition. (Digital penetration, oral sex, genital touching or penile penetration.) Most common in sexually active women of reproductive age. Etiology: caused by an overgrowth of anaerobic bacteria that produce aromatic amines and raise the pH of the vagina, promoting further bacterial growth WITHOUT the inflammatory response. Manifestations: FISHY odor, copious discharge that may be bubbly or frothy Diagnosis: "clue"cells are found on the wet mount. Diagnosis made with 3 of the 4 following criteria: gray vaginal discharge, vaginal pH greater than 4.5, amine odor, clue cells on wet mount. Treatment: Flagyl. Partners do not have to be treated. Complications: PID, chorioamnionitis, preterm labor, and postpartum endometritis. Transmission to fetus: treatment during pregnancy may cause preterm birth, so try and wait until 36 weeks.

CHLAMYDIAL (most common bacterial STI in the US)

BACTERIAL CHLAMYDIAL (most common bacterial STI in the US) Urogenital Infections (929) chlamydia** Pathology: most common reported STI in the US. Chlamydia trachomatis is an obligate, gram-negative intracellular bacterium that can only reproduce within host cells. Localizes to epithelial tissue and can spread throughout the urogenital tract. Manifestations: (chart page 930) may be asymptomatic and depend on site of infection... MEN- Epididymitis, rectal inflammation, proctitis, or reiter syndrome urethritis. WOMEN- bartholinis, slapinitis, perihepatitis, conjunctivitis, acute urethral syndrome, or arthritis-dermatitis syndrome. Diagnosis: tissue culture, direct chlamydial enzyme immunoassay, fluorescein-labeled monoclonal antibody testing, nucleic acid amplification testing. Treatment: single dose azithromycin. Treat all sexual partners Complications: Infertility and ectopic pregnancy. Transmission to fetus: passed from mother to the eyes and resp tract of newborn infants during birth. (Conjunctivitis and pneumonia)

Chancroid (925)

BACTERIAL Chancroid (925) Pathology: lesions are usually found throughout the genital regions, most commonly on the foreskin in men and the labia, clitoris or fouchette in women. Initially the papule enlarges, it then erodes into a soft, circumscribed ulcer with superficial exudate. Manifestations: - Women are generally asymptomatic and men develop inflamed, painful genital ulcers and inguinal buboes (swollen inflamed lymph node) - Incubation period 1-14days. 3-10 day incubation period. Women generally asymptomatic but can have dysuria, dyspareunia, vaginal discharge, pain on defecation, or rectal bleeding. A vesicopustule lesion forms and erodes into soft ulcer with a necrotic base, surrounding erythema, and a ragged, and serpiginous border. Unilateral painful, local lymphadenopathy presents primarily in men. Inguinal buboes (abscess) develop and fill with exudate. Lesions spread through autoinoculation. Diagnosis: easily confused with other genital ulcers. Chacrodial ulcers are painful, tender and nonindurated. Culture specimens positive for h. ducreyi. Treatment: single dose therapy with injected ceftriaxone or oral azithromycin in BOTH partners.

Granuloma Inguinale (donovanosis) (928)

BACTERIAL Granuloma Inguinale (donovanosis) (928) Pathology: Rare. Bacteria are gram negative and survive within macrophages. And is progressively destructive if untreated. Manifestations: localized nodules coalesce to form granulomas and ulcers on the penis in men and labia in women. Diagnosis: tissue smears or biopsy from lesions containing DONOVAN BODIES (bacteria filled vacuole Treatment: Long term treatment w/ doxycycline, azithromycin, cipro, erythromycin, or trimethoprim-sulfamethoxazole. Treat all sexual partners. Relapse can occur 6-18 months later despite effective initial therapy. Complications: secondary infections to other areas. Pseudobuboes.

Lymphogranuloma Venercum (931)

BACTERIAL Lymphogranuloma Venercum (931) Pathology: primarily found in men who have sex with men. The strain of c. trachomatis that causes LGV probably penetrates skin and mucous membranes through tiny abrasions and then spreads. The infection is acquired during sexual intercourse or through contact with contaminated exudate from active lesions. Manifestations: The lesion is most commonly a herpetiform (multivesicular) ulcer. The lesion begins as a skin infection and spreads to the lymph tissue causing inflammation necrosis, buboes, and abscesses of the inguinal lymph nodes. Primary lesion appear on the penis and scrotum in men and on the cervix, vaginal wall and labia in women. Secondary lesions involve inflammation and swelling of the lymph nodes with formation of large blue buboes that rupture and from draining ulcerative lesions. Diagnosis: serologic testing and by clinical manifestations (groove sign-distinctive inguinal swelling) Treatment: 21 day or longer course of oral doxycycline or erythromycin. Treat partners. Complications: permanent lymphatic disruption and genital disfigurement. Affected nodes become chronically swollen, hardened, and enlarged. C. trachomatis also spreads systematically through the bloodstream and can enter the CNS.

Nongonococcal Urethritis (nonspecific urethritis) (932)

BACTERIAL Nongonococcal Urethritis (nonspecific urethritis) (932) Pathology: caused by mainly c. trachomatis. OR ureaplasma urealyticum. Manifestations: 7-21 day incubation period and may cause dysuria/urethra discharge or itching. NGU is associated with heterosexual men, men of higher socioeconomic status. This disease is also associated with gonorrhea and chlamydial infection and develop biphasic illness because of the longer incubation. Diagnosis: diagnosis by exclusion. Treatment: PO 1g of Azithromycin Doxycycline 100mg 2x qD x7 days

Syphilis (923)

BACTERIAL Syphilis (923) Pathology: systemic shortly after infection. Etiology: transmission through minor abrasions during sexual intercourse but can occur extragenitally as well. Caused by treponema pallidum. Manifestations: (chart page923) *stage 1- primary: chancre at the site. Microorganisms drain in to adjacent lymph node and stimulate immune responses. *stage2-secondary: systemic spread to all body systems. *stage3-latent: minimal symptoms or the development of skin lesions, silent infection. *stage4-tertiary: the most severe stage, with destruction of bone, skin and soft and neurologic tissues. Noninfectious disease. Significant morbidity and mortality occur. Cardiovascular complications. Diagnosis: darkfield microscopy and serologic testing. During latent stage CSF can be tested. Treatment: injectable PCN, sexual partners are also treated Transmission to fetus: congenital syphilis contributes to prematurity of the newborn with bone marrow depression, CNS involvement, renal failure and intrauterine growth retardation. Transmission to fetus declines with each subsequent pregnancy, but can be transmitted as early as the ninth week of gestation.

AIDS

Bad Deal!

5. What are the signs of puberty in girls and boys? What delays puberty?

Chapter 23 p 771 Chapter 24 p 802-804 7th edition Puberty is the onset of sexual maturation and differs from adolescence. Adolescence is the stage of human development between childhood and adulthood and includes social, psycho- logic, and biologic changes. In girls, puberty begins at about ages 8 to 9 years with thelarche (breast development). In boys, it begins later—at about age 11 years. Genetics, environment, ethnicity, general health, and nutrition can influence the timing of puberty. Girls who are obese mature earlier, perhaps from higher estrogen levels related to leptin and gonadotropin secretion, and girls who have low body fat, reduced body weight, and intense exercise may experience delayed maturation. Although leptin is not the trigger for puberty onset, it plays an important permissive role. Reproductive maturation involves the hypothalamic- pituitary-gonadal (HPG) axis, the central nervous system, and the endocrine system (Figure 23-3). A sequential series of hormonal events promotes sexual maturation as puberty approaches. About 1 year before puberty in girls, there is an increase in frequency and amplitude of nocturnal pulses of gonadotropin secretion, LH, and FSH and an increased response in the pituitary to GnRH --- stimulates gonadal maturation (gonadarche) with estradiol secretion in girls and testosterone secretion in boys. Estradiol causes breast development (thelarche), maturation of the reproductive organs (vagina, uterus, ovaries), and fat deposit in hips in girls. Estrogen and increased production of growth factors cause rapid skeletal growth in both boys and girls. Testosterone causes growth of the testes, scrotum, and penis. A positive feedback loop is created with gonadotropins stimulating the gonads to produce more sex hormones. The most important hormonal effects occur in the gonads. In males the testes begin to produce mature sperm that are capable of fertilizing an ovum. Male puberty is complete with the first ejaculation that contains mature sperm. In females, the ovaries begin to release mature ova. Female puberty is complete with the first ovulatory menstrual period; however, this can take up to 1 to 2 years after menarche. Adrenarche is the increased production of adrenal androgens (dehydroepi- androsterone and androstenedione, which is converted to tes- tosterone and estrogen) prior to puberty, which occurs in both sexes, and is exhibited by axillary and pubic hair growth and body odor. Puberty is complete when an individual is capable of reproduction. The process of sexual maturation, or puberty, is marked by the development of secondary sexual characteristics, rapid growth, and, ultimately, the ability to reproduce. A variety of congenital and endocrine disorders can disrupt the timing of puberty, or sexual maturation. Delayed Puberty: 3% in North America. First sign of puberty - girls - thelarche (breast development) Puberty is considered delayed if there are no clinical signs of puberty by age 13 in girls (2 standard deviation [SDs] above the mean age of pubertal onset). Clinical diagnosis also can be made in the absence of menarche by age 15 or 16. Physiologic (constitutional, 95% of cases) delay in which hormonal levels are normal and the hypothalamic-pituitary-gonadal (HPG) axis is intact, but maturation is happening slowly. Physiologic delay - familial, not as common in girls as boys, freq diagnosed retrospectively after puberty complete. Intervention (i.e., exogenous sex steroid administration) in physiologic cases of delayed puberty to reduce the psychologic effects (e.g., self-esteem issues, embarrassment). The other 5% of cases are caused by a disruption of the HPG axis of various etiologies, including any chronic condition that delays bone aging (i.e., celiac disease, anorexia, hypothyroidism). Human gonadal function - partially controlled by luteinizing hormone (LH) & follicle-stimulating hormone (FSH) - release of which is regulated by the pulsatile secretion of hypo- thalamic gonadotropin-releasing hormone (GnRH). The G-protein-coupled receptor 54 (GPR54) has been identified as the gatekeeper gene for activation of the GnRH axis. GPR54 is required for the normal function of this axis, and data suggest that the ligand kisspeptin-1 may act as a neurohormonal regulator of the GnRH axis. Mechanisms of childhood inhibition of GnRH release and activation - feedback inhibition by sex steroids and presumably other central nervous system (CNS) pathways. Numerous etiologies - thorough evaluation - physical examination, medical and family history, x-ray studies for bone age, measurement of thyroid function, serum levels of prolactin and adrenal and gonadal steroids, radioimmunoassay of plasma gonadotropins, and screening for systemic disorders. High gonadotropin levels require a karyotype to rule out genetic causes, low levels need skull imaging (lateral skull film, computed tomography [CT], or MRI) to rule out pituitary or other CNS infiltrate or tumor. Goal: development of secondary sex characteristics and fertility. Insufficient sex hormone - replacement therapy - ie estrogen. Idiopathic hypogonadotropic hypogonadism - synthetic GnRH or sex hormone administration, or both, and may be lifelong.

Hepatitis B Virus

Hepatitis B Virus Pathology: Sexually transmitted. Passes through the blood stream to the liver, where it infects liver cells and multiplies. Etiology: needle puncture, blood transfusion, cuts in the skin, and contact with infected body fluids. Can remain outside body in a dry environment for 1 week and survive. Can only be killed with bleach or VERY high temps. Manifestations: may start with rash, urticarial, polyarthralgias, arthritis, anorexia, nausea, vomiting, headache, fever, jaundice, and moderate liver enlargement with tenderness AND chronic liver disease, hepatocellular cancer.( Mild illness to severe infection) Diagnosis: serologic testing. Treatment: immunization (three injection serious beginning at birth) Supportive care and relief of symptoms. Transmission to fetus: high risk, unless receive immunoglobulin and vaccination within 12 hours of birth.

Scabies (938)

PARASITIC Scabies (938) Pathology: hands between fingers and on the flexor surfaces of the wrists and the extensor surfaces of the elbows. The groin is a common location for sexually transmitted scabies. Lesions can occur on the penile shaft, glans, scrotum or buttocks. Etiology: can be spread by skin-to-skin contact or sexual contact. Common in nursing homes, child care facilities, and prisons. Manifestations: intense pruritus, ESP at night. S shaped burrow with a tiny vesicle at one end. Diagnosis: microscopic identification of the mite, eggs, or feces is recommended. Treatment: topical permethrin.

10. Know the role of the different female hormones involved in menstruation, menopause, ovulation, dysmenorrhea, etc.

Page 780 (7th ed) Table 23-2 Female hormones Menstruation •Leptin: increase sensitivity.....regulatory hormone of appetite and energy metabolism- increases with puberty and menarche • Gonadotropin-releasing hormone (GnRH) is stimulated as a result of feedback mechanisms originating in the dominant follicle, which is determined in the first 5-7 day of the cycle. GnRH is secreted by the hypothalamus and travels to the anterior pituitary, which stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH). • Controls Ovarian events of the menstrual cycle • High FSH levels stimulate follicle and ovum maturation (follicular phase) Then a surge of LH causes ovulation which is followed by development of the corpus luteum (luteal phase) • Estrogen— Generic for ( Estradiol, estrone and estriol). Estradiol (E2) most potent and plentiful and is 95% produced by the ovaries. • Early Follicular Phase: estrogen levels low; minute amount of progesterone secreted; GnRH, FSH, and LH levels are low Ovarian follicle develops; endometrium proliferates. • Late Follicular Phase (preovulatory): estrogen levels high; progesterone increases with small surge before ovulation; GnRH, FSH, and LH all surge (LH dominates) Process of ovulation begins; endometrial proliferation complete. • Ovulatory Phase: estrogen levels dip, progesterone levels begin to rise; GnRH, FSH, and LH all fall sharply. Corpus luteum begins to develop; endometrium enters secretory phase. • Early Luteal Phase: estrogen and progesterone levels high, progesterone dominates; GnRH, FSH, and LH all gradually decline. Corpus luteum fully developed; endometrium ready for implantation. • Late Luteal Phase: estrogen and progesterone levels fall sharply; GnRH, FSH, and LH all rise slightly. Corpus luteum regresses; endometrium breaks down; menstruation begins. • Menstrual Phase: estrogen levels low; minute levels of progesterone secreted; GnRN, FSH, and LH levels all low. More ovarian follicles begin to develop; functional layer of endometrium is shed. Ovulation: Occurs between the follicular and luteal phases. • Ovulation marks the beginning of the luteal/secretory phase of the menstrual cycle. • Pulsatile secretion of LH stimulated corpus luteum to secrete progesterone • If fertilization occurs, HCG is secreted 3 days after fertilization by the blastocytes and maintains the corpus luteum once implantation occurs at about day 6 or 7. HCG can be detected in maternal blood and urine 8 to 10 days after ovulation. •The production of estrogen and progesterone continues until the placenta can adequately maintain hormone production • If conception or implementation does not occur, corpus luteum degenerates and ceases production of progesterone and estrogen- endometrium becomes ischemic- menstruation occurs (also known as the ischemic/menstrual phase). Perimenopause: Transitional period between reproductive and nonreproductive years. Period that lasts 2-8 years prior to menopause. Usually begins 5 to 10 years before menopause. erratically higher estradiol levels; decreased progesterone levels; disturbed ovarian-pituitary-hypothalamic feedback relationship with higher LH levels; estradiol levels remain in the normal to slightly elevated range until approx. 1 year before menopause Hallmark of impending menopause: Increase in FSH normal LH Increase in FSH normal LH. Causes ovarian hyper stimulation which increases the number of follicles recruited causing follicular depletion and increases estradiol. Decrease follicular reserve decreases inhibin and increases activin in FT and LP causing increase in FSH and the number of follicles recruited, partial development, and infrequent ovulation - increase estrogen and decrease progesterone. Menopause Marks the end of reproduction • Menopause is the cessation of ovulation due to loss of ovarian follicles resulting in reduced ovarian production of estradiol, increased FSH and LH, and decreased inhibin (inhibits release of FSH). •Different factors influence the age of menopause; Genetics, socioeconomic status, race, parity, oral contraceptive , smoking and weight. • Menopause: characterized by loss of ovarian function, low estradiol and progesterone levels, high FSH and LH levels, and decreased follicular inhibin secretion. Less androgens are produced but sensitivity to them is increased because of lost opposition of estrogen Dysmenorrhea • Painful menstruation • Attributed to excessive endometrial prostaglandin production (10 times as much as normal) which cause uterine hyper contractility- decreased blood flow to uterus- increase hypersensitivity-- pain • Begins with the onset of ovulatory cycles around 15-16 years of age. • Up-regulated cyclo-oxygenase (COX) enzyme activity- increased synthesis of prostaglandins Prostaglandins are released during the first 48 hours of menstruation when symptoms are most intense. • Leukotriene production elevated- pain Chief Symptoms: pelvic pain at onset of menses that often radiates into the groin and may be accompanied by backache, anorexia, vomiting diarrhea, syncope and headache. Persist for first 1-3 days of menstrual flow. Secondary Dysmenorrhea—related to pelvic pathology (ovarian cyst, endometriosis) which manifest in later reproductive years and occurs at any time in the menstrual cycle.

Trichomoniasis (937)

PARASITIC Trichomoniasis (937) Pathology: parasitic protozoan that adheres to and damages squamous epithelial cells. (Women- vaginal and urethral tissue not the cervical canal. Men- urethra, epididymis and rarely the prostate) Etiology: t. vaginalis, common cause of sexually transmitted diseases and urethritis. Induces a marked inflammatory response in the vagina causing copious discharge. Manifestations: causes vaginitis in women and urethritis in men. Women have a copious amount of malodorous, gray-green discharge with pruritus and sometime "strawberry spots" visible on the vaginal walls and cervix. Increased pH. Men usually are asymptomatic. Diagnosis: microscopic or laboratory confirmation of the presence of the trichomonads in vaginal secretions or urine provide a def diagnosis. Symptoms and Hx are not enough. Treatment: metronidazole for both partners.

Pediculosis Pubis (CRaBs) (939)

PARASITIC Pediculosis Pubis (CRaBs) (939) Pathology: one of three species of lice that infect humans. 25-30 day life cycle. They depend on blood for nutrition. Etiology: caused by crab louse, p. pubis. Either from sexual contact or contact with infected bed linens or clothing. Can live on objects (towels) for a several days. Highly contagious. Manifestations: mild and severe pruritus. Diagnosis: lice are visible to the naked eye (grayish with claws to attach to pubic hair) Treatment: topical over the counter pediculicides (permethrin cream rinse or lindane lotion.) Second line treatment is malathioin lotion kept on body for 8-12 hours. Sexual partners should be treated regardless of symptoms. Complications: secondary infections from excessive scratching.

Genital Herpes (932)

VIRAL Genital Herpes (932) Pathology: Causes blisters (cold sores) and is the most common infectious cause of genital ulcerations in the US. After initial exposure and entry of the virus at mucocuatnous sites or abraded skin the virus undergoes replication locally in the dermis and epidermis. This leads to cell destruction, transudation and vesicle formation. It then spreads to contiguous cells and into sensory nerves. Eventually transported to the dorsal root where it remains latent until reactivated. Can be reactivated by stress, menstruation, sun exposure. Etiology: transmitted through genital skin or mucosal contact with a person who is shedding the virus. Manifestations: lesions initially appear as groups of vesicles, at the site of infection, that progress to ulceration with pain, lymphadenopathy, and fever. Individuals are contagious during outbreaks and episodes of asymptomatic viral shedding. Diagnosis: viral cultures can be done, but CDC recommends serologic testing. Treatment: Acyclovir reduces symptoms but does not cure the disease. Complications: lifelong with initial outbreak and subsequent outbreaks. Transmission to fetus: does pass from mother to fetus, so mother should have C-section to prevent transfer.

HPV (934)

VIRAL HPV (934) Pathology: DNA virus. Transmission occurs through sexual contact. The initial infection follows trauma to the epithelium that allows the virus to reach and infect the basal cells of the epithelium. The cells then proliferate and may form a warty growth or cancer. May appear after 2-3 months or may not be noticed for years. Manifestations: associated with cervical dysplasia and cancer as well as condylomata acuminata (warts). The high-risk strains that produce cancer do not produce warts. Warts are highly contagious. (Velvety cauliflower-like lesions occur in the genital and anal areas, vagina and cervix and are painless.) Diagnosis: testing is available Treatment: vaccine now available. Warts can be removed but not cured. Pap tests ever 3 years. Complications: CANCER Transmission to fetus: Warts can be transferred to infant at birth causing laryngeal papillomas. Symptoms include, stridor, hoarseness, abnormal cry, and cough and resp distress. Can be infected in utero and by passage through an infected birth canal.

Molluscum Contagiosum (937)

VIRAL Molluscum Contagiosum (937) Pathology: benign viral infection of the skin. : transmitted by skin-to-skin contact in children and adults on the face, hands, lower abdomen or genitalia. Can be transmitted by sexual contact or from wet surfaces, towels, equipment, etc. Etiology: The virus is taken into epithelial cells by phagocytosis and replicates within the cytoplasm, where it produces superficial cytoplasmic inclusion and cellular hyperplasia. Manifestations: Incubation of 2-7 weeks. Then small white or flesh colored, round or oval dome shaped papules appear. The surface has a characteristic central umbilication where a thick, cream core material can be expressed. Diagnosis: appearance alone Treatment: heal spontaneously after several months but are contagious until completely healed. Can use cryotherapy, silver nitrate, topical creams or curettage.

33. Know which hormones are water soluble and which are lipid soluble.

Water Soluble Peptides: growth hormone, insulin, leptin, parathyroid hormone, prolactine Glycoproteins: follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone Polypeptides: andrenocorticotropic hormone, antidiuretic hormone, calcitonin, endorphins, glucagon, hypothalamic hormones, lipotropins, melanocyte- stimlating hormone, oxytocin, somatostatin, thymosin, thyrotropin-releasing hormone Amines: epinephrine, norepinephrine Lipid Soluble Thyroxine (an amine but lipid soluble): both thyroxine [T4] and triiodothyronine [T3] Steroids (cholesterol is a precursor for all steroids): estrogens, glucocorticoids (cortisol), mineralocorticoids (aldosterone), progestins (progesterone), testosterone Derivative of arachidonic acid (autocrine or paracrine action): leukotrienes, prostacyclins, prostaglandins, thromboxanes