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Structure of Nephron
- Afferent/Efferent Capillaries
- Glomerular Capillaries/Bowman's Space
- Proximal Convoluted Tubule
- Proximal Straight Tubule
- Thin Descending Limb
- Thin Ascending Limb
- Thick Ascending Limb
- Distal Convoluted Tubule/Macula Densa
- Collecting Duct
- constriction will decrease GFR and RBF
- (decreases glomerular hydrostatic pressure, PGC)
- constriction will increase GFR but decrease RBF
- (increases glomerular hydrostatic pressure, PGC)
- Reabsorption of:
- Glucose, amino acids, Na+, urea, lactate, bicarb
- Secretion of:
- Acids/Bases, K+
- for filtration
- where ultrafiltrate is created
- Made up of:
- Endothelium - large pores for fluid, solutes, proteins to pass
- Basement membrane - does not allow proteins to pass
- Epithelium - podocytes for more filtration
- Negatively charged glycoproteins - assist filtration by attracting positively charged solutes, and repelling negatively charged solutes (plasma proteins)
cell and protein free filtrate enters the capsular (Bowman's) space from the glomerular capillaries
Proximal Convoluted Tubule
- Most of reabsorption occurs via sodium cotransport.
- including reabsorption of glucose and amino acids
- Brush boarder of microvilli for absorption
- Glucose is reabsorbed in the PCT by sodium co-transport. This is a saturable process because it depends on cell membrane proteins. (Glucose in urine in unmanaged diabetes, threshold met at 180-200, increases urine output because it acts like osmotic load)
- 67% of salt and water of filtrate reabsorbed in PCT (isosmotic) Electrical gradient encourages Cl- to accompany the Na+ through "leaky" tight junctions, water follows.
- Volume expansion will decrease this reabsorption
- Volume contraction will increase this reabsorption
- 70% of phosphate reabsorbed in PCT, PTH can inhibit the Na+-phosphate cotransport. This decreases the threshold for phosphate reabsorption and causes phosphaturia.
- 67% of calcium is reabsorbed in PCT
- 30% of Mg2+ is reabsorbed in PCT
Proximal Straight Tubule
- between proximal convoluted tubule and thin descending limb
- 15% of phosphate is reabsorbed here
Thin Descending Limb
Permeable to water but not sodium
Thin Ascending Limb
between thin descending limb and thick ascending limb
Thick Ascending Limb
- Permeable to sodium but not water
- 25% of sodium reabsorbed
- Na+, K+, 2Cl- diffuse from the filtrate in the lumen into the cells of the thick ascending limb by co-transport.
- Sodium-Potassium pump further reabsorbs sodium to blood with Cl- following.
- Loop diuretics take affect here to block the 2Cl- and thereby also blocking Na+reabsorption (Furosemide)
- 25% of Calcium is reabsorbed here and can be inhibited by loop diuretics because of the inhibition of the Na+-K+-2Cl- cotransport and eliminating the lumen-positive potential which is the driving force for paracellular Ca2+ reabsorption. For this reason loop diuretics can be used to treat hypercalcemia.
- 60% of Mg2+ is reabsorbed here and is also inhibited by Furosemide
Distal Convoluted Tubule
- Initial portion contains macula densa for regulating GFR
- Early distal tubule is the site of action for thiazide diuretics, by blocking Cl-.
- 8% of calcium is reabsorbed in the early distal tubule which can be enhanced by PTH and thiazide diuretics. This is good for elderly with HTN.
- 5% of Mg2+ is reabsorbed here also.
- Later portion is for:
- H+ secretion
- Influenced by aldosterone (enhance water and sodium reabsorption, excrete potassium)
- 5% of sodium reabsorbed
- Late distal tubule and collecting duct is the site of action for potassium sparing diuretics by directly blocking the effects of aldosterone (spironolactone) or by blocking the epithelial sodium channels (triamterene)
- Contained in the initial portion of the distal convoluted tubule
- Regulates GFR by tubuloglomerular feedback
- First portion influenced by aldosterone (along with the later portion of the distal convoluted tubule) to enhance water and sodium reabsorption, and excretion of potassium)
- In general - ADH/vasopressin controls aquaporins to allow reabsorption of water from the filtrate
- High levels of ADH create hyperosmotic urine and negative free water clearance
- Low levels of ADH create hyposmotic urine and positive free water clearance
- 3% of sodium reabsorbed
- Urea is recycled here under the influence of ADH
Hyperosmotic medullary gradient is set up due to the thin descending limb of the loop of Henle being permeable to water but not to sodium and the thick ascending limb of the loop of Henle being permeable to sodium but not water.
- Intracellular Fluid
- 2/3 of total body water
- Extracellular Fluid
- 1/3 of total body water
- Of ECF:
- 3/4 is interstitial fluid
- 1/4 is plasma
decrease in ECF
increase in ECF
# of solutes in solution
- make cells swell
- less solute in solution
- make them shrink
- more solute in solution
- keeps cells the same size
- equal solutes
Isotonic volume contraction
- decrease in ECF without any change in ECF osmolarity
- diarrhea, burn
Hyperosmotic volume contraction
- decreased in ECF with an increase in ECF osmolarity
- sweating, fever, diabetes insipidus
Hyposmotic volume contraction
- decrease in ECF with a decrease in ECF osmolarity
- adrenal insufficency
Isosmotic volume expansion
- increase in ECF without any change in ECF osmolarity
- infusion of isotonic NaCl
Hyperosmotic volume expansion
- increase in ECF with an increase in ECF osmolarity
- high NaCl intake
Hyposmotic volume expansion
- increase in ECF with a decrease in ECF osmolarity
- syndrome of inappropriate ADH
- impaired water excretion --> concentrated urine
- ADH is continued to be excreted despite normal or elevated plasma volume
- Result of excess water, not deficiency of sodium
- (part of euvolemic hypotonic hyponatremia - treat with free water restriction)
Regulation of Renal Blood Flow
- Affect the diameter of the afferent and efferent arterioles
- Sympathetic nerves (catecholamines)
- Angiotensin II
- Nitric oxide
- Atrial Natriuretic Peptide (ANP)
- (PG - prostaglandins)
- NSAIDs inhibit PG, thereby decreasing renal blood flow and therefore damage with chronic use.
- Glomerular Filtration Rate
- volume of filtrate produced by kidneys per minute
- GFR is increased by:
- constriction of efferent arteriole
- decreased plasma protein
- GFR is decreased by:
- constriction of the afferent arteriole
- increased plasma protein
- Measured by creatinine clearance (GFR = concentration in urine x volume in urine / plasma concentration)
tightly linked to GFR levels, and so when there is a sudden decrease in GFR, there will be a corresponding rise in blood creatinine levels. GFR values are frequently estimated from from plasma creatinine levels, using formulas (e.g., Cockcroft-Gault equation) that account for age, sex, and other aspects that account for differential muscle mass.
Autoregulation of RBF and GFR
- protects the nephrons from extremes in arterial pressures by varying resistance of the arterioles
- mostly the afferent arterioles
- (by macula densa)
- Renal arterial pressure increases and ↑RBF and GFR
- Increase in [NaCl] and water to the macula densa
- Macula densa releases vasoactive substances
- Constriction of afferent arterioles
- Compensatory decrease in RBF and GFR
- Glomerular Filtration - Ultrafiltrate formed in glomerular capillaries
- Tubular Reabsorption
- Tubular Secretion
- elimination of a substance in urine
- (what continues through the tubules to the collecting duct)
- Hydrostatic Pressure in Bowman's Space (PBS)
- Hydrostatic Pressure in Glomerular Capillaries (PCG)
- Oncotic Pressure in Bowman's Space (πBS) always zero.
- Oncotic Pressure in Glomerular Capillaries (πCG)
Agents that affect internal K+ balance
- Into cells (hypokalemia):
- Insulin-stimulates K+ uptake into cells by increasing Na+/K+ ATPase.
- Stimulation of β2 adrenergic receptors causes a shift of K+ into cells.
- Alkalosis stimulates the H+/K+ exchange and causes a shift of K+ into cells.
- Out of cells (hyperkalemia):
- Stimulation of α adrenergic receptors causes a shift of K+ out of cells.
- Acidosis inhibits the H+/K+ exchange and causes a shift of K+ out of cells.
- Insulin deficiency
Factors that increase K+ secretion by principle cells include:
- High Dietary K+
- Thiazide and loop diuretics
- Luminal anions
Factors that decrease K+ secretion by principle cells include:
- Low Dietary K+
- K+ sparing diuretics
Increased Plasma Osmolarity and ADH
- (water deprivation and SIADH)
- Stimulates osmoreceptors in the anterior hypothalamus which increases thirst and water intake while also increasing ADH secretion from posterior pituitary gland.
- The increased ADH then increases the permeability of the principle cells in the late distal tubule and collecting duct so more water can be reabsorbed.
- As more water is reabsorbed the urine osmolarity increases and the urine volume decreases (concentrated/hyperosmotic urine).
- Combining the increased water intake and the decreased urine volume results in the plasma osmolarity decreasing to a normal level.
Decreased Plasma Osmolarity and ADH
- (water drinking, central diabetes insipidus, or ineffective ADH in nephrogenic diabetes insipidus)
- Inhibits osmoreceptors in the anterior hypothalamus which decreases thirst and water intake while also decreasing ADH secretion from posterior pituitary gland.
- The decreased ADH then decreases the permeability of the principle cells in the late distal tubule and collecting ducts which reduces the amount of water being reabsorbed.
- With less water being absorbed the urine osmolarity decreases and the urine volume increases (dilute/hyposmotic urine).
- Combining the decreased water intake and the increased urine volume results in the plasma osmolarity increasing to a normal level.
- Secreted by the posterior pituitary gland in response to increased blood osmolarity sensed by the hypothalamus.
- Increased blood osmolarity will also trigger thirst and water intake.
ADH secretion stimulated by
- Increased blood/serum osmolarity
- Decreased ECF volume
- Angiotensin II
ADH secretion inhibited by
- Decreased blood/serum osmolarity
- alpha-adrenergic agonists
- Atrial Natriuretic Peptide
- (e.g., volume contraction or prerenal azotemia)
- creatinine will be filtered and excreted, but urea will be filtered and reabsorbed, hence leading to a BUN/creatinine ratio >20.
- Intrarenal disease
- both BUN and creatinine will be equally affected, hence no increase in the BUN/creatinine ratio.
Hormones secreted by the Hypothalamus
- (six total)
- Dopamine or Prolactin-inhibiting factor (amine)
- Thyrotropin-releasing hormone (peptide)
- Corticotropin-releasing hormone (peptide)
- Gonadotropin-releasing hormone (peptide)
- Somatostatin or somatotropin release-inhibiting hormone (peptide)
- Growth hormone-releasing hormone (peptide)
Dopamine or Prolactin-inhibiting factor
- Inhibits secretion of prolactin
- Stimulates secretion of TSH and prolactin
- Stimulates secretion of ACTH
- Stimulates secretion of LH and FSH
Somatostatin or somatotropin release-inhibiting hormone in the Hypothalamus
- Inhibits secretion of growth hormone
Growth hormone-releasing hormone
- Stimulates secretion of growth hormone
Hormones secreted by the Anterior Pituitary
- (seven total)
- Thyroid-stimulating hormone (peptide)
- Follicle-stimulating hormone (peptide)
- Luteinizing hormone (peptide)
- Growth hormone (peptide)
- Prolactin (peptide)
- Adrenocorticotropic hormone (peptide)
- Melanocyte-stimulating hormone (peptide)
- The relationship between the anterior pituitary and hypothalamus is different due to their shared portal system. Hormones are synthesized in cell bodies within the hypothalamus, travel down axons to the median eminence of the hypothalamus, where they stimulate secretion of the hormones into the hypophysial portal vessels to the anterior pituitary. The hypothalamic hormones then stimulate release of anterior pituitary hormones which enter the systemic circulation and travel to their target tissues.
- Stimulates synthesis and secretion of thyroid hormones
- Stimulates sperm maturation in Sertoli cells of testes
- Stimulates follicular development and estrogen synthesis in ovaries
- Stimulates testosterone synthesis in Leydig cells of testes
- Stimulates ovulation, formation of corpus luteum, estrogen and progesterone synthesis in ovaries
- LH stimulates the initial conversion of cholesterol to pregnenolone, then to progesterone
- LH also stimulates the production of 17β-estradiol with the final step being stimulated by FSH (converting testosterone produced by the theca interna cells with the help of aromatase to 17β-estradiol (the major form of circulating ovarian estrogen) in the granulosa cells surrounding the oocyte)
- Stimulates protein synthesis and overall growth
- Several metabolic effects:
- In the liver, GH stimulates production of IGFs (Insulin-like growth factors or somatomedins) which mainly stimulate growth in bone and peripheral tissues and increases hepatic glucose output.
- GH stimulates cell division and growth in bone and cartilage. High levels before puberty can lead to gigantism.
- GH stimulates lipolysis in adipose tissue.
- In muscle, GH stimulates protein synthesis, inhibits breakdown of protein, but is also considered diabetogenic as it inhibits uptake of glucose.
Growth Hormone Regulation
- The hypothalamus releases GHRH, which stimulates the anterior pituitary to secrete GH. GH stimulates the production of IGFs (somatomedins in the liver) that in turn, inhibit anterior pituitary and hypothalamus to decrease secretion of GHRH and GH.
- Factors that inhibit GH production stimulate the hypothalamus to release somatostatin (SRIF) which inhibits secretion of GH by the anterior pituitary. The presense of GH and somatomedins both act to inhibit their own further production.
Growth hormone secretion stimulated by
- (Fasting state/growth)
- Decrease in glucose concentration
- Decrease in free fatty acid concentration
- Hormones of puberty
- Stage III and IV sleep
Growth hormone secretion inhibited by
- (Fed state/no growth)
- Increase glucose concentration
- Increased free fatty acid concentration
a rare condition of overproduction of GH in adults, most commonly caused by a pituitary adenoma. Clinical features include enlargement of soft tissue, organs, and bones. Symptoms include general weakness, fatigue, arthralgias as well as tumor compression symptoms such as visual field deficits and headaches.
- Stimulates milk production and secretion in breast
- Prolactin is under both stimulation (TRH) and inhibition (dopamine). Nursing helps to stimulate a neuroendocrine reflex to inhibit dopamine and so maintain high levels of prolactin
Prolactin secretion stimulated by
- Pregnancy (estrogen)
- Breast feeding
- Dopamine anatagonist
Prolactin secretion inhibited by
- Bromocriptine (dopamine agonist)
- Somatostatin (GH)
- Prolactin (negative feedback)
- Stimulates synthesis and secretion of adrenal cortical hormones (cortisol, androgens, and aldosterone)
- Stimulates melanin synthesis (? humans)
Hormones secreted by Posterior Pituitary
- (two total)
- Oxytocin (neuropeptide)
- Vasopressin or antidiuretic hormone (neuropeptide)
- These are synthesized in different nuclei of the hypothalamus, travel down axons, and are then stored in neurosecretory vesicles in the posterior pituitary. When the cell body is stimulated, the hormones are secreted into the systemic circulation and delivered to their target tissues.
- Stimulates milk ejection from breasts and uterine contractions
Vasopressin or antidiuretic hormone
- Stimulates water reabsorption in principal cells of collecting ducts and constriction of arterioles
complete loss of all hormones secreted by the pituitary gland. It can be caused by multiple things; head injury, tumor, genetic mutations, etc. It can be sudden or insidious and involve a wide variety of deficits.
Hormones secreted by the Thyroid
- (two total)
- Triiodothyronine (T3) and L-thyroxine (T4) (amine)
- Calcitonin (peptide)
- The thyroid mostly produces T4 which is then converted to T3 in the target organs
- Thyroglobulin (TG) is a glycoprotein and is used as part of thryoid hormone storage in the colloid
- Majority of thyroid hormone is bound to thyroxine-binding globulin (TBG).
- Virtually every organ in the body has receptors for thyroid hormone.
Triiodothyronine (T3) and L-thyroxine (T4) (amine)
Stimulate skeletal growth; oxygen comsumption; heat production; protein, fat and carbohydrate utilization; perinatal maturation of the central nervous system
Thyroid Hormone Regulation
- By the hypothalamic-pituitary axis.
- Thyrotropin-releasing hormone (TRH) is secreted by the hypothalamus, stimulates the anterior pituitary to secrete TSH, which then acts on the thyroid gland to secrete thyroid hormone. Increased levels of T4 and T3 will negatively feedback on the secretion of TSH.
Thyroid hormone stimulated by
- Thyroid-stimulating immunoglobulins
- Increased TBG levels (e.g. pregnancy)
Thyroid hormone inhibited by
- I- deficiency
- Propylthiouracil (inhibits peroxidase enzyme)
- Decreased TBG levels (e.g. liver disease) (with decreased TBG, less thyroid hormone is bound to it so more is free for negative feedback effects which then decrease T3 and T4)
- TSI act similarly to TSH stimulate increased thyroid hormone production as well as hypertrophy of the gland (goiter). Signs and symptoms are widespread and include unintentional weight loss, tremors, heat intolerance, palpitations, and irritability. Graves Ophthalmopathy, characterized by proptosis, lid lag, stare, and periorbital edema, is also a common finding and is caused by an infiltration of lymphocytes and edema into the orbital soft tissues and extraocular muscles.
- Elevated thyroglobulin and thyroid peroxidase antibodies. Common signs and symptoms include weight gain, lethargy, cold intolerance, constipation, and depression. The face may appear puffy, with coarse features due to the accumulation of protein complexes and sodium and water retention (aka myxedema). Thyroid hormones are needed for normal nervous system development ie. development of synapses, myelination, and cell signaling, which is why congenital hypothyroidism can lead to severe growth and mental retardation (cretinism).
- Decreases serum [Ca2+]
Horomone secreted by the Parathyroid
- (one total)
- Parathyroid hormone (PTH) (peptide)
- Increases serum [Ca2+]
- Specialized chief cells of the parathyroid gland secrete PTH in response to decreased levels of calcium.
- When calcium levels are normal, PTH is released in low levels. When calcium levels decrease, PTH levels increase.
Regulation of PTH and Calcium
- When calcium levels drop, PTH works in several ways to increase serum calcium levels.
- 1. In bone, PTH causes increase in bone resorption via activation of osteoclasts. This delivers both calcium and phosphate to ECF.
- 2. In the kidney, PTH inhibits phosphate reabsorption to increase the amount of phosphate being excreted (as we learned in renal lectures). PTH also stimulates increased calcium reabsorption in the kidneys.
- 3. In the small intestine, PTH indirectly stimulates increased calcium and phosphate absorption.
- most commonly caused by parathyroid adenomas. Excess PTH causes increases bone resorption and excess plasma calcium. Symptoms are known as "stones, bones, groans, and moans" due to:
- increased risk for renal stones, increased risk for osteoporosis, general GI discomfort from N/V/constipation, and psychic moans from depression and fatigue.
- Treatment is typically surgical.
- In osteoporosis, bone mineral is normal, but there is decreased bone mass. A major role in osteoporosis is the lack of sex steroids, with subsequent accelerated bone resorption, particularly loss of the trabecular bone. Bone loss occurs from increased resorption, decreased formation, or a combination of both. In addition to calcium and vitamin D supplementation, osteoporosis can be treated with bisphosphonates, which are chemical analogues of mineral components that inhibit osteoclast activity to prevent further bone loss.
- Bisphosphonates are also used to treat malignancy of the parathyroid which will inhibit the overproduction of PTH which will then allow Ca2+ levels to increase to normal levels.
Hormones secreted by the Adrenal Cortex
- (three total)
- Aldosterone (mineralcorticoid from the Zona glomerulosa -outer) (steroid)
- Cortisol (glucocorticoid from the Zona fasciculata - middle) (steroid)
- Dehydroepiandrosterone (DHEA) and androstenedione (adrenal adrogens from the Zona reticularis - inner) (steroid)
- The synthesis and secretion of all adrenal cortex hormones require ACTH, which is stimulated by corticotropin-releasing hormone (CRH) secreted by the hypothalamus. Cortisol secretion follows the classic hypothalamic pituitary axis with negative feedback control.
- Androgens are also under regulatory control of ACTH. Aldolsterone is unique as it is under regulatory control primarily by the renin-angiotensin-aldosterone system, with some regulation by ACTH.
Adrenal hormone stimulated by
- Decreased blood cortisol levels
- Sleep-wake transition
- Stress; hypoglycemia; surgery; trauma
- Psychiatric disturbances
- alpha-Andrenergic agonists
- beta-Andrenergic antagonists
Adrenal hormone inhibited by
- Increased blood cortisol levels
- Stimulates gluconeogenesis; inhibits inflammatory response; suppresses immune response; enhances vascular responsiveness to catecholamines
- Stimulation of gluconeogenesis in liver cells and decreased glucose utilization in muscle in fat
- Increased protein catabolism
- Abnormal lipid metabolism
- Anti-inflammatory effects by inhibiting enzymes and signals that mediate inflammation
- Increased vascular responsiveness to catecholamines by up-regulating α1 adrenergic receptors
- Increased bone resorption
- Secreted in a pulsatile fashion with a major early morning burst
- 1° Adrenocortical Insufficiency
- Symptoms include hypoglycemia, anorexia, weight loss, N/V, weakness (due to decreased cortisol), hypotension, hyperkalemia, and metabolic acidosis (due to decreased aldosterone), and in women decreased pubic and axillary hair (due to decreased androgens), and hyperpigmentation due to compensatory increase in ACTH.
excess glucocorticoids (endogenous vs. exogenous). The majority of cases of Cushing syndrome are iatrogenic (caused by exogenous steroids), but other causes include ACTH or cortisol-secreting tumors, found ectopically or within pituitary or adrenal glands. Cushing Disease is a part of this syndrome where the excess glucocorticoids are caused by an ACTH-secreting pituitary tumor.
- Increases renal Na+ reabsorption, K+ secretion, and H+ secretion
Dehydroepiandrosterone and androstenedione
- (DHEA) and (adrenal adrogens)
- Same as testes/testosterone
- In males, these hormones play a minor role as they are both converted to testosterone in the testes, but the testes produce their own supply of testosterone.
- In females, adrenal androgens are the main androgens responsible for development of pubic hair growth and libido.
Hormones secreted from the Testes
- (one total)
- Testosterone (steroid)
- Stimulates spermatogenesis; stimulates male secondary sex characteristics
- Synthesized and secreted by leydig cells
- In the testis, testosterone acts in a local fashion, so that it is required for spermatogenesis. Testosterone strongly stimulates protein production, particularly in muscle development, thickening of the skin along with increased acne, in addition to growth and then maturation of the epiphyseal plates.
- Testosterone levels peak as sex organs are being developed, then again with the descent of the testes. Levels increase with the onset of puberty, peak in mid-adulthood, and follow a gradual decline in late adulthood.
Mediated by testosterone
- Differentiation of epididymis, vas deferens, and seminal vesicles
- Increased muscle mass
- Pubertal growth spurt and cessation of growth spurt
- Growth of penis and seminal vesicles
- Deeping of voice
- Negative feedback on anterior pituitary
Mediated by dihydrotestosterone
- Differentiation of penis, scrotum, and prostate
- Male hair pattern
- Male pattern baldness
- Sebaceous gland activity (acne)
- Growth of prostate (BPH)
Negative Feedback in Testes
- Hypothalamus secretes GnRH which stimulates the anterior pituitary to secrete LH and FSH.
- LH stimulates the Leydig cells to make testosterone which then has a negative feedback to the anterior pituitary and the hypothalamus to inhibit further secretion of LH and GnRH respectively. Testosterone also acts as a paracrine to stimulate the sertoli cells along with FSH from the anterior pituitary to secrete inhibin.
- Inhibin then has a negative feed back with the anterior pituitary to inhibit further secretion of FSH.
Hormones secreted from the Ovaries
- (two total)
- Estradiol (steroid)
- Progesterone (steroid)
- Stimulates growth and development of female reproductive system, follicular phase of menstrual cycle, development of breasts, prolactin secretion; maintains pregnancy
- In addition to the ovary and endometrium, estrogens have effects on other organs:
- Bones - inhibition of growth factors/interleukins that stimulate osteoclasts (RANKL)
- Breasts - enlargement
- Skin - enhances smoothness and vascularity, with increased fat deposition subcutaneously
- Stimulates luteal phase of menstrual cycle; maintains pregnancy
Effects of Progesterone
- Maintenance of secretory activity of uterus during luteal phase
- Development of breasts
- Negative feedback effects on LH and FSH secretions
- Maintenance of pregnancy
- Raising uterine threshold to contractile stimuli during pregnancy
Hormones secreted from the Corpus Luteum
- (two total)
- Estradiol and Progesterone
Hormones secreted from the Placenta
- (four total)
- Human chorionic gonadotropin (HCG) (peptide)
- Human placental lactogen (HPL), or human chorionic somatomammotropin (peptide)
- Estriol (steroid)
- Progesterone (steroid)
Human chorionic gonadotropin
- Stimulates estrogen and progesterone synthesis in corpus luteum of early pregnancy
- Begins being secreted around 8 days post ovulation by trophoblast
- Later HCG secretion is taken over by the placenta
Human placental lactogen, or human chorionic somatomammotropin
- Has growth hormone-like and prolactin-like actions during pregnancy
- same as estradiol
- Synthesized in pregnancy
- Cholesterol from the mother goes to the placenta where it is changed to pregnenolone. Pregnenolone then goes into the fetus to the fetal adrenal gland where DHEA-sulfate is made, that goes to the liver to make 16-OH DHEA-sulfate when then goes back to the placenta and is changed to estriol by sulfatase and aromatase.
Hormones secreted by the Pancreas
- (two total)
- Insulin (peptide)
- Glucagon (peptide)
- beta cells - 65%
- Decreases blood glucose
- Synthesized as prohormone (proinsulin) and the connecting peptide (c peptide) is cleaved in the Golgi apparatus and released in equal parts with insulin.
- Glucose is the most potent stimulator of insulin secretion.
Insulin Mechanism of Action
Insulin binds to receptors on target cells activating a tyrosine kinase portion of the receptor and triggering phosphorylation and increased permeability to glucose and amino acids, e.g., through placement of GLUT 4 molecules. The insulin receptor is then taken back into the target cell and either degraded or recycled. Insulin resistance, (as associated with obesity) occurs in part when more insulin receptors are degraded than synthesized.
Actions of Insulin
- 1. Decreased blood glucose via increased uptake of glucose via facilitated diffusion through GLUT 4 transporters in the plasma membrane, increased glycogen synthesis, decreased glycogenolysis, and decreased gluconeogenesis.
- 2. Increased protein synthesis
- 3. Increased fat deposition/decreased lipolysis
- 4. Increased potassium uptake into cells by increasing Na+/K+ ATPase.
- The brain is unusual in that its cells are permeable to glucose without insulin (different glucose transporter molecules, e.g., GLUT 1 in the neurons).
Insulin is stimulated by
- Increased glucose concentration
- Increased amino acid concentration
- Increased fatty acid and ketoacid concentration
- Glucose-dependent insulinotropic peptide (GIP)
- Vagal stimulation, acetylcholine (PNS)
Insulin is inhibited by
- Decreased glucose concentration
- alpha-Andrenergic agonists (SNS)
- alpha cells - 20%
- Increases blood glucose
Glucagon is stimulated by
- Decreased glucose concentration
- Increased amino acid concentration (esp. arginine)
- beta-Adrenergic agonists
Glucagon is inhibited by
- Increased fatty acid and ketoacid concentrations
Somatostatin in the Pancreas
- delta cells - 10%
- Inhibits insulin and glucagon secretion in the pancreas
Type 1 diabetes mellitus
makes up only 5-10% of cases of diabetes and is caused by autoimmune destruction of pancreatic β cells. Patients with type 1 diabetes have a genetic predisposition, but there are environmental associations as well.
Type 2 diabetes mellitus
accounts for over 90% of diabetics. Initially, insulin production is present and may even be in excess, but tissues are insulin resistant. Most type 2 diabetics are obese, which is the number one cause of insulin resistance. A strong genetic predisposition is present in patients with type 2 DM, but lifestyle factors also play a role.
Chronic complications of diabetes mellitus include:
- Macrovascular diseases:
- CAD, PVD, stroke.
- Macrovascular conditions are associated with increased atherosclerosis and other comorbid conditions. (HTN, Hyperlipidemia, obesity)
- Microvascular diseases:
- (retinopathy, nephropathy, neuropathy)
- Chronically elevated glucose levels cause microvascular damage via several different cellular pathways involving reactive oxygen species, protein alteration, altered hemodynamics, and vascular changes.
Hormones secreted from the Kidney
- (two total)
- Renin (peptide)
- 1,25-Dihydroxycholecalciferol (steroid)
- Catalyzes conversion of angiotensinogen to angiotensin I
- Increases intestinal absorption of Ca2+; bone mieralization
- Active form of Vitamin D
Hormones secreted by the Adrenal Medulla
- (two total)
- Norepinephrine, epinephrine (amine)
- Actions of Sympathetic Nervous System (ANS)
Types of Regulatory Secretions
when secretions from a cell play a role in its own function
secretions from one cell have an effect on nearby cells.
"true hormones" where secretions are released and carried by the bloodstream to a target cell.
secretions released from neurons and carried by the bloodstream to target cells.
- The most common type of hormone and are prepared in the standard protein secretory pathway.
- Examples of peptide hormones are thyroid-stimulating hormone (TSH), Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and Prolactin.
- Most peptide hormones bind to their receptors at the cell membrane and carry out their mechanism of action via the adenylyl cyclase or phospholipase C second messenger systems. This amplification via a second messenger system accounts for the rapid cellular response to a peptide hormone.
when the product or conditions resulting from the action of a hormone suppress its further release. This mechanism prevents oversecretion of the hormone and overactivity of the target tissue.
the hormone or condition resulting from its action, stimulates more secretion of the hormone. Examples include estrogen on LH and FSH during the menstrual cycle and oxytocin secretion during labor and delivery.
- Hormones have a dose-response effect on the target cell receptors.
Occurs when a hormone increases the number or affinity of target cell receptors, increasing their sensitivity or responsiveness to that hormone.
Occurs when a hormone decreases the number or affinity of target cell receptors, decreasing their sensitivity to that hormone. Down-regulation typically occurs when there is prolonged exposure to a particular hormone. Many of the peptide hormones are secreted in a pulsatile fashion to avoid down-regulation.
Steroid hormones are derived from
- Steriod hormones have intranuclear receptors. Their action is associated with a slower-onset, but longer-lasting changes, e.g., puberty.
Amine hormones are derived from
- the amino acid tyrosine and include the catecholamines (epinephrine, norepinephrine, dopamine) and thyroid hormones.
- Amine hormones have intranuclear receptors. Their action is associated with a slower-onset, but longer-lasting changes.
divided into a posterior portion where hormones are secreted directly into systemic circulation, and an anterior portion which has its own shared portal system with the hypothalamus
relationship between the hypothalamus and pituitary is important as almost all secretion by the pituitary is controlled by the hypothalamus
- Physiologic regulation of energy balance involves several hormones. Leptin (produced by adipose tissue), insulin (from pancreas), and Peptide YY (from intestine) all simulate satiety. Ghrelin (produced by the stomach) stimulates appetite, with central processing of these hormones by the hypothalamus.
- One of the reasons why diets fail is because the loss of adipose tissue associated with weight loss causes a decrease in leptin and a compensatory increase in food intake.
Forms of Ca2+ in Blood
- Total Calcium is broken into
- 40% protein bound (albumin)
- 60% ultrafilterable
- The ultrafilterable is broken into:
- 88% (Free) ionized Calcium (50% of total calcium)
- 12% complexed to anions
- Calcium is tightly regulated among dietary absorption, bone storage, and renal excretion. It is mostly under the control of parathryoid hormone.
- Calcitonin (from parafollicular cells in the thyroid) can lower calcium via inhibition of bone resorption, but is not essential.
Acid/Base and Calcium
- Acidemia has more H+ bound to albumin so less Ca2+ is able to bind which yields increased free calcium
- Alkalemia has less H+ bound to albumin so more Ca2+ is able to bind which yields decreased free calcium
- (cholecalciferol - inactive form)
- Regulatory hormone for calcium and phosphate. There are two sources of Vitamin D; dietary intake, and via 7-dehydrocholesterol in the presence of UV light.
- Vitamin D increases plasma concentrations of calcium and phosphate to promote bone mineralization by the following actions:
- 1. In the intestine, 1,25 dihydroxy vitamin D increases absorption of calcium and phosphate, by inducing the synthesis of calbindin (a binding protein).
- 2. In the kidneys, 1,25 dihydroxy vitamin D stimulates calcium and phosphate reabsorption.
- 3. In bone, 1, 25 dihydroxy vitamin D stimulates osteoclast activity and bone resorption.
Vitamin D deficiency
- very common in adults, mainly due to decreased sun exposure and limited vitamin D intake. If untreated, it can lead to problems with calcium absorption and osteomalacia (defective bone mineralization characterized by bone pain, muscle weakness, and abnormal gait).
- Vitamin D deficiency in children leads to defective bone mineralization and rickets.
- Normal bone remodeling involves the following steps:
- 1. Osteoclasts are activated and break down bone matrix.
- 2. Osteoblasts (bone-forming cells) are recruited.
- 3. Osteoblasts lay down new bone matrix.
- 4. With adequate calcium and phosphate, osteoblasts mineralize new bone.
Cells in Testes
- Sertoli cells (for antimüllerian hormone)
- Leydig cells (for testosterone)
- The presence of antimüllerian hormone and testosterone determines that a fetus will be a male. The absence of these hormones determines a phenotypic female.
- FSH stimulates sperm maturation in Sertoli cells
- LH stimulates testosterone synthesis in Leydig cells
- Sertoli cells line the seminiferous tubules of the testes.
- Spermatogenesis is dependent on testosterone, occurs from puberty through old age.
- Full cycle of speratogenesis takes ~64 days, made up of 3 phases:
- mitosis, meiosis, and maturation into mature sperm
Cells in Ovaries
- Granulosa cells (for estradiol)
- Theca cells (for progesterone)
- Within the first 5 weeks of gestational development, the reproductive system is undifferentiated.
- Around 6-7 weeks, the male characteristics begin to develop
- At 9 weeks the female characteristics begin to develop.
- The male sex is established by the SRY gene in the Y chromosome. The absence of this gene determines female sex.
A pulsatile secretion of (hypothalamic) gonadotropin releasing hormone (GnRH) will lead to the pulsatile secretion of the gonadotropins (anterior pituitary) luteinizing hormone (LH) and follicle stimulating hormone (FSH). Eventually, gonadotropin levels will increase later in life in females compared to males with the loss of negative feedback from postmenopausal ovaries.
- triggered by GnRH activity
- The associated growth spurt/epiphyseal closure from the sex steroids starts and completes earlier in girls (11 yrs old) compared to boys (13 yrs old).
- Puberty in general starts at age:
- 9-10 for girls
- 12 for boys
Functions of the ovary
- Secretion of progesterone and estrogen (estradiol)
- Women are born with the oocytes that they will use throughout life, with high levels of attrition (2 million oocytes at birth, 400,000 at puberty, few at menopause).
- These oocytes will remain in the first meiotic division as a primordial follicle until ovulation. Elaboration of secondary follicles into enlarged Graafian (tertiary) follicles including accumulation of steroid hormones, nutrients, and FSH in the antrum of the follicle. A single Graafian follicle grows and ruptures to release an oocyte in to the peritoneal cavity (ovulation). If fertilization occurs, the ruptured follicle becomes the corpus luteum to assist in the process of implanation and maintenance of the zygote. If fertilization does not occur, the ruptured follicle regresses and becomes the corpus albicans.
- The hypothalamus secretes GnRH which stimulates the anterior pituitary to secrete LH and FSH.
- FSH stimulates ~10 follicles to grow.
- LH and FSH then stimulate the ovary to secrete estradiol.
- Estradiol then has a negative feedback affect on the anterior pituitary to inhibit further secretion of LH and FSH.
- The hypothalamus secretes GnRH which stimulates the anterior pituitary to secrete LH and FSH.
- LH and FSH then stimulate the ovary to secrete estradiol.
- Estradiol then has a positive feedback affect on the anterior pituitary to keep secreting LH and FSH, and so on.
- The LH surge is what then triggers ovulation.
- The hypothalamus secretes GnRH which stimulates the anterior pituitary to secret LH and FSH.
- LH stimulates the empty follicle to become the corpus luteum.
- The corpus luteum then secretes progesterone and estradiol. Progesterone peaks at 1 week post ovulation.
- LH and FSH then stimulate the ovary to secrete progesterone.
- Progesterone then has a negative feedback affect on the anterior pituitary to inhibit further secretion of LH and FSH. This prevents new ovulation from occurring.
- The high level of progesterone and estradiol do not persist, and when they drop off menstruation occurs.
- synthetic estrogen and progesterone taken after menstrual period to increase the levels of ovarian hormones with negative feedback inhibition of FSH and LH secretion to prevent ovulation.
- marks the point where women no longer get a menstrual cycle due to a fall in estrogens and exhaustion of the supply of ovarian follicles. FSH and LH levels are high without the negative feedback inhibition.
Breast development in pregnancy
- stems from a number of different hormones:
- estrogen to help enlarge the breast and proliferate ducts
- progesterone to enhance alveolar budding and secretion (thereby paralleling their effects on the endometrium)
- prolactin to stimulate milk production
- oxytocin to stimulate milk ejection
- Caused by loss of CO2 (<35 mmHg)
- Shifts the equation to the left as less CO2 is available
- Etiologies - Hyperventilation (excessive amounts of deep breathing)
- Retaining too much CO2 (>45 mmHg)
- Shifts the equation to the right as increased CO2, increases H2CO3, which in turn increases H+
- Etiologies - COPD, Drug overdose (narcotics), Hypoventilation
- Narcotics depress respiratory system
- Due to loss of acids from the body or the production of bases
- Simply put, the loss of too much H+ or the addition of a base, similar to HCO3-, causes metabolic alkalosis
- Etiologies - Diuretic abuse, Vomiting
- Urine is acidic normally so peeing out too much can lead to loss of H+
- Loss of stomach acid through vomit
- Due to loss of bases or production or ingestion of acids
- An increase in H+, or a loss of a base lead to metabolic acidosis
- Etiologies - Diarrhea, Overexertion
- Overexertion leads to insufficient supply of O2 to the muscles which leads to a build up of lactic acid, in excess amounts it exceeds the buffering capacity of the blood (due to anaerobic process)
- Loss of water so loss of bicarbonate along with it
Metabolic Acidosis with Increased Anion Gap
Acidosis with a widened anion gap (A- >16): there is an offending substance that dissociates into a H+ ion (hence the acidosis), and an accompanying anion (hence, the wider anion gap), e.g., aspirin overdose (salicylate intoxication), methanol poisoning, lactic acidosis, diabetic ketoacidosis, renal failure.
Acidosis with a normal anion gap
- (hyperchloremic acidosis)
- loss of bicarbonate from either kidney or GI tract. The bicarbonate loss is balanced by a [Cl-] rise in serum, e.g., diarrhea or renal tubular acidosis (e.g., failure of DCT intercalated cells of hydrogen secretion in type 1 RTA or loss of bicarbonate reabsorption in the PCT in type 2 RTA).
- RTA - renal tubule acidosis