LMP301 MIDTERM 2 NOTES (lecutres 8-13).pdf

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University of Toronto St. George
Laboratory Medicine and Pathobiology
Kenneth Yip

  Lecture  8  :  Endocrine  Disease   Principle  Endocrine  Glands   -­‐ brain:  hypothalamus  ad  pituitary  glands   -­‐ neck:  parathyroid  and  thyroid  glands   -­‐ abdominal  area:  adrenal  gland,  pancreas,  ovaries,  testes     The  Hypothalamus  Hormones:   -­‐ Releasing  Hormones   o Growth  Hormone-­‐Releasing  Hormones  (GHRH)   o Thyrotrophin-­‐Releasing  Hormone  (TRH)   o Corticotrophin-­‐Releasing  Hormone  (CRH)   o Gonadotrophin-­‐Releasing  Hormone  (GnRH)   -­‐ Inhibiting  Hormones   o Somatostatin   o Dopamin  (Prolactin-­‐Inhibiting  Factor)   Pituitary  Gland  Hormones:   -­‐ Anterior  Pituitary  releases:   o Growth  Hormone  (GH)   o Thyroid-­‐stimulating  hormone  (ACTH)   o Adrenocorticotrophic  hormone  (ACTH)   o Luteinizing  hormone  (LH)   o Follicle-­‐stimulating  hormone  (FSH)   o Prolactin  (PRL)   -­‐ Posterior  Pituitary  releases:   o Antidiuretic  hormone  (ADH,  Vasopressin)   o Oxytoxin   Thyroid  Gland  releases:   -­‐ thyroxine  (T4)   -­‐ triiodothyronine  (T3)   -­‐ calcitonin   Parathyroid  Glands  release:   -­‐ parathyroid  hormone  (PTH)   Adrenal  Gland  Hormones:   -­‐ Adrenal  Cortex:   o Mineralocorticoids  (Aldosterone)   o Glucocorticoids  (Cortisol)   o Adrenal  Androgens   -­‐ Adrenal  Medulla:   o Catecholamines:  epinephrine  and  norephinephrine   Pancreas  releases:   -­‐ glucagon  (from  α  cells)   -­‐ insulin  (from  β  cells)   -­‐ somatostatin  (from  δ)     Hormones  –  Biochemical  Regulators   -­‐ endocrine   o hormones  are  secreted  into  the  blood  vessels,  and  carried  to  distant  target  cells   –  such  as  anterior  pituitary   hormone  ACTH  (acts  on  the  adrenal)   -­‐ paracrine   o hormones  are  secreted  locally,  an d  act  on  nearby  cells  –  such  as  glucagon  (from  α  cells)  acts  on  pancreatic  β   cells  to  secrete  insulin   -­‐ autocrine   o hormones  are  secreted  locally,  and  act  on  the  originating  cells   –  such  as  1,25(OH)2vitD  from  prostate  and   pancreas  (locally  produced)     -­‐ neuroendocrine  and  neurotransmitter   o hormones  are  secreted  from  neural  axon  terminals   –  such  as  epinephrine  and  norepinephrine             Control  of  the  Endocrine  System  –  by  Feedback  and  Receptor  Regulation   -­‐ Feedback:   o Negative  –  e.g.  hypothalamus-­‐pituitary-­‐thyroid  axis     § when  upstream  gland  hypothalamus  secretes  TRH,  which  affects  the   Anterior  Pituitary  for  TSH  secretion   § TSH  affects  the  downstream  Thyroid  hormone  to  secrete  T4  and  T3   AND  TSH  can  go  back  to  the  Hypothalamus  when  there  is  enough   –   binds  to  receptors  in  the  H ypothalamus  to  stop  the  release  of  TRH   (stimulation  hormone)   § T4  and  T3  can  go  back  to  stop  the  release  of  hormones  in  the   Hypothalamus  and  Anterior  Pituitary   o Positive  –  e.g.  at  a  particular  point  in  the  menstrual  cycle   -­‐  estrogen  on  LH   surge   § Estrogen  causes  LH  secretion     -­‐ Receptor:     o Hormones  bind  to  receptor,  and  through  the  receptor,  it  affects  cell  function   o Reversible  reaction  of  hormones  with  their  receptors  (hormone  and  receptor  binding  is  reversible)   § When  hormones  bind  to  the  receptor,  they  start   producing  a  biological  effect   § When  the  cell  receives  a  signal,  its  essential  for  the  receptor  to  be  able  to  relea–  can   hormone   control  the  regulation  (or  else  the  stimulation  will  be  continuously  going)   o Hormonal  specific  receptors   § Receptors  are  specific  for  the  hormone  they  bind  to   o Tissue  specific  receptors   § Receptors  are  located  in  specific  tissues  (not  everywhere  in  any  cells)   o Down-­‐regulation  of  receptors   § When  cells  have  enough  hormone  stimulation,  it  can  down  regulate  the  production  of  the  rece   o Two  types  of  receptors:   v Cell  surface  receptors  and  intracellular  signaling  pathway   o Binds  to  the  cells’  surface  receptors  and  trigger  intracellular  signaling  pathway   o Most  peptide  hormones  tend  to  have  cell  surface  receptors   o E.g.  receptors  for  insulin,  GH,   PTH,  TSH,  LH   o Rapid  cell  response   v intracellular  receptors  and  gene  regulation   o cytosolic  or  nuclear   o binds  to  specific  hormone  regulated  transcription  factors  in  the  gene   –  causes  gene  regulation   o function  as  hormone-­‐regulated  transcription  factors   o binds  mostly  steroid  hormones   o e.g.  steroids,  T4,  1,25(OH)2vitD   o relatively  slower  response     Hypothalamus-­‐Pituitary  Regulatory  System   -­‐ the  hypothalamus  is  the  link  between  the  CNS  and   the  pituitary   -­‐ the  neurons  in  the  Hypothalamus  produces   releasing/inhibiting  hormones,  which  travels   through  the  portal  veins  into  the  Anterior  Pituitary   (binds  to  specific  receptors  on  the  Anterior  Pituitary   cells)   o this  controls  the  Anterior  Pituitary  to   release/inhibit  its  hormones   -­‐ in  the  posterior  pituitary,  ADH  and  Oxytocin  is   produced  by  the  cells  in  the  hypothalamus   o these  hormones  travel  to  the  posterior   pituitary  and  is  stored  there   o once  there  is  enough  signal  from  the  body,   the  hormones  are  released  into  circulation           Hypothalamic  Factors  Regulate  Anterior  Pituitary  Function   -­‐ GnRH  is  the  releasing  hormone  of  LH  and  FSH   –  which  then  regulates  downstream  Gonad  glands   -­‐ CRH  is  the  releasing  hormone  of  ACTH   –  which  then  stimulates  the  Adrenal  Cortex  to  produce  cortisol   -­‐ GHRH  is  the  releasing  hormone  for  GH  –  which  then  affects  the  Liver  and  other  tissues  in  the  body  to  produce  IGF -­‐1   and  stimulate  growth   -­‐ TRH  is  the  releasing  hormone  for  TSH   –  TSH  stimulates   Thyroid  gland  to  produce  T4  and  T3     o Also  stimulates  the  release  of  Prol actin   (however,  normally,  this  level  of  TRH  is  not  a   major  driving  force  for  prolactin)   o Prolactin  is  normally  inhibited  by  Dopamine   o Dopamine  is  a  major  inhibitor  and  controller  for   prolactin   o However,  during  Pregnancy,  there  is  a  massive   production  of  TRH  –  stimulation  of  TRH  will  be   large  enough  to  drive  the  production  of   Prolactin   -­‐ Somatostatin  is  an  inhibiting  hormone  for  GH  and  TSH     Endocrine  Disorders   -­‐ terminology   o hyper  –  hormone  above  normal  level   o eu  –  hormone  within  normal  range   o hypo  –  hormone  below  normal  level   -­‐ examples:   o oversecretion:  e.g.  Gigantism  where  a  pituitary  adenoma  overproduces  growth  hormone   o undersecretion:  e.g.  primary  hypothyroidism  (thyroid  gland  cannot  produce  hormones)   o failure  of  hormone  responsiveness:  e.g.  pseudohypoparathyroidism   § ex.  hormone  specific  receptors  have  mutations   –  receptor  is  unresponsive  or  downstream   intracellular  signal  pathway  is  defective   o abnormal  hormone  metabolism :  e.g.  5α-­‐reductase  deficiency  caused  abnormal  male  external  genitalia   development       § during  the  hormone  producing  pathway,  there  is  always  enzymes  that  metabolize  precursors     § of  one  enzyme  is  defective,  you  will  not  get  the  right  end  product  =  no  functioning  hormone     Variable  Concentration  of  Hormones  in  Blood     -­‐ Episodic  Secretion:  some   Hypothalamus  hormones  are  released  in  an  episodic  style   -­‐ Stress  Response:  stress  can  cause  a  surge  of  hormone  release   -­‐ Circadian  Rhythm:  some  hormones  are  present  in  different  levels  during  different  times  in  the  day   -­‐ a  single  blood  hormone  measurement  may  ha ve  little  clinical  value  –  not  reliable       Investigation  of  Endocrine  Disease   -­‐ Dynamic  Tests  (Provocative  Tests)   o Designed  for  certain  disorders   o Once  you  know  which  hormones  control  what  kind  of  downstream  hormone  or  downstream  metabolism   response,  then  you  can  give  certain  hormone  stimulation  or  suppression  substances  to  see  whether  the  body   can  produce  a  regular,  normal  response   o If  you  do  not  see  the  expected,  normal  response,  then  you  can  predict  what  is  wrong  with  the  endocrine   pathway   o Following  stimulation  or  inhibition,  testing  hormonal  response  feedback  regulation  to  demonstrate  the   abnormality  of  hormone  secretion       o Examples:   § Dexamethasone  suppression  tests   –  for  Cushing’s  syndrome   § Synacthen  (synthetic  ACTH)  test   –  for  Addison’s  disease   § Oral  glucose  tolerance  test  –  for  diabetes  and  acromegaly       Case:  Man  with  a  “spade-­‐like”  hand   -­‐ hand  is  much  wider  and  much  bigger   -­‐ patient  has  thickened  lips   -­‐ rough  skin   -­‐ jaw  is  protruding   -­‐ CT  scan  showed  a  pituitary  tumour   -­‐ Classical  case  of  acromegaly     -­‐ Due  to  over  production  of  growth  hormone  in  adults   (pituitary  tumor)   -­‐ In  adults,  many  anatomical  structures  cannot  continue  to   grow  in  length,  so  they  tend  to  grow  in  width  and  lipids   in  soft  tissues  accumulate  (thickens)     Excessive  Growth  in  Adults   -­‐ acromegaly:   o increase  GH  secretion  (in  adults)   o most  likely  cause:  pituitary  adenoma   -­‐ Clinical  features:   o Coarse  facial  features   o Soft  tissue  thickening,  e.g.  lips   o Characteristic  “spade-­‐like”  hands   o Protruding  jaw  (prognathism)   o Sweating   o Impaired  glucose  tolerance  or  diabetes  (hyperglycemia)     Growth  Hormone  (Somatotrophin)   -­‐ Protein  hormone   -­‐ 191  amino  acids,  22kDa   Major  Biological  Effects   –  Promotion  of  Growth   -­‐ GH  reduced  glucose  transport  and  metabolism:     o one  mechanism:  reduction  in  insulin  receptors  in  the  liver   o GH  reduces  insulin  receptors  =  reduced  response  to  the  hormone   o Cells  wont  respond  to  insulin  effectively  =  high  glucose  levels  in  the  blood  because  it  cannot  be  transported   into  cells   o counter  regulatory  hormone:  having  opposing  effects  to  the  actions  of  insulin   § GH  is  a  counter  regulatory  hormone   –  increases  glucose  levels  in  the  blood   § Cortisol  is  a  counter  regulatory  hormone  of  insulin  effects   § Glucagon  is  a  counter  regulatory  hormone  of  insulin  effects   § Catecholamines  is  a  counter  regulatory  hormone  of  insulin  effects   -­‐ GH  increases  lipolysis:   o free  fatty  acids  are  released  to  provide  energy  for  muscles   o because  glucose  is  unable  to  be  a  source  of  energy,  lipids  are  an  important  source  of  energy   -­‐ GH  increased  amino  acid  transport:   o into  muscle,  liver,  and  adipose  cells   -­‐ GH  increases  protein  synthesis:   o  increases  in  both  transcription  and  translation  in  the  liver  =  increase  in  protein  synthesis   -­‐ GH  increases  IGF  production:   o In  the  liver,  the  major  downstream  response  is  to  produce  IGF -­‐1  in  response  to  GH   o indirectly  promotion  of  growth  and  endocrine  effects  via  IGFs  in  bone,  soft  tissue,  gonads,  and  etc.   o IGF  can  be  used  as  a  marker           Regulation  of  GH  Secretion   -­‐ GHRH  is  a  stimulating  hormone   -­‐ Somatostatin  is  an  inhibiting  hormone   -­‐ Pituitary  produces  growth  hormone   -­‐ Liver  produces  IGF-­‐1   -­‐ IGF-­‐1  has  a  negative  feedback  to  the  pituitary   -­‐ GH  can  have  a  negative  feedback  onto  the  hypothalamus   -­‐ GH  production  can  also  be  increased  by:  sleep,  amino  acids,   exercise.  and  stress   -­‐ Glucose  can  inhibit  GH  production  and  release   o High  levels  will  suppress  GH   o Low  levels  will  increase  GH     Tests  for  Evaluation  of  GH  Status   -­‐ GH   o Cannot  rely  on  a  single  point  of  measurement  for  GH   • In  the  24hr  cycle,  in  the  middle  of  the  night,  you   have  the  highest  level  of  GH  production   • In  the  early  morning,  it’s  the  lowest  point  of  GH   production   o measure  by  immunoassay   o Dynamic  Tests:     • To  see  how  patient  responses,  and  how  GH  responds  to  stimulation  or  inhibition   • Because  GH  secretion  is  episodic  and  responsive  to  stress,  a  single  random  measurement  has  little   diagnostic  value;  demonstration  of  an  abnormal  response  to  the  dynamic  stimulation  or  suppression  will   make  the  diagnosis   § Insulin  Induced  Hypoglycemia  Test  for  GH  deficiency   • Low  GH  production   • If  we  give  the  patient  insulin,  the  patient  will  develop  hypoglycemia  (gl ucose  levels  is  low)   o On  a  normal  subject,  in  response  to  low  glucose  level,  they  will  produce  more  GH   • In  a  patient  with  pituitary  disorder,  they  cannot  produce  GH  =  wont  see  surge  of  GH  increase   § Glucose  Tolerance  Test  (GTT)  for  acromegaly     • GH  over  production   • Give  large  dose  of  glucose  =  increase  glucose  levels  in  the  blood     • Expect  to  see  normal  subjects  to  suppress  the  glucose  -­‐  see  a  glucose  level  increase  but   suppress  GH  secretion   • In  a  patient  with  tumour,  you  cannot  suppress  the  GH  production   -­‐ IGF-­‐1,  insulin-­‐like  growth  factor-­‐1  à  also  called  somatomedin  C   o Indicator  of  GH  level   o If  GH  is  high  =  IGF-­‐1  is  high  if  GH  hormone  receptor  is  normal   o Measured  by  immunoassay   o Synthesis  depends  on  GH  and  predominantly  in  the  liver  as  endocrine  hormone  as  well  as   functioning  in  a   paracrine/autocrine  fashion,  circulating  concentration  is  1000 -­‐fold  higher  than  insulin  and  relatively   constant   o Useful  marker  in  evaluation  of  GH  statues  and  monitoring  treatment   o Marker  is  much  more  stable  in  the  blood  stream,  and  easier  t o  detect  high  levels     Glucose  Tolerance  Test  (GTT)   -­‐ draw  blood  at  baseline   -­‐ measure  the  baseline  glucose  level  and  GH  level   -­‐ give  the  patient  with  a  large  dose  of  glucose     -­‐ then  measure  the  glucose  level  and  GH  level  through   a  time  course   -­‐ for  normal  subjects  (blue):  glucose  levels  increasing   with  slight  differences  with  level   –  soon,  there  is  a   suppression  of  GH  production   -­‐ for  patients  with  acromegaly  (red):  dramatic   increase  in  GH  production  in  response  –  no       suppression  of  GH  (tumors  do  not  suppress  in  respon se  to  glucose  levels)   o tumor  cells  continue  to  produce  growth  hormones  =  constant  release   Lack  of  suppression  of  GH  levels  in  response  to  a  GTT  test  =  diagnostic  test  for   acromegaly   Patients  with  acromegaly  will  have  no  response  to  glucose  suppression   A  diagnostic  test  for  acromegaly     Treatment  of  Acromegaly   -­‐ Surgery  –  remove  the  tumor   -­‐ Medical  –  give  medicine  (ex.  Somatostatin/  drugs  that  mimic  Somatostatin   à  binds  to  growth  hormone  releasing   receptors  to  stop  the  GH  production  in  the  pituitary)   o GHRH  inhibitors  are  not  very  effective:  acromegaly  is  not  due  to  the  over  production  of  GHRH,  but  it’s  a   pituitary  tumor  that  over  produces  GH   à  Somatostatin  is  more  effective   o Can  directly  inhibit  GH  or  inhibit  its   receptor   -­‐ Radiotherapy  –  kill  pituitary  tumor  cells  à  cells  cannot  produce  GH   -­‐ combinations  of  surgery,  medical,  and  radiotherapy       Lecture  9  :  Thyroid  Diseases   Goiter   -­‐ Enlarged  thyroid  gland   o May  be  associated  with  hypo,  hyper  or  eu -­‐thyroid  (no  thyroid  problem)   o Malnutrition?  Thyroid  gland  would  try  to  enlarge  the  number  of  cells  to  produce  more   tissues  and  accumulate  more  iodine  from  diet   à  goiter  is  adaptation  to  environment     Thyroid  Gland  and  Thyroid  Hormones   -­‐ thyroid  gland  secretes  mostly  T4  and  some  T3   -­‐ the  peripheral  tissues  (e.g.  the  liver  and  kidney  –  can  convert  T4  to  T3)  deiodinate    T4  to   produce  2/3  of  the  circulating  T3  (peripheral  conversion)   -­‐ thyroid  hormones  bind  to  receptors  and  triggers  the  hormonal  effects   -­‐ T3  is  more  biologically  active  than  T4 ,  but  at  a  lower  concentration  in  plasma  (2nmol/L  for  T3   vs  100nmol/L  for  T4)   -­‐ Reverse  T3  (rT3)  is  an  inactive  form  metabolized  from  T4   -­‐ T3  binds  to  receptor  and  triggers  target  cell  to  promote  metabolism   -­‐ Local  thyroid  status  can  be  modulated  b y  the  relative  production  of  T3  and  rT3   -­‐ Thyroid  hormones  are  essential  for  the  normal  maturation  and  metabolism  of  all  tissues  in  the   body     Synthesis  of  Chemical   1) tyrosine  (amino  acid)  is  a  precursor   2) from  diet,  thyroid  gland  accumulates  iodine  à  gets   converted  to  a  more  active  form  so  it  can  bind  to  a   tyrosine  molecule   3) If  there  is  only  1  iodine  attached  =   monoiodotyrosine  (MIT)   • If  there  is  2  iodines  attached  =  diiodotyrosine   (DIT)   4) If  2  of  the  diiodotyorsine  is  coupled  together  =  T4   • There  are  4  iodines  attached  to  the  2  DITs   5) If  there  is  1  monoform  and  1  diiodoform  coupled   together  =  T3   • From  T4,  they  can  also  lose  one  of  the  iodine  to   form  T3   6) In  rT3,  iodine  is  in  a  different  position  and  one  is   active,  another  is  inactive   -­‐ peripheral  tissue  (by  adjusting  how  much   conversion  to  T3  or  rT3  =  fine  tuning  of  local  thyroid  hormone  effect)           Hypothalamus-­‐Pituitary-­‐Thyroid  Axis   1) hypothalamus  produces  TRH   2) TRH  stimulates  the  Anterior  Pituitary  to  release  TSH   3) TSH  goes  to  the  thyroid  gland  and  binds  the  TSH  receptor   à  promote  thyroid   gland  to  release  T4  and  T3   -­‐ thyroid  hormones  connect  the  feedback  to  the  pituitary  ad  hypothalamus   à   when  there  are  enough  thyroid  hormone  in  the  circulation,  they  will  reduce  TRH   and  TSH  production   -­‐ same  mechanism,  TSH  can  also  have  a  negat ive  feedback  to  the  hypothalamus  to   adjust  TRH  release   -­‐ fine  tuning  of  T3  and  rT3  production  in  peripheral  tissues   à  locally  adjust  response  to  thyroid  hormone     Total  vs.  Free   -­‐ in  the  circulation,  most  of  thyroid  hormones  bind  to  their  binding  proteins   -­‐ reversibly  bound  to  carrier  proteins   o e.g.  T4-­‐binding  globulin  (TBG),  some  will  bind  to  albumin   -­‐ only  very  small  fraction  is  unbound  and  free  for  biological  activity  à  these  are  the  active  hormones  à  bind  receptors   to  cause  biological  effect     • only  0.03%  of  T4’s  are  in  the  free  form   • 0.3%  of  T3’s  are  in  the  free  form   -­‐ alterations  in  the  concentration  or  affinity  of  binding  proteins  may  change  the  concentration  of  thyroid  hormones   o in  the  circulation,  if  there  is  a  change  in  the  binding  protein  concentration,  or   binding  protein  affinity  to  the   hormone  à  balance  between  bound  and  free  will  also  change   -­‐ FT4  and  FT3  vs.  total  T4  and  total  T3   –  which  are  the  better  markers  in  routine  assessment  of  thyroid  function?     Changes  of  TBH  Binding  Affects  Thyroid  Function  Tests   Cause   Compound   Effects   Increase  TBG   Estrogen   ↑  T4,  T3  /  ↔  FT4,  TSH   (by  increasing  liver  production)   -­‐  can  decrease  TBG  synthesis  in  the  liver   à  when  there  is  an  increase   -­‐  less  binding  protein  (less  T3  and  T4  bound  to  the  binding   level  of  TBG  in  the  circulation   protein  =  bound  form  is  decreased)   à  more  binding  protein  =  more   -­‐  but  because  the  normal  patient  with  functioning  thyroid  can   thyroid  hormone  bound     immediately  respond  to  change  of  hormone  status,  they  can   à  but  in  a  normal  patient  with   maintain  normal  thyroid  status   à  adjust  T4  level  to  be  normal   a  normal  thyroid  function,  they   à  total  hormone  (because  bound  fraction  has  been  decreased)   can  maintain  normal  thyroid   à  adjust  total  hormone  level  in  response  to  bound   hormone  status  =  free  T4  is   increase/decrease  à  maintain  free  hormone  to  be  normal   maintained  as  normal,  but  total   (therefore,  TSH  also  maintained  to  be  normal   à  feedback   hormone  level  is  increase   pathway)   (bound  is  increased)   Oral  contraceptive   Decrease  TBG   Androgen   ↓  T4,  T3  /  ↔  FT4,  TSH   Glucocorticoids   Inhibit  binding  of  T4/T3  to   Salicylates   ↓  T4  /  ↔  FT4   TBG   -­‐  medication   -­‐  inhibit  binding  of  thyroid  hormones  to  TBG  à  decrease  binding   affinity   -­‐  same  effect  as  decrease  in  binding  =  l ess  bound  form   -­‐  but  because  this  medication  has  nothing  to  do  with  the  thyroid   gland  à  assume  in  normal  subject,  the  thyroid  gland  can  respond   to  change  in  binding  to  return  free  t4  to  normal,  and  decrease   total  T4  levels   -­‐  free  hormone  is  more  important  to  biological  effect  of  thyroid   gland  and  thyroid  hormone  status   -­‐  the  total  hormone  fluctuates  through  the  binding  protein   change   -­‐  measure  FT4/FT3  in  the  laboratory       MYXEDEMA:  Dry,  Waxy  Swelling  of  the  Skin,  with  A bnormal  Deposits   of  Glucosaminoglycans  (unbranched  polysaccharides )   -­‐ change  in  the  appearance  of  an  untreated  hypothyroid   female  over  11  year  period   -­‐ this  dramatic  change  reflects  thyroid  function  (not  just  age)  -­‐   hypothyroidism   -­‐ myxedema:  skin  accumulates  in  deposits  of  unsaturated   polysaccharides     -­‐ enlarged  thyroid  gland  due  to  iodine  deficiency     Symptoms  and  Signs  of  Hypothyroidism  –  Hypometabolic  Syndrome   -­‐ low  thyroid  hormone     -­‐ symptoms  and  signs:   o weight  gain   o hair  loss   o high  cholesterol   o depression   o constipation  (less   (decrease  in  LDL   o easy  fatigue  (less   intestine  movement)   receptors)   energy,  less  thyroid   o growth  retardation   o Bradycardia  (slow   hormone  to  produce   in  children   heart  rate)  à  less   energy  and   o deep,  hoarse  voice   hormone  to  produce   metabolism)   o dry,  coarse  skin   heart  beat  and  less   o lethargy   o myxedema   metabolism o cold  intolerance     Cause  of  Hypothyroidism   -­‐ primary  hypothyroidism  (targets  endocrine  gland  –  thyroid  gland)   o autoimmune  destruction  of  the  thyroid  gland     § thyroid  gland  failed  to  produce  thyroid  hormone   § Hashimoto’s  Disease:  auto-­‐antibody  targets  the  thyroid  gland   • Destroys  the  thyroid  gland  so  it  cannot  function  and  produce  hormones   o Radioiodine  or  surgical  treatment  of  hypothyroidism   o Iodine  deficiency   o Congenital  defects  in  hormone  biosynthesis  and  action   o Transient  hypothyroidism  due  to  drug  therapy  (antithyroid  drugs)   § After  stop  of  treatment,  thyroid  gland  can  go  back  to  normal   -­‐ secondary  hypothyroidism  (targets  the  pituitary)   o pituitary  disease   o pituitary  fails  to  produce  TSH   à  thyroid  gland  does  not  get  enough  TSH   à  cannot  produce  hormone   o giving  TSH  =  thyroid  gland  goes  back  to  normal  to  produce  hormones   -­‐ tertiary  hypothyroidism   o hypothalamic  disease  (caused  by  the  hypothalamus)   o hypothalamus  fails  to  produce  TRH     Diagnostic  Strategy  for  Suspected   Hypothyroidism   -­‐ if  suspected  of  hypothyroidism,  screen   test  for  TSH  and  fT4   • high/normal  TSH  and  high   fT4  =  not  hypothyroid   • high  TSH  and  low  fT4  =   primary  hypothyroidism   § low  fT4  =  less  thyroid   hormone  =   hypothyroidism   § pituitary  is  functioning,  but  thyroid  gland  failed   • high  TSH  and  normal  fT4  =  subclinical  hypothyroidism   § not  hypothyroidism  yet   § but  high  TSH  –  fT4  not  enough  to  maintain  normal  thyroid  hormone  requirements   • low/normal  TSH  and  low  fT4  =  secondary  hypothyroidism       § caused  by  the  pituitary  =  secondary  hypothyroidism     § isn’t  enough  TSH  to  promote  T4  production     Complications  of  Hypothyroidism   -­‐ depending  on  when  during  life  a  patient  is  hypothyroid,  clinical  outcomes  vary   -­‐ pregnancy:  if  the  pregnant  women  develops  hypothyroidism  =  irreversible  fetal  malformation,  growth  retardation,   and  neurological  deficits   -­‐ infancy  &  early  childhood:  if  defect  was  developed  early  =  decreased  linear  growth  (short  stature),  inadequate  brain   maturation,  low  IQ  and  psychomotor  development;  severe  condition   –  Cretinism   -­‐ adult:  severe  condition  –  death  from  myxedema  coma   o longstanding  untreated  severe  hypothyroidism  facing  a  precipitating  factor   § e.g.  infection,  a  cardiovascular  event,  sedating  medication  à  can  become  severe  hypothermia   o features:  severe  hypothermia  (<80°F)  and  loss  of  consciousness   -­‐ demonstrate  the  importance  of  thyroid  hormones  in  different  stages  of  life     Cretinism   -­‐ due  to  congenital  hypothyroidism   o severe  condition  in  untreated  infants   o occurs  with  a  frequency  of  one  in  4,000  live  births   o may  be  due  to  absence  of  the  thyroid  gland,  or  may  occur  secondarily  to  defects  of   thyroid  hormone  synthesis  à  body  cannot  produce  thyroid  hormone   § thyroid  hormone  is  low  =  TSH  is  very  high   o in  early  stages,  they  can  get  thyroid  hormone  from  mother  =  can  still  have  normal   development     § but  after  birth,  mother  cannot  give  t hem  the  hormone  anymore   Infant  with  typical  stigmata   § not  enough  thyroid  hormone  to  promote  growth   or  severe  congenital   o delays  in  treatment  results   cretinism:  mental  retardation,  short  stature,  deaf,   hypothyroidism   neurological  signs,  etc.   -­‐ note  the  coarse  features,   o if  diagnosed  at  an  early  age,  replacement  thyroid  hormone  can  be  given  and   periorbital  edema,   normal  development  can  occur   flattened  bridge  of  nose,   and  large  protruding   o treatment:  hormone  replacement   § but  have  to  find  it  EARLY   tongue   o TSH  screen  test  included  in  newborn  screen  programs   -­‐ the  infant  had  a  hoarse   cry,  somnolence     (drowsy,  sleepy),  and   Treatment  of  Primary  Hypothyroidism   constipation     -­‐ replacement  therapy  with  thyroid  hormones  (synthetic  T4,  T3)   -­‐ such  typical  stigmata  are   -­‐ monitoring:  “pituitary  lag”  hormone  response  –  4  to  8  weeks  for  serum  TSH  values  to   rare;  the  majority  of   reach  a  new  steady  state  after  starting  the  therapy  or  dosing  changes   hypothyroid  newborns   identified  in  newborn   o gradually  adjust  to  new  thyroid  status   à  patient  with  high  TSH,  after  treatment:   gradually,  pituitary  will  decrease  TSH  productio n  to  reach  normal  TSH  level   screening  programs  are   o at  early  stage  of  treatment:  TSH  level  is  still  elevated   not  clinically  suspected   o do  not  measure  T4  or  T3,  because  patient  receives  the  treatment  to  synthesize  T4   or  T3  à  measurement  of  T3  or  T4    may  not  reflect  true  status  of  the  hormone     § may  just  reflect  the  dose  taken   o if  treatment  has  effectively  replaced  the  thyroid  hormone,  we  can  expect  feedback  will  suppress  TSH   production   § normal  TSH     Symptoms  and  Signs  of  Hyperthyroidism  –  Hypermetabolic  Syndrome     -­‐ symptoms  and  signs   o weight  loss   o restless   o glucose  intolerance   o fatigue   o nervousness   àinsulin  is  cleared   • too  much  hormone,  so  it   o oligomenorrhoea   quickly  because  of  high   metabolic  rate   makes  muscle  and  body   • heavy  menstruation     have  a  high  metabolic   o fine  hair,  thin  skin   o Tachycardia  (rapid  heart   state  à  tired   o stare,  lid  lag   rate)   o muscle  weakness   o goiter   o Widened  pulse  pressure   o heat  intolerance   o low  cholesterol   o Tremor  (involuntary   o increase  sweating     movements  of  the   o diarrhea     outstretched  upper  limit)     Causes  of  Hyperthyroidism   -­‐ Graves’  disease  (due  to  autoimmune  disease),  diffuse  toxic  hyperplasia   -­‐ Toxic  multinodular  goiter  à  lots  of  hormone  production  (Plummer’s  disease)   -­‐ Hyperfunctioning  thyroid  carcinoma  (Thyroid  cancer  à  cancer  cells  produce  lots  of  thyroid  hormones)   -­‐ Thyroiditis  (inflammation  of  thyroid  gland  –  can  cause  hyperthyroidism  à  cells  are  damaged  and  releases  more   thyroid  hormone)   -­‐ TSH  secreting  pituitary  tumor  (secondary  hyperthyroidism)  à  tumors  produce  large  amount  of  TSH   -­‐ HCG  secreting  trophoblastic  tumor   o HCG:  marker  for  pregnancy  screening   o Because  HCG  is  increased  so  significantly,  and  shares  the  same  alpha  unit  with  TSH   o TSH  and  HCG  all  have  alpha  and  beta  units   o Beta  units  is  unique  to  the  molecule,  but  alpha   unit  is  shared   o Increase  in  HCG,  because  it  shares  the  same  alpha  unit  as  TSH,  it  can  bind  to  TSH  receptor  to  stimulate   thyroid  glands  to  produce  thyroid  hormone   -­‐ Iodine  or  iodine-­‐containing  drugs  induced   o Too  much  substrate  to  synthesize  thyroid  hormone  prod uction   -­‐ Excessive  T4  and  T3  ingestion     Graves’  Disease   -­‐ Eyelid  is  retracted,  and  eyelid  lag   à  patient  looks  like  its  always  staring   -­‐ most  common  cause  of  hyperthyroidism   -­‐ autoimmune  disease   o autoantibodies  bind  to  TSH  receptor  to  mimic  TSH  action     o causes  thyroid  gland  to  produce  a  large  amount  of  thyroid  hormone   o large  amount  of  thyroid  hormone?  Negative  feedback  to  pituitary  to  reduce  TSH  production  from  pituitary   o expect:  high  T4  and  T3,  but  low  (or  undetectable)  TSH  because  autoantibody  mimics  TSH  action  (don’t   need  TSH)  –  TSH  suppressed  in  pitutiary   -­‐ normal  regulatory  controls  of  thyroid  hormone  synthesis  and  secretion  are  lacking   -­‐ pituitary  TSH  is  completely  inhibited  by  the  high  concentration  of  circulating  T4  and  T3   -­‐ Diagnosis:     o TSH  low,  FT4  high   o Anti-­‐TSH  receptor  antibodies   o Radionuclide  ( 99m Tc,  3I  or I)  uptake  and  scan   § Radioactive  isotopes,  thyroid  glands  will  accumulate  these  radioactive  iodine’s   à  x-­‐ray  scan  will     depict  a  hot  thyroid  gland  (accumulation  of  radioactive  isoforms)   -­‐ Treatment:   o Antithyroid  drugs  (block  iodide  uptake,  inhibit  T4  synthesis  and  T4  to  T3  conversion,  etc)   § Use  medication  to  decrease  hormone  production   o Radioiodine,  sodium   131 I   § Thyroid  gland  accumulates  iodine   –  will  also  accumulate  radioactive  iodine  =  destroys  thyroid   gland   o Surgery   § Remove  thyroid  gland   -­‐ Monitoring:  recurrence  or  developing  hypothyroidism   o Because  thyroid  gland  is  removed/destroyed   o Have  to  get  thyroid  hormone  replacement  after  treatment     Diagnostic  Strategy  for  Suspected  Hyperthyroidism   -­‐ if  we  measure  TSH  and  fT4   o normal  level  of  TSH  and  fT4  =  rule  out   hyperthyroidism   o increase  in  TSH  and  increase  in  fT4  =  TSH-­‐ secreting  pituitary  tumor  producing  TSH   (increasing  fT4)   o decrease  TSH  but  normal  fT4  =  have  to  measure   fT3   § if  fT3  is  normal  =  subclinical   hyperthyroidism  (will  need  regular       follow  up  to  see  if  patient  will  develop  true  hyperthyroidism)   § if  fT3  is  increased  (decreased  TSH,  normal  fT4)  =  T3  caused  hyperthyroidism  (T3  toxicosis)   § primary  hyperthyroidism     o decreased  TSH  and  increased  fT4  =  primary  hyperthyroidism     § high  thyroid  hormones  suppresses  TSH  production   § problem  in  thyroid  gland  =  primary     Case  2:  18  year  old  Girl  with  Fever  and  Weakness   -­‐ presentation  of  illness:   o mild  weight  loss:  from  150  to  128lb   o tired,  difficulty  of  climbing  stairs   o fever,  dyspnea  (difficulty  breathing)   -­‐ physical  exam:   o temperature  38.5°C,  pulse  145  (normally  60-­‐80),  respiratory  24,  BP  180/120   o Thyroid  gland  enlarged  more  than  3  times,  smooth  goiter  bilateral  (on  both  side  of  thyroid  gland)   o Lid  retraction  of  both  eyes   -­‐  palms  are  sweaty,  tremor  of  fingers   -­‐ Laboratory  results:   TSH   0.001mU/L   0.4  –  5.5   Free  T3   30  pmol/L   3  –  7     Free  T4   77.2  pmol/L   7.5  -­‐    20     -­‐ Diagnosis:   o Hyperthyroid  crisis  (endocrine  emergency)   o Thyroid  storm   o Emergency  status  of  hyperthyroidism   o Life-­‐threatening     Summary:  Thyroid  Function  Tests   -­‐ TSH  assay   -­‐ Free  T4  and  free  T3  assays   -­‐ TRH  stimulation  test:  investigation  of  secondary/tertiary  hypothyroidism   o Give  TRH  to  see  response  of  TSH,  fT4,  fT3   -­‐ Autoantibody  tests  in  diagnosis  and  monitoring  of   autoimmune  thyroid  disease   o E.g.  TSH  receptor  antibodies  in  Graves’  disease       Lecture  10:  Adrenal  Disease   Adrenal  Glands  and  Hormones     -­‐ small  triangular  shaped  glands  situated  just  above  the  kidney   -­‐ they  enlarge  in  chronic  stress   -­‐ the  hormones  of  the  adrenal  glands  are  essential  for  survival     -­‐ adrenal  gland  can  be  separated  into  2  layers:   1) outside  layer:  cortex   -­‐ can  be  separated  into  3  layers:   1. zona  glomerulosa:  most  outside  layer   à  produces  aldosterone   2. zona  fasciculate,  and  zona  reticularis :  inside  layers  à   produces  cortisol,  adrenal  androgens,  and  estrogens   2) inside  layer:  medulla   -­‐  produces  neuroendocrine  hormones   à  epinephrine,   norepinephrine,  and  dopamine     Biosynthesis  of  Steroid  Hormones   -­‐ all  of  these  hormones  start  from  a  common  precursor  –   cholesterol   -­‐ cortisol  and  aldosterone  and  androgens  goes  through   pathways  that  require  cholesterol   -­‐ because  aldosterone  is  from  the  most  outside  layer  of  the   adrenal  gland,  they  require  unique  enzymes  (18  OH ’ase  à       absent  in  other  layers)  à  reason  why  only  the  most  outside  layer  (zona  glomerulosa)  can  produce  aldosterone   -­‐ ACTH  is  the  main  driving  force  for  cortisol  and  androgens   -­‐ For  aldosterone,  there  are  different  regulation  pathways  (ACTH  also  involved,  but  n ot  important)   -­‐ Since  aldosterone  and  cortisol  share  the  same  enzyme,  their  precursors  may  share  similar  biological  functions     Cortical-­‐Physiology   -­‐ effects  on  metabolism:   o carbohydrate  –  promotion  of  gluconeogenesis  in  liver  (stimulates  liver  to  synthesize  glucose  release  to   circulation),  reduction  in  glucose  use  and  uptake  in  peripheral  tissues   o protein  –  increase  of  muscle  proteolysis   o fat  –  activation  of  lipolysis  and  release  of  free  fatty  acids  into  circulation   § when  present  in  excess:  glucocorticoids  cause  central  distribution  of  fat   –  face,  neck,  and  trunk   -­‐ circulating  forms:   o most  cortisol  circulating  are  bound,  free  cortisol  are  the  biologically  active  ones   o 90-­‐98%  protein  bound  to  cortisol -­‐binding  globulin  (CBG)  and  albumin   o CBG  synthesis  is  increased  in  pregnancy  and  estrogen  treatment  =  increasing  total  cortisol   -­‐ Metabolic  fate:  after  liver  conjugation,  cortisol  is  excreted  in  urine   o Excessive  cortisol  produced?  Free  cortisol  can  also  be  excreted  in  urine   à  present  in  some  disorders     Regulation  of  Cortisol   -­‐ hypothalamus  produce  CRH   -­‐ CRH  stimulates  pituitary  to  produce  ACTH   -­‐ ACTH  stimulates  adrenal  cortex  to  produce  cortisol   -­‐ Cortisol  can  have  negative  feedback  to  hypothalamus  and  pituitary   –   central  hypothalamus-­‐pituitary  axis   -­‐ Stress  and  sleep/wake  cycle  can  als o  affect  cortisol  levels   -­‐ Under  stress,  cortisol  synthesis  and  release  will  increase   o Patients  with  chronic  stress  will  have  enlarged  adrenal   glands  à  increase  of  cortisol  synthesis  =  cortisol  excess       Cushing’s  Syndrome   -­‐ results  from  prolonged  excessive  exposure  of  body  tissues  to   cortisol  or  other  glucocorticoid     -­‐ Causes:   -­‐ Pituitary  ACTH-­‐producing  tumor:  Cushing’s  disease  à  specific  to  pituitary  ACTH-­‐producing  tumors   -­‐ Ectopic  ACTH-­‐producing  tumor:  ACTH  produced  by  cells  other  than  pituitary   § e.g.  small  cell  carcinoma  in  the  lunch  may  secrete  ACTH   • if  the  tumors  produce  a  large  amount  of  ACTH,  you  can  expect  patient  (under  ACTH   stimulation)  to  have  a  lot  of  cortisol  produced   • tumors  producing  ACTH  can  cause  cortisol  excess  =  Cushing’s  syndrome   -­‐ Adrenal  cortisol-­‐producing  tumor  (Adenoma  or  carcinoma)  à  local  tumors  producing  cortisol  à  cause  of   Cushing’s  syndrome   -­‐ Exogenous  glucocorticoids  (taken  orally,  inhaled  or  applied  topically)  à  therapy  for  asthma,  skin  problems,   etc.  will  receive  a  large  dose  of  exogenous   glucocorticoids  à  can  cause  Cushing’s  Syndrome     Clinical  Features  of  Cushing’s  Syndrome   -­‐ common  features  we  see  in  patients  with  Cushing’s  syndrome:   -­‐ moon  shaped  face   -­‐ acne  on  face   -­‐ buffalo  hump  (fat  redistribution  in  the  back)   -­‐ abdominal  affect  redistribution   -­‐ may  present  skin  thinning   à  accumulation  of  fat  in   abdominal  area  will  stretch  the  skin  (thin  is  so  thin,   blood  vessels  are  visible)  =  abdominal  striae   -­‐ osteoporosis  –  cortisol  can  promote  bone  breakdown   and  stop  bone  regrowth  à  loss  of  bone  mass   -­‐ hypertension       -­‐ muscle  weakness  à  protein  breakdown     Diagnosis  of  Cushing’s  Syndrome   -­‐ need  more  than  50%  reduction  in  cortisol  to  say  there  is  enough  suppression   -­‐ screening  test:  24hour  urinary  free  cortisol   -­‐ cortisol  is  usually  bound  to  its  protein  in  the  circulation,  but  if  there  is  too  much  cortisol,  it  can  exceed  the   binding  capacity,  therefore,  increasing  plasma  cortisol  levels   -­‐ cortisol  exceeds  the  plasma  protein  binding  capacity,  so  unbo und  cortisol  is  filtered  into  urine   –  elevated   free  cortisol  in  Cushing’s;  but  stress  and  obesity  can  cause  false  positive  results   -­‐ plasma  cortisol:  measured  at  8am  and  10pm   -­‐ cortisol  produces  at  the  same  time  as  ACTH   à  follow  24  hour  circadian  rhythm   -­‐ high  peak  in  morning  (8am)  and  lowest  at  the  mid  of  night  (10pm)   -­‐ dramatic  difference  between  2  levels   à  cortisol  production  still  follows  normal  circadian  rhythm   à  can   rule  out  Cushing’s   -­‐ the  normal  ACTH  DEPENDENT  circadian  rhythm  (high  peak  in  the  morning)  is   not  apparent  in  the  patient   with  Cushing’s   -­‐ however,  in  Cushing’s  patients,  cortisol  production  is  not  controlled  =  do  not  follow  circadian  rhythm  =  no   difference  in  cortisol  levels  in  morning  and  night   -­‐ low  dose  (1mg)  dexamethasone  (cortisol  analogue)  test:  suppresses  cortisol  production  (>50%)  in  normal  subject   but  not  in  patients  with  Cushing’s  syndrome   -­‐ more  potent  than  cortisol   -­‐ if  you  measure  cortisol,  you  wont  detect  dexamethasone  (wont  interfere  with  assay)   -­‐ cortisol-­‐like  compound  à  should  be  able  to  suppress  ACTH  production  and  internal  cortisol  production  in   normal  subjects   -­‐ in  Cushing’s,  this  low  dose  dexamethasone  is  not  strong  enough  to  suppress  Cushing’s  syndrome   -­‐ if  you  do  not  see  expected  suppression  =  patient  may  have  Cushing’ s  syndrome   -­‐ cause  cannot  be  determined  with  this  test   -­‐ High  dose  dexamethasone  test   –  for  differential  the  cause  of  Cushing’s   -­‐ Suppresses  cortisol  production  (>50%)  in  Cushing’s   disease  but  not  in  other  Cushing’s  syndrome   caused  by  adrenal  adenoma  or  carcinom a,  ectopic  production  of  ACTH   -­‐ Strong  enough  to  suppress  the  pituitary  ACTH  producing  tumor,  but  not  strong  enough  to  suppress  ectopic   and  adrenal  ACTH  producing  tumor   -­‐ High  dose  dexamethasone  test  differentiates  between  Cushing’s  disease  and  other  causes  of  Cushing’s   syndrome   -­‐ Plasma  ACTH:  suppressed  in  adrenal  tumors  and  very  high  in  ectopic  ACTH  secreting  tumors   -­‐ Differentiates  between  ectopic  production  of  ACTH  and  adrenal  tumor  caused  syndrome   -­‐ ectopic  production  of  ACTH  in  cancer  patients:  their  ACTH  level  =  high   -­‐ adrenal  tumor  caused  syndrome:  tumor  producing  large  amount  of  cortisol,  local  ACTH  production  in   pituitary  will  be  low  à  negative  feedback  suppresses  pituitary  to  produce  ACTH     Case  1:  30  year  old  man  with  Cushing’s   -­‐ clinical  presentation:  obese,  hypertensive,  glucose  intolerance,  wasting  of  proximal  limb  muscles,  and  abdominal   striae   -­‐ laboratory  findings:   1) screening:  plasma  cortisol  concentrations  measured  at  8am  was  400nmol/L,  and  at  10pm  it  was  400nmol/L   -­‐  no  difference  between  morning  and  night  =  Cushing’s   2) conformation  of  Cushing’s:  low  dose  dexamethasone  test:  baseline  420nmol/L,  post  410nmol/L   -­‐  no  suppression  –  Cushing’s  syndrome  (do  not  know  cause)     3) differential  diagnosis  of  cause  of  Cushing’s:   -­‐ high  does  dexamethasone  test:  baseline  420nmol/L,  post  400nmol/L   -­‐ no  suppression  –  exclude  Cushing’s  disease  (Cushing’s  disease  caused  by  pituitary  ACTH  producing   tumor  with  large  dose  of  dexamethasone  –  large  dose  is  strong  enough  to  suppress  Cortisol  production   -­‐ don’t  see  suppression,  so  patient  has  either  adrenal  tumor  or  ectopic  ACTH  tumor   -­‐ plasma  ACTH:  at  8am,  150ng/L  (normal  range:  7-­‐51)   -­‐ significantly  elevated   -­‐ diagnosis:  ectopic  ACTH  producing  tumor   -­‐ glucose  intolerance  –  patient  with  excessive  cortisol  producti on  à  cortisol  affects  glucose  metabolism,   increase  liver  synthesis  of  glucose,  and  reduce  peripheral  tissue  uptake  of  glucose   § glucose  levels  increased  in  these  patients       § cortisol  is  a  counter-­‐hormone  of  insulin  (causes  glucose  uptake  by  cells)         • note*  the  4  counter  hormones  of  insulin:   1) cortisol   2) growth  hormone   3) produces  catecholamine’s  (epinephrine’s  and  norepinephrine’s)   4) glucagon   -­‐ all  can  increase  glucose  levels   -­‐ when  patient  has  hypoglycemia,  these  4  hormones  kick  in  and  quickly  increase  glucose  levels   -­‐ hypoglycemia  is  life  threatening     Aldosterone  –  Physiology     -­‐ produced  exclusively  by  the  zona  glomerulosa  (because  of  the  unique  enzyme)   -­‐ lacks  17-­‐  hydroxylase  but  has  18-­‐hydroxylase  and  18-­‐hydroxysteroid  dehydrogena se  for  aldosterone   biosynthesis   -­‐ Regulation  of  synthesis  and  secretion:   primarily  by  the  renin-­‐angiotensin  system   -­‐ Other  factors,  including  AC TH,  potassium  are  also  involved   -­‐ Biological  effect:     -­‐ Regulates  water  and  electrolytes   -­‐ Increase  sodium  and  water  retention   -­‐ Promote  potassium  and  hydrogen  ion  secretion   -­‐ Sodium  and  water  retention  à  Raises  BP   -­‐ Patients  with  aldosterone  excess  will  have  high  blood  pressure  (hypertension)   à  like  patients  with   Cushing’s  also  have  hypertension  (during  cortisol  synthesis  pathways,  all  the  precursors  after  the  e nzyme   21  OH’ase  share  the  same  biological  effect  with  aldosterone   à  aldosterone-­‐like  effect   -­‐ All  of  the  21-­‐hydroxylated  steroids  (e.g.  cortisol  precursors)  have  mineralocorticoid  effects  to  varying  degrees   -­‐ THEREFORE,  hypertension  is  seen  in  patients  with   Cushing’s   syndrome     Renin-­‐Angiotensin  System   -­‐ renin  is  released  in  response  to  low  tubular  Na+,  low  renal   arteriolar  BP,  and  stimulation  via  sympathetic  nerves.   -­‐ Renin  converts  angiotensinogen  into  angiotensin  1,  angiotensin  1  will   be  converted  into  angioten sin  2  by  the  enzyme  angiotensin-­‐ converting-­‐enzyme   -­‐ Angiotensin  2  will  bind  to  adrenal  glands ,  producing  aldosterone   -­‐ Aldosterone  will  increase  sodium  and  water  retention   à  which   increases  blood  pressure  in  response   -­‐ Increased  K+:  stimulating  factor   -­‐ Increase  in  potassium  will  also  increase  aldosterone   production  to  make  kidney  excrete  more  potassium   -­‐ ACTH:  contribute  but  relatively  unimportant  in  normal  situation     Aldosterone  Excess   -­‐ Clinical  features:   -­‐ hypertension   -­‐ neuromuscular  abnormalities,  e.g.    ness,  par esthesias   and  tetany  (due  to  K+ depletion)   -­‐ low  potassium  can  also  cause  the  renal  tubular  to  be  resistant  to  ADH  (decreases  water  urine  secretion)   -­‐ polydipsia  and  polyuria  (hypokalemia  caused  renal  tubule  ADH  resistance   –  nephrotic  diabetes   insipidus)   § lose  a  lot  of  water?  Drink  a  lot  to  compensate   à  polydipsia  and  polyuria   § nothing  to  do  with  glucose  diabetes   § fully  ADH  resistance   § if  ADH  cannot  be  produced  due  to  hypothalamus  central  nervous  system   à  central  diabetic  insipidus   § because  this  is  due  to  renal  tub ular  à  peripheral  diabetic  insipidus     § but  both  central  and  peripheral  causes  polydipsia  and  polyuria   -­‐ Primary  hyperaldosteronism,  also  called   Conn’s  syndrome  or  low -­‐renin  hyperaldosteronism;  rare,  most  cases       due  to  adrenal  tumors   o Aldosterone  excess  can  be  c aused  by  adrenal  over  production  or  other  factors   o If  its  because  of  adrenal  over  production   à  primary  hyperaldosteronism   o Adrenal  tumors  over  produce  aldosterone  à  Conn’s  syndrome   § Since  there  is  aldosterone  excess,  it  will  feedback  to  stop  renin  release  =   low  renin  and  high   aldosterone   -­‐ Secondary  hyperaldosteronism  ( high  renin),  common,  associated  with  renal,  heart  or  liver  disease   o e.g.  renal  artery  stenosis       Mechanism  of  Path ophysiologic  Changes  in  Primary   Sequence  of  events  in  Secondary  Hyperaldosteronism   Hyperaldosteronism  (Adrenal  Tumour)   (Renal  disease,  heart  disease,  liver  disease)   -­‐  aldosterone  already  is  increased    -­‐  block  on  blood  vessel,  there  is  reduced  blood  flow  =  renal   -­‐  negative  feedbacked  and  renin  is  decreased   arterial  stenosis   -­‐  sodium  increase,  loss  of  potassium  increased  in  urine   -­‐  kidney  senses  decrease  blood  pressure  and  produces  a  lot   -­‐  adrenal  tumors  are  rare   of  renin  (which  will  increase  aldosterone  for  water   retention  to  increase  blood  pressure)   -­‐  increase  in  renin,  angiotensin  2,  aldosterone   -­‐  in  response  to  increase  of  aldosterone,  there  will  be  an   increase  in  sodium  and  potassium  loss   -­‐  more  common   Aldosterone  Excess   -­‐ Diagnosis:   o serum  K+  low  and  urine  K+  excretion  elevated   o high  serum  aldosterone     § exceeds  upper  limit  of  normal,  or  inappropriate  to  the  low  serum  K+ level   -­‐ renin  low  in  primary  and  high  in  secondary  hyperaldosteronism   -­‐ acid  base  status?  Metabolic  alkalosis     o aldosterone  promotes  water  and  sodium  retention   à  increases  potassium  and  hydrogen  excretion   into  the  urine     Hypoadrenalism  –  Adrenal  Insufficiency   -­‐ Autoimmune  –  selective  destruction  of  cortex,  Addison’s   Disease   o Autoantibodies  against  adrenal  tissues  to  destroy  the   gland   o Causes  cortisol  and  aldosterone   deficiency   -­‐ Total  gland  destruction  –  causes:  tuberculosis,  bacterial   and  fungal  infections;  metastatic  carcinoma   -­‐ Secondary  or  tertiary  –  ACTH  deficiency  (pituitary  or   hypothalamic  diseases)  à  can  impact  the  production  of  cortisol   by  the  adrenal  gands   -­‐ long-­‐term  corticosteroid  therapy  –  suppression  and   subsequent  impairment  of  the  hypothalamic -­‐  pituitary-­‐     adrenocortical  axis   o exogenous  corticosteroid  therapy  can  suppress  pituitary  and  hypothalamus   à  under  extreme  stress  or  withdrawal   of  exogenous  therapy,  suppressed  pituitary  and  hypothalamus  cannot  return  to  normal  function   à  adrenal   insufficiency  à  need  time  to  recover   Primary  Adrenocortical  Insufficiency   -­‐ adrenal  gland  failure   -­‐ adrenal  glands  fail  to  produce  cortisol   -­‐ pituitary  will  increase  ACTH     Secondary  Adrenocortical  Insufficiency   -­‐ pituitary  failure  to  produce  ACTH   -­‐ adrenal  cannot  produce  cortisol     Hypoadrenalism  –  Adrenal  Insufficiency   -­‐ Clinical  features:   o Lethargy  (fatigue),  anorexia  (lack  of  appetite)  &  weight  loss   o increased  pigmentation  in  primary  hypoadrenalism   § ex.  If  adrenal  glands  fail  to  produce  cortisol     • negative  feedback  to  increase  ACTH  production   à  the  first  produced  precursor  has   multiple  peptides  (one  is  ACTH,  another  is  MSH   à  MSH  can  increase  skin  pigmentation)     § Addison’s  disease,  particularly  hands  &  mouth   § in  primary  disease,  melanocyte-­‐stimulating  hormone  (MSH)  secreted  with  ACTH  from  a  common   peptide  precursor  (pro-­‐opiomelanocortin,  POMC)     o abdominal  pain   -­‐ Acute  crisis:  -­‐  life  threatening   o Lack  of  aldosterone  and  lack  of   cortisol   o Lots  of  water  loss  à  hypertension   and  dehydration   o No  cortisol  =  hypoglycemia   o dehydration,  hypotension,  nausea  &  vomiting   Pigmentation  in  a  Patient  with  Addison’s  Disease   -­‐ Addison’s  –  primary  cause  of  adrenal  failure   -­‐ Hands  and  around  the  mouth  have  dark  pigmentation   -­‐ Given  cortisol  replacement  therapy,  ACTH  production  is  suppressed  =  skin  pigmentation  is  corrected   Hypoadrenalism  –  Adrenal  Insufficiency   -­‐ Biochemical  features:   o hyponatremia,  hyperkalemia,  mild   metabolic  acidosis  à   response  to  lack  of  aldosterone   o without  aldosterone,  you  lose  sodium  in  the  urine  and  retain  a   lot  of  potassium  and  hydrogen  ions   § acidosis   § increase  in  ACTH  (primary  cause)   o hyperuremia  (due  to  dehydration  –  renal  cannot  properly   excrete  urea,  therefore,  blood  level  of  urea  is  increase) ,   hypoglycemia   o increased  plasma  ACTH  (primary  adrenal  failure  only)   -­‐ Diagnosis:   o No  value  to  serum  aldosterone  or  random  single  cortisol  assay   § Patients  under  stress  will  greatly  affect  results   o Short  Synacthen  (1-­‐24  ACTH  analogue)  test:   § also  called  ACTH  stimulation  test   -­‐  measure  baseline  serum  cortisol  and  30  min  post  i.v.  Synacthen   • give  a  compound  with  ACTH  activity   à  synthesizes  ACTH  analog   • then  measure  response   • normal  subjects:  rapid  rise  of  cortisol  production  when  stimulated  with  ACTH   • Addison’s  disease:  no  increase   • adrenal  atrophy  (due  to  exogenous  glucocorticoid  treatment  or  pituitary  dysfunction):       slight  rise   o long  term  suppression  of  adrenal  cannot  immediately  respond  to  stimulation       Case  2,  a  20-­‐yr  man  with  abdominal  pain  and  vomiting   -­‐ Clinical  presentation:     o muscle  weakness   o dry  flaky  skin  with  pigmentation  in  palmar  creases  and  pressure  points   o BP  110/65  mmHg,  pulse  88  and  regular   -­‐ Initial  laboratory  test  results:     o Na+  125  (135-­‐145)  –  hyponatremia   o K+  6.5  (3.5-­‐5.0)  –  hyperkalemia     o Cl-­‐    95  (96-­‐108)  –  low  à  some  metabolic  acidosis   o HCO3-­‐  20  (22-­‐30)   o Urea  20  (3-­‐7)  à  increased  greatly     o Creatinine  200  (50-­‐120)  à  increased     -­‐ Urea  has  been  increased  at  a  much  higher  level  than  creatinine   à  due  to  dehydration  instead  of  renal  failure   o If  its  due  to  renal  failure,  you’d  expect  to  see  both  markers  to  increase  in  a  relatively  similar  proportion   o In  dehydration,  there  will  be  a  greater  urea  increase  than  creatinine   -­‐ Diagnosis:  metabolic  acidosis,  hypernatremia,  hyperkalemia,  dehydration   -­‐ Next  level  of  testing  =  conformation  using  ACTH  stimulation  test,  then  measure  serum  cortisol  level  based  on  the   baseline  (and  again  after  stimulation)   o Short  Synacthen  test:  serum  cortisol  less  than  60  nmol/L  at  both  baseline  and  again  30  min  post  i.v.   Synacthen  injection  (cortisol  RI  280 -­‐720  nmol/L)   o Result  has  no  increase  from  60nmol/L  =   ACTH  stimulation  cannot  stimulate  the  adrenal  to  produce   cortisol  =  adrenal  insufficiency  caused  by  Addison’s  Disease   o Serum  ACTH  =  increased     § because  of  Addison’s  disease,  adrenal  failure  caused  negative  feedback  to  the  pituitary  to  increase   ACTH  production     Based  on  Renin-­‐Angiotensin-­‐Aldosterone  Regulation  Pathway,  what  Types  of  Antihypertensive  Agents  can  be  designed?   -­‐ drug  to  stop  aldosterone  production?   -­‐ Use  ACE  inhibitor  –  block  enzyme  so  you  don’t  have  angiotensin  2   -­‐ Angiotensin-­‐receptor-­‐blockers   -­‐ Block  receptors  in  the  renal  tubular   à  aldosterone  receptor  blocker   -­‐ Block  renin  =  blocks  pathway         Lecture  11:  Infertility     Case:  The  infertile  couple     -­‐ married  3  yr,  trying  to  have  child  for  1  year  w/o  success   -­‐ Sue:  weight  65  kg  and  height  150  cm     o dark  hair  on  upper  lip;  terminal  hairs  on  chin  (hirsutism);  acne  on  forehead  (too  much  androgen   production  -­‐  hyperandrogen)   o normal  early  development  &  puberty,  irregular  menstruation   -­‐ Bill:  normal  physical  exam     -­‐ Family  history   o Sue’s  mother  had  difficulty  conceiving  until  her  first  child     -­‐ Sue’s  basal  body  temperature  chart:  monophasic  (  =  no  ovulation)   -­‐ Body  mass  index  (BMI)  =  weight  (k g)  /  (height) (m) (normal  =  20-­‐25)   o Sue’s  BMI:  29  (higher  than  normal  =  overweight)   -­‐ Patient  has  hirsutism,  hyperandrogen,  no  ovulation,  and  overweight       -­‐   o free  T4  and  TSH  =  normal  range  =    no  thyroid  disease  that’s  causing  infertility   o prolactin  levels  are  normal  =  not  hyperprolactinemia   o FSH  is  normal   o LH  is  elevated     o Estradiol  is  increased   o Free  AND  total  testosterone  is  increase   o DHEAS  is  increased   o Low  FSH,  high  LH  –  both  estrogen  and  androgen  is  increased   -­‐ Laboratory  investigation:   o Sue  -­‐  Abdominal  ultrasound,  both  ovaries  enlarged,  containing  multiple  cysts   o Bill  -­‐  semen  analysis:  normal  color,  volume  and  sperm  morphology   -­‐ Diagnosis:  PCOS   -­‐ Level  of  SHBG:  decreased  level   -­‐ Treatment:  can  be  treated     Infertility   -­‐ Definition:  failure  to  conceive  after  one  y ear  of  regular,  unprotected  intercourse   o Less  than  one  year  wont  count   -­‐ Causes  of  infertility:     o male  factors,  40%   of  the  cases   § NOTE:  assessment  of  male  is  equally  important  as  female   o female  factors,  50%  of  the  ca
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