LMP301 2014 Lecture 8.pdf

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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  releas–  the  hormone   can  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  recep   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
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