LMP301 2014 Lecture 11.pdf

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

  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  cases   o unknown  (no  abnormality  found),  10%   -­‐ In  female,  endocrine  abnormalities  are  found  in  1/3  of  cases     o hormone  dysfunction  is  a  rare  cause  of  male  infertility     Sex  Steroid  Hormones   -­‐ Sources:  Gonads  (testis  and  ovary)  and  peripheral  conversion  (adrenal  &  adipose  tissues)   -­‐ Testosterone  and  androgens   o in  women:  1/2  from  ovary  &  1/2  from  peripheral  conversion  of  dehydroepiandrosterone  (DHEA)  and   DHEA-­‐Sulphate  (DHEAS)  secreted  by  adrenal  cortex   o if  a  female  patient  comes  in  with  excess  androgen,  is  it  from  ovaries?  Or  adrenal?   –  differential  marker  is   DHEAS   o DHEAS,  marker  in  differential  diagnosis  of  the  source  of  excessive  androgen  production  in  women       § If  DHEAS  is  elevated  =  adrenal  production  of  androgens  that  caused  the  spike   -­‐ Estradiol  and  estrogens  (female  sex  hormones)   o In  normal  male,  estradiol  present  in  low  concentrations   -­‐ Sex  hormone-­‐binding  globulin  (SHBG)   o Higher  affinity  for  te stosterone  than  for  estradiol   o Estradiol  stimulates  SHBG  synthesis  in  liver;  testosterone  decreases  it   § Similar  to  Estrogen  stimulation  of  binding  protein  production  through  GN  r egulation   o The  plasma  concentration  of  SHBG  in  females  is  twice  that  in  males   o Factors  which  alter  SHBG  concentration  alter  the  ratio  of  unbound  te stosterone  to  unbound  estradiol   § Alteration  of  the  ratio  between  bound  and  unbound,  and  testosterone  and  estroge n  level   § Adjustment  due  to  SHBG  concentration  due  to  binding  affinity  difference     Control  of  Testicular  Function  (male  hormone  production  regulation)   -­‐ done  through  hypothalamus  pituitary  access   -­‐ hypothalamus  produces  GnRH   à  stimulates  pituitary  to  produce  FSH  and  LH   -­‐ production  of  testosterone  and  dihydrotestosterone  will  have  hormonal   functions   -­‐ testosterone  can  negative  feedback  to  hypothalamus  and  the  pituitary   -­‐ dihydrotestosterone  converted  FROM  testosterone   à  more  potent  than   testosterone   o important  in  regulating  virilization   o important  for  male  fetus  during  sex  organ  development   o important  for  male  puberty  (male  sex  pattern  requires   normal  level  of  dihydrotestosterone)   -­‐ factors  that  affect  testosterone’s  conversion  to   dihydrotestosterone:  disorders   Conversion  of  Testosterone  to  Dihydrotestosterone   -­‐ testosterone  is  converted  to  dihydrotestosterone  by  the  enzyme   5α-­‐reductase  (DHT)   o 5α-­‐reductase  is  the  controlling  factor   o if  there  is  a  deficiency  in  5α-­‐reductase  =  deficiency  in  DHT   § male  fetus  cannot  develop  correctly   à  affect  sex   organ  development     Disorders  of  Male  Sex  Hormones   -­‐ Hypogonadism     o Primary:  hypergonadotropic  hypogonadism   –  testicular   failure  (testes  abnormality)   § Congenital  defects   § Acquired  defects     § If  testosterone  cannot  be  produced,  then  the  negative  feedback  will  increase  FSH  and  LH   à   hypergonadotrophic  Hypogonadism   • Testosterone  is  low,  FSH  and  LH  is  high   à  primary  cause   o Secondary  and  tertiary:  hypogonadotropic  hypogonadism   § Due  to  pituitary  or  hypothalamus   § Pituitary  tumors  à  fail  to  produce  FSH  or  LH  à  can  cause  secondary  disorder   § hypothalamic  disorders,  e.g.  Kallmann’s  syndrome  (GnRH  deficiency   à  hypothalamus  cannot   product  GnRH)  –  affects  both  male  and  female   o GnRH  stimulation  test  –  for  investigation  of  the  causes   o Give  GnRH  to  patient  to  see  response  of  FSH,  LH,  and  testosterone  production   –  will  differentiate   between  primary,  secondary,  and  tertiary   o Low  GnRH   o Due  to  decrease  in  testosterone  level   -­‐ Defects  in  androgen  action  –  sexual  differentiation   o Testicular  feminization  syndrome  (Androgen  Insensitivity  Syndrome  –  due  to  androgen  receptor  def.)   § Androgen  receptor  defect:  androgen  receptor  cannot  receive  androgen  stimulation   § Abnormal  response  to  testosterone   • CAN  have  high  testosterone   à  negative  feedback  to  produce  more  testosterone  to   compensate  the  defected  androgen  receptor         • However,  since  receptor  cannot  pass  on  the  signal  =   female  like  presentation   o 5α-­‐reductase  deficiency  (DHT  deficiency,  only  affect  chromosomal  46XY  males)   § dihydrotestosterone  cannot  be  converted   à  enzyme  deficiency   § if  a  male  fetus  has  a  46XY  karyotype,  they  cannot  develop  testes  and  other  sex  functions   § depending  on  the  severity  of  the  deficiency,  these  patients  can  either  have  total  female  feature,  or   partial   § so  far,  this  enzyme  deficiency  only  affects  46XY  males   –  no  reported  case  in  females  of  this   enzyme  deficiency       Investigation  of  Infertility  in  Men   -­‐ first  do  a  sperm  analysis   -­‐ if  its  normal:  no  further  endocrine  tests   -­‐ abnormal:    further  tests  on  testosterone ,  FSH,  LH,  prolactin   o if  testosterone  is  low,  but  high  LH  and  FSH:   primary  disease   o if  testosterone  is  low,  FSH  and  LH  is  also  low:   secondary/tertiary  disease   § further  use  of  GnRH  stimulation  to  figure   out  if  its  secondary  or  tertiary  disease   o prolactin:  produced  in  the  pituitary   § prolactin  overproduction:  hyperprolactinemia  (affects  both  male  and  females   –  infertility)   § most  likely  due  to  prolactin  producing  tumor  in  the  pituitary   § this  disorder  can  cause  infertility  in  both  males  and  females       How  the  Female  Hormones  are  Regulated   -­‐ GnRH  (produced  by  the  hypothalamus)   -­‐ Adjustment  of  pulse  speed  will  regulate  cycle  between  FSH   and  LH  production  (also  regulates  menstrual  cycle)   o Slow  pulses:  favor  FSH  production   o Fast  pulse:  LH  production   -­‐ LH  and  FSH  can  further  trigger  estrogen  production   -­‐ In  estrogen  production,  there  are  2  effects   1) negative  feedback:  adjusts  production  of  GnRH,  FSH,  and   LH   2) positive  feedback:  estrodial  can  have  a  positive   stimulation  effect  during  menstrual  cycle     -­‐ red  line:  estrogen  levels   o at  12  days:  production  is  at  peak   o with  increase  in  estrogen,  FSH  levels  decreases   –   negative  feedback
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