Evolution of Pit->to urinary- top P FSH to r-FSH gonadotrohins

History of development of gonadotropin  preparations-When ??

 First step: Pituitary gonadotrophins:-The first   gonadotropin  preparations were extracted in 1958  from the human  pituitary these compounds were available   only in very   small amounts   and  had a high   cost  indeed their   clinical impact  was weak Furthermore   by the   mid 1980s   some cases  of dementia and   death for iatrogenic Ctautzfeld Jacob   disease were   related  to the pituitary  growth   hormone administration    this     concern   definitively forced  out of marketing the pituitary derived  gonadotropins   .

Second  step of gonadotrophin :--in 1960:-urine of post menopausal  women contains FSH LH The clinical history    of the gonadotropins starts in the 1960^th when a   gonadotropin  formulation  obtained from   the urine of post menopausal  women became   available. This   compound   called human    menopausal   gonadotropin    was characterized by a content    of both FSH  and LH  activity    in  a ratio   of one  of one. Other  hMG  preparations     were  devised  to reduce   the amount  of LH  activity   per ampoule  of    product. For many   years hMG   was the  only  gonadotropin    used  for ovulation induction  and it is  still available   worldwide   although   adjustments   in hormone   content   and product   purity   have been   introduced   over the years.

Low   grade of purity  because as much as   only 3 to 4% of protein   content be injected only  IM :The first  hMG  formulations   had a low   grade of purity  because      only 3 to 4% of protein   content  is gonadotropin for this reason  these drugs could  be injected only  IM.

Step 3:-- p-FSH :: In  the mid 1980s   No protein in Menopausal gonadotrophins :--A new  preparation of so called  purified FSH   became  available  which contained   only a  little amount of LH activity      but still had up to 95%  of protein   impurity .

 Highly purified FSH  After   in the 1993  :- highly purified FSH  was extracted. HP  FSH  was  virtually devoid of LH   activity    but most  importantly    his content  of protein impurity was very   low  and the drug could  be given  subcutaneously . Even the hMG   preparations have been  improved   with the introduction  of highly purified  formulations which  contain only  a small  amount   of non hormonal   contaminant thus allowing SC  administration ultimately a sort of recombinant   hMG  was manufactured    containing  both rFSH  and R LH   in a ratio  of 2 to 1 

So today  when we  say simply gonadotropins   we indicate   a wide    spectrum of compounds    with some relevant differences   in term of origin pharmacokinetics and costs  but   that all   are extensively   employed in ovulation  induction.

R-FSH . In the following  years   genetically  engineered  gonadotropins were   synthesized   and became   available for clinical  use first recombinant FSH was   developed totally  devoid   of LH   activity   and of pertinacious impurity. There are two rFSH   available   and registered  as   Follitropin  alpha and Follitropin  beta there is  actually no proof   that  the subtle    differences in structure   of these  two compounds   may have   some clinical   relevance.

More  recently the family of  the recombinant   gonadotropins was expanded to include recombinant   LH and recombinant coriognadotropin   .

As  previously  indicated  the crucial characteristic of hMG   is the presence of   both FSH   and LH   activity usually in the same nominal amount of  75 IU each per amp   However the LH   activity  of all menotropins   is provided   not only  by  LH but even by human CG this is especially  true for HP  hMG  . We   studied extensively this compound in 2003. When the hormonal   and clinical profiles were   compared in two groups of patients   undergoing  ICSI and stimulated   with recombinant   aFSH    or HP hMG   . In this   prospective and randomized     trial all patients   were pretreated with a depot GnRH  agonist administered  in the luteal  phase of the cycle preceding  stimulation   ovulation induction was conducted with a fixed  dse of 150 IU/ day   of recombinant   FSH or  HP   hMG   . Blood  samples    were driven   daily to assess   the reproductive  hormone levels . LH levels  were close  similar in both  treatment    groups thus showing  that LH   amount in HP hMG   is negligible. Conversely  serum levels   of hCG  significantly   increased in the patients   stimulated   with HP hMG   reaching a plateau by the 4^th or 5 th day of stimulation   these findings   demonstrated that  hCG is  critical  contributor   and provides almost  all the LH    activity  of HP hMG