PCO -how best to induve ovulation and achieve pregancy

The other uncommon methods of Ovulation inductions:--chronic  low dose  protocol:

there   are various protocols of gonadotrophins. These are step up , step – down   , step up stepdown and chronic low dose   protocol Out of all chronic  low dose protocol is the preferred  one in PCOs   patients . the incidence  of OHSS is reduced from 4.6% to 1%   and multiple   pregnancy rate is  reduced to 5.7% as compared  to  22-34 % . Uniovulatory   cycle rate of 70 %    is achieved  with rFSH with chronic  low dose   protocol. In chronic    low dose   protocol from 5^th day 75iu  of rFSH is started from day 5 of the cycle though  what should  be the initial  dose can be better decided by baseline  scan  as discussed  in the   chapter   on cycle  assessment . The  same dose  which is usually 75 iu  is continued   for 14 days  . Increasing   the dose   before 14 days looses   the advantage of chronic low dose  protocol. Though ovulation  monitoring  is done   during  this period   and in most   of the cases a mature follicle develops    within  these 14 days . If it does  not then  the dose of  gonadotrophin is   increased  by half of the initial dose   for another   seven days. If after that the follicle does  not develop   again half  of the original   initial  dose is increased. Remember  each increment in  dose is half the initial   dose and   one has  to wait for seven  days for the follicular  to develop   with the same dose. This protocol gives   monofollicular development  and therefore  higher  pregnancy   rates. Multifollicular    development   leads  to high E2 and progesterone   levels   their   altered ratios and therefore low   implantation   rates.

Can rFSH   replace  CC as a first   line of treatment :

Prof Roy  Homburg  and Collin Howles published  a study  in 2005  stating  that if rFSh  is used as  the first line of treatment for ovulation induction   the pregancy rates can be doubled to that   of  CC. This   study   showed  a clear   superiority     of low dose FSH  over CC for   treating  anovulatory patients   with PCOS . In first  cycle pregnancy   rates are 30 %  with rFSH  as compared   to 14%  with CC  and in second cycle  it is 50 %   with rFSH  as compared  to 32%  with  CC. This explains that the time to achieve   pregnancy   is significantly   reduced. If cost  is not a prohibiting   factor  rFSH   in a chronic low dose protocol  is to be preferred over  CC .

We have found   a combination of Letrozole with rFSH  very useful. It is cost effective  as it reduces  the consumption  of rFSH  and also  gives monofollicular development. Letrozole  is given    from day 3-7   and rFSH  is started  from day 8. This regime     decreases    the incidence   of OHSS and multiple pregnancies   with comparable  results ad those of fRSH alone.  Unfortunately it has  been lately   banned in our country .

Antagonist :

GnRh  antagonist has a definite place  in PCOS patients . In   PCOS patients  there is a tonic rise of LH  particularly in thin lean PCOS patients. There  is always a  possibility of premature LH   surge because    of high oestrogen  levels. Therefore  antagonist is started when at   least one follicle has grown  to 14 mm to prevent   LH  surge and is continued till follicle matures i.e. the day of hCG. If antagonist is started early and the LH level is   not high at that time the follicle  will regress   as certain amount of LH  is required for final stages    of maturation  of the follicle. Gonadotrophin  dose does not require increment   when antagonist  is started. Antagonist   also helps  in correct   timing of IUI. But   remember   antagonist is not to be   added  when not required, it   then causes  damage rather    than improvement   to the developing follicle because  of sudden fall of LH.

GnRh  Agonist :

GnRh is very useful as  ovulation   trigger  in PCOS patients  The main   advantage   is that the duration of action is shorter than  hCG  and therefore  leads  to lesser  rise   in E2 ad progesterone    levels   and therefore gives better implantation   rates  and chances of   OHSS is also reduced, But  we need to remember   that whenever   agonist is used luteal support  is mandatory.

GnRH agonist for downregulation   is an established  treatment   in IVF cycles but should not be  used in IUI cycles for the same  purpose. This is so because   downregulation in IUI cycles increases   gonadotrophin consumption multiple pregnancy   rate and incidence  of OHSS without any benefit . Chronic   low dose protocol  gives better   pregnancy   rat3e as compared to that and multiple pregnancy  rate from 22% to 5%

Antagonist + agonist protocol

a. In  PCOS patients GnRh  antagonist is  used to prevent  LH   surge and agonist for final oocyte  maturation  by triggering  LH  instead of  using hCG.

b.            But   agonist has 24 -36  hours  duration of action. It  leads to  lower FSH   and LH  resulting in  luteal phase deficiency . We   know that  endogenous LH plays a crucial role   during luteal  phase.

c. Therefore   luteal support with 1500 iu hCG every third day can be used  along with progesterone.

d.            The advantage   of agonist as trigger  is that if causes FSH &    LH surge. The role   of FSH  surge is not   known in human  being    but in animals    it causes nuclear maturation   and cumulus expansion.

e.If there are multiple follicles all embryos   can be freezed and can be   used next month in natural  cycle.

f.   Now in soft  protocols  for IVF  majority of centres use   this antagonist agonist protocol

Ovarian drilling :

Ovarian drilling is an excellent procedure for PCOS  patients . In the words of Howard Jacobs  As it gives  monofollicular   development  it outwaves  other methods only because  of this single benefit.

Indications of ovarian drilling:

a. CC resistant  cases

b.                        Before   starting gonadotrophins 

c. Thin  lean PCOS with high LH

d.                        Recurrent pregnancy   loss due to PCOS

e.Alternative   to gonadotrophins when cost  is prohibiting factor.

f.   I have  personally found ovarian    drilling very useful  before gonadotrophin  therapy    as it reduces  the amount of gonadotrophin  with excellent  pregnancy   rates.

g. Cochrane review   says  that twelve   months  pregnancy   rate after drilling and six months  gonadotrophin  stimulation both  have similar  pregnancy  rates.

h.                        Contrary  to the  former belief   that drilling works for 6 months   effect  of drinlling   lasts for nine years   in majority  of cases. It has also been quoted by Prof  Roy   Homburg that spontaneous pregnancy can occur   after   several  years of drilling Ovarian  drilling gives 70-80 % of ovulation rate and 60 %  of pregnancy  rates  .

i.     According to Neil Johnson evidence   based medicine has proved drilling to be better than gonadotrophins  for PCOS patients

Mechanism of action :

Various   explanations have been described in literature   as to why drilling works. But  the most  acceptable theory is that drilling  decreases androgen  level  by destroying  ovarian stroma. This decrease in androgen will decrease   LH   and change FSH/ LH ratio. Stein – Leventhal had long long back suggested  that larger  the ovary  larger portion of its stroma  needs to be removed to decrease   androgen   and insulin levels. So what  I have   found in may practice only  four punctures does not    work in majority of  cases. Larger   the stromal  volume    larger amount  of stroma  needs to be destroyed   and therefore   more punctures  need tobe done to decrease   the androgen  levels  to effective limits.

Advantages :

a. One  time  procedure

b.            No follow up  required

c. No   monitoring   required

d.            Cheaper   than   gonadotrophins

Methods :

It should be done with unipolar cautery and   has excellent  results  similar   to laser therapy Various   other methods   have been described  in literature    without   added advantage   . The only one contraindication to ovarian drilling is PCO like ovary . What   does this mean ? Many   a times drilling is done by looking at it at  the time   of laparoscopy . Such    decision of drilling should not be     considered at the time of laparoscopy,.

Prior   to laparoscopy baseline ultrasound scan    must be done   and diagnosis of PCO is   mandatory We have not   come across   a  single case of ovarian failure  after drilling because   we always   confirm PCO  on baseline  scan  before   doing drilling.

We have not even    seen   significant adhesions after  drilling  during  caesarean section of the patients  in whom  we have   done ovarian drilling . ovarian   malignancy  after drilling has not  been proved.

Number of punctures :

1.According to Adam   Balen  &  Armer’s  technique   4 punctures for 4 seconds  at 40 w

2.According  to Naether and colleagues : 5-20  punctures  for 1 second    at 400 W

3.According  to Gjoumas : 5-8  punctures   for 5-6  seconds  ate 300-400 w

4.If the above  data is closely  observed  and analysed puncture duration  is decreased    when the power   of current   is increased and number   of punctures are less if each puncture is continued for longer   time.

5.E.g. : 5-20 punctues for 1 sec of Naether et al is equivalent to 5-8  punctures for 5-6  seconds which is again equivalent  to 25-45  punctures for  1 second   of Gjoumas again   that is equivant  to 16  punctures of Adam Balen.

6.So I believe   that number  of punctures   depend on the stromal volume and ratio   of stromal  volume to  ovarian    volume. We have  always done  punctures  between 20-40 in number   for one second with  400  watt cautery . All usually  used cauteries in our   country   are of 400 watts. We have   done drilling only  after  confirming insulin resistance and stromal   area as well as stromal   volume and   have results as follows:

The study   was conducted from 2002-2009 and total  number  of patients  with CPOS  enrolled  were 2733. Out of these 134  patients  did not    turn  up after initial  investigations and 2699  patients   were taken for study. Out of these 2699 patients   1566   patients  had come after   taking treatment   for subfertility  for more than a year  If  we move   over directly to result .

It is clearly seen that  the number of cycles for  conception are fewer when   ovarian drilling  was done  and the total  conception  rate is also high .

But I would like to emphasize  the we have not come across a single case of ovarian failure .

PCOS and ART

a. PCOS is not an  indication of IVF

b.            Treat anovulation  as a cause of infertility

c. ART in PCO is done when  there  is an associated  pathology .

d.            ART is preferred in countries where single embryo  transfer   is done.

e.Results are poor in IVF  in PCOS patients   because of high E2  and progesterone  which prevents   implantation .

f.   So in IVF    antagonist  protocol with agonist   trigger  is preferred. Even though  there are  more embryos  they are    freezed and transferred in subsequent  cycles.

Invitro maturation

IVM is a new advance  in ART  especially for patients  with PCOS as it is 100 %  OHSS free treatment  . The treatment   cost is low as consumption   of gonadotrophins is very low.

For  this  technique  stimulation  is stopped  as the follicle  size reaches 10-11  mm. hCG   10,000iu is given to the patient  for final maturation and ovum   pick up is done after 34-36  hours  Period   for invitro   maturation  is  24-48  hours. Thereafter   ICSI   is doe  on these  mature oocytes.