Step protocol what does it mean ? In WHO type II anovulation resistant to Clomiphen or letrozole prior to ART??

 

Advantages? Why Low dose step up?

 

1)The purpose is to achieve monofollicular growth, thereby avoiding  multiple pregnancies and also minimize the incidence of OHSS.

2)                 Treatment Efficacy:-How effective is low dose step-up protocol ?

In WHO Group II Anovulatory PCOS who are resistant to Letrozole/ CC or failing to conceive with Letrozole/ CC despite ovulation - As many as 50% of women will achieve monofollicular growth.

 

Dose schedule? When to Initiate?:-

 

 

 By  starting with HP-FSH 75 IU daily subcut from day ( any day 2 – to day 5, may be initiated after P withdrawal as well) . G’trophin is available as powder with solvent-prepd soln which is usually  1 ml for both HP-FSH/R-FSH subcut, So, one should  start with Gonadotrophins 75-150 I.U. OD from Day3:- better at evening hours.   On  day 8 morning estimate serum E2. Once the serum E2 starts rising then, alt day serum E2

 

  For first 7 days such dose of 75 units is to be maintained and looking at response after 7 days of 75 i.u. of G’trophin à then dose is to be increased by another 37.5 i.u. Any dose change must be maintained for at least 7 days in this schedule. Maximum dose was 225 Iu per day and maximum duration of Inj were as long as 6 weeks. AS mentioned earlier, this protocol of dealing with high dose of  should G’trophin never be done outside ART center.

 

When to stop Gonadotrophins & go for trigger?

 

  When  at least one follicle was > 17 mm B)  or two-three follicles were > 15 mm. C) additionally if there was no response after as long as 6 weeks of G’trophin Ry. The proportion of patients who reach the criteria for hCG-administration within 14 days of FSH stimulation. [ Time Frame: 14 days of FSH stimulation ]

The HCG-criteria is defined as:

a.           One follicle with a diameter of >17 mm or two or three follicles > 15 mm (verified by transvaginal ultrasound).

b.           HCG should not be given if there is no response after 35 days or > 4 follicles > 15 mm (unless converted to IVF/ICSI).

c.           If a patient is seen with one to three follicles of 15 - 16 mms HCG can be administered on the same or on the next day due to a presumed growth of follicles of + 2 mm/day.

 

Trigger by which agent?-

HCG 5000 iu by subcut   -i.e.- and serum P   is to be assessed 9 days after HCG  when  if for some reason or other no luteal support was implemented.

 

                    When not to push trigger?  

If no. of follicles > 4 follicles above 15 mm in diameter and or E2 > 2000 pg/ml.

   Luteal support- is  a  not  a must:

- No luteal support  may be administered.

 

Don’t hate Carbohydrates!!!!! :: Types of gonadotrophins preparations:-Does result vary with urinary gonadotrophins (cheaper)?

 

It is the carbohydrate moiety that matters!!!! :- The degree of sialylation and sulfation-changes in carbohydrate part of G’trophin-modifies/ controls the bioactivity of G’trophin molecules in diff batches. Receptor binding and metabolic clearance too varies on carbohydrate moiety.

The degree of sialylation correlates with acidic moleculeàdifferent FSH isoforms. The efficacy of p-FSH vs r-FSH in non-down regulated cycles and down regulated cycles were little evaluated so far.

What are newer gonadototrophin??

Now by using optimized chromatographic techniques –a predetermine & predefined isoforms can be prepared from u-FSH.(Bravelle).Bravelle contain less acidic residue. Less acidic form is better to yield good results as in Bravelle.

Protein content as impurity:-In HP preparations the protein content is minimal/ if not nil .

Few points as r-FSH:- Follitrophin-α   (  Gonal-F)              β

 

 

 

How to judge & compare between two such types of agents?

 

The primary end point is Ovulation, but secondary end points were a) whether monofollicular b) Size of follicles-How many 12,>15 & > 18 mm follicles are there? c)PR d)ET d) Incidence of OHSS e) Inj sites pain/ reactions) Multiple preg rates

 

Choice of gonadotrophins? –

 

 Both the p-urinary FSH (ovulation rate was 85%) & rFSH (91%) are equally effective.     Efficacy comparison between two types of gonadotrophins:-PR(pregnancy rate)  of singletons in u-FSH was 15% in each group.

Conclusion:-

 

U-p-FSH was not inferior as a method of OI  in ) WHO Group II Anovulatory PCOS who are resistant to CC/ Letrozole

FM is essentialà to note no & size of follicles.  & alt. day Serum E2 estimation.

      The effective dose of gonadotrophins required in each cycle to have a response must be recorded so as to plan the future stimulation.

Thank you