Step up –Low dose protocol Indications of step-up?

Step up –Low dose protocol

Indications of step-up? : -

 Primary indication of Chr low dose protocol is Letrozole or  CC resistance women

Treatment with CC is effective only in patients with sufficient serum estradiol levels After correction of underlying problems, including those related to stress, exercise and eating disorders, treatment with gonadotropins is effective in patients with low FSH levels, but it must be started at a low dose because of the possibility that ovaries unaccustomed to FSH will be hyperstimulated .

 Like all other Gonadotrophin Ry: - indications are 1) WHO Group II Anovulatory PCOS who are resistant to CC or failing to conceive with CC despite ovulation.

Advantages?  Why Low dose step up? The purpose is to achieve Monofollicular growth, thereby avoiding multiple pregnancies and also minimize the incidence of OHSS.

 Inclusion criteria: Who are suitable? 1) She must have been tried at least 3 cycles of OI with 100 mg of CC.  2) WHO Group II women-PCOS women-with Chr anovulation as was diagnosed by amenorrhea/oligomenorrhea/ or women with regular cycle length but anovulation was documented by serum P assay in cycle length of 21-35 days.

3) Infertility of at least 1 year, BMI 19-35 kg/M²

4) At least one tube must be patent.

 5) TVS- exhibits normal pelvic anatomy

6) Day 2 FSH ranging from 1-12 IU/Lit

7) Normal Prolactin & total Testosterone

8) Normal semen/ Donor

   9) Signed informed consent.

Exclusion criteria:-A)More than 12 unsuccessful OI B) persistent Ov cyst> 15 mm. C) Ovarian endometriomata D) Keep a gap of at least 1-2 months –after previous CC. Metformin , gonadotrophins E) Cong malformations of genital organs.

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

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

Dose schedule? Initiation: - 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) available as powder with solvent-prepared soln. was 1 ml for both HP-FSH/R-FSH subcuts,

 For first 7 days such dose of 75 units was maintained and looking at response after 7 days of 75 i.u. Of Gtrophin à then dose was increased by another 37.5 i.u. Any dose change must be maintained for at least 7 days in that schedule. Maximum dose was 225 IU per day and maximum duration of Inj were as long as 6 weeks.

When to stop Gonadotrophins & go for trigger? A) at least one follicle was > 17 mm .b) or two-three follicles were > 15 mm. additionally if there was no response after as long as 6 weeks of Gtrophin Ry.

Trigger by which agent? - HCG 5000 IU by subcut   -i.e. - and serum P was assessed 9 days after HCG as 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-a necessity: - No luteal support was administered.

Types of gonadotrophins preparations:-Does result vary?

The carbohydrate moiety: - The degree of sialylation and sulfation-changes in carbohydrate part of Gtrophin-modifies/ controls the bioactivity of Gtrophin molecules in diff batches. Receptor binding and metabolic clearance varies.

The degree of sialylation correlates with acidic moleculeàdifferent FSH isoforms. 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 purity:-

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

The efficacy of p-FSH vs r-FSH in non-down regulated cycles and down regulated cycles were little evaluated so far. 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 f) Inj sires pain/ reactions’) Multiple preg rates .

Choice of gonadotrophins? Comparison between two types of gonadotrophins: - Bothe p-urinary FSH (ovulation rate was 85%) & rFSH (91%) are equally effective.

Efficacy comparison between two types of gonadotrophins:-PR of singletons in u-FSH was 15% IN EACH GROUP.

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.

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

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. Bilateral   PCO drilling 2 yrs later if unsuccessful.