Gonadotrophins -What clinician should know

Do you know that here are four different urinary gonadotrophins !!! And we must be aware that Many brands available in India - do contain LH & proteins as impurity and possibly some bacteria.

Four kinds of  Urinary Gonadotrophins  though all are from     menopausal urine.

 : Do not fall in the trap of MRs advertisement ,It’s your own duty to choose which brand conatins how much  impurity like urinary Proteins and Pirons!! - In fact there are four different urinary gonadotrophins depending on the amount of proteins and LH activity.

In some the ratio of FSH & LH in 1:1 ratio and others contain only FSH and minimal LH. For instance :-

1) U-HMG containg both FSH & LH and urinary proteins.

2) u-FSH-contain both FSH & LH. contain some proteins but 3) FSH- HP product of u-FSH contain minimal or no protein. 4) Coming to HP preparations (highly purified)  such preparations are  without any proteins.

What is HP ?? These are of two types 3) HP-hMG (both FSH & LH) & 4) HP-FSH.   Even if proteins are present such proteins seldom cause allergic reaction and seldom transmit prions (causing prions disease) or slow viruses. Urinary purified HP (no LH virtually) and purified (without proteins are available commercially).

Mostly urinary products are administered   as IM route.

How is r-FSH administerd?  By contrast recombinant preparations are administered as subcutaneous route and usually as self administered PFS pack. Therefore products from urinary sources are 1) u-HMG (FSH & LH)   2) u-FSH (with proteins)    3)    HP-HMG (No proteins but do contain identical amounts of FSH and LH in a ratio of 1:1     and 4) HP-FSH (no proteins & virtually no LH).

2) R-FSH: - was in the market since 1990s.  FSH-α and FSH- α similarly rec. HCG & Rec LH are also available.

Which political party is dedicated to people??  Which gonadotrophin is best for infertile woman ::;Urinary Vs. Recombinant :-

The advantages of U-FSH: - Easy to administer (usually by IM route), Low cost. The theoretical question of allergic reaction /local inflammation due to protein contaminants is not tenable neither the possibility viral transmission as all urinary preparations is refined from humans.

A great surprise indeed!!!!! Corona is like ordinary influenza. Surprisingly members will be glad to know that in case of Ov induction the  a) Ovulation  rates,   b) preg rates,        c) OHSS rates    d) MISCARRIAGE rates and e) Congenital Malformation  rate were identical for both –Urinary  & Recombinant  Gonadotrophins.

 Disadv:-  1) Biological activity   of such urinary gonadotrophins is poorly standardized / controlled- In fact when an ampoule of HMG/HSH is opened it may have biological potency   ranging from as 50-120 IU. That’s the main problem and therefore may be considered as gonadotrophin unsuitable for women who are susceptible for hyperresponse. But then again it has been proved that hMG do not increase the already existing high LH to that great extent that only Rec FSH has to be used. So, in conclusion, U-HMG can be safely used in PCOS women for Ov induction even where high basal LH was .In fact LH is only warranted in  OI protocol in  cases of HH(hypothalamic Hypogonadism)  & in that quite high and definitive dosage of LH is needed as they also lack in endogenous LH and E2. In such cases only U-HMG/ Rec FSH will not suffice. Instead one has to supplement LH as Exogenous HCG/ Rec LH. As much as daily 75 U of Rec LH is needed. In clinical practice, there is no clear clinical superiority between U-FSH and R-FSH neither between HMG and pure FSH. The selection of gonadotrophins appears to be clinically relevant only in OI protocol of HH where there is no endogenous LH. In such cases one has to add LH exogenously   intentionally.

 2) Another drawback of U-FSH/ U-HMG is that: - be it only U or HP-u products- “unit for unit” the biological potency of all Urinary products are less than Rec products. So if one uses U gonadotrophins much higher dosage has to be used where as in cases Rec products slightly lower dosage will suffice.

What is the relevance of slight presence of LH in late follicular phase? Any beneficial effects?

This is called “ceiling effect “of LH in late follicular phase. Presence of some amount of LH will help to arrest of growth of nondominant follicles and therefore allow having monofollicular growth. (

Can we add high dosage of Rec LH in compare to FSH in cases where there are multiple growths of follicles in late midfollicular growth to arrest dev of nondominant follicles?? àTherefore, in cases of hyperresponders in midfollicular level we can add high dosage of Rec LH in compare to FSHà thereby causing   growth / progress of nondominant follicles.

Drawbacks of Conventional Step up protocol? In this age old protocol the starting dose is 75 IU of HMG/P-FSH/Rec FSH of 75 daily, and the increasing after 5-7 days by another 75 Units. In this protocol as multiple follicles are recruited therefore the prevalence of severe OHSS is 4.6% and multiple pregnancies are > 34% which are simply unacceptable. This is due to “very high initial threshold dose”.

What is the number of available FSH sensitive antral follicles in their cohort of PCOS women? Compared to normal women the PCOS women have double the number of available FSH sensitive antral follicles in their cohort compared to normal women. Some claim that such highly FSH -sensitive antral  follicles are more than 6 times in number than normal ovaries .Only threshold dose will help to develop monofollicular growth without any incremental dose in most cases.

This is possibly an effect of hyperandrogenism. A very slight amount of exogenous FSH -, therefore, can stimulate development of large number of follicles and be a cause of OHSS-even severe OHSS. In fact, it is the small and intermediate number of follicles which determine the possibility of OHSS.

What about Chronic Low dose protocol?  “The initial low dose Initial Low dose: The dose threshold dose: This protocol was devised by FRANK and colleagues (or at least 14 days and then use incremental dose of r-FSH. Low starting dose of 50 IU is commenced. Very rarely 75 IU may be used as starting dose, at least 37.5 IU as a minimal starting dose ,Better 50 IU à No dose changes for 14daysà incremental dose of 25/ 37.5 IUà Change the dose after again after 7 days at least .Success rate is monofollicular growth rate of 70% and a pregnancy rate of 40%. Thereafter   incremental dose if necessary, then again it is adhered to for at least 7days. Majority of women develop DF by stimulation day 14-16days. And multiple preg rates are about 5.7% only. The pregnancy rate is 20% per cycle.. The usual time frame when the DF becomes ready for HCG administration is stimulation day 14 days.  The OHSS rate is only 014% only(

Some  ART specialists has also used modified Chr low dose protocol:- In such situation 52.5 IU as initial dose for an minimal of 14 days period with incremental dose of 22.5 IU or 37.5 IU in obese women. Smaller incremental dose is always beneficial. Even incremental dose of 8.3 IU may be adopted with promising results after 7 days of stimulation. Much patience is warranted in such cases. E

What should be ideal starting dose ?  25- IU in low weight women// 37.5 IU for average weight women/ 50 IU in obese Indians: In low weight women a very small starting dose for 14 days may be adopted –daily 25 IU if BMI is < 24. In lean women an incremental dose of 8.5 may be recommended.

What is the harm if dose increment is done after 7 days? There will be more chance of multiple pregnancies if dose increment is done after 7 days of stimulation..

What type of gonadotrophins??  Any gonadotrophin will do. Even u-HMG will help. Not that it should be r-FSH or p-FSH. 

Q. What to do in cases of failed Cycle?

In some obese women such a low starting dose (say, 50 IU) may not work. And in such an event DF may not be obvious even after 28-35 days of stimulation with standard  Chr low dose protocol  when the cycle has to be abandoned in such cases at a later date one can opt for  same protocol with higher initial dose which was administered in last couple days of previously failed cycle.

 Any dose alteration should be adhered to at least 7 days till incremental dose is applied. This low dose protocol-both step up and step down can be used of which step up is more worthy. The most acceptable protocol for Chr low dose is small starting dose in the first cycle for 14 days then reassessà without any dose changesà then a small incremental dose rise if required. FSH should be administered in a manner that a threshold sufficient to initiate growth and development of a number of follicles but any overstepping the threshold dose may cause development of multiple follicles. This threshold dose has to be maintained. But quite high doses are required in superovulation programme as in IVF.

Rationality of adding FSH in day 3 of cycles in addition to CC?

 In cases of PCOS there is little FSH in the initial part of the cycle. So the threshold dose of FSH is lacking (insufficient stimulatory threshold) or FSH is there but there are inhibitory intrinsic factors or more commonly there prevail a dysfunctional feedback mechanism. It is the attainment of sensitivity of receptors to FSH molecules which determine which follicle is going to mature.

IUI.

Roy  Homburg-p. 137,

Indications :-1)Mild male Factor infertility with  density of < 5-15 million/ml. and or < progressive motility < 20-32%. Usually no stimulation is needed. Only IUI alone will suffice in natural cycle. The role of IUI alone without stimulation is 8.4% per cycle but increases to 13.7% per cycle if stimulated along with IUI. Therefore ovarian stimulation is not a must in pure male factor infertility. IUI alone will be initial treatment of choice.

2) Unexplained subfertility along with Gonadotrophins & IUI.:- For Gonadotrophins are always  better  in unexplained infertility and Gonadotrophin stimulation is a must while planning for IUI. In cases where no cause can be substantiated for couples subfertility problem, in such unexplained infertility cases,  gonadotrophins alone have little effect rather than G & IUI combination.

Which stimulation protocol will be most effective along with IUI?

Results are as follows:-

Mode of stimulation	Success rate per cycle.
Natural cycle	4%
CC	6.7%
Letrozole
HMG	18%