L.G. Westergaard

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       It has been suggested, that the outcome of assisted reproduction  is deteriorated, when HMG is used for ovarian stimulation as compared to  use of pure FSH preparations. Moreover, it has been assumed that this  negative effect is caused by the content of LH in HMG. However, most  prospective, randomized trials have shown equality of results between  HMG and pure FSH, and a few even improved outcome with HMG as compared  to pure FSH. Indeed, some recent data indicate, that the commonly used  combination of pituitary down-regulation and recombinant human FSH,  which is completely devoid of LH activity, results in such low levels of  circulating LH, that the outcome of IVF is compromised. In a  retrospective study we found, that half of normogonadotrophic women  after GnRH agonist down-regulation combined with ovarian stimulation  with recombinant FSH had mid-follicular levels of LH in serum below 0.5  IU/L. In this group of women a significantly increased risk of early  pregnancy loss and a significantly lower chance of delivery was found  when compared to the women with mid-follicular LH above 0.5 IU/L.  Whether use of HMG or addition of exogenous LH to FSH stimulation  protocols will improve the prognosis in these women remains to be proven  in future prospective studies. 





       Although the first baby born after conception in vitro resulted  from oocyte retrieval in a natural, unstimulated cycle, it was soon  realised that increasing the number of mature oocytes by controlled  ovarian hyper stimulation (COH) improved the success rates of IVF  significantly. Up to the mid-eighties only human menopausal  gonadotropins (HMG) containing equivalent FSH- and LH activity were  available for COH. Using this stimulation method, however, the outcome  of IVF was often jeopardised due to frequent occurrence of an untimely,  spontaneous LH surge. In addition, some studies showed, that increased  tonic levels of circulating LH during the follicular phase was  associated with a poor reproductive outcome. During the 1980’s two  measures were introduced in the IVF treatment to deal with these  problems ascribed to harmful effects of LH:

       i) use of GnRH agonist to suppress endogenous pituitary LH (and FSH) secretion, so-called down-regulation. 

       ii) use of “pure” FSH preparations with reduced or virtually no content of LH. 

       Pure FSH preparations were at the beginning like HMG derived from  the urine of post menopausal women such as Metrodin and Metrodin HP  (highly purified), Serono. During recent years, however, the recombinant  human FSH preparations (Gonal-F Serono and Puregon Organon), which are  devoid of any LH activity, have been introduced in COH. 

       While stimulation protocols using GnRH agonist down-regulation  undoubtedly have improved the success rates of IVF treatment, it can be  questioned whether there is a genuine clinical benefit and  cost-effectiveness in replacing of HMG with pure FSH for ovarian  stimulation. 





       A meta-analysis of clinical trials comparing HMG and urinary FSH  in IVF has shown better results with FSH than with HMG, due to  significantly fewer cases of complete failure of fertilization in the  FSH group (Daya et al., 1995) Based on this study and more recent  results from a larger prospective, randomized trial comparing HMG and  FSH in GnRH agonist flare-up it was concluded, that the LH contained in  HMG may be detrimental to the outcome of IVF, and that FSH should  replace HMG in COH for IVF. This notion, however, has been challenged in  a number of other prospective, randomized trials showing either  equivalency between HMG and FSH or even an improved IVF-outcome with HMG  as compared to urinary, highly purified FSH , due to a significantly  higher fertilization rate and lower frequency of complete failure of  fertilization in the HMG group (Westergaard et al., 1996). In contrast  to the study of Daya et al. LH concentrations were monitored in this  study and found significantly higher in the HMG group as compared to the  FSH group. Therefore, these results contradict a harmful effect of the  LH contained in HMG and indicate, that it may even be beneficial with  regard to oocyte maturity and fertilizability. Moreover, recent studies  have shown, that the combination of GnRH agonist down-regulation with  urinary FSH-HP alone in a substantial subgroup of women results in such  profound suppression of endogenous LH secretion (< 0.5 IU/L) during  the mid-follicular phase, that oestradiol biosynthesis is significantly  decreased and oocyte maturation and fertilisation capacity may be  compromised, although the capacity of embryos to develop to the  blastocyst stage in vitro seemed unaffected (Fleming et al., Hum.Reprod.  1998). 

       In an attempt to further unravel the possible influence of  profoundly depressed LH levels during ovarian stimulation for IVF, we  conducted a retrospective study on 200 women, who were all  normogonadotropic, and were treated with GnRH agonist down-regulation  combined with recombinant FSH, which is completely devoid of LH  activity. We found that 50% of these the women had mid-follicular serum  concentrations of LH below 0.5 IU/L and the remainder above this level.  With the exception of serum oestradiol concentration, which was  significantly lower in the low LH group, all other parameters  characterising the stimulation protocol, such as number of retrieved  oocytes, fertilization rates and pregnancy rate per started cycle, were  similar between the two groups. However, in the group of women with  mid-follicular LH below 0.5 IU/L the frequency of early pregnancy loss  was significantly higher than in the “normal” LH group; 45% versus 9%, p  < 0.05 (Westergaard et al., 1999). These results indicate, that  possible detrimental effects of profound suppression of endogenous LH  may become manifest only after pregnancy is established. The explanation  for this is unclear and needs further investigation in future  prospective clinical studies.





       Available evidence from prospective randomized trials does not  indicate a detrimental effect of the LH contained in HMG on the outcome  of IVF. On the contrary, some recent data indicate, that the combination  of GnRH agonist down-regulation and recombinant FSH in a substantial  number of normogonadotropic women results in such low levels of  circulating LH, that the outcome of IVF is compromised. Whether these  women would benefit from treatment with HMG or recombinant FSH combined  with recombinant LH remains to be proven in future prospective  randomized trials.

DAYA.S et al.: Randomized controlled trial of follicle stimulating hormone versus human menopausal gonadotrophin in in-vitro fertilization. Hum. Reprod., 10,n 392-396, 1995.

FLEMING R. et al.: Effects of profound suppression of luteinizing hormone during ovarian stimulation on follicular activity, oocyte and embryo function in cycles stimulated with purified follicle stimulating hormone. Hum. Reprod., 13, 1788-1792, 1998. 

WESTERGAARD L. et al.: The effect of human menopausal gonadotrophin and highly purified, urine-derived follicle stimulating hormone on the outcome of in-vitro fertilization in down-regulated normogonadotrophic women. Hum. Reprod., 11, 1209-1213, 1996.

WESTERGAARD L. et al.: Low circulating levels of LH during ovarian stimulation affect the outcome of IVF negatively. In. Proceedings from the 11th World Congress on In Vitro Fertilization and Human Reproductive Genetics, Monduzzi Editore, Italy, pp. 279-282, 1999.2

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