Human Reproduction Update Advance Access originally published online on March 31, 2006
Human Reproduction Update 2006 12(3):325-326; doi:10.1093/humupd/dml005
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Letter to the Editor |
Are endogenous LH levels during ovarian stimulation for IVF using GnRH analogues associated with the probability of ongoing pregnancy? A systematic review
The Fertility Clinic, Sygehus Viborg, Skive Sygehus, Resenvej 25, 7800 Skive, Denmark
E-mail: peter.humaidan{at}sygehusviborg.dk
I read with interest the review article by Kolibianakis et al. (2006)
on the possible impact of circulating endogenous LH levels on the clinical pregnancy rates after either GnRH agonist down-regulation or GnRH antagonist down-regulation. From their review, the authors were able to summarize that low endogenous LH levels in normogonadotropic patients and WHO II patients after GnRH agonist down-regulation are not associated with a reduced clinical pregnancy rate. Thus, according to present scientific evidence, LH activity supplementation in patients with low endogenous LH levels after down-regulation does not seem to be justified.
More interesting, the authors mention two prospective randomized studies (Humaidan et al., 2002; Kolibianakis et al., 2004), one involving a GnRH agonist for down-regulation (Humaidan et al., 2002) and the other a GnRH antagonist, both showing a reduced pregnancy outcome in the group of patients with high endogenous mid-follicular LH levels.
In this context, I would like to draw the attention of the authors to a more recent study including 231 cycles (Humaidan et al., 2004). In this study, after a long GnRH agonist down-regulation, normogonadotropic patients were randomized to receive stimulation with either recombinant FSH (rFSH) or, from day 8, a combination of rFSH and rLH in a ratio of 2:1. Blood samples were prospectively collected and retrospectively analysed. Like in the previous study (Humaidan et al., 2002), we were able to identify a group of patients with low endogenous LH levels (<1.21 IU/l) on stimulation day 8. This group performed well in terms of reproductive outcome and did not benefit from LH supplementation from stimulation day 8. However, as in the previous study (Humaidan et al., 2002), we identified a group of patients, comprising more than one-third of the patients, with high endogenous LH levels (>1.99 IU/l) on day 8. In this group of patients, the implantation rate was significantly reduced as compared with patients who had lower LH levels on day 8. Surprisingly and interestingly, however, these patients obtained good implantation rates, similar to patients with lower LH levels on day 8, if they were supplemented with rLH from day 8. This, of course, was an intriguing finding which needs confirmation in future randomized trials. However, we must bear in mind that a high endogenous LH level after down-regulation does not necessarily mean a high degree of bioactivity of LH, as there might exist a discrepancy between the immunoreactivity and bioactivity of the LH molecule (Huhtaniemi et al., 1999; Jiang et al., 1999; Ropelato et al., 1999; De Placido et al., 2005).
Firstly, do these patients actually constitute a group of patients with a lower activity of the LH molecule, and is this the reason why they achieve better implantation rates, once they receive LH activity supplementation? Secondly, which role do the dynamic changes of the endogenous LH level during the follicular phase of the down-regulated cycle play for the reproductive outcome?
In our first study (Humaidan et al., 2002), patients with high endogenous LH levels on day 8 had a stable LH level from day 1 to day 8 (1.90 and 2.04 IU/l, respectively) instead of, as normally seen, a reduction, whereas patients with lower LH levels had a reduction as expected.
In the latest study (Humaidan et al., 2004), we see the same feature. Patients with high levels at day 8, actually have experienced a rise in LH from day 1 to day 8, despite down-regulation, whereas patients with lower LH levels at day 8 have a fall in LH levels from day 1 to day 8. At the time of ovum retrieval, all groups have low LH levels (<0.15 IU/l). This indicates that the high LH group has experienced an increase/stable LH level from day 1 to day 8, followed by a sudden decrease in LH levels from day 8 to day of ovum retrieval, contrasting the gradual decrease of the other LH groups from day 1 to day of ovum retrieval. The question arises whether these changes may have a negative impact on oocyte competence and endometrial receptivity in a group of patients with a reduced bioactivity of the LH molecule.
Conclusively, I agree that the use of LH activity supplementation in patients with low endogenous LH levels after GnRH agonist down-regulation is not supported by the results of the recent trials. More interesting, however, three studies until now have identified a group of patients with high endogenous LH levels involving either a GnRH agonist (Humaidan et al., 2002, 2004) or a GnRH antagonist (Kolibianakis et al., 2004). The reproductive outcome of this group was significantly reduced without, but normalized with, LH activity supplementation from day 8 of the down-regulated cycle (Humaidan et al., 2004).
Mid-follicular LH levels have a significant impact on ovarian response and pregnancy outcome. Concerning the group of patients with high LH levels after down-regulation, we have to await the results of future trials to draw firm conclusions. The dynamic changes of the endogenous LH levels during down-regulation outcome as well as the bioactivity of the LH molecule in individual patients, however, should receive more attention, as they seem to be of importance for the reproductive outcome of the down-regulated cycle.
 |
References |
|---|
 TOP References |
|---|
De Placido G, Alviggi C, Perino A, Strina I, Lisi F, Fasolino A, De Paolo A, Ranieri A, Colacurci N and Mollo A (2005) Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomised controlled trial. Hum Reprod 20,390–396.
Huhtaniemi I, Jiang M, Nilsson C and Pettersson K (1999) Mutations and polymorphisms in gonadotropin genes. Mol Cell Endocrinol 151,89–94.[CrossRef][Web of Science][Medline]
Humaidan P, Bungum L, Bungum M and Andersen CY (2002) Ovarian response and pregnancy outcome related to mid-follicular LH levels in women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH stimulation. Hum Reprod 17,2016–2021.
Humaidan P, Bungum M, Bungum L and Andersen CY (2004) Effects of recombinant LH supplementation in women undergoing assisted reproduction with GnRH agonist down-regulation and stimulation with recombinant FSH: an opening study. Reprod Biomed Online 8,635–643.[Web of Science][Medline]
Jiang M, Pakarinen P, Zhang FP, El-Hefnaw T, Koskimies P, Pettersson K and Huhtaniemi I (1999) A common polymorphic allele of the human luteinizing hormone beta-subunit gene: additional mutations and differential function of the promoter sequence. Hum Mol Genet 8,2037–2046.
Kolibianakis EM, Collins J, Tarlatzis B, Papanikolaou E and Devroey P (2006) Are endogenous LH levels during ovarian stimulation for IVF using GnRH analogues associated with the probability of ongoing pregnancy? A systematic review. Hum Reprod Update 12,3–12.
Kolibianakis EM, Zikopoulos K, Schiettecatte J, Smitz J, Tournaye H, Camus M, Van steirteghem AC and Devroey P (2004) Profound LH suppression after GnRH antagonist administration is associated with a significantly higher ongoing pregnancy rate in IVF. Hum Reprod 19,2490–2496.
Ropelato MG, Garcia-Rudaz MC, Castro-Fernandez C, Ullora-Aguirre A, Escobar ME, Barontini M and Veldhuis JD (1999) A preponderance of basic luteinizing hormone (LH) isoforms accompanies inappropriate hypersecretion of both basal and pulsatile LH in adolescents with polycystic ovarian syndrome. J Clin Endocrinol Metab 84,4629–4636.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||