This is the first study exploring the v-betaLH frequency in a Danish IVF population. V-betaLH was present in 10.9% of patients, whereas the allelic frequency was 12.2%, quite similar to that reported for a number of other European populations, however somewhat lower than that of the Finnish population .
The study confirms data reported in a previous paper , demonstrating that v-betaLH is associated with a higher consumption of r-hFSH during COS. More specifically, a relationship between the r-hFSH cumulative dose and the LH genotype was found, where the gonadotropin cumulative dose showed a positive trend in v-betaLH women. Although only three women with the variant in homozygosis were analyzed, it is interesting to remark that a sort of gradient in r-hFSH consumption was observed, with the lowest in the wt/wt group and the highest in v-betaLH homozygotic carriers (Figure 1). The mean number of oocytes retrieved was not related to the LH genotype (Table 3). This parameter was preferred to the number of dominant follicles as indicator of ovarian response. This choice was related to the fact that evaluation of dominant follicles, usually performed by different physicians, is more subjective, mainly when ovaries are “crowded”. In contrast, ovum pick up is a more standardized procedure which was performed by the same operator in all cases (P.H.). A cumulative dose of r-hFSH 1862.5 IU was identified as the most predictive cut-off for the presence of LH variant. Taken together, these data raise the question of whether v-betaLH assessment of all patients should be employed prior to ovarian stimulation, or whether one should await the results of the first stimulated cycle. Following this line, a good prognosis patient who, despite a starting dose of 150 IU of r-hFSH needed a cumulative dose higher than 2000 IU to achieve an apparently normal response (i.e. at least 5 oocytes retrieved) should be recommended for LH genotyping. If the patient was either homo-or heterozygotic for v-betaLH, the recommendation would be to add exogenous LH rather than increase the FSH dose during the subsequent cycle [2–4].
In the present study, serum samples from a previous study  were analyzed, which in turn made not possible the use of molecular biology approach (i.e., polymerase chain reaction). Nevertheless, the immuno-assay adopted is a well established method which has been validated in previous studies .
Wild-type and v-betaLH hormones are functionally different. More specifically, v-betaLH seems to possess a shorter half-life, however, with a more potent action at the receptor level when compared to the wild-type [12, 18]. Thus, it is expected that the phenotypic expression of the hormone types may be different. Also the combination of the two forms of LH, i.e. heterozygous for wild-type and v-betaLH, could differ from both of the wt and v-betaLH homozygous phenotypes. Furthermore, a number of different LH-receptors genotypes exist and whether the interaction between the subtypes of LH and the different subtypes of the LH-receptor is unequal is currently unknown. Due to the low frequency of the v-betaLH homozygotes, no clear picture of the phenotypic effects of the variant has yet emerged. Several authors ascribe a higher activity to the variant LH due to elevated levels of serum estradiol, testosterone and sex hormone-binding globulin compared to wild-type LH women . On the other hand, there is evidence that v-betaLH protects obese women from developing symptomatic polycystic ovarian syndrome . Moreover, observational trials suggest that v-betaLH is related to a reduced gonadal function and subfertility . Finally, differences in the circulatory kinetics between the two types of LH may explain the diversities in LH function between patients with ovulatory disorders and women with normal ovulatory cycles . This study confirms that v-betaLH carriers need a higher FSH dose during COS, supporting the idea that this polymorphism represents a biologically less active form of LH, unable to adequately support FSH activity during follicular stimulation. In this series of patients no difference in terms of fertilization and pregnancy rates were found between groups, indicating that increasing r-hFSH dose during COS may counteract lower v-betaLH activity. Nevertheless, women with v-betaLH showed a statistically significant reduction in the mean number of embryos transferred (Table 3). This observation may be consistent with the evidence that cooperation between FSH and LH is also crucial in regulating finals steps of follicle-oocyte maturation, including resumption of oocyte meiosis [23–25]. Taken together, these aspects raise the question whether the use of higher doses of r-hFSH is able to totally overcome the impact of the LH variant on oocyte competence and on the outcome of IVF. This point could be addressed by further investigation in a larger study population. On the other hand, it could be argued that exogenous LH supplementation in v-betaLH carriers is capable of correcting ovarian response to FSH. This hypothesis is consistent with studies demonstrating that young, normogonadotrophic women showing slower and suboptimal response to exogenous r-hFSH benefit from r-hLH supplementation [2–4].
Interestingly, the serum androstenedione level on the day of triggering final oocyte maturation was significantly elevated in patients with v-betaLH. A previous study found that women following a standard long GnRH-agonist protocol stimulated with r-hFSH showed a significant positive association between serum levels of LH and androstenedione on day 8 of stimulation , supporting that LH has a pronounced effect on the circulatory concentration of androstenedione. This paradox may be related with the augmented FSH consumption in the v-betaLH group. In fact, FSH may via the granulosa cells increase the capacity of the theca cell compartment to produce androgens by stimulating the expression of Cytochrome P450 17alpha-hydroxylase (CYP17). This hypothesis is consistent with evidence from rats model .