Since 1990 several studies underlined a pathogenic role for inherited thrombophilia in women with RPL [24, 25]. A pathogenic role was identified for inherited deficiency of protein C, protein S and antithrombin and for inherited gene polymorphism of factor V Leiden and A20210G of prothrombin, and also for acquired thrombophilia, in particular antiphospholipid syndrome [12–19].
Also a potential pathogenic role of HHCY has been recently suggested, because the association of HHCY and thrombosis, but not univocal data are available. Increasing evidences are available for the relationship between HHCY and MTHFR C677T gene polymorphism and unexplained recurrent pregnancy loss. Several reports, in fact, described an association between early RPL and HHCY and/or MTHFR C677T gene polymorphism [2, 3, 26, 27]. A different point of view on the association between HHCY and RPL has been reported only by Makino et al. .
Only a few studies are available on the association between sterility and HHCY and they are focused only on women with in vitro fertilization failures. Moreover, available data seem to be in contrast: Martinelli et al. did not find an association between inherited thrombophilia and patients with in vitro fertilization failure , while Azem et al. and Qublan et al. underlined a possible role of inherited thrombophilia and IVF failure [20, 21]. However, both studies were not based on a possible association of homocysteine metabolism and IVF failure but only on the C677T gene polymorphism of MTHFR.
In the present study we evaluated not only homocysteinemia and MTHFR C677T gene polymorphism but also other common variables associated with homocysteine metabolism such as folate and vitamin B12 serum levels both in women showing RPL and women with UFS.
We found that women with RPL and UFS showed HHCY compared to control group (Table 1 and 2). We did not find differences in homocysteine levels between women with RPL and women with UFS. Although data concerning HHCY and RPL seem to be in agreement with those already reported [2, 3, 26, 27], data focusing the association between of HHCY and UFS are innovative because rarely described so far.
Data concerning MTHFR C677T gene polymorphism seem to support this hypothesis because we found a high frequency of homozigosity of TT genotype not only in women with RPL but also in women with UFS (Table 1). TT genotype of MTHFR C677T gene polymorphism has been already underlined in pathophysiology of RPL by several Authors but its role in pathophysiology of UFS is still a matter of discussion. Therefore, our data support the hypothesis concerning the involvement of homocysteine metabolism in cases of UFS because frequency of TT genotype was similar to that observed in women with RPL (Table 2). Moreover, our data may also support previous observations of an increased frequency of thrombophilia in women with infertility showing repeated IVF failures.
Serum folate and vitamin B12 levels were also tested to support this hypothesis because strongly associated to homocysteine metabolism, also in terms of a possible therapeutic support. Although, vitamin B12 levels were lower both in women with RPL and with UFS compared to control subjects, and these differences did not reach statistical significance (Table 1 and 2). On the other hand we found significantly lower folate levels both in women with RPL and UFS when compared with control subjects (Table 1 and 2). These data confirm the strict association between folate metabolism and homocysteine levels also in pathophysiology of women with infertility, in particular if referred to adverse pregnancy outcome such as early RPL. Moreover, for the first time we underlined a possible association between low serum folate and HHCY and UFS. Furthermore, from another point of view our data offer a new scenario on the possible therapeutic support with folic acid fortification both in women with RPL and UFS carrying HHCY.
In conclusion our study provides several data concerning the involvement of homocysteine metabolism in women with infertility: we confirmed a strict association between HHCY and TT genotype of MTHFR C677T in women with RPL without other causes of recurrent abortion. Yet, for the first time, we suggested also that homocysteine metabolism may be involved in pathophysiology of these cases of UFS because of the association between HHCY, low serum folate and TT genotype of MTHFR C677T. However, because of the small number of selected patients, our data should be confirmed by further studies based on larger population.