Cigarette Smoking and IVF

Sérgio R. Soares; Marco A. Melo

Disclosures

Expert Rev of Obstet Gynecol. 2008;3(4):555-563. 

In This Article

Tobacco & Uterine Receptiveness

In contrast to all the information available on the interference of tobacco constituents on male and female gamete physiology, few studies have investigated the effect of cigarette smoking on uterine receptiveness. Increased resting uterine tonus in female smokers was described decades ago.[89] Literature on the effect of cigarette smoking on endometrial blood flow reported a significantly lower endometrial and subendometrial vascularity and flow intensity throughout the menstrual cycle in smokers,[90] although no such effect was detected during IVF treatments.[91] In addition, some authors reported lower pregnancy and implantation rates in smokers undergoing IVF cycles, in which the number of morphologically 'good' embryos replaced was similar to that in nonsmokers.[36] This suggested that altered uterine receptiveness might be a factor in the former group of women, although reduced implantation could also be due to embryonic factors that belie a good morphology on day 3 of development.[88]

Oocyte donation (OD) is the model that most objectively ascertains the presence of a uterine factor in the outcome of assisted reproduction cycles. To the best of our knowledge, only one study exploring this model has been published on the association between a smoking habit in oocyte recipients and cycle outcome. In this retrospective study, husband and donor smoking status were controlled variables, as well as donor and recipient age, recipient body mass index and embryo number and quality. Pregnancy rate in nonheavy smokers (0-10 cigarettes/day) was significantly higher than in heavy smokers (52.2 vs 34.1%, respectively).[92] Interestingly, the multiple pregnancy rate (MPR) was significantly higher in heavy smokers (60 vs 31%).

Literature on the impact of cigarette smoking on uterine physiology is almost exclusively limited to the field of oncology. Loss of cell adhesion and reduced basement membrane invasion were observed in human RL95-2 endometrial adenocarcinoma cell cultures exposed to tobacco constituents (namely benzo[a]pyrene).[93] This cell line serves as an in vitro model for the receptive endometrium, due to its adhesiveness for trophoblast cells. Studies with rats demonstrate a deleterious effect of nicotine on the decidualization process and on the blastocyst-endometrium interaction.[94] As in many target organs, tobacco constituents may affect physiological processes in the endometrium by altering the activation of the apoptotic pathway and the production, release and action of enzymes, hormones, growth factors and cytokines, by impairing cell division and through direct oxidative cell toxicity.[95] Endometrial and embryonic homeostasis may be disrupted by these processes, as well as their complex molecular interactions.

The other significant finding of the study on smoking and OD was the increased incidence of dizygotic gestations among heavy smokers.[92] The increased MPR observed in heavy smokers is of great interest. A significant increase in dizygotic twin gestations in IVF cycles performed on couples in which either the male or the female partner were heavy smokers had been described previously.[40] The same finding observed in OD cycles suggests that the underlying mechanism is related to the uterus, rather than the gametes. The association of reduced pregnancy rate and increased twin gestation rate suggests a paradoxical effect of tobacco constituents, with some women displaying impaired implantation and others presenting the opposite phenomenon. It is interesting that paradoxical dose- and tissue-dependent effects of tobacco constituents have already been described. In the ovary, high doses of nicotine can inhibit endothelial cell division and promote cell death, while at lower concentrations this alkaloid stimulates endothelial cell DNA synthesis and cell proliferation.[48] In addition, high cadmium concentrations inhibit P450scc transcriptional activity in the ovary, while low concentrations stimulate P450scc transcriptional activity.[45,48] In the case of molecules that act by binding to receptors, their effect depends not only on their concentration, but also on the concentration of their receptors in a certain tissue and the cellular environment as a whole.[59] Therefore, the same molecular concentration may result in opposite effects in different tissues and individuals. If tobacco compounds trigger this kind of paradoxical response in the endometrial tissue and/or the embryo itself, resulting in the prevalence at times of proimplantation cytokines and growth factors and at other times of anti-implantation molecules, a reduced general pregnancy rate and an increased MPR may be jointly observed. In addition to the confirmation of this finding in a higher number of OD cycles in heavy smokers, it would be enlightening to study differences in gene expression in the endometrium of heavy smokers that fail to get pregnant after OD and in those whose cycles culminate in a twin gestation.

In conclusion, tobacco consumption determines reduced uterine receptiveness. Patients should be informed of this. The question of the increased incidence of MPR among smokers due to a uterine factor is very intriguing and deserves further investigation.

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