Cigarette Smoking and IVF

Sérgio R. Soares; Marco A. Melo

Disclosures

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

In This Article

Cigarette Smoking & Ovarian Function in IVF

An increased incidence of premature ovarian failure and earlier menopause observed in smokers leaves no doubt regarding the impact of cigarette smoking on ovarian physiology.[42,43,44] Therefore, ovarian performance in IVF cycles performed on couples with a smoking female partner has always been under scrutiny.

The complex process of follicular and oocyte maturation can be affected by a number of tobacco constituents. Cadmium, polycyclic aromatic hydrocarbons and tobacco alkaloids (i.e., nicotine and its metabolite cotinine) are the most studied molecules. These chemicals interact directly or indirectly with germ cells, affecting their function and viability. The complexity of interactions in the reproductive system is high, but in vitro and in vivo studies can be useful for identifying disruptions in the reproductive pathway.

Follicular Health: Granullosa-lutein Cells & Steroidogenesis

Many physiological processes observed during follicular maturation are reported to be altered by tobacco compounds.[45] Tobacco is the major source of cadmium, a heavy metal that accumulates in ovarian follicles and in many organs and tissues.[46,47] At low concentrations (0.6-3 µM), cadmium stimulates transcription of the P450scc gene and the steroidogenic pathway in the ovary, while at higher concentrations (>2-5 µM) it inhibits the expression of the aforementioned enzyme[48] and also facilitates changes in cell morphology and cell death.[48,49] Several studies indicate that cigarette smoke has an antiestrogenic effect.[48,49,50,51,52,53] In fact, changes induced by cadmium on P450scc gene expression in granulosa cells could affect the synthesis of all steroid hormones in the ovary.[50,51,52] Lower estradiol levels in cigarette smokers might also be related to its increased rate of 2-hydroxylation. Higher conversion rate to catecolestrogen could reduce the availability of estradiol.[54]

Oxidative stress was observed in follicular fluid from smokers.[53] Benzo[a]pyrene (a polycyclic aromatic hydrocarbon) was found in the nucleus of granullosa-lutein cells, indicating a potential risk for the formation of DNA adducts that may affect follicular function and viability.[55] This might also be related to impaired ovarian steroidogenesis and suboptimal follicle growth observed in smokers undergoing IVF.

Cotinine, the main metabolite of nicotine, is detected in follicular fluid and was also associated with impaired ovarian steroidogenesis. This molecule has an antimitotic and apoptotic effect on granulosa-luteal cells[50,56] and may be involved in the inhibition of granulosa-luteal cell function, leading to reduced progesterone production and luteal insufficiency.[57] It was also suggested that nicotine could induce luteal insufficiency by inhibiting progesterone release through altered modulation of the prostaglandin system (increased luteolytic prostaglandin F-2α release and inhibited luteotropic PGE-2 release from luteal cells).[57]

Another process through which tobacco constituents might have a negative effect on follicular physiology, is reduced ovarian vascularization. Follicular fluid from smoking women undergoing IVF was shown to have significantly higher amounts of soluble VEGF receptor 1, which may result in decreased availability of VEGF and impaired angiogenesis and oocyte maturation.[58] However, the effect of tobacco exposure on follicular vascularization is not elucidated: nicotine was reported to have a nonsignificant impact on the angiogenesis of ovarian follicles freely transplanted to the skinfold chamber of rodents, although an adverse influence on follicular growth was observed.[59] Increased granulosa cell apoptosis was seen in follicular grafts exposed to tobacco.

Oocyte-cummulus Complex & Oocyte Maturation

The optimal expansion of cumulus cells is associated with normal ovulation, fertilization and subsequent embryo development.[45] The effect of tobacco compounds on the expansion of oocyte-cumulus complexes was investigated in vitro. High concentrations (100 µM) of cadmium and nicotine were associated with a significant suppression of hyaluronic acid synthesis by cumulus cells and its retention within the extracellular matrix, respectively.[50]

Oocyte maturation involves resumption of meiosis, progression of the meiotic spindle to metaphase II and cytoplasmic changes that prepare the oocyte for fertilization and subsequent embryo development. Numerical chromosome abnormalities are the leading cause of miscarriage or congenital defects.[60] It is well known that, in most cases, aneuploidy derives from meiotic errors of chromosomal segregation[60] and that the oocyte is more prone to numerical abnormalities than spermatozoa.[61]

As mentioned previously, cotinine and cadmium were detected in follicular fluid from smokers.[46,47] The association between cigarette smoking and the maturity of oocytes from women undergoing IVF was investigated.[62] Cytogenetic data from 286 unfertilized oocytes demonstrated that smokers displayed an increased frequency of diploid oocytes resulting from nonextrusion of the first polar body. This finding suggests that these substances may disrupt meiotic maturation in the developing oocyte.

Studies in animal models confirmed the effect of tobacco constituents on meiotic and early embryo mitotic progression.[63,64,65] In cattle and mice, nicotine was demonstrated to alter oocyte spindle integrity and chromosome alignment, leading to an increased frequency of premature centromere separation, premature anaphase, anaphase lag and diploid oocytes.[63,64] It is of note that nicotine concentrations that determined premature centromere separation and premature anaphase were also associated with a reduced proportion of ovulated oocytes.

Early embryo development was also shown to be affected by tobacco. OS was shown to damage telomeres, leading to chromosomal instability and apoptosis. Zygotes exposed to cigarette smoke condensate and cadmium exhibited significantly reduced cleavage and compromised development in a time- and dose-dependent manner.[64,65] Zygotes exposed to 100 µM of cadmium for 12 h arrested at the one-cell stage with no cleavage, followed by cell death, and continuous exposure to 20 µM of cadmium led to embryo arrest before the blastocyst stage. Affected embryos showed telomere shortening and loss.[65]

Finally, a thickened early zona pellucida was also described in oocytes from smokers,[66] but the natural thinning of zona pellucida observed during the first 48 h after fertilization did not appear to be affected. It is well known that the zona pellucida thickness is one of the factors influencing embryonic hatching ability and implantation and pregnancy rates.[67,68]

IVF Parameters

The disruption of the physiological steps related to follicular and oocyte maturation indicated that the quality of ovarian response in IVF cycles may be worse in cigarette smokers. However, there is not absolute agreement in the literature pertaining to this issue. This may be due to many biases, such as the sample size; the definition of active, passive, light, heavy, former and nonsmokers; and the amount, frequency, type and timing of smoking. Furthermore, the contribution of the male partner's smoking history was omitted in the majority of studies.[69]

Although contradictory results have been reported,[36,70,71,72,73,74,75,76] studies analyzing the effect of female smoking on IVF showed a clear trend to fewer mature oocytes,[37,38,40,44,77,78,79] requirement of higher doses of gonadotrophin and a longer stimulation period.[44,74,79,80] These cycles also displayed lower fertilization rates,[37,76,81] fewer embryos per cycle[77] and lower embryo score.[78]

A meta-analysis of early studies demonstrated that smokers would need approximately twice as many IVF attempts to get pregnant compared with nonsmokers.[82] Subsequent studies observed lower implantation and pregnancy rates in smokers[36,40,79] and an increased miscarriage rate was also reported.[40,83,84] Lower pregnancy rate in IVF cycles has been recently associated with benzo[a]pyrene concentrations in follicular fluid.[85] Consequently, a smoking habit unfavorably affects the live-birth rate per cycle.[84] The impact of cigarette smoking on live-birth rate in cycles performed on women aged 20-30 years was reported to be equivalent to an increase of 10 years in female's age.[84] Indeed, current smoking is associated with elevated basal follicle-stimulating hormone, a finding that is more evident with increasing age.[86]

Lower ovarian response seen in IVF cycles of smoking women may simply be the expression of the chronic process of accelerated ovarian reserve consumption, but might also be the consequence of short-term effects of tobacco compounds in the process of meiotic maturation. In animals and humans, cigarette compounds were demonstrated to affect oocyte nuclear maturation (more specifically, the assembly and function of the meiotic spindle), leading to a high incidence of chromosomal errors and lower proportion of mature oocytes.[62,63,64,65,87,88] If this short-term mechanism of meiotic arrest is partly responsible for the worse ovarian response in IVF cycles seen in smokers, this worse response would be reversible in a certain degree.

In summary, female smoking affects oocyte number and quality and has significantly negative implications on IVF cycle outcome. Cumulative data support the importance of discouraging cigarette smoking.

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