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Do some addictions interfere with fertility?
Do some addictions interfere with fertility? Silvia Alvarez, M.D. dical d’Assistance Me dicale a la Procre ation, Eylau-Muette, Paris, France Reproductive Medicine Department, Centre Me
Management of infertile couples should focus on the effects of their professional environment and quality of life, such as stress, smoking, alcohol, weight, diet, and the use of electronic devices. It should also focus on reducing these negative factors and improving the couples' quality of life in conjunction with assisted reproduction treatments. The challenge for human reproduction now, and in the decades to come, is to introduce the concept of ‘‘ecofertility’’ in our practices. Early education and prevention are essential to preserve fertility. (Fertil SterilÒ 2015;103:22–6. Ó2015 by AmerUse your smartphone ican Society for Reproductive Medicine.) to scan this QR code Key Words: Infertility, toxic factors, assisted reproductive techniques (ART), lifestyle, and connect to the prevention Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/alvarezs-addictions-interfere-fertility/
T
he causes of infertility have changed significantly over the past 30 years, and the impact of environment and lifestyle on the difficulties experienced by couples plays an important role in fertility alteration. Recording of these factors began about 10 years ago (1, 2). The fertility of a generation would appear to be linked to toxic factors, the activity of which began during the intrauterine life of the mother, i.e., pollutants, which seem to act as endocrine disruptors, especially on male fetuses, and other behaviordependent toxic factors, such as smoking, alcohol, and lifestyle. Fertility in adults may be altered by factors such as cannabis, antidepressants, weight, diet, profession, intense exercise, stress, sexual intercourse targeted at the date of ovulation, and infertilityrelated stress (3). Infertility-related toxic factors and lifestyles are still often not detected and the diagnosis and early treatment of these problems would enable natural
fertility to be improved and would reduce the need for medically assisted procreation. They would also reduce the complications associated with the latter (4) by producing spontaneous pregnancies without the need for major procedures (5).
FACTORS THAT MAY INFLUENCE THE FERTILITY OF COUPLES AND ARE CONTINGENT UPON LIFESTYLE Smoking Tobacco. In women, the Augood et al. meta-analysis (6) shows that smoking generates a delay in conception of more than a year. This is both dose and duration dependent for the exposure. There is double the risk of being infertile, reduction in ovarian reserve, and a lower level of antim€ ullerian hormone (AMH), as well as short irregular cycles, greater ovarian insufficiency, and dysmenorrhea in the group of smokers (7). Products contained in to-
Received September 9, 2014; revised October 31, 2014; accepted November 4, 2014. S.A. has nothing to disclose. dical Procreanat, 15 Avenue Raymond Poincare , Reprint requests: Silvia Alvarez, M.D., Cabinet Me Paris, France (E-mail: [email protected]). Fertility and Sterility® Vol. 103, No. 1, January 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.11.008 22
discussion forum for this article now.*
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bacco, i.e., cotinine, cadmium, and oxygen peroxide, can be found in follicular fluid with an alteration in oocyte meiotic resumption. Hydrocarbons present in tobacco interact with the aryl hydrocarbon receptor, which activates apoptosis causing ovotoxicity (8) and increased onset of ovarian insufficiency. In men, during the antenatal period maternal exposure to tobacco has an impact resulting in an increased risk of bilateral cryptorchidism, a 20% decrease in the total number of spermatozoa in the adult male children of women who smoked more than ten cigarettes per day (9), and a reduction in testicular volume (10). Tobacco consumption by adults affects erectile function and increases chromosomal aberrations in the spermatozoa, causing an increase in the number of miscarriages. Although the direct action of tobacco is not well understood, stopping smoking for 3 months allows sperm quality to improve: 72 million versus 29 million per ejaculate, 79% motility versus 33%, 20% versus 60% necrotized, and 23 million grade A spermatozoa count after swim-up per ejaculate versus 3 million (11). The negative impact of smoking during pregnancy is a cause for concern to researchers, owing to the likelihood VOL. 103 NO. 1 / JANUARY 2015
Fertility and Sterility® of the future fertility of children exposed in utero being compromised. Recently, Sobinoff and al. (12) showed in a mouse model that maternal exposure impairs the fertility of male offspring. Pregnant women should be given as much information as possible. In assisted reproductive technology (ART) cycles, studies have shown that, in both men and women, smoking causes a reduction of >40% in their chances of successful ART and an intracytoplasmic sperm injection (ICSI) failure rate three times higher than in nonsmokers. Furthermore, the risk of not conceiving during IVF/ICSI is four times higher in those who smoked for >5 years (13). It would appear that female smokers have a lower level of E2 during ovarian stimulation, fewer oocytes and embryos are obtained, and there is also a probable increase in the thickness of the oocyte zona pellucida (14). Stopping smoking is essential, at least while a pregnancy is planned, to halt the negative effect on ovarian function and increase the chances of spontaneous pregnancy. Marijuana. In men, consuming cannabis several times a week for 5 years causes a reduction in the volume and number of spermatozoa and changes in morphology and motility, with sperm hyperactivity and reduction in their fertilization capacity (12). Cannabis is eliminated very slowly compared with tobacco, and the harmful effects are more significant. Marijuana reduces T production, with more than one-third of consumers presenting oligospermia. Marijuana also causes reduced libido, gynecomastia, and erectile disorders (15). Marijuana contains the delta-9-tetrahydrocannabinol (THC) cannabinoid, which blocks the release of GnRH from the hypothalamus and LH production by the adenohypophysis. THC activates the endocannabinoid receptors, thus producing abnormalities in acrosome reaction and a reduction in sperm motility (15). In the testis, marijuana reduces T production and interferes with spermatogenesis. In nonhuman animal models, chronic administration of THC impairs spermatogenesis at both mitotic and meiotic stages, with mature sperm showing severe morphologic defects. These findings are mirrored in humans, with more than one-third of chronic marijuana users having oligospermia. Although human studies are scarce, and those that do exist are limited by their observational nature, the available evidence substantiates the claim that marijuana use, whether illicit or prescribed, has a detrimental effect on male reproductive potential. In women, a disturbed menstrual cycle, a reduced number of oocytes harvested during in vitro fertilization, and a higher risk of prematurity have been observed (16). Cohort studies are required, but current studies show that marijuana has a negative effect on fertility. There is no fundamental evidence about the direct effects of THC on ART cycles.
Alcohol The available information on the potential effects of alcohol is less clear, particularly because of the diversity of alcoholic drinks available and the difficulty in determining a threshold consumption frequency. In men, the risk threshold for an impact on male infertility would appear to be 30 g alcohol VOL. 103 NO. 1 / JANUARY 2015
per day, e.g., three glasses of wine (17). Excessive alcohol consumption has been suggested as a risk factor for male infertility. Studies (18) have demonstrated that ethanol has an effect on the hypothalamus, where it blocks the secretion of GnRH and the binding of the GnRH precursor, pre–pro-GnRH, to a functionally active GnRH hormone. This process results in a reduction in both LH and FSH, with subsequent spermatogenic impairment. Recently, Jensen et al. (19) showed a significant increase in serum free T with increasing alcohol consumption in the week preceding the visit to the IVF center. That study suggested that even modest habitual alcohol consumption of more than five units per week had adverse effects on semen quality. The most pronounced effects were seen in men who consumed more than 25 units per week. Alcohol consumption was also linked to changes in T and SHBG levels. The alcohol threshold level required to affect semen adversely remains unclear. Nevertheless, young men and men undergoing ART cycles should be advised to avoid habitual alcohol consumption. In women, moderate consumption of wine (more than two glasses per day) appears to reduce the time taken to conceive. As regards ART cycles, studies are quite scarce (20). Wdowiak et al. (21) showed that alcohol consumption may cause the development of embryos of inferior quality. Significantly more class B embryos came from oocytes of women who consumed alcohol, compared with class A embryos. In that study, 42.59% of the women consumed alcohol. Prevention of alcohol consumption among women of reproductive age should be promoted to safeguard their fertility and future motherhood.
Medications Many medications have been associated with an alteration of fertility in men and women (22). These include some antihypertensives (calcium antagonists), chemotherapy, radiotherapy, and treatments for neuropsychiatric diseases (antidepressants) and stomach ulcers (23). Amory and Swerdloff (24) recently implicated dutasteride and finasteride (hair loss treatments) as contributing factors for infertility in men. Conclusive literature on the medications and their effects on fertility remain insufficient. More information on medications should be sought from infertile patients during consultation.
Caffeine The mechanism of the effect of caffeine on fertility is unknown. In men, Belloc et al. (25) found that 75.6% of men drank coffee (3.0 1.8 cups/d). Among caffeine consumers, semen volume was slightly higher (3.2 1.6 mL vs. 3.1 1.6 mL; P< .01) for the pH (P< .01), but concentration was lower (60.0 90.7 million/mL vs. 69.6 124.9 million/mL; P< .01). No relationship was observed for motility and morphology, or for DNA fragmentation and chromatin decondensation. In a multivariate model including age, results were confirmed for volume (P< .01), but not for 23
VIEWS AND REVIEWS concentration. Caffeine intake was associated with a lower risk of elevated fragmentation (odds ratio 0.92, 95% confidence interval 0.92–0.99). In that study, there was no detrimental effect from caffeine consumption on semen characteristics. IVF patients who consume caffeine might have lower live birth rates. Caffeine is a phosphodiesterase inhibitor. The phosphodiesterase inhibitor, ORG 9935, inhibited oocyte maturation in rhesus macaques stimulated with gonadotropins. Pauli et al. (26) have hypothesized that reducing caffeine intake before IVF would decrease the number of immature oocytes retrieved. Numerous lifestyle habits are associated with infertility. No clear evidence was found for caffeine consumption alone in male and female patients.
pregnancy in infertility. Stress, as measured by increased salivary alpha-amylase, is associated with lower fertility among women. However, smoking is one of the most common environmental exposures causing oxidative stress. In this study, smoking on the day before oocyte collection was shown to have no effect on alpha-amylase levels. It would seem wise to consider stress as a potential factor for couples who have failed to achieve a pregnancy despite 6 months of targeted intercourse, given that the effect of stress becomes apparent after the fifth cycle. This prospective study did not provide a definitive answer regarding causality: It simply provides further evidence of the independent adverse role that stress might play. The biologic mechanism by which stress might affect fecundity remains unknown.
DISCUSSION Mobile Phone Use The literature suggests (27–29) that mobile phone use alters sperm parameters, particularly motility and morphology, and increases oxidative stress. Moreover, these abnormalities seem to have a direct correlation with the duration of mobile phone use. However, carrying out a prospective randomized study appears to be difficult, considering the intensive use of mobile phones and computers by men and women. The use of new technologies should be evaluated for the next 20 years.
THE ROLE OF ENVIRONMENTAL AND OCCUPATIONAL POLLUTANTS AND OXIDATIVE STRESS Environmental Exposure A review of the literature reveals that occupational exposure of men or women to lead and cadmium, as well as exposure to pesticides and solvents, might have some effects. Exposure to solvents and pesticides suggests associations that require further confirmation. A meta-analysis shows an increase in hypospadias associated with parents who are farmers. Some diseases and disorders, such as endometriosis and menstrual cycle abnormalities, have yet to be studied in detail (30, 31). Despite the need for more in-depth studies, the Garlantezec and Multigner (32) report highlights the relationship between exposure to pesticides or solvents in certain professions (farmers, foundry workers, horticulturists, armed forces, hairdressers, workers in shoe and food-processing factories, cleaning ladies, and nurses) and the fertility problems experienced by some couples. It should be noted that contact with toxic products is often accompanied by higher stress levels, adding to the detrimental nature of the workplace. Cohort studies with biomarker measurements would help to improve the understanding of occupational exposure.
Stress The role played by stress in infertility remains controversial largely because, despite medical advances, a high percentage of infertility remains unexplained (33). Lynch et al. (34) show an association between salivary stress biomarkers and time to 24
Screening lifestyles and toxic factors that affect infertile couples is the first stage of infertility treatment, because it is essential to treat those factors to reduce or even eliminate them. We carried out a national survey based on a written questionnaire completed by couples before any infertility consultation in 43 French departments (35).
Accumulation of Risk Factors In our study, when the 16 factors analyzed were considered together, the accumulation of factors was greater in women: 65% had four or more factors and 20% had seven or more; whereas 58% of men had four or more factors and 12% had seven or more (Table 1). Absence of factors was rare: 1.4% of women and 2.3% of men. Women had 4.60 2.3 cumulative factors (range 0–11), and men had 4.03 2.1 (range 0–12), which was a significant difference (P< .001). Hassan and Killick (36) showed that the accumulation of toxic factors resulted in the time taken to conceive being seven times longer. Infertility stress was present in one-half (53%) of the women; in men, stress was less marked (23%; P< .0001). This prospective study demonstrated that numerous factors are detrimental to fertility in both men and women. Considering that one couple in four requests ART without presenting fertility problems (33), it is essential to take both behavioral and environmental factors into account. The detection and correction of these factors in the absence of any cause of infertility should lead to a natural pregnancy without medical intervention. This accumulation of factors does not, however, apply only to the individual, but also to the couple. In fact, our analyses have shown that women with factors such as smoking, cannabis, alcohol, sleep disorders, family stress, and infertility-related stress are very likely to live with a man with the same type of factors. This first French study showed a trend for certain toxic factors to affect both members of the couple at the same time. On the other hand, the stress level at work was higher for both women and men, 41% and 43%, respectively, in our sample, compared with 28.2% and 19.6%, respectively, in a sample of 24,486 salaried workers without infertility (32). Smoking was noticeably similar for the women in our sample and for pregnant women who had not required ART: VOL. 103 NO. 1 / JANUARY 2015
Fertility and Sterility®
TABLE 1 Proportion of men and women concerned by each toxic factor studied. Factors Problems during sexual intercourse Adolescence Appetite-related disorders Treatments Surgical history Tobacco Cannabis Medication Alcohol Appetite-related disorders Loss of weight Hair loss treatment Contact with chemical products at work Sleep disorders Sports Infertility Quality of life Stress at worke Family Stress Stress associated with infertilityf
Womena
Men
95% CIb
Menc
Mend
95% CIb
12%
1.7%
0.030–0.192***
7.0%
1.0%
0.003–0.12*
6.3% 7.8% 8.6% 20% 1.4% 22% 23% 10% 21% 3.2% 2.9%
1.4% 7.2% 2.9% 32% 6.4% 18% 32% 2% 10% 3.4% 8.6%
0.02–0.08** 0.03–0.05 0.02–0.09** 0.19– 0.06*** 0.09– 0.02** 0.02–0.1 0.16– 0.03** 0.04–0.11*** 0.06–0.16*** 0.03–0.03 0.09– 0.02**
4.5% 11% 8.30% 63% 75% 23% 68% 2.9% 17% 18% 20%
1.2% 6.9% 3.60% 25% 5.5% 16% 22% 2.2% 8.0% 3.0% 8.3%
0.01–0.12 0.05–0.22 0.03–0.34 0.24–0.51*** 0.16–0.94*** 0.03–0.19 0.34–0.56*** 0.02–0.11 0.001–0.19* 0.002–0.46 0.05–0.47
13% 34% 72%
18% 58% 49%
0.11–0.01 0.31– 0.17*** 0.16–0.3***
36% 65% 63%
15% 55% 11%
0.05–0.39** 0.01–0.21 0.42–0.59***
41% 14% 54%
43% 12% 23%
0.09–0.05 0.03–0.07 0.22–0.39***
56% 44% 33%
34% 6.7% 6.9%
0.11–0.32 0.11–0.32*** 0.17–0.35***
*P< .05; ** P< .01; *** P< .001. a Out of a population of 348 couples. b 95% confidence interval (CI) calculated on the basis of the difference in proportion. c Men concerned by the factor with a woman partner who is also concerned. d Men concerned by the factor with a woman partner who is not concerned. e For working men and women. f For men and women with infertility. Alvarez. Do some addictions interfere with fertility? Fertil Steril 2015.
20% versus 18%. However, alcohol consumption by the men in our study was higher than that of the future fathers with pregnant partners who had not required ART: 32% versus 14%, according to data from a survey of 1,000 pregnant women (35). We observed lower consumption of medicines and alcohol and very similar consumption of tobacco and drugs compared with the report by Hammiche et al. (37). Although their study focused more on the impact of a consultation giving personalized advice on the couple's habits, our results converge in that our studies demonstrate the specificity of the population that attends consultations for ART and the need for follow-up, which includes a change of lifestyle.
CONCLUSION In parallel with the diagnosis of the cause of infertility, treatment of the infertile couple requires screening to detect environmental and lifestyle factors that influence fertility. This approach is even more necessary for the one-fourth of couples whose difficulties in their attempts to procreate are not associated with an infertility problem (33). Our study, like the recent studies by Hammiche et al. (37) and Domar et al. (38), emphasizes the necessity of detecting toxic factors and unfavorable lifestyle factors to correct them before any medically assisted procreation treatment takes place. The main difficulty in many studies is that they consider isolated toxic factors, not cumulative factors. VOL. 103 NO. 1 / JANUARY 2015
Indeed, the prospective observations we carried out showed an increased incidence of smoking, exacerbation of sexual disorders (reduced intercourse, dyspareunia), dysmenorrhea in women, detection of work and family stress, and stress induced by infertility, which were typical characteristics of the infertile couples who took part in this study. A global treatment should be offered to the couple regarding the factors identified during earlier screening. Reduction in excess weight, alleviation of toxic factors, stress management, and advice on job-specific toxic factors are fundamental for treating infertility. Toxic factors (particularly smoking) should be reduced starting 3–6 months before resorting to any assisted reproductive technique (39). Detecting and correcting unfavorable lifestyles and toxic factors is fundamental for improving spontaneous fertility and ART results (40). Information campaigns and collaborative actions taken with health care regulation authorities, couples, physicians, and nurses are necessary to help improve the fertility of couples.
REFERENCES 1. 2.
3.
ESHRE Task Force on Ethics and Law. Lifestyle-related factors and access to medically assisted reproduction. Human Reprod 2010;25:578–83. Hammarberg K, Setter T, Norman R, Holden C, Michelmore J, Johnson L. Knowledge about factors that influence fertility among Australians of reproductive age: a population-based survey. Fertil Steril 2012;99:502–7. Domar AD, Conboy L, Denardo-Roney J, Rooney KL. Lifestyle behaviors in women undergoing IVF. Fertil Steril 2011;96:S185. 25
VIEWS AND REVIEWS 4.
5. 6. 7.
8.
9.
10.
11. 12.
13.
14. 15. 16. 17. 18. 19.
20.
21.
22.
23.
26
Finnstrom O, Kallen B, Lindam A, Nilsson E, Nygren KG, Olausson PO. Maternal and child outcome after in vitro fertilization—a review of 25 years of population-based data from Sweden. Acta Obstet Gynecol Scand 2011; 90:494–500. Zollner U, Dietl J. Perinatal risks after IVF and ICSI. J Perinat Med 2013;41: 17–22. Augood C, Dukitt K, Templeton A. Smoking and female infertility: a systemic review and meta-analysis. Human Reprod 1998;13:1532–9. Freour T, Masson D, Mirallie S, Bach JM, Dejoie T. Active smoking compromises IVF outcome and affects ovarian reserve. Reprod Biomed Online 2008; 16:96–102. Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet 2001;28:355–60. Thorup J, Cortes D, Petersen BL. The incidence of bilateral cryptorchidism is increased and the fertility potential is reduced in sons born to mothers who have smoked during pregnancy. J Urol 2006;176:734–7. Jensen TK, Jorgensen N, Punab M, Haugen TB, Suominen J, Zilaitiene B. Association of in utero exposure to maternal smoking with reduced semen quality and testis size in adulthood: a cross-sectional study of 1,770 young men from the general population in five European countries. Am J Epidemiol 2004;159:49–58. Santos EP, Lopez-Costa S, Chenlo P. Impact of spontaneous smoking cessation on sperm quality: case report. Andrologia 2011;43:431. Sobinoff AP, Sutherland JM, Beckett EL, Stanger SJ, Johnson R, Jarnicki AG, et al. Damaging legacy: maternal cigarette smoking has long-term consequences for male offspring fertility. Hum Reprod 2014;29:2719–35. Hull MG, North K, Taylor H, Farrow A, Ford WC. Avon Longitudinal Study of Pregnancy and Childhood Study Team. Delayed conception and active and passive smoking. Fertil Steril 2000;74:725–33. Commenges-Ducos M, Carre-Pigeon F. Reproduction, toxiques et environnement. Gynecol Obstet Fertil 2006;34:938–9. Park B, McPartland JM, Glass M. Cannabis, cannabinoids and reproduction. Prostaglandins Leukot Essent Fatty Acids 2004;70:189–97. Wang H, Dey SK, Maccarrone M. Jekyll and Hyde: two faces of cannabinoid signaling in male and female fertility. Endocr Rev 2006;27:427–48. Muthusami KR. Effect of chronic alcoholism on male fertility hormones and semen quality. Fertil Steril 2005;84:919–24. Emanuele MA, Emanuele N. Alcohol and the male reproductive system. Alcohol Res Health 2001;25:282–7. Jensen T, Gottschau M, Broby Madsen J, Andersson AM, Harmer T, Skakkebæk N, et al. Habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young Danish men. BMJ Open 2014;4:e005462. Klonoff-Cohen H, Lam-Kruglick P, Gonzalez C. Effects of maternal and paternal alcohol consumption on the success rates of in vitro fertilization and gamete intrafallopian transfer. Fertil Steril 2003;79:330–9. Wdowaik A, Sulima M, Sdowaska M, Grzegorz B, Bojar I. Alcohol consumption and quality of embryos obtained in programmes of in vitro fertilisation. Ann Agric Environ Med 2014;21:450–3. Sigman M. Medications that impair male fertility. Sexuality, Reproduction, and Menopause: A clinical publication of the American Society for Reproductive Medicine 2007;5:11–6. Meltzer H, Bastani B, Jayathilake K. Fluotexine but not tricyclic antidepressants, potentiates the 5-hydroxytryptophan–mediated increase in plasma
24.
25.
26.
27. 28.
29.
30.
31.
32.
33.
34.
35.
36. 37.
38.
39.
40.
cortisol and prolactin secretion in subjects with major depression or with obsessive disorder. Neuropsychopharmacology 1997;17:1–11. Amory JK, Swerdloff RS. The effect of 5 alpha-reductase inhibitions with dutasteride and finasteride on semen parameters and serum hormones in healthy men. J Clin Endocrinol Metab 2007;92:1659–65. Belloc S, Cohen-Bacrie M, Dalleac A, Amar E, Hazout A, de Mouzon J. Caffeine intake and sperm parameters. Analysis of a cohort of 4474 consecutive semen samples. Fertil Steril 2013;100:S212. Pauli SA, Browne AC, Seydafkan S, Session DR. Counseling patients regarding reducing caffeine consumption before in vitro fertilization (IVF) is associated with a decreased number of immature oocyte. Fertil Steril 2010;94:S262. Merhi ZO. Challenging cell phone impact on reproduction: a review. J Assist Reprod Genet 2012;29:293–7. la Vignera S, Condorelli RA, Vicari E. Effects of the exposure to mobile phones on male reproduction: a review of the literature. J Androl 2012; 33:350–6. Agarwal A, Deepinder F, Sharma RK. Effect of cell phone usage on semen analysis in men attending infertility clinic: an observational study. Fertil Steril 2008;89:124–8. Rouiller-Fabre V, Muczynski V, Lecureuil C, Livera G, Moison D, Frydman R, et al. Polluants environnementaux et troubles de la reproduction masculine: les phtalates au cœur du debat. [Environmental pollutants and male reproductive disorders: phthalates at the heart of the debate.]. Cah Nutri Diet 2011;46:75–81. Mauduit C, Florin A, Amara S, Bozec A, Siddeek B, Cunha S, et al. Effets a long terme des perturbateurs endocriniens environnementaux sur la fertilite masculine. [Long-term effects of environmental endocrine disruptors on male fertility.]. Gynecol Obstet Fertil 2006;34:978–84. Garlantezec R, Multigner L. Relation entre exposition professionnelle, anomalies de la fertilite et troubles de l’appareil reproducteur, revue de la litterature recente. [Relation between occupational exposure, fertility anomalies, and reproductive system disorders: review of recent literature.]. Bull Epidemiol Hebd 2012;7–9:119–24. Kamath MS, Bhattacharya S. Demographics of infertility and management of unexplained infertility. Best Pract Res Clin Obstet Gynaecol 2012;26: 729–38. Lynch MD, Sumdaram R, Maisog JM, Sweeny AM, Buck Louis GM. Preconception stress increases the risk of infertility: results from a couple-based prospective cohort study—the LIFE study. Hum Reprod 2014;29:1067–75. Alvarez S, Devouche E. Premiere enqu^ete nationale franc¸aise sur les modes de vie et les facteurs toxiques chez les couples infertiles [First French national survey on lifestyle and toxic factors in infertile couples.]. Gynecol Obstet Fertil 2012;40:765–71. Hassan MA, Killick SR. Negative lifestyle is associated with a significant reduction in fecundity. Fertil Steril 2004;81:384–92. Hammiche F, Laven JSE, van Mill N, de Cock M, de Vries JH, Lindemans J. Tailored preconceptional dietary and lifestyle counselling in a tertiary outpatient clinic in the Netherlands. Hum Reprod 2011;26:2432–41. Domar AD, Conboy L, Denardo-Roney J, Roone KN. Lifestyle behaviors in women undergoing in vitro fertilization: a prospective study. Fertil Steril 2012;97:697–701. de Ziegler D, Santulli P, Seroka A, Decanter C, Meldrum D, Chapron C. In women, the reproductive harm of toxins such as tobacco smoke is reversible in 6 months: basis for the ‘‘olive tree’’ hypothesis. Fertil Steril 2013;100:927–8. Alvarez S. Role of toxic factors in the fecundity of the couple. J Gynecol Obstet Biol Reprod 2010;39(Suppl 1):39–40.
VOL. 103 NO. 1 / JANUARY 2015
Management of infertile couples should focus on the effects of their professional environment and quality of life, such as stress, smoking, alcohol, weight, diet, and the use of electronic devices. It should also focus on reducing these negative factors and improving the couples' quality of life in conjunction with assisted reproduction treatments. The challenge for human reproduction now, and in the decades to come, is to introduce the concept of ‘‘ecofertility’’ in our practices. Early education and prevention are essential to preserve fertility. (Fertil SterilÒ 2015;103:22–6. Ó2015 by AmerUse your smartphone ican Society for Reproductive Medicine.) to scan this QR code Key Words: Infertility, toxic factors, assisted reproductive techniques (ART), lifestyle, and connect to the prevention Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/alvarezs-addictions-interfere-fertility/
T
he causes of infertility have changed significantly over the past 30 years, and the impact of environment and lifestyle on the difficulties experienced by couples plays an important role in fertility alteration. Recording of these factors began about 10 years ago (1, 2). The fertility of a generation would appear to be linked to toxic factors, the activity of which began during the intrauterine life of the mother, i.e., pollutants, which seem to act as endocrine disruptors, especially on male fetuses, and other behaviordependent toxic factors, such as smoking, alcohol, and lifestyle. Fertility in adults may be altered by factors such as cannabis, antidepressants, weight, diet, profession, intense exercise, stress, sexual intercourse targeted at the date of ovulation, and infertilityrelated stress (3). Infertility-related toxic factors and lifestyles are still often not detected and the diagnosis and early treatment of these problems would enable natural
fertility to be improved and would reduce the need for medically assisted procreation. They would also reduce the complications associated with the latter (4) by producing spontaneous pregnancies without the need for major procedures (5).
FACTORS THAT MAY INFLUENCE THE FERTILITY OF COUPLES AND ARE CONTINGENT UPON LIFESTYLE Smoking Tobacco. In women, the Augood et al. meta-analysis (6) shows that smoking generates a delay in conception of more than a year. This is both dose and duration dependent for the exposure. There is double the risk of being infertile, reduction in ovarian reserve, and a lower level of antim€ ullerian hormone (AMH), as well as short irregular cycles, greater ovarian insufficiency, and dysmenorrhea in the group of smokers (7). Products contained in to-
Received September 9, 2014; revised October 31, 2014; accepted November 4, 2014. S.A. has nothing to disclose. dical Procreanat, 15 Avenue Raymond Poincare , Reprint requests: Silvia Alvarez, M.D., Cabinet Me Paris, France (E-mail: [email protected]). Fertility and Sterility® Vol. 103, No. 1, January 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.11.008 22
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
bacco, i.e., cotinine, cadmium, and oxygen peroxide, can be found in follicular fluid with an alteration in oocyte meiotic resumption. Hydrocarbons present in tobacco interact with the aryl hydrocarbon receptor, which activates apoptosis causing ovotoxicity (8) and increased onset of ovarian insufficiency. In men, during the antenatal period maternal exposure to tobacco has an impact resulting in an increased risk of bilateral cryptorchidism, a 20% decrease in the total number of spermatozoa in the adult male children of women who smoked more than ten cigarettes per day (9), and a reduction in testicular volume (10). Tobacco consumption by adults affects erectile function and increases chromosomal aberrations in the spermatozoa, causing an increase in the number of miscarriages. Although the direct action of tobacco is not well understood, stopping smoking for 3 months allows sperm quality to improve: 72 million versus 29 million per ejaculate, 79% motility versus 33%, 20% versus 60% necrotized, and 23 million grade A spermatozoa count after swim-up per ejaculate versus 3 million (11). The negative impact of smoking during pregnancy is a cause for concern to researchers, owing to the likelihood VOL. 103 NO. 1 / JANUARY 2015
Fertility and Sterility® of the future fertility of children exposed in utero being compromised. Recently, Sobinoff and al. (12) showed in a mouse model that maternal exposure impairs the fertility of male offspring. Pregnant women should be given as much information as possible. In assisted reproductive technology (ART) cycles, studies have shown that, in both men and women, smoking causes a reduction of >40% in their chances of successful ART and an intracytoplasmic sperm injection (ICSI) failure rate three times higher than in nonsmokers. Furthermore, the risk of not conceiving during IVF/ICSI is four times higher in those who smoked for >5 years (13). It would appear that female smokers have a lower level of E2 during ovarian stimulation, fewer oocytes and embryos are obtained, and there is also a probable increase in the thickness of the oocyte zona pellucida (14). Stopping smoking is essential, at least while a pregnancy is planned, to halt the negative effect on ovarian function and increase the chances of spontaneous pregnancy. Marijuana. In men, consuming cannabis several times a week for 5 years causes a reduction in the volume and number of spermatozoa and changes in morphology and motility, with sperm hyperactivity and reduction in their fertilization capacity (12). Cannabis is eliminated very slowly compared with tobacco, and the harmful effects are more significant. Marijuana reduces T production, with more than one-third of consumers presenting oligospermia. Marijuana also causes reduced libido, gynecomastia, and erectile disorders (15). Marijuana contains the delta-9-tetrahydrocannabinol (THC) cannabinoid, which blocks the release of GnRH from the hypothalamus and LH production by the adenohypophysis. THC activates the endocannabinoid receptors, thus producing abnormalities in acrosome reaction and a reduction in sperm motility (15). In the testis, marijuana reduces T production and interferes with spermatogenesis. In nonhuman animal models, chronic administration of THC impairs spermatogenesis at both mitotic and meiotic stages, with mature sperm showing severe morphologic defects. These findings are mirrored in humans, with more than one-third of chronic marijuana users having oligospermia. Although human studies are scarce, and those that do exist are limited by their observational nature, the available evidence substantiates the claim that marijuana use, whether illicit or prescribed, has a detrimental effect on male reproductive potential. In women, a disturbed menstrual cycle, a reduced number of oocytes harvested during in vitro fertilization, and a higher risk of prematurity have been observed (16). Cohort studies are required, but current studies show that marijuana has a negative effect on fertility. There is no fundamental evidence about the direct effects of THC on ART cycles.
Alcohol The available information on the potential effects of alcohol is less clear, particularly because of the diversity of alcoholic drinks available and the difficulty in determining a threshold consumption frequency. In men, the risk threshold for an impact on male infertility would appear to be 30 g alcohol VOL. 103 NO. 1 / JANUARY 2015
per day, e.g., three glasses of wine (17). Excessive alcohol consumption has been suggested as a risk factor for male infertility. Studies (18) have demonstrated that ethanol has an effect on the hypothalamus, where it blocks the secretion of GnRH and the binding of the GnRH precursor, pre–pro-GnRH, to a functionally active GnRH hormone. This process results in a reduction in both LH and FSH, with subsequent spermatogenic impairment. Recently, Jensen et al. (19) showed a significant increase in serum free T with increasing alcohol consumption in the week preceding the visit to the IVF center. That study suggested that even modest habitual alcohol consumption of more than five units per week had adverse effects on semen quality. The most pronounced effects were seen in men who consumed more than 25 units per week. Alcohol consumption was also linked to changes in T and SHBG levels. The alcohol threshold level required to affect semen adversely remains unclear. Nevertheless, young men and men undergoing ART cycles should be advised to avoid habitual alcohol consumption. In women, moderate consumption of wine (more than two glasses per day) appears to reduce the time taken to conceive. As regards ART cycles, studies are quite scarce (20). Wdowiak et al. (21) showed that alcohol consumption may cause the development of embryos of inferior quality. Significantly more class B embryos came from oocytes of women who consumed alcohol, compared with class A embryos. In that study, 42.59% of the women consumed alcohol. Prevention of alcohol consumption among women of reproductive age should be promoted to safeguard their fertility and future motherhood.
Medications Many medications have been associated with an alteration of fertility in men and women (22). These include some antihypertensives (calcium antagonists), chemotherapy, radiotherapy, and treatments for neuropsychiatric diseases (antidepressants) and stomach ulcers (23). Amory and Swerdloff (24) recently implicated dutasteride and finasteride (hair loss treatments) as contributing factors for infertility in men. Conclusive literature on the medications and their effects on fertility remain insufficient. More information on medications should be sought from infertile patients during consultation.
Caffeine The mechanism of the effect of caffeine on fertility is unknown. In men, Belloc et al. (25) found that 75.6% of men drank coffee (3.0 1.8 cups/d). Among caffeine consumers, semen volume was slightly higher (3.2 1.6 mL vs. 3.1 1.6 mL; P< .01) for the pH (P< .01), but concentration was lower (60.0 90.7 million/mL vs. 69.6 124.9 million/mL; P< .01). No relationship was observed for motility and morphology, or for DNA fragmentation and chromatin decondensation. In a multivariate model including age, results were confirmed for volume (P< .01), but not for 23
VIEWS AND REVIEWS concentration. Caffeine intake was associated with a lower risk of elevated fragmentation (odds ratio 0.92, 95% confidence interval 0.92–0.99). In that study, there was no detrimental effect from caffeine consumption on semen characteristics. IVF patients who consume caffeine might have lower live birth rates. Caffeine is a phosphodiesterase inhibitor. The phosphodiesterase inhibitor, ORG 9935, inhibited oocyte maturation in rhesus macaques stimulated with gonadotropins. Pauli et al. (26) have hypothesized that reducing caffeine intake before IVF would decrease the number of immature oocytes retrieved. Numerous lifestyle habits are associated with infertility. No clear evidence was found for caffeine consumption alone in male and female patients.
pregnancy in infertility. Stress, as measured by increased salivary alpha-amylase, is associated with lower fertility among women. However, smoking is one of the most common environmental exposures causing oxidative stress. In this study, smoking on the day before oocyte collection was shown to have no effect on alpha-amylase levels. It would seem wise to consider stress as a potential factor for couples who have failed to achieve a pregnancy despite 6 months of targeted intercourse, given that the effect of stress becomes apparent after the fifth cycle. This prospective study did not provide a definitive answer regarding causality: It simply provides further evidence of the independent adverse role that stress might play. The biologic mechanism by which stress might affect fecundity remains unknown.
DISCUSSION Mobile Phone Use The literature suggests (27–29) that mobile phone use alters sperm parameters, particularly motility and morphology, and increases oxidative stress. Moreover, these abnormalities seem to have a direct correlation with the duration of mobile phone use. However, carrying out a prospective randomized study appears to be difficult, considering the intensive use of mobile phones and computers by men and women. The use of new technologies should be evaluated for the next 20 years.
THE ROLE OF ENVIRONMENTAL AND OCCUPATIONAL POLLUTANTS AND OXIDATIVE STRESS Environmental Exposure A review of the literature reveals that occupational exposure of men or women to lead and cadmium, as well as exposure to pesticides and solvents, might have some effects. Exposure to solvents and pesticides suggests associations that require further confirmation. A meta-analysis shows an increase in hypospadias associated with parents who are farmers. Some diseases and disorders, such as endometriosis and menstrual cycle abnormalities, have yet to be studied in detail (30, 31). Despite the need for more in-depth studies, the Garlantezec and Multigner (32) report highlights the relationship between exposure to pesticides or solvents in certain professions (farmers, foundry workers, horticulturists, armed forces, hairdressers, workers in shoe and food-processing factories, cleaning ladies, and nurses) and the fertility problems experienced by some couples. It should be noted that contact with toxic products is often accompanied by higher stress levels, adding to the detrimental nature of the workplace. Cohort studies with biomarker measurements would help to improve the understanding of occupational exposure.
Stress The role played by stress in infertility remains controversial largely because, despite medical advances, a high percentage of infertility remains unexplained (33). Lynch et al. (34) show an association between salivary stress biomarkers and time to 24
Screening lifestyles and toxic factors that affect infertile couples is the first stage of infertility treatment, because it is essential to treat those factors to reduce or even eliminate them. We carried out a national survey based on a written questionnaire completed by couples before any infertility consultation in 43 French departments (35).
Accumulation of Risk Factors In our study, when the 16 factors analyzed were considered together, the accumulation of factors was greater in women: 65% had four or more factors and 20% had seven or more; whereas 58% of men had four or more factors and 12% had seven or more (Table 1). Absence of factors was rare: 1.4% of women and 2.3% of men. Women had 4.60 2.3 cumulative factors (range 0–11), and men had 4.03 2.1 (range 0–12), which was a significant difference (P< .001). Hassan and Killick (36) showed that the accumulation of toxic factors resulted in the time taken to conceive being seven times longer. Infertility stress was present in one-half (53%) of the women; in men, stress was less marked (23%; P< .0001). This prospective study demonstrated that numerous factors are detrimental to fertility in both men and women. Considering that one couple in four requests ART without presenting fertility problems (33), it is essential to take both behavioral and environmental factors into account. The detection and correction of these factors in the absence of any cause of infertility should lead to a natural pregnancy without medical intervention. This accumulation of factors does not, however, apply only to the individual, but also to the couple. In fact, our analyses have shown that women with factors such as smoking, cannabis, alcohol, sleep disorders, family stress, and infertility-related stress are very likely to live with a man with the same type of factors. This first French study showed a trend for certain toxic factors to affect both members of the couple at the same time. On the other hand, the stress level at work was higher for both women and men, 41% and 43%, respectively, in our sample, compared with 28.2% and 19.6%, respectively, in a sample of 24,486 salaried workers without infertility (32). Smoking was noticeably similar for the women in our sample and for pregnant women who had not required ART: VOL. 103 NO. 1 / JANUARY 2015
Fertility and Sterility®
TABLE 1 Proportion of men and women concerned by each toxic factor studied. Factors Problems during sexual intercourse Adolescence Appetite-related disorders Treatments Surgical history Tobacco Cannabis Medication Alcohol Appetite-related disorders Loss of weight Hair loss treatment Contact with chemical products at work Sleep disorders Sports Infertility Quality of life Stress at worke Family Stress Stress associated with infertilityf
Womena
Men
95% CIb
Menc
Mend
95% CIb
12%
1.7%
0.030–0.192***
7.0%
1.0%
0.003–0.12*
6.3% 7.8% 8.6% 20% 1.4% 22% 23% 10% 21% 3.2% 2.9%
1.4% 7.2% 2.9% 32% 6.4% 18% 32% 2% 10% 3.4% 8.6%
0.02–0.08** 0.03–0.05 0.02–0.09** 0.19– 0.06*** 0.09– 0.02** 0.02–0.1 0.16– 0.03** 0.04–0.11*** 0.06–0.16*** 0.03–0.03 0.09– 0.02**
4.5% 11% 8.30% 63% 75% 23% 68% 2.9% 17% 18% 20%
1.2% 6.9% 3.60% 25% 5.5% 16% 22% 2.2% 8.0% 3.0% 8.3%
0.01–0.12 0.05–0.22 0.03–0.34 0.24–0.51*** 0.16–0.94*** 0.03–0.19 0.34–0.56*** 0.02–0.11 0.001–0.19* 0.002–0.46 0.05–0.47
13% 34% 72%
18% 58% 49%
0.11–0.01 0.31– 0.17*** 0.16–0.3***
36% 65% 63%
15% 55% 11%
0.05–0.39** 0.01–0.21 0.42–0.59***
41% 14% 54%
43% 12% 23%
0.09–0.05 0.03–0.07 0.22–0.39***
56% 44% 33%
34% 6.7% 6.9%
0.11–0.32 0.11–0.32*** 0.17–0.35***
*P< .05; ** P< .01; *** P< .001. a Out of a population of 348 couples. b 95% confidence interval (CI) calculated on the basis of the difference in proportion. c Men concerned by the factor with a woman partner who is also concerned. d Men concerned by the factor with a woman partner who is not concerned. e For working men and women. f For men and women with infertility. Alvarez. Do some addictions interfere with fertility? Fertil Steril 2015.
20% versus 18%. However, alcohol consumption by the men in our study was higher than that of the future fathers with pregnant partners who had not required ART: 32% versus 14%, according to data from a survey of 1,000 pregnant women (35). We observed lower consumption of medicines and alcohol and very similar consumption of tobacco and drugs compared with the report by Hammiche et al. (37). Although their study focused more on the impact of a consultation giving personalized advice on the couple's habits, our results converge in that our studies demonstrate the specificity of the population that attends consultations for ART and the need for follow-up, which includes a change of lifestyle.
CONCLUSION In parallel with the diagnosis of the cause of infertility, treatment of the infertile couple requires screening to detect environmental and lifestyle factors that influence fertility. This approach is even more necessary for the one-fourth of couples whose difficulties in their attempts to procreate are not associated with an infertility problem (33). Our study, like the recent studies by Hammiche et al. (37) and Domar et al. (38), emphasizes the necessity of detecting toxic factors and unfavorable lifestyle factors to correct them before any medically assisted procreation treatment takes place. The main difficulty in many studies is that they consider isolated toxic factors, not cumulative factors. VOL. 103 NO. 1 / JANUARY 2015
Indeed, the prospective observations we carried out showed an increased incidence of smoking, exacerbation of sexual disorders (reduced intercourse, dyspareunia), dysmenorrhea in women, detection of work and family stress, and stress induced by infertility, which were typical characteristics of the infertile couples who took part in this study. A global treatment should be offered to the couple regarding the factors identified during earlier screening. Reduction in excess weight, alleviation of toxic factors, stress management, and advice on job-specific toxic factors are fundamental for treating infertility. Toxic factors (particularly smoking) should be reduced starting 3–6 months before resorting to any assisted reproductive technique (39). Detecting and correcting unfavorable lifestyles and toxic factors is fundamental for improving spontaneous fertility and ART results (40). Information campaigns and collaborative actions taken with health care regulation authorities, couples, physicians, and nurses are necessary to help improve the fertility of couples.
REFERENCES 1. 2.
3.
ESHRE Task Force on Ethics and Law. Lifestyle-related factors and access to medically assisted reproduction. Human Reprod 2010;25:578–83. Hammarberg K, Setter T, Norman R, Holden C, Michelmore J, Johnson L. Knowledge about factors that influence fertility among Australians of reproductive age: a population-based survey. Fertil Steril 2012;99:502–7. Domar AD, Conboy L, Denardo-Roney J, Rooney KL. Lifestyle behaviors in women undergoing IVF. Fertil Steril 2011;96:S185. 25
VIEWS AND REVIEWS 4.
5. 6. 7.
8.
9.
10.
11. 12.
13.
14. 15. 16. 17. 18. 19.
20.
21.
22.
23.
26
Finnstrom O, Kallen B, Lindam A, Nilsson E, Nygren KG, Olausson PO. Maternal and child outcome after in vitro fertilization—a review of 25 years of population-based data from Sweden. Acta Obstet Gynecol Scand 2011; 90:494–500. Zollner U, Dietl J. Perinatal risks after IVF and ICSI. J Perinat Med 2013;41: 17–22. Augood C, Dukitt K, Templeton A. Smoking and female infertility: a systemic review and meta-analysis. Human Reprod 1998;13:1532–9. Freour T, Masson D, Mirallie S, Bach JM, Dejoie T. Active smoking compromises IVF outcome and affects ovarian reserve. Reprod Biomed Online 2008; 16:96–102. Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet 2001;28:355–60. Thorup J, Cortes D, Petersen BL. The incidence of bilateral cryptorchidism is increased and the fertility potential is reduced in sons born to mothers who have smoked during pregnancy. J Urol 2006;176:734–7. Jensen TK, Jorgensen N, Punab M, Haugen TB, Suominen J, Zilaitiene B. Association of in utero exposure to maternal smoking with reduced semen quality and testis size in adulthood: a cross-sectional study of 1,770 young men from the general population in five European countries. Am J Epidemiol 2004;159:49–58. Santos EP, Lopez-Costa S, Chenlo P. Impact of spontaneous smoking cessation on sperm quality: case report. Andrologia 2011;43:431. Sobinoff AP, Sutherland JM, Beckett EL, Stanger SJ, Johnson R, Jarnicki AG, et al. Damaging legacy: maternal cigarette smoking has long-term consequences for male offspring fertility. Hum Reprod 2014;29:2719–35. Hull MG, North K, Taylor H, Farrow A, Ford WC. Avon Longitudinal Study of Pregnancy and Childhood Study Team. Delayed conception and active and passive smoking. Fertil Steril 2000;74:725–33. Commenges-Ducos M, Carre-Pigeon F. Reproduction, toxiques et environnement. Gynecol Obstet Fertil 2006;34:938–9. Park B, McPartland JM, Glass M. Cannabis, cannabinoids and reproduction. Prostaglandins Leukot Essent Fatty Acids 2004;70:189–97. Wang H, Dey SK, Maccarrone M. Jekyll and Hyde: two faces of cannabinoid signaling in male and female fertility. Endocr Rev 2006;27:427–48. Muthusami KR. Effect of chronic alcoholism on male fertility hormones and semen quality. Fertil Steril 2005;84:919–24. Emanuele MA, Emanuele N. Alcohol and the male reproductive system. Alcohol Res Health 2001;25:282–7. Jensen T, Gottschau M, Broby Madsen J, Andersson AM, Harmer T, Skakkebæk N, et al. Habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young Danish men. BMJ Open 2014;4:e005462. Klonoff-Cohen H, Lam-Kruglick P, Gonzalez C. Effects of maternal and paternal alcohol consumption on the success rates of in vitro fertilization and gamete intrafallopian transfer. Fertil Steril 2003;79:330–9. Wdowaik A, Sulima M, Sdowaska M, Grzegorz B, Bojar I. Alcohol consumption and quality of embryos obtained in programmes of in vitro fertilisation. Ann Agric Environ Med 2014;21:450–3. Sigman M. Medications that impair male fertility. Sexuality, Reproduction, and Menopause: A clinical publication of the American Society for Reproductive Medicine 2007;5:11–6. Meltzer H, Bastani B, Jayathilake K. Fluotexine but not tricyclic antidepressants, potentiates the 5-hydroxytryptophan–mediated increase in plasma
24.
25.
26.
27. 28.
29.
30.
31.
32.
33.
34.
35.
36. 37.
38.
39.
40.
cortisol and prolactin secretion in subjects with major depression or with obsessive disorder. Neuropsychopharmacology 1997;17:1–11. Amory JK, Swerdloff RS. The effect of 5 alpha-reductase inhibitions with dutasteride and finasteride on semen parameters and serum hormones in healthy men. J Clin Endocrinol Metab 2007;92:1659–65. Belloc S, Cohen-Bacrie M, Dalleac A, Amar E, Hazout A, de Mouzon J. Caffeine intake and sperm parameters. Analysis of a cohort of 4474 consecutive semen samples. Fertil Steril 2013;100:S212. Pauli SA, Browne AC, Seydafkan S, Session DR. Counseling patients regarding reducing caffeine consumption before in vitro fertilization (IVF) is associated with a decreased number of immature oocyte. Fertil Steril 2010;94:S262. Merhi ZO. Challenging cell phone impact on reproduction: a review. J Assist Reprod Genet 2012;29:293–7. la Vignera S, Condorelli RA, Vicari E. Effects of the exposure to mobile phones on male reproduction: a review of the literature. J Androl 2012; 33:350–6. Agarwal A, Deepinder F, Sharma RK. Effect of cell phone usage on semen analysis in men attending infertility clinic: an observational study. Fertil Steril 2008;89:124–8. Rouiller-Fabre V, Muczynski V, Lecureuil C, Livera G, Moison D, Frydman R, et al. Polluants environnementaux et troubles de la reproduction masculine: les phtalates au cœur du debat. [Environmental pollutants and male reproductive disorders: phthalates at the heart of the debate.]. Cah Nutri Diet 2011;46:75–81. Mauduit C, Florin A, Amara S, Bozec A, Siddeek B, Cunha S, et al. Effets a long terme des perturbateurs endocriniens environnementaux sur la fertilite masculine. [Long-term effects of environmental endocrine disruptors on male fertility.]. Gynecol Obstet Fertil 2006;34:978–84. Garlantezec R, Multigner L. Relation entre exposition professionnelle, anomalies de la fertilite et troubles de l’appareil reproducteur, revue de la litterature recente. [Relation between occupational exposure, fertility anomalies, and reproductive system disorders: review of recent literature.]. Bull Epidemiol Hebd 2012;7–9:119–24. Kamath MS, Bhattacharya S. Demographics of infertility and management of unexplained infertility. Best Pract Res Clin Obstet Gynaecol 2012;26: 729–38. Lynch MD, Sumdaram R, Maisog JM, Sweeny AM, Buck Louis GM. Preconception stress increases the risk of infertility: results from a couple-based prospective cohort study—the LIFE study. Hum Reprod 2014;29:1067–75. Alvarez S, Devouche E. Premiere enqu^ete nationale franc¸aise sur les modes de vie et les facteurs toxiques chez les couples infertiles [First French national survey on lifestyle and toxic factors in infertile couples.]. Gynecol Obstet Fertil 2012;40:765–71. Hassan MA, Killick SR. Negative lifestyle is associated with a significant reduction in fecundity. Fertil Steril 2004;81:384–92. Hammiche F, Laven JSE, van Mill N, de Cock M, de Vries JH, Lindemans J. Tailored preconceptional dietary and lifestyle counselling in a tertiary outpatient clinic in the Netherlands. Hum Reprod 2011;26:2432–41. Domar AD, Conboy L, Denardo-Roney J, Roone KN. Lifestyle behaviors in women undergoing in vitro fertilization: a prospective study. Fertil Steril 2012;97:697–701. de Ziegler D, Santulli P, Seroka A, Decanter C, Meldrum D, Chapron C. In women, the reproductive harm of toxins such as tobacco smoke is reversible in 6 months: basis for the ‘‘olive tree’’ hypothesis. Fertil Steril 2013;100:927–8. Alvarez S. Role of toxic factors in the fecundity of the couple. J Gynecol Obstet Biol Reprod 2010;39(Suppl 1):39–40.
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