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Food intake and its relationship with semen quality: a case-control study

      Objective

      To compare dietary habits in normospermic and oligoasthenoteratospermic patients attending a reproductive assisted clinic.

      Design

      An observational, analytical case-control study.

      Setting

      Private fertility clinics.

      Patient(s)

      Thirty men with poor semen quality (cases) and 31 normospermic control couples attending our fertility clinics.

      Intervention(s)

      We recorded dietary habits and food consumption using a food frequency questionnaire adapted to meet specific study objectives. Analysis of semen parameters, hormone levels, Y microdeletions, and karyotypes were also carried out.

      Main Outcome Measure(s)

      Frequency of intake food items were registered in a scale with nine categories ranging from no consumption to repeated daily consumption.

      Result(s)

      Controls had a higher intake of skimmed milk, shellfish, tomatoes, and lettuce, and cases consumed more yogurt, meat products, and potatoes. In the logistic regression model cases had lower intake of lettuce and tomatoes, fruits (apricots and peaches), and significantly higher intake of dairy and meat processed products.

      Conclusion(s)

      Frequent intake of lipophilic foods like meat products or milk may negatively affect semen quality in humans, whereas some fruits or vegetables may maintain or improve semen quality.

      Key Words

      Several studies have suggested that human semen quality and fecundity have been declining during the past decades (
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      • Carlsen E.
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      Evidence for decreasing quality of semen during the past 50 years.
      ,
      • Auger J.
      • Kunstmann J.M.
      • Czyglik F.
      • Jouannet P.
      Decline in semen quality among fertile men in Paris during the past 20 years.
      ,
      • Adamopoulus D.A.
      • Pappa A.
      • Nicopoulou S.
      • Andreou E.
      • Karamertzanis M.
      • Michopoulos J.
      • et al.
      Seminal volume and total sperm number trends in men attending subfertility clinics in the Greater Athens area during the period 1977–1993.
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      • Richardson D.
      • Macdonald E.
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      Evidence of deteriorating semen quality in the United Kingdom: birth cohort study in 577 men in Scotland over 11 years.
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      ) or xenoestrogens like some polychlorinated biphenyls (
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      World PCBs map: storage and effects in man and his biologic environment in the 1970's.
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      • Rozati R.
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      Role of environmental estrogens in the deterioration of male factor fertility.
      ,
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      • Rescia M.
      • Rignell-Hydbom A.
      • et al.
      Exposure to PCB and p,ṕ-DDE in European and Inuit populations: impact on human sperm chromatin integrity.
      ), organochlorine compounds (pesticides) (
      • Juhler R.K.
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      • Jensen N.D.
      • Spanò M.
      • Giwercman A.
      • et al.
      Human semen quality in relation to dietary pesticide exposure and organic diet.
      ,
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      Semen quality in fertile US men in relation to geographical area and pesticide exposure.
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      • Mariscal M.
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      Exposure of young men to organochlorine pesticides in Southern Spain.
      ), and phthalate esters (
      • Duty S.M.
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      Phthalate exposure and human semen parameters.
      ) may compromise reproductive male function.
      A recent study carried out by Swan et al. (
      • Swan S.H.
      • Liu F.
      • Overstreet J.W.
      • Brazil C.
      • Skakkebaek N.E.
      Semen quality of fertile US males in relation to their mothers' beef consumption during pregnancy.
      ) suggests that maternal beef consumption, and possibly xenobiotics (anabolic steroids) in beef, may alter a male fetus' testicular development in utero and adversely affect his reproductive capacity. Sperm concentration was inversely related to the mother's beef intake per week. In sons of “high beef consumers” (>7 beef meals/week), sperm concentration was 24.3% lower than in the men whose mothers ate less beef (
      • Swan S.H.
      • Liu F.
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      Semen quality of fertile US males in relation to their mothers' beef consumption during pregnancy.
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      ).
      It is speculated that there may be a causal link between male reproductive anomalies (hypospadias, cryptorchidism) (
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      • Skakkebaek N.E.
      Evidence for decreasing quality of semen during the past 50 years.
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      ).
      Although, traditionally, estrogen (E) was perceived as having a minor role in male reproduction, it is now clear that E have a major role in male gonadal development, spermatogenesis, and fertility (
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      Possible health impact of phytoestrogens and xenoestrogens in food.
      ). We found only one report in which adult men were given phytoestrogen supplements (isoflavone) for 20 days and no effect was observed on semen quality (
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      ).
      The aim of the study is to compare dietary habits in normospermic and oligoasthenoteratospermic patients attending a reproductive assisted clinic.

      Materials and methods

       Design and Patients

      The present work is methodologically designed as an analytical observational case-control study. The patients were men of couples attending our fertility clinics of the Instituto Bernabeu (IB) Cartagena, Elche, and Alicante (southeast of Spain), between 2005 and 2007. Two groups were formed on the basis of seminal quality and following World Health Organization (WHO) criteria (
      • World Health Organisation
      Laboratory manual for the examination of human semen and sperm–cervical mucus interaction.
      ): [1] cases (n = 30) composed of men with severe or moderate oligozoospermia (<5 × 106 million of sperms/mL or between 5 and 20 million of sperms/mL, respectively) and severe teratozoospermia (<6% normal forms, strict criteria according to Kruger et al.) (
      • Kruger T.F.
      • Menkveld R.
      • Stander F.S.
      • Lombard C.J.
      • Van der Merwe J.P.
      • van Zyl J.A.
      • et al.
      Sperm morphologic features as a prognostic factor in in vitro fertilization.
      ), and [2] controls (n = 31) composed of normospermic patients (≥20 × 106 million of sperms/mL, ≥50% motile sperm, and ≥14% normal forms, strict criteria). An additional 10 patients and 12 controls, who were invited to participate, refused to be included in the study. Therefore, there were no significant differences between the refusal rates in cases and controls. Subjects provided at least two semen samples after an abstinence period of 3–5 days. Analyses of samples were done following WHO criteria (
      • World Health Organisation
      Laboratory manual for the examination of human semen and sperm–cervical mucus interaction.
      ). We excluded patients who showed a clinical history of varicocele, cryptorchid or endocrine hypogonadism (abnormal hormonal levels), chemotherapy or radiotherapy, and anomalies in the karyotype, or presented Y chromosome microdeletions. The mean body mass index (BMI) for cases was 23.2 (95% confidence interval [CI] 22.8–23.6) and for controls 23.5 (95% CI 23.1–23.9). Only two cases and two controls had BMI more than 25 kg/m2 and all of them were less than 26 kg/m2. This study was approved by the Institutional Review Board (IRB) of our clinics and patients were included in the study after giving informed written consent.

       Questionnaire

      All patients were interviewed face-to-face by the same professional before or after the first semen sample was obtained. Men were asked about the average frequency of consumption of 96 food items during the past year (
      • Willett W.C.
      • Sampson L.
      • Stampfer M.J.
      • Rosner B.
      • Bain C.
      • Witschi J.
      • et al.
      Reproducibility and validity of a semiquantitative food frequency questionnaire.
      ). Food frequency questionnaire was designed in five blocks, each of them addressing a general group of foods: [1] dairy products, [2] eggs, red and pork meat, chicken, cold meats, meat processed products, organs, fish, and shellfish, [3] raw or cooked vegetables, potatoes, legumes, and fruits, [4] vegetable oils and sweets, and [5] alcoholic and nonalcoholic drinks. Frequency of food consumption was registered in a scale with nine values ranging from no consumption to repeated daily consumption. The specific categories were: [1] never or less than once a month, [2] 1–3 times per month, [3] once per week, [4] 2–4 times/week, [5] 5–6 times/week, [6] once daily, [7] 2–3 times/day, [8] 4–5 times/day, and [9] 6 or more times/day. The questionnaire has been adapted from the Food Frequency Questionnaire developed in the United States (
      • Willett W.C.
      • Sampson L.
      • Stampfer M.J.
      • Rosner B.
      • Bain C.
      • Witschi J.
      • et al.
      Reproducibility and validity of a semiquantitative food frequency questionnaire.
      ) and adapted and validated in Spain (

      Vioque J, Guillén M, García M, González L, Vicente MC, Quiles J. Reproducibility and validity of a food frequency questionnaire among men and women of Alicante, Spain. In: International Epidemiological Association. Epidemiology for sustainable health. Abstract Book II. The XV International Scientific Meeting of the International Epidemiological Association. Florence, Italy, August 31–September 4, 1999.

      ). Administration of the questionnaire took an hour, on average. All questionnaires were completed by the same interviewer. A different questionnaire recorded information on current environmental and lifestyle exposures (e.g., toxic habits, house environment, hobbies, daily clothes, underwear).

       Statistical Analysis

      Means of intake frequencies for the different food items in cases and controls were compared using nonparametric methods (Mann-Whitney U). Odds ratios (OR) and 95% CI were used to explore differences in lifestyle or other exposures. We used multiple logistic regression model for certain analyses. Only food items that were statistically significant in the crude analyses were included in the stepwise logistic regression model. Significance level for all tests was set at P≤.05. Analyses were performed using the statistical package SPSS 13.0 (SPSS Inc., Chicago, IL).

      Results

      Table 1 shows the semen parameters and hormone levels between the cases and controls. Hormonal values were normal and similar between the two groups. There were no significant differences between the two semen samples within groups. As expected, due to study's methodological design, semen parameters (except seminal volume) were significantly lower in cases than in controls (P≤.001). Table 2 provides a summary of lifestyle and toxin or pollutant exposures in the two groups. No statistically significant differences were found between cases and controls. Table 3 summarizes the differences in average food intakes between the two groups for selected food items. Cases presented a higher intake of yogurt, meat products, and potatoes (P≤.05). Controls had significantly higher intakes of skimmed milk, shellfish, raw or cooked vegetables, apricots and peaches, and sweets. Other food items did not show statistically significant differences between the groups. In a logistic regression model, cases had lower intake of lettuce and tomatoes (OR = 0.4; 95% CI 0.2–0.8), fruits (apricots and peaches) (OR = 0.3; 95% CI 0.1–0.6), and a significantly higher intake of dairy products (OR = 3.1; 95% CI 1.1–8.5) and meat processed foods (OR = 2.6; 95% CI 1.2–5.4).
      Table 1Sperm quality and hormonal levels.
      Cases (n = 30)Controls (n = 31)
      1st sample2nd sampleAverage
      No significant differences were found between the first and second samples between cases or controls.
      1st sample2nd sampleAverage
      No significant differences were found between the first and second samples between cases or controls.
      Variables(mean ± SD)(mean ± SD)(mean ± SD)(mean ± SD)(mean ± SD)(mean ± SD)P value
      Semen samples
       Volume (mL)3.9 ± 1.33.7 ± 1.13.8 ± 1.23.6 ± 1.03.4 ± 1.73.5 ± 1.4.376
       Concentration (106/mL)3.2 ± 2.33.7 ± 1.83.3 ± 4.141.7 ± 15.637.4 ± 13.639.5 ± 14.6<.001
       Sperm motility (grade a+b)29.2 ± 19.825.5 ± 17.427.4 ± 18.651.1 ± 10.353.3 ± 14.352.2 ± 12.3<.001
       Percent normal morphology
      Strict criteria (54).
      3.6 ± 1.33.8 ± 1.73.7 ± 1.523.4 ± 4.921.1 ± 4.122.3 ± 4.5<.001
      Hormonal levels
       FSH6.4 ± 2.16.5 ± 1.4.717
       LH4.2 ± 1.24.1 ± 1.4.815
       T5.3 ± 1.65.4 ± 1.3.799
      a No significant differences were found between the first and second samples between cases or controls.
      b Strict criteria
      • Lewis V.
      • Kochman L.
      • Herko R.
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      • Song G.
      Dietary antioxidants and sperm quality in infertile men. American Society of Reproductive Medicine Annual Meeting, New Orleans, LA, October 21–25.
      .
      Table 2Comparison of general characteristics in cases and controls.
      Cases (n = 30)Controls (n = 31)
      Variablesn%n%OR95% CI
      Age (y, mean ± SD)34.2 ± 3.732.8 ± 3.9NS
      Clinics
       IB Alicante1446.71858.1
       IB Cartagena1343.31341.9
       IB Elche310
      Current smoker826.71135.50.660.22–1.97
      No. of years smoking (mean ± SD)18.8 ± 4.115.8 ± 3.5NS
      Ever smoking1136.71135.41.060.37–2.99
      Passive smoking at home13.3
      Passive smoking at work516.7412.91.350.33–5.60
      Current alcohol drinking1446.71858.10.630.23–1.74
      Nail biting723.31135.50.550.18–1.70
      Self car repair516.7412.91.350.33–5.60
      Hobbies or handicrafts with toxic products62026.53.620.67–19.63
      Recently reformed home620412.91.470.47–6.60
      Lead pipeline at home13.3412.90.230.02–2.21
      Living near pollutant areas31026.51.610.25–10.40
      Heavy traffic near home1343.31238.71.210.44–3.36
      Use of synthetic clothes1240.01548.41.410.51–3.88
      Fitted trousers1446.71651.60.820.30–2.24
      Fitted underwear2686.72580.71.560.39–6.19
      Cell phone in pocket2686.72993.50.450.08–2.65
      Note: No significant differences were found in any of the variables.
      CI = confidence interval; NS = not significant; OR = odds ratio.
      Table 3Average food intake of selected food items in cases and controls.
      Cases (n = 30)Controls (n = 31)
      Variables(mean ± SD)
      Mean values represent the average yearly consumption of specific food items, with the following correspondence between numeric values and categories of consumption: “1” = never or less than once a month; “2” = 1–3 times per month; “3” = once per week; “4” = 2–4 times/week; “5” = 5–6 times/week; “6” = once daily; “7” = 2–3 times/day; “8” = 4–5 times/day, and “9” = 6 or more times/day.
      (mean ± SD)
      Mean values represent the average yearly consumption of specific food items, with the following correspondence between numeric values and categories of consumption: “1” = never or less than once a month; “2” = 1–3 times per month; “3” = once per week; “4” = 2–4 times/week; “5” = 5–6 times/week; “6” = once daily; “7” = 2–3 times/day; “8” = 4–5 times/day, and “9” = 6 or more times/day.
      P value
      Whole milk3.13 ± 2.492.61 ± 2.38.407
      Semi-skimmed milk2.53 ± 3.391.97 ± 2.01.320
      Cheese4.17 ± 1.493.71 ± 1.64.259
      Yogurt3.4 ± 1.572.48 ± 1.59.016
      All 4 dairy products
      “Dairy products” includes yogurt, whole milk, cheese, and semi-skimmed milk. There was a significantly and negative correlation between intake of these products and intake of skimmed milk (r = −0.6, P<.001).
      3.3 ± 1.572.7 ± 1.19.03
      Skimmed milk1.50 ± 1.383.03 ± 2.61.013
      Eggs3.43 ± 0.933.26 ± 0.99.482
      Red meat2.77 ± 0.903.03 ± 0.88.247
      Pork meat2.73 ± 1.022.45 ± 1.09.301
      Chicken3.37 ± 0.623.35 ± 0.88.950
      Cold meats4.27 ± 1.264.06 ± 1.55.578
      Organs1.10 ± 0.311.00 ± 0.00.073
      Fish2.33 ± 1.122.55 ± 0.96.425
      Legumes3.20 ± 0.892.97 ± 0.91.318
      Vegetable oils6.50 ± 1.306.90 ± 1.23.880
      Nonalcoholic drinks3.63 ± 1.993.03 ± 1.54.191
      Coffee5.13 ± 2.165.16 ± 2.10.959
      Alcoholic drinks3.40 ± 1.653.32 ± 1.56.851
      Meat processed products2.80 ± 1.132.13 ± 1.26.012
      Potatoes3.43 ± 0.942.74 ± 1.39.028
      Fruits (apricots and peaches)1.73 ± 1.302.23 ± 1.49.021
      Shellfish1.73 ± 0.742.19 ± 0.48.006
      Raw vegetables (lettuce and tomatoes)4.55 ± 1.355.65 ± 1.27.002
      Lettuce4.50 ± 1.375.61 ± 1.43.004
      Tomatoes4.60 ± 1.385.68 ± 1.19.002
      Sweets2.57 ± 1.303.68 ± 1.92.027
      a Mean values represent the average yearly consumption of specific food items, with the following correspondence between numeric values and categories of consumption: “1” = never or less than once a month; “2” = 1–3 times per month; “3” = once per week; “4” = 2–4 times/week; “5” = 5–6 times/week; “6” = once daily; “7” = 2–3 times/day; “8” = 4–5 times/day, and “9” = 6 or more times/day.
      b “Dairy products” includes yogurt, whole milk, cheese, and semi-skimmed milk. There was a significantly and negative correlation between intake of these products and intake of skimmed milk (r = −0.6, P<.001).

      Discussion

      Our study suggests that semen quality may be influenced by food intake. Men with poor semen quality had a more frequent intake of some food items that may adversely affect semen quality or that act as carriers of deleterious products to the reproductive system. Our results are consistent with poor semen quality associated with a higher intake of products that may incorporate xenobiotics, mainly xenoestrogens or certain anabolic steroids (
      • Swan S.H.
      • Liu F.
      • Overstreet J.W.
      • Brazil C.
      • Skakkebaek N.E.
      Semen quality of fertile US males in relation to their mothers' beef consumption during pregnancy.
      ,
      • Santti R.
      • Mäkelä S.
      • Strauss L.
      • Kokman J.
      • Kostian M.L.
      Phytoestrogens: potential endocrine disruptors in males.
      ). The use of these compounds in the food industry results in an increased total level of xenoestrogens and sex steroids in processed foods, such as meat or milk, whose intake contributes significantly to daily exposures. Xenoestrogens are highly lipophilic substances that can accumulate in fat-rich foods like meat or milk, and are suspected as partially responsible for the decline in semen quality. They include polychlorinated biphenyls (
      • Rozati R.
      • Reddy P.P.
      • Reddanna P.
      • Mujtaba R.
      Role of environmental estrogens in the deterioration of male factor fertility.
      ,
      • Spanò M.
      • Toft G.
      • Hagmar L.
      • Eleuteri P.
      • Rescia M.
      • Rignell-Hydbom A.
      • et al.
      Exposure to PCB and p,ṕ-DDE in European and Inuit populations: impact on human sperm chromatin integrity.
      ), organochlorine compounds (pesticides) (
      • Swan S.H.
      Semen quality in fertile US men in relation to geographical area and pesticide exposure.
      ,
      • Carreño J.
      • Rivas A.
      • Granada A.
      • Jose López-Espinosa M.
      • Mariscal M.
      • Olea N.
      • et al.
      Exposure of young men to organochlorine pesticides in Southern Spain.
      ), and phthalate esters (
      • Duty S.M.
      • Silva M.J.
      • Barr D.B.
      • Brock J.W.
      • Ryan L.
      • Chen Z.
      • et al.
      Phthalate exposure and human semen parameters.
      ). In a study, Rozati and colleagues (
      • Rozati R.
      • Reddy P.P.
      • Reddanna P.
      • Mujtaba R.
      Role of environmental estrogens in the deterioration of male factor fertility.
      ) found that total motile sperm counts in infertile men were inversely proportional to their xenoestrogen concentrations, which also were significantly lower in the controls.
      In our study the association with poor semen quality was observed in meat processed foods (sausages and others) with especially high saturated fat content. The control group had a significantly higher intake of skimmed milk and a lower intake of all four dairy products, and consequently, a possibly lower intake of products containing lipophilic substances like xenoestrogens (
      • O'Donnell L.
      • Robertson K.M.
      • Jones M.E.
      • Simpson E.R.
      Estrogens and spermatogenesis.
      ,
      • Santti R.
      • Mäkelä S.
      • Strauss L.
      • Kokman J.
      • Kostian M.L.
      Phytoestrogens: potential endocrine disruptors in males.
      ).
      Other food items were associated with a better semen quality. The control group had a higher intake of lettuce and tomatoes, and some fruits. These findings are consistent with a higher intake of antioxidants and micronutrients, which would have a positive influence in maintaining or improving semen quality in this group. It is known that human spermatozoa generate reactive oxygen species (ROS) in physiologic amounts (
      • Saleh R.A.
      • Agarwal A.
      Oxidative stress and male infertility: from research bench to clinical practice.
      ), but an excessive production causes impairment of seminal quality by many mechanisms (
      • Agarwal A.
      • Saleh R.A.
      • Bedaiwy M.A.
      Role of reactive oxygen species in the pathophysiology of human reproduction.
      ). In fact, a higher antioxidant diet has been associated with higher sperm numbers and motility in healthy nonsmoking men (
      • Eskenazi B.
      • Kidd S.A.
      • Marks A.R.
      • Sloter E.
      • Block G.
      • Wyrobek A.J.
      Antioxidant intake is associated with semen quality in healthy men.
      ). Oxidative stress associated with increased ROS generation and reduced antioxidant capacity is negatively correlated with sperm concentration and motility in infertile men (
      • Pasqualotto F.F.
      • Sharma R.K.
      • Nelson D.R.
      • Thomas A.J.
      • Agarwal A.
      Relationship between oxidative stress, semen characteristics, and clinical diagnosis in men undergoing infertility investigation.
      ) and recently, with morphology (
      • Agarwal A.
      • Sharma R.K.
      • Nallella K.P.
      • Thomas Jr., A.J.
      • Alvarez J.G.
      • Sikka S.C.
      Reactive oxygen species as an independent marker of male factor infertility.
      ). In the same recent study Agarwal et al. (
      • Agarwal A.
      • Sharma R.K.
      • Nallella K.P.
      • Thomas Jr., A.J.
      • Alvarez J.G.
      • Sikka S.C.
      Reactive oxygen species as an independent marker of male factor infertility.
      ) found that among the male factor infertility patient groups, mean ROS levels were significantly higher in the subgroup of those who had abnormal sperm parameters compared with male factor infertility patients with normal sperm parameters. There are several published studies in the review by Agarwal (
      • Agarwal A.
      Role of antioxidants in treatment of male infertility: an overview of the literature.
      ) where the antioxidant therapy has improved certain seminal parameters in male factor infertility patients, and in its conclusions summarized that rationale and evidence supporting the use of antioxidants in infertile male patients with elevated oxidative stress do exist. However, those foods items could also show a larger presence of xenoestrogens like pesticides (
      • Rozati R.
      • Reddy P.P.
      • Reddanna P.
      • Mujtaba R.
      Role of environmental estrogens in the deterioration of male factor fertility.
      ), but their beneficial effects would outweigh the negative consequences.
      We have only found a few references in the scientific literature about observational studies relating semen quality and food intake. A poster communication presented to the American Society of Reproductive Medicine (ASRM) 62nd Annual Meeting in New Orleans in 2006 found that the proportion of men with low intake of fruits and vegetables (<5 servings/day) was greater among infertile men than in controls (83% vs. 40%, P=.0036). In that study, men with the lowest intake of dietary antioxidants had the lowest sperm motility (
      • Lewis V.
      • Kochman L.
      • Herko R.
      • Brewer E.
      • Andolina G.
      • Song G.
      Dietary antioxidants and sperm quality in infertile men. American Society of Reproductive Medicine Annual Meeting, New Orleans, LA, October 21–25.
      ). From the same research group, Song and colleagues (
      • Song G.
      • Kochman L.
      • Andolina E.
      • Herko R.C.
      • Brewer K.J.
      • Lewis V.
      Beneficial effects of dietary intake of plant phytoestrogens on semen parameters and sperm DNA integrity in infertile men. 62nd American Society of Reproductive Medicine Annual Meeting, New Orleans, LA, October 21–25.
      ), in another communication, described beneficial effects of dietary intake of plant phytoestrogens on semen parameters and sperm DNA integrity in infertile men. They concluded that population-based studies and basic research are both needed to confirm and clarify the mechanism of the effects of phytoestrogens on sperm physiology. A recent oral communication was presented at the ASRM 63rd Annual Meeting in Washington in 2007 by Chavarro and colleagues (
      • Chavarro J.E.
      • Sadio S.M.
      • Toth T.L.
      • Hauser R.
      Soy food and isoflavone intake in relation to semen quality parameters. 63rd American Society of Reproductive Medicine Annual Meeting, Washington, DC, October 13–17.
      ), of a cross-sectional study exploring the association of soy foods and soy isoflavone intake with semen quality parameters. They suggest that higher intake of these foods was associated with lower sperm concentration.
      Some possible limitations of our study design should be discussed. The main concern with our study refers to sample size, which would specially affect the power to detect differences between the two groups. However, sample size would not affect the validity of the associations observed, but we may have failed to observe other true differences between the groups. Selection of controls is an important concern in case-control studies (
      • Schlesselman J.J.
      Case-control studies: design, conduct, analysis.
      ). The main criteria for selecting appropriate controls are to ensure comparability between the two groups. Our controls would have been cases if they had had poor semen quality, as they both were recruited in the clinics.
      The other major concerns with case-control studies are information bias, specially recall bias, and confounding (
      • Schlesselman J.J.
      Case-control studies: design, conduct, analysis.
      ). Recall bias is certainly one of the most serious concerns in case-control studies, and our study may not be an exception. Recall bias would be a concern if recall of diet were different among cases and controls. In our study, both cases and controls were patients attending the fertility clinic for couple infertility. Two semen samples were requested of all men seeking fertility treatment. The final diagnosis of semen quality is not given until the results of the second sample are available. Interviews and questionnaires were applied at the visit made by patients to give the second semen sample, and therefore before those final results were available. Therefore, it is unlikely that knowledge of semen quality might have influenced differentially the recall of cases and controls. All interviews were made under similar circumstances and by the same trained person.
      A different consideration refers to the temporal relation between possible exposures and the impact of the reproductive system that resulted in low seminal quality. The association we are observing could be due to an actual effect of the current diet on seminal quality or the reflection of the consequences of exposure at a younger age. Having had a higher intake of some food products in the past at a younger age may also have had a permanent effect on semen quality (
      • Swan S.H.
      • Liu F.
      • Overstreet J.W.
      • Brazil C.
      • Skakkebaek N.E.
      Semen quality of fertile US males in relation to their mothers' beef consumption during pregnancy.
      ,
      • Santti R.
      • Mäkelä S.
      • Strauss L.
      • Kokman J.
      • Kostian M.L.
      Phytoestrogens: potential endocrine disruptors in males.
      ).
      Finally, the case-control study, as an observational design, does not allow us to infer causality in the associations (
      • Schlesselman J.J.
      Case-control studies: design, conduct, analysis.
      ). The link between xenobiotics and other exposures on diet and semen quality is controversial (
      • Amann R.P.
      • Seidel G.E.
      Testis development, beef consumption and study methods.
      ,
      • Swan S.H.
      • Liu F.
      • Overstreet J.W.
      • Brazil C.
      • Skakkebaek N.E.
      Reply: Testis development, beef consumption and study methods.
      ). Therefore we concur that more research is needed to check the influence and effect of food intake and other exposures throughout the life cycle, testing the impact of prenatal and perinatal exposures, as well as during infancy, childhood, puberty, and adulthood on reproduction and fertility in men. Ideally, a prospective design would be more suitable to address the effect of possible exposures along each stage of a patient's life cycle.

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