Abstract

BACKGROUND

Dairy foods and lactose may impair fertility by affecting ovulatory function. Yet, few studies have been conducted in humans and their results are inconsistent. We evaluated whether intake of dairy foods was associated with anovulatory infertility and whether this association differed according to fat content.

METHODS

We prospectively followed 18 555 married, premenopausal women without a history of infertility who attempted a pregnancy or became pregnant during an 8-year period. Diet was assessed twice during the study using food—frequency questionnaires

RESULTS

During follow-up, 438 women reported infertility due to an ovulatory disorder. The multivariate-adjusted relative risks (RR) [95% confidence interval (CI); P, trend] of anovulatory infertility comparing women consuming ≥ 2 servings per day to women consuming ≤1 serving per week was 1.85 (1.24–2.77; 0.002) for low-fat dairy foods. The RR (95% CI; P, trend) comparing women consuming ≥ 1 serving per day of high-fat dairy foods to those consuming ≤1 serving per week was 0.73 (0.52–1.01; 0.01). There was an inverse association between dairy fat intake and anovulatory infertility (P, trend = 0.05). Intakes of lactose, calcium, phosphorus and vitamin D were unrelated to anovulatory infertility.

CONCLUSIONS

High intake of low-fat dairy foods may increase the risk of anovulatory infertility whereas intake of high-fat dairy foods may decrease this risk. Further, lactose (the main carbohydrate in milk and dairy products) may not affect fertility within the usual range of intake levels in humans.

Introduction

Lactose, the main carbohydrate in milk and other dairy foods, is cleaved in the intestine into glucose and galactose, sugars which are subsequently absorbed and metabolized. Women with galactosemia, an inborn error of metabolism in which galactose cannot be adequately metabolized, often develop premature ovarian failure (POF) (Kaufman et al., 1981; Waggoner et al., 1990; Guerrero et al., 2000). In animal experiments, rodents fed high amounts of galactose have decreased ovulatory rates and develop POF (Swarts and Mattison, 1988; Bandyopadhyay et al., 2003). These observations have led to the hypothesis that high intake of milk and dairy products may increase the risk of infertility due to ovulatory dysfunction in otherwise healthy women (Cramer et al., 1994). However, few studies have been conducted in humans (Cramer et al., 1994; Greenlee et al., 2003) and their results are not consistent. In addition, there are reasons to believe that dairy foods may be beneficial to ovarian function, and that not all dairy foods have the same relation to fertility. Dairy food intake has been associated with a lower risk of insulin resistance syndrome and type 2 diabetes (Pereira et al., 2002; Choi et al., 2005) which have been associated with ovulatory dysfunction (Hjollund et al., 1999; Azziz et al., 2001; Brettenthaler et al., 2004), suggesting that dairy foods may actually improve ovarian function. Also, intake of low-fat dairy foods, but not high-fat dairy foods, has been associated with clinical manifestations of androgen excess (Adebamowo et al., 2005), a component of the polycystic ovary syndrome (PCOS) (The Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group, 2004) which may also lead to anovulatory infertility (Ehrmann, 2005). To address these issues, we prospectively evaluated whether the intakes of low-fat dairy foods, high-fat dairy foods, lactose and other nutrients concentrated in dairy foods were associated with anovulatory infertility in a large cohort of healthy women.

Materials and methods

Study population

The Nurses' Health Study II (NHS II) is a prospective cohort started in 1989 when more than 116 000 female registered nurses aged 24–42 completed and returned a mailed baseline questionnaire. Participants have been followed every 2 years since then with mailed questionnaires, including information on exposures and disease outcomes. Here we present a prospective analysis of incident anovulatory infertility among participants of this cohort. The association between dietary factors and infertility overall or due to other causes is not addressed in this report. The study was approved by the Institutional Review Board of Brigham and Women's Hospital.

Follow-up for the current analysis started in 1991, when diet was first measured, and concluded in 1999. On biennial questionnaires, participants were asked if they had tried to become pregnant for more than 1 year without success since the previous questionnaire administration, and to indicate whether their inability to conceive was caused by tubal blockage, ovulatory disorder, endometriosis, cervical mucous factor and spousal factor was not found, was not investigated or was due to another reason. Women were also asked if they became pregnant during the preceding 2-year period, including pregnancies resulting in spontaneous abortions or induced abortions. Using this information, we identified a cohort of women most likely attempting to become pregnant. Only married women, with available dietary information and without a history of infertility, were eligible to enter the analysis. These women contributed information to the analysis during each 2-year period in which they reported a pregnancy or a failed pregnancy attempt, and were followed until they reported an infertility event from any cause, reached menopause or underwent a sterilization procedure (themselves or their partner), whichever came first. Ten diabetic women met these criteria. Insulin resistance and hyperinsulinemia, hallmark characteristics of type 2 diabetes, may affect ovulatory function (Hjollund et al., 1999; Cataldo et al., 2006) and have been associated with intake of dairy products (Pereira et al., 2002; Choi et al., 2005). Since the small number of diabetics would preclude meaningful statistical adjustment or exploration of modification of the associations by diabetes, diabetic women were excluded from the analysis. After exclusions, we identified 18 555 women without a history of infertility who tried to become pregnant or became pregnant during the 8-year follow-up period.

Women who met the selection criteria for the study and reported infertility due to ovulatory disorder, including those reporting multiple diagnoses for infertility, were considered cases. If a pregnancy and infertility were reported in the same 2-year period it was assumed that infertility preceded the pregnancy. In a validation substudy, self-reported diagnosis of anovulatory infertility was confirmed by review of medical records in 95% of the cases (Rich-Edwards et al., 1994).

Dietary assessment

Dietary information was collected in 1991 and 1995 using a food-frequency questionnaire (FFQ) with more than 130 food items and 11 individual dairy foods. Participants were asked to report how often, on average, they consumed each of the foods and beverages included in the FFQ during the previous year. The questionnaire offered nine options for frequency of intake, ranging from never or less than once per month to six or more times per day. Nutrient intakes were estimated by summing the nutrient contribution of all food items in the questionnaire, taking into consideration the use of dietary supplements. The nutrient content of each food and specified portion size was obtained from a nutrient database derived from the US Department of Agriculture (2001) and additional information obtained from food manufacturers. To reduce extraneous variation in nutrient intakes, nutrient intakes were adjusted for total energy intake using the nutrient residual method (Willett and Stampfer, 1986).

The FFQ has been previously found to provide valid estimates of intake of dairy foods and nutrients concentrated in them (Salvini et al., 1989; Willett and Lenart, 1998). The de-attenuated correlation coefficients between estimated intake from the average of four 1-week diet records and from the FFQ were 0.81 for skim/low-fat milk, 0.62 for whole milk, 0.94 for yogurt, 0.73 for ice cream, 0.80 for cottage cheese and 0.57 for other (hard) cheeses (Salvini et al., 1989). The corresponding de-attenuated correlation coefficient for calcium intake was 0.75 (Willett and Lenart, 1998).

Analyses were performed using the most recent intakes, whereby the 1991 diet was assigned to events reported in 1993 and 1995 and the 1995 diet was assigned to events reported in 1997 and 1999, and cumulative averaged intakes, whereby the 1991 diet was assigned to events reported in 1993 and the average of the 1991 and 1995 diets was assigned to the remainder of the follow-up period. The results obtained using both methods were similar. Since cumulative averaged intakes reduce measurement error due to within-person random variation over time (Hu et al., 1999), only results using this method are presented.

Statistical analyses

Intakes of individual dairy foods were added to obtain intakes of low-fat dairy foods (skim/low-fat milk, sherbet, yogurt and cottage cheese), high-fat dairy foods (whole milk, cream, ice cream, cream cheese and other cheese) and total dairy foods. Spearman correlation coefficients were used to estimate the association between intakes of low-fat dairy foods, high-fat dairy foods and dairy fat. Relative risks (RR's) relating intakes of dairy foods to incidence of anovulatory infertility were estimated using logistic regression. The generalized estimating equation approach (Fitzmaurice et al., 2004), with an exchangeable working correlation structure, was used to account for the within-person correlation in outcomes at different time periods. We also performed secondary analyses using only the first event reported in the study for each person to avoid any within-person correlation in outcomes. We first divided women into groups according to their intake frequency of total, low-fat, high-fat and specific dairy foods. Women were also divided into five groups according to quintiles of intake of dietary components of dairy foods intake (dairy fat, lactose, calcium, phosphorus and vitamin D). Tests for linear trend were conducted using the median values of intake in each category as a continuous variable. The RR associated with a 1 serving per day increase in dairy food consumption was estimated using the intake of dairy foods as a continuous variable.

All models were adjusted for total energy intake, age and calendar time at the beginning of each questionnaire cycle. Multivariate models included additional terms for body mass index [wt (kg) ht−2 (m)] (BMI), parity, smoking history, physical activity (measured in metabolic equivalents), history of contraceptive use and dietary factors found to be related to infertility in preliminary analyses (use of multivitamins and intakes of alcohol, coffee and iron). Values of the dietary and non-dietary variables were updated as new data became available from the follow-up questionnaires.

Lastly, we examined whether the association between dairy food intake and anovulatory infertility was modified by subject characteristics (age, parity and BMI), or the presence of long menstrual cycles (>40 days), by introducing cross-product terms between dairy foods intake and the variable of interest. Using the same methodology, we also evaluated whether the association between high-fat dairy food intake and anovulatory infertility was modified by the intake level of low-fat dairy foods and vice versa. All P-values were two sided. Analyses were performed using SAS version 9.1.

Results

Between 1991 and 1999, 26 971 eligible pregnancies and pregnancy attempts were accrued among 18 555 women. Of these events, 3 430 were incident reports of infertility from any cause, of which 2 165 were of women who underwent medical investigation for infertility and 438 were incident reports of anovulatory infertility. At baseline, women who consumed more low-fat dairy foods were less likely to smoke or drink more than two cups of coffee per day, and had a higher average level of physical activity (Table I). Women who consumed more high-fat dairy foods were more likely to consume alcohol and less likely to be nulliparous and to exercise. In addition, women consuming more dairy foods, regardless of fat content, were also more likely to use multivitamins and less likely to use oral contraceptives. Intakes of low-fat and high-fat dairy foods were positively related (r = 0.07). Low-fat dairy intake was inversely related to whole milk intake (r = −0.12) and positively related to skim/low-fat milk intake (r = 0.93). Dairy fat intake was positively related to the intakes of low-fat (r = 0.26) and high-fat dairy foods (r = 0.64).

Table I.

Baselinea characteristics of the study population by levels of low-fat and high-fat dairy foods intake

 Low-fat dairyb High-fat dairyc 
 ≤1 serving per week ≥2 per day ≤1 per week ≥1 per day 
Age, years 32.7 32.3 33.4 32.2 
Alcohol intake, g day−1 2.9 2.3 2.5 3.1 
Coffee intake ≥2 cups day−1, % 27 19 24 24 
Multivitamin use, % 46 65 53 59 
Current smoker, % 13 
Body mass index (BMI), kg m−2 23.3 24.2 23.7 23.9 
Physical activity, METs week−1d 17.6 22.6 23.2 21.0 
Cycles ≥40 days, % 
Hyperandrogenism, % 0.3 0.3 0.3 0.3 
Nulliparous, % 23 17 32 18 
Oral contraceptive use at the beginning of the mailing cycle, % 19 13 17 15 
Low-fat dairy, servings per day — — 1.5 1.7 
High-fat dairy, servings per day 1.0 0.9 — — 
 Low-fat dairyb High-fat dairyc 
 ≤1 serving per week ≥2 per day ≤1 per week ≥1 per day 
Age, years 32.7 32.3 33.4 32.2 
Alcohol intake, g day−1 2.9 2.3 2.5 3.1 
Coffee intake ≥2 cups day−1, % 27 19 24 24 
Multivitamin use, % 46 65 53 59 
Current smoker, % 13 
Body mass index (BMI), kg m−2 23.3 24.2 23.7 23.9 
Physical activity, METs week−1d 17.6 22.6 23.2 21.0 
Cycles ≥40 days, % 
Hyperandrogenism, % 0.3 0.3 0.3 0.3 
Nulliparous, % 23 17 32 18 
Oral contraceptive use at the beginning of the mailing cycle, % 19 13 17 15 
Low-fat dairy, servings per day — — 1.5 1.7 
High-fat dairy, servings per day 1.0 0.9 — — 

aBaseline refers to the year of entry into the study for each individual. Values are presented as age-standardized means and proportions with the exception of values for age.

bIncludes skim/low-fat milk, sherbet, yogurt and cottage cheese.

cIncludes whole milk, cream, ice cream, cream cheese and other cheese.

dMETs (metabolic equivalents) = metabolic rate consuming 1 kcal kg−1 body weight h−1.

Intake of total dairy foods was not associated with the risk of anovulatory infertility (Table II). When low-fat and high-fat dairy foods were considered separately, we found a positive association between low-fat dairy food intake above 5 servings per week and risk of anovulatory infertility and an inverse association between high-fat dairy food intake and risk of developing this condition. Adjustment for known and suspected risk factors for infertility, especially adjustment for parity, changed these associations but they remained statistically significant. After adjustment, an increase in low-fat dairy foods of 1 serving per day, while holding calories constant, was associated with an 11% greater risk of anovulatory infertility [95% confidence interval (CI) = 2–21%]. The corresponding RR (95% CI) associated with an increase in intake of high-fat dairy foods by 1 serving per day was 0.78 (0.64–0.95). Simultaneously, including low-fat and high-fat dairy food intake in the same model did not substantially change the results. In this model, the multivariate-adjusted RRs (95% CIs) associated with increasing intake by 1 serving per day, keeping energy intake constant, were 1.09 (1.01–1.19) for low-fat dairy foods and 0.80 (0.65–0.97) for high-fat dairy foods.

Table II.

Relative risks (RRs) (95% CIs) for anovulatory infertility by cumulative averaged frequency of intake of total, low fat and high fat dairy products

Food      P, trenda 
Total dairy foods (servings) <1 day−1 1 day−1 2–3 day−1 ≥4 day−1   
 Cases/non-cases 50/3102 172/8284 175/11 219 41/3928   
 Age and energy-adjustedb 1.00 (referent) 1.36 (0.99–1.88) 1.13 (0.81–1.56) 0.88 (0.55–1.40)  0.09 
 Multivariate-adjustedc 1.00 (referent) 1.36 (0.98–1.88) 1.30 (0.93–1.82) 1.12 (0.69–1.82)  0.94 
Low-fat dairy foodsd ≤1 week−1 2–4 week−1 5–6 week−1 1 day−1 ≥2 / day  
 Cases/non-cases 34/3014 64/4085 51/2183 147/7693 142/ 9558  
 Age and energy-adjustedb 1.00 (referent) 1.37 (0.90–2.08) 2.06 (1.33–3.18) 1.76 (1.21–2.56) 1.58 (1.07–2.32) 0.13 
 Multivariate-adjustedc 1.00 (referent) 1.24 (0.81–1.91) 1.86 (1.19–2.91) 1.71 (1.16–2.52) 1.85 (1.24–2.77) 0.002 
High-fat dairy foodse ≤1 week−1 2-4 week−1 5–6 week−1 ≥1 day−1   
 Cases/non-cases 80/3679 199/9855 61/4398 98/8601   
 Age and energy-adjustedb 1.00 (referent) 0.97 (0.75–1.27) 0.69 (0.49–0.98) 0.61 (0.45–0.85)  <0.001 
 Multivariate-adjustedc 1.00 (referent) 1.05 (0.80–1.37) 0.76 (0.53–1.07) 0.73 (0.52–1.01)  0.01 
Food      P, trenda 
Total dairy foods (servings) <1 day−1 1 day−1 2–3 day−1 ≥4 day−1   
 Cases/non-cases 50/3102 172/8284 175/11 219 41/3928   
 Age and energy-adjustedb 1.00 (referent) 1.36 (0.99–1.88) 1.13 (0.81–1.56) 0.88 (0.55–1.40)  0.09 
 Multivariate-adjustedc 1.00 (referent) 1.36 (0.98–1.88) 1.30 (0.93–1.82) 1.12 (0.69–1.82)  0.94 
Low-fat dairy foodsd ≤1 week−1 2–4 week−1 5–6 week−1 1 day−1 ≥2 / day  
 Cases/non-cases 34/3014 64/4085 51/2183 147/7693 142/ 9558  
 Age and energy-adjustedb 1.00 (referent) 1.37 (0.90–2.08) 2.06 (1.33–3.18) 1.76 (1.21–2.56) 1.58 (1.07–2.32) 0.13 
 Multivariate-adjustedc 1.00 (referent) 1.24 (0.81–1.91) 1.86 (1.19–2.91) 1.71 (1.16–2.52) 1.85 (1.24–2.77) 0.002 
High-fat dairy foodse ≤1 week−1 2-4 week−1 5–6 week−1 ≥1 day−1   
 Cases/non-cases 80/3679 199/9855 61/4398 98/8601   
 Age and energy-adjustedb 1.00 (referent) 0.97 (0.75–1.27) 0.69 (0.49–0.98) 0.61 (0.45–0.85)  <0.001 
 Multivariate-adjustedc 1.00 (referent) 1.05 (0.80–1.37) 0.76 (0.53–1.07) 0.73 (0.52–1.01)  0.01 

aCalculated with median intake in each category as a continuous variable.

bAdjusted for age (continuous), total energy intake (continuous) and calendar time (four 2-year intervals).

cAge and energy-adjusted model further adjusted for BMI (<20, 20–24.9, 25–29.9, ≥30 kg m−2 and missing), parity (0, 1, ≥2 and missing), smoking history (never, past 1–4 cigarette per day, past 5–14 cigaretter per day, past 15–24 cigarette per day, past ≥25 cigarette per day or unknown amount, current 1–4 cigarette per day, current 5–14 cigarette per day, current 15–24 cigarette per day and current ≥25 cigarette per day or unknown amount), physical activity (<3, 3–8.9, 9–17.9, 18–26.9, 27–41.9, ≥ 42 MET-h week−1 and missing), contraceptive use (current user, never user, past user 0–23 months ago, past user 24–47 months ago, past user 48–71 months ago, past user 72–95 months ago, past user 96–119 months ago, past user ≥ 120 months ago and missing), use of multivitamin supplements (yes/no), intake of alcohol (no intake, <2, 2–4.9  and ≥5 g day−1), coffee (<1 cup per month, 1 cup per month, 2–6 cups per week, 1 cup per day, 2–3 cups per day, ≥4 cups per day) and quintiles of iron intake.

dIncludes skim/low-fat milk, sherbet, yogurt and cottage cheese.

eIncludes whole milk, cream, ice cream, cream cheese and other cheese.

When only the first event for each woman was considered in the analysis, the associations between dairy foods intake and anovulatory infertility persisted. For low-fat dairy foods, the multivariate-adjusted RRs (95% CIs) for ovulatory infertility were 1.32 (0.83–2.11) for women consuming 2–4 servings per week, 1.77 (1.06–2.94) for women consuming 5–6 servings per week, 1.64 (1.06–2.52) for women consuming 1 serving per day and 1.67 (1.07–2.62) for women consuming 2 or more servings per day, when compared with women consuming 1 serving per week or less (P, trend = 0.05). For high-fat dairy foods, the corresponding RRs (95% CIs) were 0.91 (0.67–1.24) for women consuming 2–4 servings per week, 0.77 (0.52–1.15) for women consuming 5-6 servings per week and 0.68 (0.46–0.98) for women consuming 1 or more serving per day (P, trend = 0.02).

The results for intakes of specific dairy foods generally followed the aggregated results for low-fat and high-fat dairy products (Table III). Among the low-fat dairy foods, adding one serving per day of yogurt or sherbet/frozen yogurt without changing total energy intake was associated with a greater risk of anovulatory infertility in multivariate-adjusted models. Although there was not a linear relationship between skim/low-fat milk intake and anovulatory infertility, women consuming one or more servings per week of skim/low-fat milk had a significantly higher risk of anovulatory infertility when compared with women consuming less than one serving per week [RR (95% CI) = 1.40 (1.04–1.88)], after adjusting for potential confounders. Among the high-fat dairy foods, adding a daily serving of whole milk without increasing energy intake was associated with a reduction in the risk of anovulatory infertility of more than 50% after accounting for potential confounders. Likewise, the multivariate-adjusted RRs (95% CIs) of anovulatory infertility for women in successively higher intakes of ice cream were 0.85 (0.64, 1.12) for women consuming ice cream once a week and 0.62 (0.43, 0.89) for women consuming ice cream twice or more each week, when compared with women consuming ice cream less than once weekly (P, trend = 0.01).

Table III.

RR (95% CIs) of anovulatory infertility associated with increasing the intake of specific dairy foods by 1 serving per day

Food Age and energy-adjusteda Multivariate-adjustedb 
RR (95% CI) P RR (95% CI) P 
All milk 0.90 (0.82–0.99) 0.04 1.02 (0.92–1.12) 0.74 
Skim or low fat milkc 0.95 (0.87–1.04) 0.29 1.06 (0.96–1.17) 0.26 
Whole milk 0.37 (0.19–0.70) 0.002 0.46 (0.25–0.84) 0.01 
Sherbet or frozen yogurt 2.16 (1.60–2.91) <0.001 1.86 (1.35–2.57) <0.001 
Ice cream 0.46 (0.12–1.72) 0.25 0.70 (0.22–2.27) 0.55 
Yogurtd 1.67 (1.32–2.11) <0.001 1.34 (1.03–1.74) 0.03 
Creame 1.25 (0.65–2.40) 0.50 1.31 (0.64–2.69) 0.46 
Cottage or ricotta cheese 1.43 (0.93–2.21) 0.11 1.40 (0.90–2.17) 0.14 
Cream cheese 0.79 (0.35–1.75) 0.56 0.66 (0.28–1.57) 0.35 
Other cheese 0.82 (0.63–1.05) 0.12 0.86 (0.67–1.09) 0.21 
Food Age and energy-adjusteda Multivariate-adjustedb 
RR (95% CI) P RR (95% CI) P 
All milk 0.90 (0.82–0.99) 0.04 1.02 (0.92–1.12) 0.74 
Skim or low fat milkc 0.95 (0.87–1.04) 0.29 1.06 (0.96–1.17) 0.26 
Whole milk 0.37 (0.19–0.70) 0.002 0.46 (0.25–0.84) 0.01 
Sherbet or frozen yogurt 2.16 (1.60–2.91) <0.001 1.86 (1.35–2.57) <0.001 
Ice cream 0.46 (0.12–1.72) 0.25 0.70 (0.22–2.27) 0.55 
Yogurtd 1.67 (1.32–2.11) <0.001 1.34 (1.03–1.74) 0.03 
Creame 1.25 (0.65–2.40) 0.50 1.31 (0.64–2.69) 0.46 
Cottage or ricotta cheese 1.43 (0.93–2.21) 0.11 1.40 (0.90–2.17) 0.14 
Cream cheese 0.79 (0.35–1.75) 0.56 0.66 (0.28–1.57) 0.35 
Other cheese 0.82 (0.63–1.05) 0.12 0.86 (0.67–1.09) 0.21 

aAdjusted for age (continuous), total energy intake (continuous) and calendar time (four 2-year intervals).

bAge and energy-adjusted model further adjusted for BMI (<20, 20–24.9, 25–29.9, ≥30 kg m−2 and missing), parity (0, 1, ≥2 and missing), smoking history (never, past 1–4 cigarette per day, past 5–14 cigarette per day, past 15–24 cigarette per day, past ≥ 25 cigarette per day or unknown amount, current 1–4 cigarette per day, current 5–14 cigarette per day, current 15–24 cigarette per day and current ≥ 25 cigarette per day or unknown amount), physical activity (<3, 3–8.9, 9–17.9, 18–26.9, 27–41.9, ≥42 MET-h week−1 and missing), contraceptive use (current user, never user, past user 0–23 months ago, past user 24–47 months ago, past user 48–71 months ago, past user 72–95 months ago, past user 96–119 months ago, past user ≥ 120 months ago and missing), use of multivitamin supplements (yes/no), intake of alcohol (no intake, <2, 2–4.9, ≥5 g day−1), coffee (<1 serving per month, 1 serving per month, 2–6 servings per week, 1 serving per day, 2–3 servings per day, ≥4 servings per day) and quintiles of iron intake.

cIncludes skim, 1% and 2% milk.

dIncludes flavoured and plain yogurt.

eIncludes whipped, heavy and sour cream.

We then evaluated whether the intake of dairy fat, lactose, calcium, phosphorus and vitamin D was associated with anovulatory infertility (Table IV). In age and energy-adjusted analyses, there were inverse associations between the intakes of dairy fat, calcium, vitamin D and the risk of developing anovulatory infertility. After adjusting for other variables that could explain these associations, only dairy fat intake was associated with a lower risk of anovulatory infertility. The intakes of lactose and phosphorus were not associated with anovulatory infertility in any of the models.

Table IV.

RR (95% CIs) for anovulatory infertility by intake quintiles of dairy fat, lactose, calcium, phosphorus and vitamin D

Nutrient Quintile of Intake P, trenda 
Dairy fat       
 Median intake (g day−18.6 11.8 14.5 17.3 22.7  
 Cases/non-cases 108/5285 96/5290 97/5315 65/5317 72/5326  
 Age and energy-adjustedb 1.00 (referent) 0.91 (0.69–1.20) 0.91 (0.69–1.21) 0.62 (0.45–0.84) 0.67 (0.49–0.91) 0.002 
 Multivariate-adjustedc 1.00 (referent) 0.95 (0.71–1.26) 1.00 (0.75–1.33) 0.70 (0.51–0.97) 0.79 (0.58–1.08) 0.05 
Lactose       
 Median intake (g day−15.8 12.2 18.4 26.3 38.4  
 Cases/non-cases 85/5306 93/5308 98/5292 89/5306 73/5321  
 Age and energy-adjustedb 1.00 (referent) 1.11 (0.83–1.50) 1.16 (0.86–1.55) 1.10 (0.81–1.49) 0.85 (0.62–1.16) 0.21 
 Multivariate-adjustedc 1.00 (referent) 1.21 (0.89–1.63) 1.28 (0.95–1.74) 1.36 (0.99–1.86) 1.11 (0.80–1.55) 0.47 
Calcium       
 Median intake (mg day−1634 844 1049 1270 1621  
 Cases/non-cases 95/5289 98/5308 114/5275 64/5331 67/5330  
 Age and energy-adjustedb 1.00 (referent) 1.03 (0.77–1.37) 1.25 (0.94–1.64) 0.71 (0.51–0.98) 0.71 (0.52–0.98) 0.003 
 Multivariate-adjustedc 1.00 (referent) 1.10 (0.82–1.48) 1.51 (1.13–2.03) 0.93 (0.66–1.32) 1.02 (0.71–1.45) 0.81 
Phosphorus       
 Median intake (mg day−11127 1288 1412 1548 1743  
 Cases/non-cases 92/5293 80/5319 91/5316 82/5296 93/5309  
 Age and energy-adjustedb 1.00 (referent) 0.86 (0.63–1.16) 1.00 (0.74–1.34) 0.92 (0.68–1.24) 1.01 (0.76–1.36) 0.77 
 Multivariate-adjustedc 1.00 (referent) 0.94 (0.69–1.28) 1.07 (0.79–1.45) 1.09 (0.80–1.49) 1.22 (0.90–1.66) 0.13 
Vitamin D       
 Median intake (IU day−1162 285 419 578 783  
 Cases/non-cases 105/5272 106/5299 91/5318 66/5310 70/5334  
 Age and energy-adjustedb 1.00 (referent) 1.04 (0.79–1.36) 0.91 (0.68–1.22) 0.67 (0.49–0.92) 0.64 (0.47–0.87) <0.001 
 Multivariate-adjustedc 1.00 (referent) 1.12 (0.84–1.48) 1.12 (0.80–1.56) 0.98 (0.66–1.45) 1.01 (0.65–1.57) 0.91 
Nutrient Quintile of Intake P, trenda 
Dairy fat       
 Median intake (g day−18.6 11.8 14.5 17.3 22.7  
 Cases/non-cases 108/5285 96/5290 97/5315 65/5317 72/5326  
 Age and energy-adjustedb 1.00 (referent) 0.91 (0.69–1.20) 0.91 (0.69–1.21) 0.62 (0.45–0.84) 0.67 (0.49–0.91) 0.002 
 Multivariate-adjustedc 1.00 (referent) 0.95 (0.71–1.26) 1.00 (0.75–1.33) 0.70 (0.51–0.97) 0.79 (0.58–1.08) 0.05 
Lactose       
 Median intake (g day−15.8 12.2 18.4 26.3 38.4  
 Cases/non-cases 85/5306 93/5308 98/5292 89/5306 73/5321  
 Age and energy-adjustedb 1.00 (referent) 1.11 (0.83–1.50) 1.16 (0.86–1.55) 1.10 (0.81–1.49) 0.85 (0.62–1.16) 0.21 
 Multivariate-adjustedc 1.00 (referent) 1.21 (0.89–1.63) 1.28 (0.95–1.74) 1.36 (0.99–1.86) 1.11 (0.80–1.55) 0.47 
Calcium       
 Median intake (mg day−1634 844 1049 1270 1621  
 Cases/non-cases 95/5289 98/5308 114/5275 64/5331 67/5330  
 Age and energy-adjustedb 1.00 (referent) 1.03 (0.77–1.37) 1.25 (0.94–1.64) 0.71 (0.51–0.98) 0.71 (0.52–0.98) 0.003 
 Multivariate-adjustedc 1.00 (referent) 1.10 (0.82–1.48) 1.51 (1.13–2.03) 0.93 (0.66–1.32) 1.02 (0.71–1.45) 0.81 
Phosphorus       
 Median intake (mg day−11127 1288 1412 1548 1743  
 Cases/non-cases 92/5293 80/5319 91/5316 82/5296 93/5309  
 Age and energy-adjustedb 1.00 (referent) 0.86 (0.63–1.16) 1.00 (0.74–1.34) 0.92 (0.68–1.24) 1.01 (0.76–1.36) 0.77 
 Multivariate-adjustedc 1.00 (referent) 0.94 (0.69–1.28) 1.07 (0.79–1.45) 1.09 (0.80–1.49) 1.22 (0.90–1.66) 0.13 
Vitamin D       
 Median intake (IU day−1162 285 419 578 783  
 Cases/non-cases 105/5272 106/5299 91/5318 66/5310 70/5334  
 Age and energy-adjustedb 1.00 (referent) 1.04 (0.79–1.36) 0.91 (0.68–1.22) 0.67 (0.49–0.92) 0.64 (0.47–0.87) <0.001 
 Multivariate-adjustedc 1.00 (referent) 1.12 (0.84–1.48) 1.12 (0.80–1.56) 0.98 (0.66–1.45) 1.01 (0.65–1.57) 0.91 

aCalculated with median intake in each category as a continuous variable.

bAdjusted for age (continuous), total energy intake (continuous) and calendar time (four 2-year intervals).

cAge and energy-adjusted model further adjusted for BMI (<20, 20–24.9, 25–29.9, ≥30 kg m−2 and missing), parity (0, 1, ≥2 and missing), smoking history (never, past 1–4 cigarette per day, past 5–14 cigarette per day, past 15–24 cigarette per day, past ≥ 25 cigarette per day or unknown amount, current 1–4 cigarette per day, current 5–14 cigarette per day, current 15–24 cigarette per day and current ≥ 25 cigarette per day or unknown amount), physical activity (<3, 3–8.9, 9–17.9, 18–26.9, 27–41.9, ≥42 MET-h week−1 and missing), contraceptive use (current user, never user, past user 0–23 months ago, past user 24–47 months ago, past user 48–71 months ago, past user 72–95 months ago, past user 96–119 months ago, past user ≥ 120 months ago and missing), use of multivitamin supplements (yes/no), intake of alcohol (no intake, <2, 2–4.9, ≥5 g day−1), coffee (<1 serving per month, 1 serving per month, 2–6 servings per week, 1 serving per day, 2–3 servings per day, ≥4 servings per day) and quintiles of iron intake.

Next, we examined the possibility that the association between intake of high-fat dairy foods and anovulatory infertility was mediated through the intake of dairy fat by including in the same multivariate-adjusted model terms for intake of high-fat dairy foods and dairy fat. Adjustment for dairy fat intake attenuated the association between intake of high-fat dairy foods and anovulatory infertility, although a suggestion of a linear trend was still present. The RRs (95% CI) for women in successively higher intakes of high-fat dairy were 1.06 (0.79, 1.42) for women consuming 2 to 4 servings weekly, 0.78 (0.53, 1.15) for women consuming 5 to 6 servings per week and 0.77 (0.51, 1.17) for women consuming at least one serving per day, when compared with women consuming one or less servings of high-fat dairy each week (P, trend = 0.07). Dairy fat intake was unrelated to anovulatory infertility in this model.

Lastly, we assessed the possibility that the associations between intake of dairy foods and anovulatory infertility could be modified by personal characteristics, including age, menstrual cycle length, BMI and parity. The positive association between of low-fat dairy foods intake and anovulatory infertility appeared to be stronger among women above the median age (32 years), eumenorrhoeic women, women with a BMI below 25 kg m−2 and parous women (Table V). The association between intake of high-fat dairy foods and anovulatory infertility appeared to be stronger among women above 32 years, eumenorrhoeic women and overweight or obese women. However, none of the tests for effect modification reached statistical significance. There were no appreciable differences in the association between low-fat dairy food intake and anovulatory infertility by levels of high-fat dairy food intake or in the association between high-fat dairy food intake and ovulatory infertility by levels of low-fat dairy food intake.

Table V.

RR and 95% CIa of anovulatory infertility associated with increasing dairy foods intake by 1 serving/day in subgroups of the study population

Subgroup Cases (nLow fat dairyb High-fat dairyc 
RR (95% CI) P, interaction RR (95% CI) P, interaction 
Age ≤ 32 years 214 1.08 (0.97–1.20) 0.35 0.86 (0.69–1.09) 0.08 
Age > 32 years 224 1.14 (1.03–1.26)  0.67 (0.52–0.87)  
Cycles ≥ 40 days 52 0.94 (0.73–1.21) 0.16 1.09 (0.66–1.79) 0.16 
Cycles < 40 days 386 1.14 (1.04–1.24)  0.75 (0.61–0.92)  
BMI < 25 248 1.17 (1.05–1.29) 0.11 0.85 (0.67–1.08) 0.23 
BMI ≥ 25 190 1.03 (0.91–1.17)  0.67 (0.50–0.91)  
Nulliparous 208 1.07 (0.95–1.21) 0.45 0.77 (0.55–1.07) 0.93 
Parous 230 1.14 (1.02–1.26)  0.78 (0.62–0.99)  
High fat dairy <5/week 279 1.11 (1.01–1.23) 0.66 — — 
High fat dairy ≥5/week 159 1.07 (0.95–1.22)  —  
Low fat dairy <1/day 149 — — 0.81 (0.62–1.06) 0.82 
Low fat dairy ≥1/day 289 —  0.78 (0.59–1.02)  
Subgroup Cases (nLow fat dairyb High-fat dairyc 
RR (95% CI) P, interaction RR (95% CI) P, interaction 
Age ≤ 32 years 214 1.08 (0.97–1.20) 0.35 0.86 (0.69–1.09) 0.08 
Age > 32 years 224 1.14 (1.03–1.26)  0.67 (0.52–0.87)  
Cycles ≥ 40 days 52 0.94 (0.73–1.21) 0.16 1.09 (0.66–1.79) 0.16 
Cycles < 40 days 386 1.14 (1.04–1.24)  0.75 (0.61–0.92)  
BMI < 25 248 1.17 (1.05–1.29) 0.11 0.85 (0.67–1.08) 0.23 
BMI ≥ 25 190 1.03 (0.91–1.17)  0.67 (0.50–0.91)  
Nulliparous 208 1.07 (0.95–1.21) 0.45 0.77 (0.55–1.07) 0.93 
Parous 230 1.14 (1.02–1.26)  0.78 (0.62–0.99)  
High fat dairy <5/week 279 1.11 (1.01–1.23) 0.66 — — 
High fat dairy ≥5/week 159 1.07 (0.95–1.22)  —  
Low fat dairy <1/day 149 — — 0.81 (0.62–1.06) 0.82 
Low fat dairy ≥1/day 289 —  0.78 (0.59–1.02)  

aAdjusted for age (continuous), total energy intake (continuous), calendar time (four 2-year intervals), BMI (<20, 20–24.9, 25–29.9, ≥30 kg m−2 and missing), parity (0, 1, ≥2 and missing), smoking history (never, past 1–4 cigarette per day, past 5–14 cigarette per day, past 15–24 cigarette per day, past ≥ 25 cigarette per day or unknown amount, current 1–4 cigarette per day, current 5–14 cigarette per day, current 15–24 cigarette per day and current ≥25 cigarette per day or unknown amount), physical activity (<3, 3–8.9, 9–17.9, 18–26.9, 27–41.9, ≥42 MET-h week−1 and missing), contraceptive use (current user, never user, past user 0–23 months ago, past user 24–47 months ago, past user 48–71 months ago, past user 72–95 months ago, past user 96–119 months ago, past user ≥120 months ago and missing), use of multivitamin supplements (yes/no), intake of alcohol (no intake, <2, 2–4.9, ≥ 5 g day−1), coffee (<1 serving per month, 1 serving per month, 2–6 servings per week, 1 serving per day, 2–3 servings per day, ≥4 servings per day) and quintiles of iron intake.

bSkim/low-fat milk, sherbet, yogurt and cottage cheese.

cWhole milk, cream, ice cream, cream cheese and other cheese.

Discussion

In this cohort of healthy women, we found that intake of low-fat dairy foods was associated with a greater risk of anovulatory infertility, whereas intake of high-fat dairy foods was associated with a lower risk of this condition. We found no evidence of an association between lactose and anovulatory infertility within the intake range of consumption in this population. In addition, we did not observe any association between important constituents of dairy foods and anovulatory infertility, with the exception of an inverse association for intake of dairy fat.

Only two previous studies have examined whether intake of milk or dairy foods could affect fertility in women. Cramer et al. (1994) found a positive correlation between per capita milk consumption and age-related decrease in fertility rates in 31 countries; milk consumption statistically explained 36% of the variation in the fertility decline associated with age. Following-up on these findings, Greenlee et al. (2003) questioned participants of a case–control study of agricultural occupations and female infertility about their usual milk consumption. In this study, women who consumed three or more glasses of milk daily had a 70% lower risk of infertility when compared with women who did not consume milk (Greenlee et al., 2003).

Our study has overcome many of the limitations of the previous studies. We were able to account for differences in several personal, behavioural and dietary characteristics that could be alternative explanations for these associations. The prospective nature of the study, in which dietary information was collected 2–4 years before events were reported, makes it unlikely that our results are affected by disease status at the time dietary information was collected: an issue of concern in case–control studies. The use of previously validated questionnaires for dietary and outcome assessments also adds to the strength of our results. A limitation of our study is that it was not a cohort of women known to be planning a pregnancy. Cases were clearly trying to conceive, whereas some pregnancy non-cases may have conceived accidentally. However, we simulated a cohort of pregnancy planners by restricting the study to married women and by considering as non-cases women who were diagnosed with infertility from other causes, making it less likely for pregnancy intention to affect our results. Another potential limitation of our study is that we did not collect information on exposures of the participants' partners that might influence female fertility, such as smoking. This situation, however, is unlikely to have major impact on our results since the potential bias would be limited by the association between the partner risk factor for anovulatory infertility, which is likely to be non-existent or small in the case of smoking status of the partner (Hull et al., 2000; Greenlee et al., 2003), and could be accounted for in part by adjusting for the same factor in women, as we did for smoking and other lifestyle characteristics, since spouses often share environmental exposures and lifestyle practices (Knuiman et al., 2005; Jurj et al., 2006).

We found that eating low-fat dairy foods was associated with an increased risk of anovulatory infertility. It is possible that this association is spurious. If women who have been diagnosed with or suspect they have PCOS made health-conscious changes to their diet, such as consuming low-fat dairy instead of high-fat dairy, a positive association between any of these dietary changes and anovulatory infertility would be expected. If this situation arose, one would also expect that in analyses stratified by PCOS or PCOS symptoms, the association between low-fat dairy foods and anovulatory infertility remained only among women with PCOS or symptoms of this condition. This is not, however, the case in our data. Although the tests for effect modification did not reach statistical significance, our results suggest that the association between low-fat (and high-fat) dairy foods intake and infertility due to anovulation is stronger among women without some clinical manifestations of PCOS than among women with them.

There are other potential explanations for our results regarding low-fat dairy foods intake. Assuming that dietary factors associated with an increased frequency of phenotypic features of PCOS would increase the risk of infertility due to ovulatory disorders, we had anticipated the observed association for low-fat dairy foods. Adebamowo et al. (2005) found intakes of skim milk, low-fat milk, sherbet and cottage cheese to be associated with an increased frequency of physician-diagnosed acne. They hypothesized that the association between skim milk consumption and acne could be explained by milk's content of androgen precursors (Hartmann et al., 1998), the ability of milk to increase circulating IGF-I levels (Heaney et al., 1999; Holmes et al., 2002; Giovannucci et al., 2003). Also, changes in milk composition during the fat extraction process, such as the addition of some whey proteins including α-lactalbumin, have been found to have androgenic effects in animals (Bouthegourd et al., 2002). Several of these mechanisms may be particularly relevant for anovulatory infertility, in particular, the increased IGF-I levels resulting from increased dairy intake as this association may be driven by the intake of low-fat dairy foods (E. Giovannucci, personal communication). Some have proposed that IGF-I may be involved in the pathogenesis of PCOS (Giudice, 1992), and in human ovarian cells, IGF-I can induce thecal cell function changes observed in PCOS (Duleba et al., 1998). Also, exogenous IGF-I administration to women with specific endocrinopathies has resulted in clinical manifestations of PCOS (Klinger et al., 1998). Whether changes in circulating IGF-I levels induced by diet can result in subclinical PCOS-like disorders is unknown, but this would be consistent with our results and should be addressed by future studies.

In contrast with the results for low-fat dairy, greater intake of high-fat dairy foods was associated with a lower risk of anovulatory infertility. Intake of dairy fat was also inversely associated with infertility due to anovulatory disorders and appeared to be partially responsible for the high-fat dairy food association. Although particular fatty acids in dairy products could potentially have a beneficial effect on ovulatory function, a more likely explanation is that a fat-soluble substance present in dairy products may exert this action. Whole milk and other high-fat dairy products have a higher estrogen concentration than their low-fat counterparts (Wolford and Argoudelsi, 1979). Since estrogens decrease circulating IGF-I levels (Jorgensen et al., 2004; Veldhuis et al., 2005), it is possible that their presence in high-fat dairy foods could explain the observed association. Alternatively, increased insulin sensitivity among high-fat dairy consumers may have improved ovulatory function. High-fat, but not reduced-fat, dairy foods were found to decrease the risk of developing abnormal glucose homeostasis in young adults (Pereira et al., 2002), although this finding conflicts with another study suggesting the opposite (Choi et al., 2005).

We did not observe an association between lactose intake and risk of infertility due to ovulatory problems. Our findings contrast with previous clinical and experimental evidence (Kaufman et al., 1981; Swarts and Mattison 1988; Waggoner et al., 1990; Guerrero et al., 2000; Bandyopadhyay et al., 2003) but are not unexpected. Although it has been reported that carriers of gene variants affecting galactose metabolism have an increased risk of infertility (Cramer et al., 1989), these results have not been replicated (Herrington et al., 1996; Lukac Bajalo et al., 2005). In addition, rodents exposed to diets containing 42% lactose, rather than galactose, do not develop the alterations of ovarian morphology and function observed in rodents exposed to high galactose diets (Lui et al., 2005). Also, the exposure to galactose in galactosemia and the rodent models where ovarian consequences have been observed may be well beyond the range of usual dietary exposure in humans. The diets in rodent models that have induced ovarian dysfunction on a high galactose diet usually provide between 35% and 50% of the animal's total energy intake as galactose (Swarts and Mattison, 1988; Bandyopadhyay et al., 2003). For humans, this would require feeding exclusively or almost exclusively on dairy foods which would be, at the very least, challenging. Our findings for associations in opposite directions for low-fat and high-fat dairy foods and the fact that the strength of the associations did not seem to depend on the lactose content of the food (e.g. strong associations for sherbet/frozen yogurt which has a low lactose content) also suggest that intake of lactose at the usual levels of human intake is not deleterious to fertility. We also did not find associations between intake of calcium, phosphorus or vitamin D and anovulatory infertility. These nutrients have been important determinants of fertility in animal models under certain conditions (Johnson and De Luca, 2001, 2002). Our data cannot exclude the possibility, however, that intakes of lactose, calcium, phosphorus or vitamin D could have some effect on ovulatory function and fertility among women carrying gene variants affecting galactose or vitamin D metabolism.

In summary, we observed a positive association between intake of low-fat dairy foods (especially yogurt and sherbet/frozen yogurt) and anovulatory infertility and an inverse association between intake of high-fat dairy foods (especially whole milk and ice cream) and this disease. The intake of dairy fat, or a fat-soluble substance present in dairy foods, may partly explain the association between high-fat dairy and anovulatory infertility. Further, our data do not support the hypothesis that, within the observed range of intake, lactose significantly impairs ovulatory function to the point of affecting fertility. Given the scarcity of studies in this area, it is important that our findings are confirmed or refuted. It is also important to investigate whether dairy foods have an impact on fertility beyond their association with anovulatory infertility. Clarifying the role of dairy foods intake on fertility is particularly important since the current Dietary Guidelines for Americans recommend that adults consume three or more daily servings low-fat milk or equivalent dairy products (United States Department of Health and Human Services and United States Department of Agriculture, 2005); a strategy that may be deleterious for women planning to become pregnant.

Acknowledgements

The work reported in this manuscript was supported by CA50385, the main Nurses' Health Study II grant, and by the training grant T32 DK-007703. The Nurses Health Study II is supported for other specific projects by the following NIH grants: CA55075, CA67262, AG/CA14742, CA67883, CA65725, DK52866, HL64108 and HL03804.

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