Milk consumption and acne in adolescent girls
1. Departments of Nutrition, Harvard School of Public Health, Boston, Division of Oncology, Department of Surgery, University of Ibadan, University College Hospital, Ibadan, Oyo State, Nigeria
There has been a remarkable paucity of evidence for an association between diet and acne. Our previous studies suggest that there is an association between milk intake and teenage acne. This is a prospective cohort study to evaluate that relationship. We studied 6,094 girls, aged 9-15 years in 1996, who reported dietary intake on up to three food frequency questionnaires from 1996 to 1998. Presence and severity of acne was assessed by questionnaire in 1999. We computed multivariate prevalence ratios (PR) and 95 percent confidence intervals for acne. After accounting for age at baseline, height and energy intake, the multivariate PRs (95 % CI; p-value for test of trend) for acne comparing highest (2 or more servings per day) to lowest (<1 per week) intake categories in 1996, were 1.20 (1.09, 1.31; <0.001) for total milk, 1.19 (1.06, 1.32; <0.001) for whole milk, 1.17 (1.04, 1.31; 0.002) for low fat milk and 1.19 (1.08, 1.31; <0.001) for skim milk. This result did not change appreciably when we excluded girls who reported use of contraceptives and when we restricted our analysis to those younger than 11 years of age at baseline. We found a positive association between intake of milk and acne. This finding supports earlier studies and suggests that the metabolic effects of milk are sufficient to elicit biological responses in consumers.
Teenage acne is a common, chronic and self-limiting skin disease that is associated with physical and psychological morbidity in up to 90 percent of adolescents and young adults . In Western countries, acne affects all ages, but its maximum prevalence peaks at 16-18 years when 75-98 percent of this age group is affected . Acne is more common in girls, both overall and below the age 12 years.
Acne results from hyperkeratinization and obstruction of the pilosebaceous follicles secondary to androgen-stimulated failure of normal desquamation of the follicular epithelium, androgen-stimulated sebum production, subsequent colonization of the follicles by Propionibacterium acnes and other organisms, and variably, inflammation . Ecological studies suggest an association between the Western diet and acne , but the relevant dietary factors are unclear. At least one clinical trial failed to find an association with chocolate intake . In another study, subjects were fed large quantities of foods that they claimed worsened their acne but no acne flares occurred . Robinson reported that among 1,925 patients who kept a food diary, the majority implicated milk in acne flares . In a previous study of US female nurses who reported their high school diet and the prevalence of physician-diagnosed severe teenage acne, we found a positive association with intake of total and skim milk .
In this study, we examined data from a prospective study of US youth to evaluate intake of dairy foods and other factors in relation to occurrence of acne among girls. The study was approved by the Institutional Review Boards of the Brigham and Women's Hospital and the Harvard School of Public Health.
The Growing Up Today Study (GUTS) is an ongoing cohort study of 9,039 girls and 7,843 boys, aged 9-15 years at baseline in 1996. These patients were followed by yearly questionnaire to ascertain lifestyle factors. Participants are offspring of the women in the Nurses Health Study II (NHS II) cohort and have been described in detail elsewhere . In this analysis, we examined the association between milk consumption and occurrence of acne among female members of the cohort. After exclusion of participants who had implausible values ( <500 and >5000 kcal/day) for energy intake (n = 96), those who left more than 70 response items blank (n = 33), and those who did not respond to the 1999 questionnaires that contained the acne question (n = 2,945), there were 6,094 girls who completed a detailed food frequency questionnaire (FFQ) in 1996 and another FFQ in either 1997 or 1998.
Semi-quantitative food-frequency questionnaires and calculation of nutrient intake
The development and validation of the GUTS food-frequency questionnaire has been previously described [9, 10]. In brief, participants were asked how frequently they used a typical portion size of specified foods on average during the past year. The dairy food group included total milk, chocolate milk, instant breakfast drink, ice cream, yogurt, cottage cheese, cream cheese, other (hard) cheese, frappe (milkshake), and butter. In addition they were asked "What type of milk do you usually drink" and the options were 'whole milk', '2 percent milk', '1 percent milk', 'skim/nonfat milk', 'soy milk', 'don't know', and 'don't drink milk'. Consumption of the specific types of milk was derived from the cross-classification of the responses to the usual type of milk consumed and the frequency of total milk consumption. Whole milk and 2 percent milk were grouped because of their similar fat content. Other food items that were studied include French fries, pizza, and chocolate candy because these have often been perceived as causes of acne. The response categories for some of the food items such as non-milk dairy foods, pizza, French fries and chocolate candy were collapsed because of small cell sizes.
Nutrient intakes were computed by multiplying the frequency of consumption of each unit of food and the nutrient content of the specified portions based on the nutrient values in foods obtained from US Department of Agriculture sources and food manufacturers . In addition, portion sizes were determined by reviewing the US Department of Agriculture Handbook No. 8 serving sizes , the Nationwide Food Consumption Survey (NFCS) Foods Commonly Eaten by Individuals (specifically for ages 9-18) and the natural serving sizes for foods like a slice of bread or one apple. Nutrients were energy-adjusted by using the residuals from the regression of nutrient intake on total caloric intake . Total intake of vitamin D was calculated from all sources of vitamin D, combining diet and supplements. Intake of vitamin D from foods was calculated from all dietary sources without supplements. Dairy fat was computed from milk, butter and cheese as a whole food and as ingredients in other foods reported in the FFQs.
Validation of the food-frequency questionnaire was done in a random sample of children of 399 participants in the Nurses Health Study II, of whom 305 agreed to participate . Most, 263 (86 %) returned the two food frequency questionnaires administered at an interval of 1 year apart, and completed three 24-hour diet recalls over the same period. The mean of de-attenuated Pearson correlation coefficients between the diet recalls and the food frequency questionnaire was 0.54, which is similar to findings in adults . To evaluate the reproducibility of milk intake over the period of the study, we computed the Spearman correlation coefficients for intake of types of milk at baseline in 1996 and in 1998. These correlations were 0.81 for total milk, 0.65 for whole milk, 0.54 for low fat milk, and 0.68 for skim milk. We note that reported intake can reflect both true changes in intakes and error in reporting.
Assessment of non-dietary factors
Age, Tanner stage, use of oral contraceptives, weight and height were obtained from the yearly mailed questionnaires. See Table 1.
Identification of acne cases
In 1999, members of the GUTS cohort were asked "Compared to other people your age, how would you describe your acne"; possible responses were 'I almost never have any pimples', 'I sometimes get a few pimples', 'I usually have a few pimples', 'I sometimes get a lot of pimples', and 'I usually get a lot of pimples'.
To assess the potential for selection bias, we compared the girls who responded to the 1999 questionnaire that included the item on acne with those who did not, using the Wilcoxon rank-sum test for continuous variables and the χ² test for categorical variables. Age-adjusted Mantel-Haenszel Prevalence Ratios (PR)[15, 16] were used to identify variables that were significantly associated with acne at p-value less than or equal to 0.1. These were then used in multivariate stratified models to identify statistically significant predictors at a p-value of 0.05 or less and those variables that changed the PR of the variables of primary interest by 10 percent or more using the frequency procedure with the Cochran-Mantel-Haenszel option in SAS .
In our primary analysis, to more clearly distinguish respondents with substantial acne from those without, we excluded those who said they had "sometimes a few" pimples and dichotomized the responses between the 'almost never' and the combined categories of 'usually a few, sometimes a lot or usually a lot' levels. This left 3,841 girls for our primary analysis. However we repeated our analysis including all respondents, but dichotomizing the response to the acne question at different levels in order to test the robustness of our findings.
Because we did not know the exact onset of acne and we desired to best simulate a prospective study, we examined the association between diet reported in 1996 and the history of acne that was reported in 1999. We also examined diet responses for 1997 and 1998 separately and the cumulative average of the diet responses from 1996 to 1998 in relation to the occurrence of acne. To further reduce the possibility that the results may be due to change in milk intake as a result of having acne and to examine the association during a period of low prevalence of contraceptive use, we repeated the analysis by examining the association between diet reported by girls aged 11 years and younger in 1996, and acne reported in 1999.
In multivariate analysis, we adjusted for age in months at baseline in 1996 (quintiles), energy intake (quintiles), height (quintiles), BMI (quintiles) and Tanner's stage (Stages 1 and 2, 3, 4, and 5). The food items were modeled as categories of servings per week or per day. The PR and 95 percent confidence intervals (95% CI) were calculated for each category of intake and compared with the lowest category of intake as the reference value. The lowest category of intake for each type of milk included low intakes of all types of milk. In tests for linear trend, food intake was modeled as continuous variables of servings per day.
We categorized the energy-adjusted values of each nutrient into quintiles (except for vitamin D from supplements which we categorized into quartiles) and modeled the prevalence ratio for each quintile with the lowest quintile as the reference category. In tests for linear trend across quintiles of nutrient intake, ordinal scores were modeled as continuous variables. Missing value indicators were created for those with missing covariates because we had few missing data [18, 19]. We present two-sided 95 percent confidence intervals for all PR.
Girls who did not respond to the 1999 questionnaire that was used to define acne were slightly older (mean age = 147 compared to 144 months) than those who did, otherwise there was no notable difference between the two groups. Most of the girls, 40 percent, drank whole or 2 percent milk, 23 percent drank low fat milk, 33 percent drank skim milk, 0.4 percent drank soy milk and 4 percent didn't drink milk at baseline in 1996. Most, 80 percent reported "sometimes a few" pimples or more and 43 percent reported "usually a few" or more pimples. Table 1 shows the age-standardized prevalence of the risk factors for acne according to categories of total milk intake in the cohort. Calcium, total vitamin D, vitamin D from foods, vitamin D from supplements and energy intake increased with increasing intake of total milk. The prevalence of acne according to the intake of total milk was 0.60 for < 1 serving/week, 0.66 for 2-6 servings/week, 0.68 for 1 serving/day and 0.72 for 2 or more servings/day.
Table 2 shows the multivariate PR (95% CI; p-value for test of trend), adjusted for age at baseline, height and energy intake comparing the highest (2 or more servings per day) to lowest (<1 serving per week) categories of food intakes in 1996. These were 1.20 (1.09, 1.31; <0.001) for total milk, 1.19 (1.06, 1.32; <0.001) for whole milk, 1.17 (1.04, 1.31; 0.002) for low fat milk and 1.19 (1.08, 1.31; <0.001) for skim milk. Additional adjustments for BMI or Tanner stage did not alter the PRs appreciably. A weak inverse association was found with intakes of cream cheese; the multivariate PR (95% CI; p-value for test of trend) comparing intakes once a day or more with once a week or less was 0.66 (0.28, 1.55; 0.03). In our questionnaire, chocolate milk was asked as a separate item and this was positively associated with prevalence of acne. The multivariate PR (95% CI; p-value for test of trend) comparing intakes of 2 or more servings per day with one serving or less a week was 1.29 (1.08, 1.53; 0.02). There were no associations between acne and intakes of other dairy foods, chocolate candy or pizza (data not shown). Intakes of total fat, specific types of fat and dairy fat were not associated with acne.
The results for milk intake and the prevalence of acne using the questionnaires completed in 1997, 1998 or the cumulative averaged intake from 1996 to 1998 were similar (data not shown). We tested the robustness of the findings to our definition of acne by repeating the multivariate analysis, first by including the 'sometimes a few' as cases of acne (they were omitted entirely initially) and secondly by including them among the non-cases. The findings were similar to what we reported above (data not shown). Furthermore, to reduce the likelihood of reverse causation and possible interaction with use of oral contraceptives, we examined these associations in a sub-cohort of participants who were aged less than 11 years at baselinea time of relatively low acne prevalenceand the PR, 95% CI and p-value test for trend comparing extremes of intakes were 1.19, 1.08 - 1.31, <0.001. In addition, we repeated the analysis without those girls who reported either use of oral (n = 188) or injectable contraceptives (n = 21) and the PR, 95 percent CI and p-value test for trend comparing extremes of intakes of skim milk were identical, 1.19, 1.08 - 1.31, <0.001.
In this prospective study of US girls whose ages ranged from 9 to 15 years in 1996, we found that greater consumption of milk was associated with higher prevalence of acne. We did not find an association with dairy fat. This suggests that the fat content of milk is not important in comedogenicity. This finding is consistent with the result of our previous study of US female nurses who reported on their high school diet and prevalence of physician-diagnosed severe teenage acne. In that study, we found a positive association with intake of total and skim milk .
Milk intake may affect acne severity through the Insulin-like Growth Factor-1 (IGF-1) pathway. In two large cross-sectional studies, milk consumption was positively associated with higher plasma IGF-1 levels [20, 21] and in both studies, this was predominantly an association with skim milk. In a randomized clinical trial of the effect of milk intake on bone remodeling, intakes of skim and low fat milk were associated with increased serum IGF-1 levels in both sexes . It is not clear whether the increased IGF-1 is endogenousreleased in response to milk intakeor exogenous IGF-1 from milk. Human and bovine IGF-1 share the same amino acid sequences  and several milk proteins, including IGF-binding proteins (IGFBPs) protect IGF-1 from digestion in the gut [24, 25]. Animal studies have shown that milk borne IGF-1 can be absorbed after oral intake . IGF-1 directly stimulates basal keratinocytes' proliferation [26,27]. Although both serum androgens and IGF-1 levels rise at puberty, the period of maximum prevalence of acne and the course of the condition follow the levels of IGF-1 more closely than levels of androgens . There is also a stronger correlation in women between acne lesions and IGF-1 compared to androgens .
Milk intake may influence comedogenesis because it contains several bioactive molecules that can act on the pilosebaceous unit including androgens, 5α-reduced steroids and other steroid hormones [30, 31]. Many of these bioactive molecules survive processing and in the case of cheese, fermentation results in the production of more testosterone from precursors in milk . The level of androgens in milk has generally been considered low and first-pass metabolism in the liver may further reduce its bioavailability compared to the daily endogenous production in young children and adolescents. However, recent studies have questioned the methodology and assays on which estimates of daily production rates of endogenous steroid hormones in pre-pubertal children are based . Dietary intake may be a more significant source of androgens than previously thought . Milk also contains estrogens, some of which are produced in the lactating bovine mammary gland and are direct suppressors of sebaceous gland function .
Some hormones in milk are carried by whey proteins, including α-lactalbumin, which also have intrinsic biological functions . Animals fed α-lactalbumin-enriched whey protein show increased will and capacity to engage in physical activities, gains in lean body mass, improved efficiency of exercise training, and decreased percentage body fat mass; all of which are similar to the effect of androgens [35, 36, 37]. In addition, α-lactalbumin undergoes pressure-induced conformational alteration, possibly because of centrifugation stresses during processing; this leads to changes in biological function . Whey proteins are also added to low fat and skim milk to simulate the consistency of whole milk. These proteins might therefore play a role in acne. We note an inverse association with cream cheese, which may be due to reverse causation because girls with acne may avoid cream cheese in the belief that it is associated with acne. The group of girls who regularly eat cream cheese may also be too small to draw conclusions. Alternatively, the fermentation phase of cheese production is associated with changes in the relative concentration of bioactive molecules in cheese that may explain this finding .
Vitamin D, present in milk because of fortification, plays an important role in epidermal differentiation by inhibiting the proliferation of keratinocytes and this could possibly affect acne risk . However, supplemented vitamin D was not associated with acne prevalence in this study (PR = 1.02, 95% CI = 0.96, 1.08 for highest compared to lowest quartile of intake, p-value for test for trend = 0.81). This suggests that vitamin D was not responsible for the observed association with milk consumption.
Although some of the girls in this study did not respond to the questionnaire that included the question on acne, we do not think that this is likely to bias our result because this is a prospective study and response rate was not appreciably related to milk consumption or to teenage acne. We did not have an opportunity to validate the self-report of teenage acne but other studies have shown that young people's perception of acne severity is closely related to objective clinical assessment . Our sensitivity analysis also shows that our results are robust to different ways of classifying acne in our study population. We did not exclude girls whose acne may be part of the symptom complex of an underlying clinical disorder because we did not have data on this; had we, the association with milk consumption may have been stronger. Our questionnaire did not specify a body location for the acne. However, truncal acne, with absence of a facial component occurs in less than 5 percent of sufferers .
The dietary assessment that we used has been well validated and the use of energy-adjustment corrects for over- or under-reporting of overall dietary intake . We computed Mantel-Haenszel prevalence ratios, a method that intrinsically controls for main effects and higher order interactions of all confounders, whether these confounders are relevant or not. It leads to loss of statistical power and gives a conservative estimate of effect. For example, the odds ratio (95% CI; p-value for test of trend) from the multivariate logistic regression analysis adjusted for age at baseline, height and energy intake comparing the highest (2 or more servings per day) to lowest (<1 serving per week) categories of skim milk intakes in 1996, were 2.27 (1.47, 3.52; <0.001).
In conclusion, our study suggests that milk may have biological effects in the consumer. Because milk contains androgenic hormones and other bioactive molecules, moderation of milk intake may be useful as part of the management of teenage acne. Furthermore, this finding raises the possibility that other hormone-sensitive glands may be affected by the hormonal constituents of milk. Because of the potential detrimental effect of milk products on acne, breast cancer , and prostate cancer, these relationships should be evaluated further.
Acknowledgment: The authors thank Gideon Aweh and Ellen Hertzmark for their support with the data analysis, and the participants in GUTS who made this work possible.
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