By Ted Schettler MD, MPH
Vitamin D plays an essential role in a number of biologic processes throughout the body. In addition to its long-recognized importance for bone health, vitamin D deficiency is increasingly acknowledged to be associated with a number of other diseases and disorders, including various kinds of cancer. A recently published study adds considerable support to yet another health impact—earlier age of menarche in otherwise healthy girls. If this finding holds up in future studies, the implications are profound.
If sunlight exposure is sufficient, adequate amounts of vitamin D are synthesized in the body. But many people, particularly those living in higher latitudes, are not exposed to enough sunlight to generate adequate stores. And, even in sunny places, skin cancer concerns limit sun exposure. Therefore some foods are fortified with modest amounts of vitamin D in an attempt to address the deficiency. Nonetheless, vitamin D insufficiency remains common in the general population. A recent report from the Institute of Medicine addressing this is available here: http://www.ncbi.nlm.nih.gov/books/NBK56070/
Previous studies reported earlier menarche in girls who live increasing distances from the equator, up to about 45-50 degrees latitude. Since vitamin D status is significantly sunshine dependent, vitamin D insufficiency has been proposed as one explanation. But these ecologic, observational studies are inherently limited and best suited to hypothesis generation. However, the more recent study measured vitamin D levels in a group of girls living in a single city before they experienced menarche and followed them for more than two years. It adds important new data.
This study was published in the October, 2011 issue of The American Journal of Clinical Nutrition. It was a prospective, longitudinal study of 242 girls in Bogota, Columbia whose average age at baseline was 8.8 years when plasma vitamin D (25(OH)D) was measured. They were followed for an average of 30 months and periodically asked about the occurrence and date of menarche.
Fifty-seven percent of the girls who were vitamin D deficient (<50 nmol/L) reached menarche during the follow-up period compared to just 23% of those who had sufficient levels of vitamin D (>75 nmol/L). The average age of menarche in these two groups was 11.8 yrs and 12.6 yrs, respectively. These findings held up after adjustment for age and BMI, so that the results could not be explained by overweight or obesity. The authors concluded that inadequate levels of vitamin D were highly significantly associated with earlier menarche in this group of girls. The biologic mechanisms that might explain this remain speculative.
These findings are likely to have extremely important public health and research implications—particularly if they hold up in studies of larger populations.
1) If there is a causal relationship between inadequate vitamin D status and earlier age of menarche, it’s yet another reason to do more about widespread vitamin D deficiency in the general population. In this study, just 11.6% of girls were vitamin D–deficient. For comparison, other studies show that 52% of Hispanic and African-American teens in Boston are vitamin D deficient, and a small sample of white pre-teen girls in Maine showed a 48% deficiency with at least one level of 25(OH)D below 50 nmol/L over a three-year period. (Sullivan, J Am Diet Assoc. 2005;105:971-974)
2) Among the various kinds of cancer linked to low vitamin D levels, the evidence for increased risk of colorectal cancer is probably the strongest and most consistent. However, a link to breast cancer is sometimes although not always observed. A number of laboratory studies show that vitamin D can inhibit cellular proliferation and promote programmed cell death (apoptosis) and cellular differentiation in breast tissue. Laboratory rodents fed low levels of vitamin D develop more mammary tumors when exposed to a carcinogen than animals fed adequate amounts. The effect is most marked in animals that are also fed a high-fat diet. It appears that vitamin D can inhibit both early and later events in mammary tumor development.
In addition, adequate amounts of vitamin D are necessary for normal mammary gland development. For example, in mammary gland organ culture studies, vitamin D–like compounds inhibit estrogen-induced ductal proliferation and branching. This suggests that vitamin D status in pre-pubertal and pubertal girls could influence breast development and, thereby, breast cancer risk.
Epidemiologic studies virtually always look for associations between adult vitamin D status and breast cancer risk. None has attempted to study the influence of childhood vitamin D status on later breast cancer risk. This would of course be difficult to do and would require decades of data collection.
Thus, although laboratory and epidemiologic data confirm the plausibility of a causal connection between inadequate vitamin D and increased breast cancer risk, considerable uncertainty remains.
3) Collectively, these observations raise an additional question—one having to do with research study design and statistical analyses. Epidemiologic studies examining the relationship between vitamin D status and breast cancer risk usually “control for” age of menarche, since earlier menarche is itself associated with increased breast cancer risk. But this recent study suggests that controlling for age at menarche may not always be appropriate. If childhood vitamin D status influences age of menarche, it could thereby influence breast cancer risk. In general, variables within a causal pathway of an exposure-outcome of interest should not be controlled. In the recent IOM report Breast Cancer and the Environment: A Life Course Approach the committee said:
Moreover, confounders need to be understood as operating, not one-by-one, but rather in a complex network of causal relationships. Graphical tools, such as directed acyclic graphs (DAGs), are sometimes used to identify the appropriate confounders for control, and to identify which factors should not be controlled (Greenland et al., 1999; Hernan et al., 2002). This latter group consists of two categories of variables: (1) factors that are downstream of the exposure, and (2) factors that block a pathway between exposure and disease (e.g., they have antecedents, one that is associated with exposure and the other with disease). Some factors that are downstream of exposure may be intermediates on a causal pathway, but whether they are or not, control for them can introduce bias, except in very specific circumstances (Petersen et al., 2006). In most instances, factors that block an exposure–disease pathway should also not be controlled, in order to obtain unbiased measures of the association of interest.
Thus, in future studies of vitamin D and breast cancer risk, consideration will need to be given to a) childhood as well as adult levels of vitamin D and b) whether or not to control for age at menarche when that variable may be influenced by the exposure of interest (vitamin D status).
In summary, we can add earlier age of menarche to the list of potential health impacts that may be caused by inadequate levels of vitamin D—a common condition in the general population. This finding should be verified in a larger prospective study. The public health implications should not be underestimated.
For those who are interested, the Institute of Medicine report finds the evidence for many of the vitamin D–health endpoints, including breast cancer, insufficient to use for determining a recommended daily intake. But for those health endpoints with consistent, strong evidence here is their recommendation:
Recommended daily allowance (RDA) 600 IU daily, except 800 IU daily for men and women > 70 yrs of age;
Safe upper limit (UL): 1000-1500 IU infants; 2500-3000 IU children; 4000 IU adolescents and adults
The IOM report estimates that the average vitamin D intake for males in the US is 300-400 IU daily; for females 200-400 IU daily (varies with age; does not account for vitamin D from sun exposure). Thus, on average, vitamin D intake in the US is well below the RDA of 600 IU daily and well below the estimated safe upper limit.