З. Стоянов, П. Николова «Левшество и риск рака молочной железы: изобилие противоречивых данных» (C.15-20)

Z. Stoyanov, P. Nikolova

Left-handedness and Risk of Breast Cancer: Abundance of Conflicting Data

Department of Physiology and Pathophysiology, Medical University “Prof. Paraskev Stoyanov”, Varna, Bulgaria

Левшество и риск рака молочной железы: изобилие противоречивых данных
З. Стоянов, П. Николова
Left-handedness and Risk of Breast Cancer: Abundance of Conflicting Data

Z. Stoyanov, P. Nikolova
The present short review summarizes controversial data regarding the putative association between left-handedness and breast cancer. Factors thought to be involved in the etiology and pathogenesis of breast cancer are outlined: prenatal and postnatal levels of sex steroids, maternal age, age at menarche and age at menopause. The same factors are discussed with regard to handedness and apparent conflicts are revealed.
Keywords: left-handedness, breast cancer, sex hormones, age at menarche, age at menopause

Convincing evidence suggests that functional brain asymmetry is spread over the neural control of autonomic physiologic functions (Neveu, 1992; Wittling, 1995; Fokin et al., 2011): the left and right hemispheres are differently involved in the control of cardiac activity, endocrine functions, and in neuroimmunomodulation. Against this background, it is reasonable to expect associations between the patterns of brain asymmetry and some somatic diseases.

It is widely accepted that manual asymmetry is a reflection of the general asymmetry of brain (Gutnik et al., 2010) and that left-handedness is associated with peculiarities in the patterns of brain lateralization (Llaurens et al., 2009). In the context of the above mentioned putative associations between brain asymmetry and diseases, many researchers analyze the incidence of left-handedness in clinical populations (Geschwind and Behan, 1982; Coren, 1992; King and Nixon, 1995; Bryden et al., 2005; Gardener et al., 2009).

According to several publications, left-handed women should be included in the high-risk groups of breast cancer, the most common cancer in women (López-Otín and Diamandis, 1998; Armstrong et al., 2000; Persson, 2000). Titus-Ernstoff et al. (2000) found out a modest association between left-handedness and breast cancer risk in women over 60 years of age. Ramadhani et al. (2005) estimate that as a whole the risk of breast cancer is 39% higher in left-handed women. The same authors pointed out that in younger left-handed women (pre-menopausal ones) the risk is increased more than twofold. Fritschi et al. (2007) replicated the finding of Titus-Ernstoff et al. (2000): the risk of developing post-menopausal breast cancer is significantly higher for left-handed women compared to right-handed. The authors of the articles cited above speculated that the origin of the association between left-handedness and breast cancer may lie (partly at least) in intrauterine hormonal milieu: exposure to sex steroids, which have been considered as aetiological factors for both left-handedness and breast cancer.

It should be noted, however, that contrary data exist. The study of Stellman et al. (1997) establishes that the risk of breast cancer is lower in left-handed women. The results of Stellman et al. (1997) are in accordance with the earlier ones of Olsson and Ingvar (1991): among breast cancer patients, left-handed are 1.5%, while the incidence of left-handedness in the observed referent population is 5%.

In their review on aetiology and pathogenesis of breast cancer López-Otín and Diamandis (1998) summarized: “1/ Breast cancer is not a purely genetic disease…; 2/ Environmental factors either acting alone or in association with genetic factors are likely to be very important; 3/ Endogenous and exogenous sex hormones appear to be linked to the pathogenesis. …the endogenous hormonal milieu is very important especially early in life; 4/ It appears that the risk is established at a very early stage, e.g., during prenatal, neonatal, and pubertal life…”. The last two statements are the core of the hypothesis suggested by Trichopoulos (1990; 2003): that intrauterine exposure to elevated concentrations of estrogens increases the risk of breast cancer in the offspring. As Trichopoulos (2003) acknowledges himself, “this hypothesis is very difficult to directly evaluate”. Some comparisons can, however, be made with conditions or anthropometric indicators (pregnancy toxemia, birth weight, second to fourth digit ratio), for which it is known that they correlate with the levels of pregnancy estrogens (Ekbom et al., 1997; Potischman and Troisi, 1999; Manning and Leinster, 2001; Park et al., 2008). It is accepted, for instance, that the ratio between the lengths of the 2nd and 4th digit of the hand (2D:4D ratio) correlates negatively with prenatal exposure to testosterone and positively with prenatal estrogens. The high ratio of testosterone/estrogens (relative low levels of estrogens) determines lower values of 2D:4D, and vice versa; that is, low testosterone/estrogens ratio (relative high levels of estrogens) is associated with higher values of 2D:4D (Lutchmaya et al., 2004). If high in utero exposure to estrogens predisposes to breast cancer, then 2D:4D ratios should positively correlate with cancer risk, suggested Manning and Leinster (Manning and Leinster, 2001). They found out that 2D:4D ratios in breast cancer patients were similar to ratios in controls. In a patients’ group, however, women with high 2D:4D ratios (i.e., high prenatal estrogens) developed breast cancer earlier than women with low 2D:4D ratios (i.e. low prenatal estrogens).

If left-handed women are at higher risk to develop breast cancer and that can be attributed to specificity in the intrauterine hormonal environment and especially to relative high levels of estrogens, then 2D:4D ratios in left-handed women, as a rule, should be higher than 2D:4D ratios in right-handed women. In one of our studies, however, we found out handedness-related peculiarities in the 2D:4D ratios, suggesting that left-handed women were not subjected to higher levels of estrogens in utero: right-hand 2D:4D ratio in left-handed women was lower than right-hand 2D:4D ratio in right-handed (Stoyanov et al., 2011). Our results are in concordance with the hypothesis of Geschwind and Galaburda (1985): that the high intrauterine levels of testosterone (relative low levels of estrogens respectively) impede the growth of certain regions of the left hemisphere, which leads to “anomalous cerebral dominance” and increase of left-handedness.

According to the results of some studies, the risk of breast cancer is to a certain extent higher in women born by older mothers (Ekbom et al., 1997; Park et al., 2008). On the other hand, there is data indicating increased incidence of non-right-handedness and left-handedness in the offspring of older mothers (Badian, 1983; McKeever et al., 1995; Ooki, 2006). Panagiotopoulou et al. (1990) and Zhang et al. (1995) associate older maternal age with high levels of pregnancy estrogens. In studies in primates, however, Hopkins et al. (2000) established a marked reduction of estrogen levels in older multipara and a correlation between that reduction and increased left-handedness among the offspring.

Early age at menarche (<12 years) and late age at menopause (≥55 years) are considered as predictors of increased breast cancer risk (Armstrong et al., 2000; Persson, 2000). The results of our study showed that the mean age at menarche in left-handed women (12 years 1 month of age) is significantly lower than the mean age at menarche in right-handed (13 years 4 months of age) (Nikolova et al., 1994). That corresponds with the data for increased risk of breast cancer in left-handed women. Another of our studies, however, showed that left-handed women also have an earlier average age at menopause – 43 years 6 months of age against 50 years of age in right-handed women (Nikolova et al., 1996). Several publications reported similar to our data age at menarche (Orbak, 2005) and age at menopause in left-handers (Leidy, 1990; Dane et al., 1999), while other studies did not establish an association between handedness and these reproductive indices (Pavia et al., 1994; Kalichman and Kobyliansky, 2008).

Based on findings from several studies, Epplein et al. (2010) concluded that early menarche contributes to increase of breast cancer risk in two ways: “by resulting in a greater lifetime number of menstrual cycles, leading to a greater cumulative exposure to endogenous estrogens; and through elevated circulating estrogen levels throughout the reproductive years”. Using our data for ages at menarche and at menopause, we can approximate the average reproductive life span for left- and right-handed women: it is 31 years 5 months for left-handed and 36 years 8 months for right-handed (Nikolova et al., 1994; Nikolova et al., 1996). We have established that the average length of menstrual cycle in left-handed women is shorter (27 days) as compared to right-handed (30 days) (Nikolova et al., 2003). Due to the shorter reproductive life span, however, the average lifetime number of menstrual cycles in left-handed is less – about 425 cycles, against approximately 444 cycles in right-handed. In regard to elevated circulating estrogen levels throughout the reproductive years in women with early menarche, we have actually observed higher serum levels of estradiol in left-handed women of reproductive age as compared to right-handed (Negrev et al., 2001).

According to the suggested aetiological model for breast cancer (Persson, 2000), the probability of breast cancer developing depends on the amount of susceptible cells in the breast parenchyma. А number of mammotrophic hormones affect the cells at risk. Ovarian estrogens and progesterone, prolactin and IGF-1[1] increase the proliferation of breast epithelial cells and may determine breast cancer risk during adolescence and in adult life (Persson, 2000). It is interesting to note in this context that our data showed not only higher levels of estradiol in left-handed when compared to right-handed women, but of progesterone and prolactin as well (Negrev et al., 2001). Unfortunately, research on sex hormone levels and handedness are scarce (Tan, 1992) and it is difficult to make comparisons.

In conclusion, we think that the data presented, even if controversial, should be taken into account and discussed both by researchers who find an association between left-handedness and breast cancer, and by those who deny such a relation.

References.

  1. Armstrong, K., Eisen, A., Weber, B. Assessing the risk of breast cancer. N Engl J Med 342, 2000, 564-571.
  2. Badian, N.A. Birth order, maternal age, season of birth, and handedness. Cortex 19, 1983, 451-463.
  3. Bryden, P.J., Bruyn, J., Fletcher, P. Handedness and health: an examination of the association between different handedness classifications and health disorders. Laterality 10(5), 2005, 429-440.
  4. Corrine, S. The Left-Hander Syndrome: The Causes and Consequences of Left-Handedness. Free Press, 1992, New York.
  5. Dane, S., Reis, N., Pasinlioğu, T. Left-handed women have earlier age of menopause. J Basic Clin Physiol Pharmacol 10, 1999, 147-150.
  6. Ekbom, A., Hsieh, C.C., Lipworth, L., Adami, H.Q., Trichopoulos, D. Intrauterine environment and breast cancer risk in women: a population-based study. J Natl Cancer Inst 89, 1997, 71-76.
  7. Epplein, M., Novotny, R., Daida, Y., Vijayadeva, V., Onaka, A.T., Le Marchand. L. Association of maternal and intrauterine characteristics with age at menarche in a multiethnic population in Hawaii. Cancer Causes Control 21, 2010, 259-268.
  8. Fokin, V.F., Ponomareva, N.V., Krotenkova, M.V., Konovalov, R.N., Tanashian, M.M., Lagoda, O.V. Factors determining dynamic properties of functial interhemispheric asymmetry. Journal of Asymmetry 5(1), 2011, 5-20.
  9. Fritschi, L., Divitini, M., Talbot-Smith, A., Knuiman, M. Left-handedness and risk of breast cancer. Br J Cancer 97, 2007, 686-687.
  10. Gardener, H., Munger, K., Chitnis, T., Spiegelman, D., Ascherio, A. The relationship between handedness and risk of multiple sclerosis. Multiple Sclerosis 15(5), 2009, 587-592.
  11. Geschwind, N., Behan, P. Left-handedness: association with immune disease, migraine, and developmental learning disorder. Proc Natl Acad Sci USA 79, 1982, 5097-5100.
  12. Geschwind, N., Galaburda, A.M. Cerebral lateralization. Biological mechanisms, associations, and pathology: II. A hypothesis and program for research. Arch Neurol 42, 1985, 521-552.
  13. Gutnik, B., Ieder, P., Arhangelskaya Y. Critique of some traditional approaches to research in the field of asymmetry CNS. Journal of Asymmetry 4(4), 2010, 38-46.
  14. Hopkins, W.D., Dahl, J.F., Pilcher, D. Birth order and left-handedness revisited: some recent findings in chimpanzees (Pan troglodytes) and their implications for developmental and evolutionary models of human handedness. Neuropsychologia 38, 2000, 1626-1633.
  15. Kalichman, L., Kobyliansky, E. Laterality and reproductive indices. Menopause 15, 2008, 991-995.
  16. King, J.C., Nixon, P.G. Effects of non-right-handedness on risk for sudden death associated with coronary artery disease. Am J Cardiol 75(16), 1995, 1187.
  17. Leidy, L.E. Early age at menopause among left-handed women. Obstet Gynecol 76, 1990, 1111-1114.
  18. Llaurens, V., Raymond, M., Faurie, C. Why are some people left-handed? An evolutionary perspective. Phil Trans R Soc B 364, 2009, 881-894.
  19. López-Otín, C., Diamandis, E.P. Breast and prostate cancer: an analysis of common epidemiological, genetic, and biochemical features. Endocr Rev 19, 1998, 365-396.
  20. Lutchmaya, S., Baron-Cohen, S., Raggatt, P., Knickmeyer, R., Manning, J.T. 2nd to 4th digit ratios, fetal testosterone and estradiol. Early Hum Dev 77, 2004, 23-28.
  21. Manning, J.T., Leinster, S. 2nd to 4th digit ratio and age at presentation of breast cancer. The Breast 10, 2001, 355-357.
  22. McKeever, W.F., Suter, P.J., Rich, D.A. Maternal age and parity correlates of handedness: gender, but no parental handedness modulation of effects. Cortex 31, 1995, 543-553.
  23. Negrev, N.N., Nikolova, P.P., Nikolova, R.I. Dynamics of blood serum levels of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone in right- and left-handed women. Human Physiol 27, 2001, 468-471.
  24. Neveu, P.J. Asymmetrical brain modulation of the immune response. Brain Res Brain Res Rev 17, 1992, 101-107.
  25. Nikolova, P., Negrev, N., Stoyanov, Z., Nikolova, R. Functional brain asymmetry, handedness and age characteristics of climacterium in women. Int J Neurosci 86, 1996, 143-149.
  26. Nikolova, P., Stoyanov, Z., Negrev, N. Functional brain asymmetry, handedness and menarcheal age. Int J Psychophysiol 18, 1994, 213-215.
  27. Nikolova, P.P., Negrev, N.N., Nikolova, R.I., Dzhebarov, S.S. Menstrual Rhythm, menstrual interval, and duration of menstruation in Left-Handed and Right-Handed Women.Human Physiol 29, 2003, 390-391.
  28. Olsson, H., Ingvar, C. Left handedness is uncommon in breast cancer patients. Eur J Cancer 27, 1991, 1694-1695.
  29. Ooki, S. Nongenetic factors associated with human handedness and footedness in Japanese twin children. Environ Health Prev Med 11, 2006, 304-312.
  30. Orbak, Z. Does handedness and altitude affect age at menarche? J Trop Pediatr 51, 2005, 216-218.
  31. Panagiotopoulou, K., Katsouyanni, K., Petridou, E., Garas, Y., Tzonou, A., Trichopoulos, D. Maternal age, parity, and pregnancy estrogens. Cancer Causes Control 1, 1990, 119-124.
  32. Park, S.K., Kang, D., McGlynn, K.A., Garcia-Closas, M., Kim, Y., Yoo, K.Y., Brinton, L.A. Intrauterine environments and breast cancer risk: meta-analysis and systematic review. Breast Cancer Res 10, 2008, R8.
  33. Pavia, M., Hsieh, C.C., Ekbom, A., Adami, H.O., Trichopoulos, D. Handedness, age at menarche, and age at menopause. Obstet Gynecol 83, 1994, 579-582.
  34. Persson, I. Estrogens in the causation of breast, endometrial and ovarian cancers – evidence and hypotheses from epidemiological findings. J Steroid Biochem Mol Bio 74, 2000, 357-364.
  35. Potischman, N., Troisi, R. In-utero and early life exposures in relation to risk of breast cancer. Cancer Causes Control 10, 1999, 561-573.
  36. Ramadhani, M.K., Elias, S.G., van Noord, P.A., Grobbee, D.E., Peeters, P.H., Uiterwaal, C.S. Innate left handedness and risk of breast cancer: case-cohort study. BMJ 331, 2005, 882-883.
  37. Stellman, S.D., Wynder, E.L., DeRose, D.J., Muscat, J.E. The epidemiology of left-handedness in a hospital population. Ann Epidemiol 7, 1997, 167-171.
  38. Stoyanov, Z., Pashalieva, I., Nikolova, P. Finger length ratio (2D:4D) in left- and right-handed females: evidence supporting Geschwind and Galaburda hypothesis. Journal of Asymmetry 5(2), 2011, 20-25.
  39. Tan, U. Testosterone and estradiol in right-handed men, but only estradiol in right-handed women is inversely correlated with the degree of right-hand preference. Int J Neurosci 66, 1992, 25-34.
  40. Titus-Ernstoff, L., Newcomb, P.A., Egan, K.M., Baron, J.A., Greenberg, E.R., Trichopoulos, D., Willett, W.C., Stampfer, M.J. Left-handedness in relation to breast cancer risk in postmenopausal women. Epidemiology 11, 2000, 181-184.
  41. Trichopoulos, D. Hypothesis: does breast cancer originate in utero? Lancet 335, 1990, 939-940.
  42. Trichopoulos, D. Intrauterine environment, mammary gland mass and breast cancer risk. Breast Cancer Res 5, 2003, 42-44.
  43. Wittling, W. Brain asymmetry in the control of autonomic-physiologic activity. In: Davidson, R.J., Hugdahl, K. (Eds.), Brain Asymmetry. MIT Press, 1995, Cambridge, p.p. 305-357.
  44. Zhang, Y., Cupples, L.A., Rosenberg, L., Colton, T., Kreger, B.E. Parental ages at birth in relation to a daughter’s risk of breast cancer among female participants in the Framingham Study (United States). Cancer Causes Control 6, 1995, 23-29.

[1] Insulin-like Growth Factor 1

Комментарии и пинги к записи запрещены.

Комментарии закрыты.

Дизайн: Polepin