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DIR Papers of the Month

By Eddy Ball
April 2007

Exercise May Help Women Prevent Fibroids

An NIEHS-funded study of 1,189 white and African-American Women in Washington, D.C., could give women yet another reason to exercise regularly. In the study, published in the March issue of the American Journal of Epidemiology, investigators found an inverse association between physical activity and development of uterine leiomyomata (benign tumors known as fibroids). Fibroids significantly impact female reproductive health and are a leading cause of hysterectomy.

Investigators randomly selected women between the ages of 35 and 49 who were members of a prepaid health plan in Washington, D.C., and participants in the NIEHS Uterine Fibroid Study. In order to become a part of the study population, the women needed acceptable fibroid data, based on sonogram (76 percent), medical records (7 percent) or self-report of fibroid diagnosis (9 percent). Participants included 734 African-Americans and 455 Whites who self-reported their physical activity. The team collected data about potential confounders, such as reproductive history, smoking, alcohol intake and education.

Consistently reported risk factors for the condition are non-modifiable. The association found in this study between physical activity and fibroid status suggests that exercise may be protective against the development of fibroids in a dose response pattern, offering women the opportunity of making a lifestyle change that could benefit their reproductive health.

Citation: Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM( Exit NIEHS. 2007. Association of physical activity with development of uterine leiomyoma. Am J Epidemiol 165(2):157-163.

Obesity Impacts Ability to Conceive

Intramural researchers from the NIEHS Epidemiology and Biostatistics Branches have found that obesity was associated with reduced fecundity for all subgroups of women participating in their recent study of more than 7300 pregnant women. Their results, published in the February issue of Human Reproduction, suggests that weight loss could increase fertility for overweight and obese women, regardless of menstrual cycle regularity, parity, smoking habits or age.

The researchers selected the subjects from the more than 55,000 pregnant women enrolled in the Collaborative Perinatal Project at 12 study centers in the United States between 1959 and 1965. The team selected the 7,327 participants with complete physical and lifestyle data needed for statistical analysis. The study compared more fertile women, those who became pregnant in three months or less, with less fertile women. The team also compared women who planned their pregnancies with women had not, using BMI, age, smoking, parity and other demographic, gynecological and reproductive characteristics.

In their discussion, the authors of the study hypothesized that obesity-induced excess estrogen may be responsible for reduced fecundity. They suggest that "weight loss and improved knowledge of the fertile window should be encouraged as non-invasive first attempts for treating infertility for overweight and obese women."

Citation: Gesink Law DC, Maclehose RF, Longnecker MP( Exit NIEHS. 2007. Obesity and time to pregnancy. Hum Reprod (2):414-420.

Involvement of Estrogen Receptor-α in Airway Hyperresponsiveness

An interdisciplinary research team has found a variety of lung function abnormalities and enhanced airway responsiveness to inhaled methacholine and serotonin in estrogen receptor-a knockout (αERKO) mice. Published in the American Journal of Respiratory and Critical Care, the NIEHS-funded study was a collaboration among researchers from NIEHS, the Environmental Protection Agency, the Medical College of Wisconsin and the National Jewish Medical and Research Center.

The team of investigators examined basal lung function and airway hyperresponsiveness in wild type, aERKO and ßERKO mice using a variety of approaches including non-invasive and invasive measurements of lung function in vivo, and ex vivo measurements of airway tension in isolated bronchial rings. They found that while ERß had little influence on most aspects of lung function, disruption of ERα resulted in significant changes in a variety of respiratory parameters and played a critical role in regulating breathing and respiratory rhythmogenesis in mice. Moreover, lack of ERα led to spontaneous airway hyperresponsiveness via a mechanism that involved altered regulation of M2 muscarinic receptor expression and function. Importantly, absence of ERα in mice led to airway hyperresponsiveness without increased inflammation after allergen sensitization and challenge. Airway hyperresponsiveness is an important feature of human asthma.

Together, the findings in this study provide further insight into the mechanisms which underlie gender differences in lung function and response to environmental agents.

Citation: Carey MA, Card JW, Bradbury JA, Moorman MP, Haykal-Coates N, Gavett SH, Graves JP, Walker VR, Flake GP, Voltz JW, Zhu D, Jacobs ER, Dakhama A, Larsen GL, Loader JE, Gelfand EW, Germolec DR, Korach KS, Zeldin DC( Exit NIEHS. 2007. Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice. Am J Respir Crit Care Med 175(2):126-135.

Breast Enlargement in Prepubertal Boys

In a study funded by NIEHS, Laboratory of Reproductive and Developmental Toxicology investigators collaborated with University of Colorado School of Medicine pediatricians to report on the cases of three young boys, aged four through ten, with prepubertal gynecomastia. Previously, clinicians rarely have been able to identify a specific cause for breast enlargement in boys who have not reached puberty. Gynecomastia in older boys occurs in more than 60% of males during puberty and is usually linked to endogenous hormone levels.

The study, which gained considerable publicity after its publication in the New England Journal of Medicine, linked resolution of breast enlargement in the children to discontinuation of soaps, lotions and shampoos containing lavender and tea tree oils. The researchers demonstrated in vitro the capacity of the oils to disrupt the endocrine system and lead to imbalance in estrogen and androgen pathway signaling. Using human breast cancer cells, they showed that the oils modulated the expression of estrogen-related endogenous genes and produced inhibitory effects on androgen receptor activity.

This study appears to establish a connection between endocrine disruption in vitro and prepubertal gynecomastia. Thus, it offers clinicians an additional option to pursue when confronted by idiopathic cases of this kind.

Citation: Henley DV, Lipson N, Korach KS, Bloch CA( Exit NIEHS. 2007. Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med 356(5):479-485.

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