ANNE B. LOUCKS
Professor
Department of Biological Sciences
College of Arts and Sciences
Ohio University, Athens, OH 45701
TEL: (740) 593-2286 FAX: (740) 593-0300


A.     The Clinical Significance of My Research

My research concerns the integrative processes whereby exercise and nutrition affect energy balance and reproductive function in humans. I aim to learn whether the menstrual disorders observed in physically active women are caused by the stress of exercise itself or by under-nutrition, or by some other factor; to identify the mechanism(s) by which the causal behavioral factor(s) disrupt reproductive function; and to develop practical means to prevent and reverse these conditions.

At any given time, half of the girls and women in America are on a diet while millions exercise regularly. Many exercise and restrict their diets. A high proportion of these women experience either amenorrhea (i.e., absence of menstrual cycles), which is obvious to the affected woman, or luteal suppression, which is entirely asymptomatic. Beyond the impacts of these conditions on fertility, the chronically low estrogen levels in young amenorrheic women cause a progressive and apparently irreversible loss of bone mineral over time, just like that which occurs in menopausal women. Instead of accumulating bone density, girls and women with athletic and dietary amenorrhea are at steadily increasing risk of stress fractures in the short term and of osteoporotic fractures later in life.

Early in my career, I found that part of the reason that these disorders were not understood was our ignorance about the normal regulation and development of the female reproductive system. We did not understand how a healthy and active reproductive system in the fetus turns off in infancy, or how it turns on again at puberty, or how it turns off again temporarily in pregnancy or permanently at menopause. Through my research on physically active women, I aim to contribute to a better general understanding of the regulation of the human female reproductive system.

The results of my research have important practical implications. The first implication is that athletes in particular and women in general may not need to choose between their cardiovascular fitness and their reproductive and skeletal health. Physically active women may be able to reverse or to prevent reproductive disorders by dietary reform, without moderating their exercise regimen. The second implication is that certain recommendations in the U.S. Public Health Service publication Healthy People 2010 may need to be revised. This document advises all adults to restrict their dietary energy intake and to exercise for the prevention and treatment of cardiovascular disease and obesity, but it offers no guidance regarding diet and exercise regimens that may put them below a threshold of energy availability needed for reproductive health. Nor does it warn women that they may need more energy than men relative to their body size to maintain their reproductive and skeletal health.


B.     Current Research

In recent years, the major hypothetical causes of reproductive disorders in physically active women have been the stress of exercise and under-nutrition. Because all previous animal and human studies of the influence of exercise on the reproductive system had confounded the stress of exercise and its energy cost, I designed a randomized, prospective experimental protocol to distinguish the independent effects of these factors. In this protocol, we independently control the energy availability (operationally defined as dietary energy intake minus exercise energy expenditure) and exercise stress (operationally defined as everything associated with exercise except its energy cost) that we administer for several days to regularly menstruating young women. We then measure the effects of these treatments on various metabolic and endocrine parameters.

We are currently conducting our fifth experiment with this protocol. The first experiment revealed that thyroid hormones (which are low in amenorrheic athletes) are suppressed by low energy availability, and not by exercise stress (Loucks & Callister, 1993). The second experiment showed that this suppression of thyroid metabolism occurs abruptly at a particular threshold of energy availability. The third experiment showed that LH pulsatility, like thyroid metabolism, is disrupted by low energy availability, and not by exercise stress (Loucks & Heath, 1994, Loucks, Verdun, & Heath, 1998). This was true, regardless of whether energy availability was reduced by dietary restriction alone, by exercise energy expenditure alone, or by combinations of diet and exercise regimens. This experiment also contributed new knowledge about leptin (Hilton & Loucks, 2000). Others had hypothesized leptin to be the long-sought chemical messenger by which body fat stores regulate reproductive function. We found that disruptions of LH pulsatility by low energy availability were, indeed, associated with 70% declines in leptin levels, but that body weight declined only 3%. Thus, if leptin is involved in the control of LH pulsatility, leptin is more likely driven by changes in daily energy availability than by changes in fat stores. In this experiment, we also saw evidence that LH pulsatility may depend not on the availability of energy in general, but rather on the availability carbohydrates, which is the preferred metabolic fuel of the brain.

The fourth experiment in this series showed that aggressive refeeding is unable to restore normal LH pulsatility in energy deficient women within twenty-four hours, in contrast to observations in other mammalian species from mice to primates (Loucks & Verdun, 1998). This finding is consistent with the hypothesis that LH pulsatility depends on carbohydrate availability. For the carbohydrate requirement of the human brain is uniquely extreme amongst mammals. In adults, the brain consumes 20% of resting energy metabolism (in children it consumes 50%), in contrast to only 8% in lower primates and 2% in other mammals.

The fifth experiment is investigating the incremental effect of energy availability on LH pulsatility in men and women (Loucks et al., 1998; Loucks et al., 1999; Loucks et al., 2000) So far, we have shown that in women LH pulsatility is disrupted at the same threshold of energy availability at which thyroid metabolism is suppressed. Lower energy availabilities also disrupt LH pulsatility in men, but the magnitude of the effect is smaller, suggesting that in humans as in other mammals the dependence of reproductive function on energy availability operates principally in females. In this same experiment, we are investigating whether biochemical markers of bone metabolism are also disrupted at the same threshold of energy availability.