Normal reproductive function requires an optimal nutritional intake, and both caloric deprivation and consequent weight loss, as well as excessive food intake and obesity, are associated with impaired reproductive function (26). Sexual maturation may be substantially delayed during food deprivation (27,28); small animals with a short life span may not even achieve puberty before death during periods of food scarcity (29). Undernutri-tion caused by famine, eating disorders, or exercise results in weight loss and changes in body composition and the endocrine milieu that can impair reproductive function (30). As a general rule, weight loss and body composition changes resulting from undernutri-tion are associated with reduced GnRH secretion, and the decrease in follicle-stimulating hormone (FSH) and LH levels correlates with the amount of weight loss (30). However, both hypogonadotropic and hypergonadotropic hypogonadism have been described in cachexia associated with certain chronic illnesses, such as HIV infection (5). Collectively, these observations provide compelling evidence that energy balance is an important determinant of reproductive function in all mammals.
The precise nature of the biochemical pathways that connect these two body systems that are essential for survival is not known. It is generally believed that the regulatory signals that modulate hypothalamic GnRH secretion are mediated through leptin and neuropeptide Y (29,31-34). Leptin, the product of the obesity (ob) gene, is a circulating hormone secreted by fat cells that acts centrally to regulate the activity of CNS effector systems that maintain energy balance (35). Leptin stimulates LH secretion by activation of the nitric oxide synthase (NOS) in gonadotropes (34). Leptin inhibits neuropeptide Y secretion, which has a tonic inhibitory effect on both leptin and GnRH secretion. Leptin also stimulates nitric oxide production in the mediobasal hypothalamus; nitric oxide stimulates GnRH secretion by the hypothalamic GnRH-secreting neurons. Therefore, the net effect of leptin action is stimulation of hypothalamic GnRH secretion (31,33,34).
Caloric deprivation in experimental animals is associated with reduced leptin levels and a concomitant reduction in circulating LH levels (31). Leptin administration to calorically deprived mice reverses the inhibition of gonadotropin secretion that attends food restriction. Similarly, genetically ob/ob mice with leptin deficiency have hypogo-nadotropic hypogonadism and are infertile; treatment of these mice with leptin restores gonadotropin secretion and fertility. Collectively, these observations suggest that energy deficit and weight loss are associated with impaired GnRH secretion, in part, because of decreased leptin secretion and a reciprocal increase in neuropetide Y activity. Although there is agreement that leptin is an important metabolic signal that links energy balance and reproductive axis, it is doubtful that it is the primary trigger for the activation of the GnRH pulse generator at the onset of puberty. Emerging evidence suggests that leptin is essential but not sufficient for initiation of puberty.
Susser and Stein (36,37) studied the effects of acute food scarcity during World War II on a previously healthy and nutritionally replete population. Between October 1944 and May 1945, during the German occupation of the Netherlands, the German army restricted food supplies into certain Dutch cities, resulting in a substantial reduction in average daily energy intake to fewer than 1000 kcal. Adjacent cities, in which food supplies were not curtailed by the Germans, were not affected by the famine. Fifty percent of women who were affected by the famine developed amenorrhea. The conception rate dropped to 53% of normal (based on control cities) and correlated with the decreased caloric ration. In addition to the decrease in fertility, undernutrition resulted in an increase in perinatal mortality, congenital malformations, schizophrenia, and obesity. These observations indicate that optimal caloric intake is essential for normal fertility and prenatal growth.
The Kung San of Botswana were a tribe of hunter-gatherers until approx 20 yr ago. The body weight of the men and women in the tribe varied substantially throughout the year, depending on the availability of food. In the summer months, the food supply was more abundant, and the body weight increased, whereas the nadir of body weight was achieved in winter months. The number of births in the tribe peaked approx 9 mo after the peak of body weight. This is another example of how food availability can affect fertility patterns in nature (38).
These nature experiments have led to speculation that androgen deficiency is an adaptive response to malnutrition and illness. Therefore, some investigators have questioned whether it is wise to administer anabolic/androgenic therapies to men with chronic illness.
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