Leptin and Age at Menarché

Leptin Is Inversely Related to Age at Menarche in Human Females, Velimir Matkovic, Jasminka Z. Ilich, Mario Skugor, Nancy E. Badenhop, Prem Goel, Albert Clairmont, Dino Klisovic, Ramzi W. Nahhas and John D. Landoll

Over the last century there has been a trend toward an earlier onset of menarche attributed to better nutrition and body fatness. With the discovery of the obesity gene and its product, leptin, we reexamined this hypothesis from a new perspective. As delayed menarche and leanness are considered risk factors for osteoporosis, we also evaluated the relation between leptin and bone mass......

A critical blood leptin level is necessary to trigger reproductive ability in women, suggesting a threshold effect. Leptin is a mediator between adipose tissue and the gonads. Leptin may also mediate the effect of obesity on bone mass by influencing the periosteal envelope. This may have implications for the development of osteoporosis and osteoarthritis.


THE AGE AT which women develop menarche is an important factor in determining population size, breast cancer, and osteoporosis, all of which are of enormous present-day concern (1, 2, 3). Therefore, understanding all potential factors responsible for early menarche is of considerable interest. Over the last century there has been a trend toward earlier onset of puberty and menarche in affluent societies, attributed primarily to the improvement in nutritional status and general health of younger generations of women (4, 5). The onset of menarche was closely related with the achievement of a certain body weight (6) or percent body fat (7, 8). The only explanation given for this association was the influence of an unknown mediator on the hypothalamic-pituitary-gonadal axis.

With the recent discovery of the obesity gene (ob) and its product, leptin (11), it is possible to reexamine the relationship between body fatness and the timing of menarche from a new perspective. In support of this are recent discoveries in ob/ob mice treated with leptin showing signs of early onset of ovarian maturation and reproductive function (12, 13, 14). Similar data for humans do not exist.

According to our knowledge this is the first study to examine longitudinally the influence of body fatness and serum leptin on the timing of menarche in human females. In addition, this is the first study to evaluate, either cross-sectionally or longitudinally, the relationship between leptin and body fat in children. Serum leptin is strongly associated with body fat and indexes of body fatness (percent body fat and BMI) as well as with the change in body fat over time. As leptin is encoded by the ob gene and produced only in the fat cells, its serum concentration indirectly reflects body fat stores (11, 20). The above data are in agreement with the results obtained in a small group of teenage females who participated in a diurnal variation study of leptin (21) and also with the data obtained in adults (22)

It is anticipated, therefore, that leptin deficiency is a primary reason for delayed puberty and menarche in individuals and in populations accustomed to absolute or relative dietary energy deficiency. In menstruating women, a negative energy balance caused by either fasting and/or exercise could cause secondary amenorrhea (24, 25, 26), presumably due to low levels of circulating leptin. Low serum leptin levels were found in young amenorrheic athletes (27) and in women suffering from anorexia nervosa (28). A decrease in the serum leptin concentration was documented in older women in response to exercise.