Early menarche, a risk factor for breast cancer, indicates early onset of ovulatory cycles

The associations between age at menarche and the hormonal patterns of adolescent menstrual cycles were investigated to obtain information as to why early menarche is an important risk factor for breast cancer. An initial group of 200 schoolgirls, 7-17 yr old, was investigated longitudinally 3 times at 1.5-yr intervals. A serum progesterone concentration in the latter part of the cycle exceeding 6.4 nmol/liter (2.0 ng/ml) was considered to signify an ovulatory cycle, and a concentration less than 1.6 nmol/liter (0.5 ng/ml) an anovulatory cycle. The frequency of ovulation depended significantly on both the time since menarche and the age at menarche (P less than 0.001 for both variables). Early menarche was associated with early onset of ovulatory cycles. The times from menarche until 50% of the cycles were ovulatory were about 1, 3, and 4.5 yr when the ages at menarche were less than 12.0, 12.0-12.9, and more than or equal to 13.0 yr, respectively. Girls with a menarcheal age below 12.0 yr had higher serum estradiol but lower testosterone and dehydroepiandrosterone concentrations than subjects with later menarche. The estradiol to dehydroepiandrosterone ratio was already higher before menarche in subjects who displayed early menarche during follow-up. These findings show that the increase in adrenal androgen secretion was mainly related to chronological age and was not affected by the time of menarche. The demonstration of early ovulation after early menarche is in conflict with the estrogen-window hypothesis suggesting a longer duration of anovulatory cycles to explain the increased risk of breast cancer after early menarche. Other theories should therefore be considered, among them the following: 1) high serum progesterone concentration in association with normal or high serum estradiol at puberty increases the risk, 2) only the early and relatively high estrogen concentrations are important, or 3) the estrogen to androgen ratio is the critical factor, with androgens having a protective effect.