Effects of exogenous estrogenic agents on pubertal growth and reproductive system maturation in female rhesus monkeys.

Concern has been raised that environmental contaminants with estrogenic properties can alter normal sexual maturation. Monkeys, like humans, undergo a long and complex period of development during adolescence, which makes them important models for understanding exogenous estrogen effects during this period. This study examined the consequences of treatment with estrogenic agents (methoxychlor, MXC, 25 and 50 mg/kg/day; diethylstilbestrol, DES, 0.5 mg/kg/day) given in the peripubertal period (6 months before and after the expected age at menarche) to female rhesus monkeys. These treatments increased estrogen activity of serum as determined with an in vitro estrogen receptor alpha (ERa) transcription assay. DES completely suppressed adolescent growth (weight and height) and menses in a reversible manner; smaller effects of MXC on the timing of growth and menarche were also detected. Both DES and MXC led to premature emergence of a secondary sex characteristic, reddening and swelling of skin, but retarded growth of the nipple. As evaluated by ultrasound after an 8-month recovery period, uterine size was not affected by exogenous estrogen, but there was some indication of increased incidence of ovarian cysts/masses in MXC- and DES-treated groups. Ovarian cyclicity, as reflected in urinary hormone metabolites, demonstrated shorter follicular stages in the MXC-treated monkeys. In conclusion, the data indicate that DES had a striking effect on adolescent maturation and that the estrogenic pesticide MXC also altered development during this period. The pattern of effects across agents and doses may be based on specifics of estrogenic action, such as relative ERalpha and ERbeta binding and activation. Long-term consequences of this disruption of pubertal development are being studied in this cohort of monkeys as adults.