Adverse effects of methylphenidate on the reproductive axis of adolescent female rats

Objective: To examine the effects of chronic methylphenidate use on the reproductive axis of adolescent female rats. Design: Controlled prospective study. Setting: University research laboratory. Animal(s): Twenty prepubertal female Sprague Dawley rats. Intervention(s): Subcutaneous implantation of drug-filled Alzet minipumps (Durect Corporation, Cupertino, CA) for infusing methylphenidate (450 μg/d, treated) or physiological saline (control) for 4 weeks. Estrous cyclicity was checked from 3 weeks of pump implantation till the termination of the experiments. Animals were killed after 4 weeks of treatment. Main Outcome Measure(s): Estrous cyclicity, pituitary and peripheral FSH and LH, serum estrogen and progesterone, ovarian histology, and immunocytochemistry for localizing growth differentiation factor-9 and activin receptors-I. Result(s): Compared with the control group, the treated animals exhibited the following: [1] poor vaginal opening and erratic estrous cyclicity; [2] undeveloped, disrupted, or prematurely luteinized ovarian follicles; [3] absence of growth differentiation factor-9 and of activin receptors I and IB in the oocyte; and [4] high levels of LH in the pituitary. Conclusion(s): Chronic methylphenidate administration during adolescence perturbs pubertal onset, adversely affects maturation of the female reproductive axis by retarding pituitary LH release, and adversely affects ovarian folliculogenesis. These novel findings may have significant clinical implications in evaluating the effects of methylphenidate abuse on adolescent health.