Uptake of Medroxyprogesterone Acetate by Progestin and Androgen Target Neurons in the Brain and Pituitary Gland of Male Cynomolgus Monkeys

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Abstract
Medroxyprogesterone acetate (MPA), a synthetic progestin that reduces plasma testosterone levels, has been used in the treatment of male sex offenders. It also reduces the sexual activity of male macaques. To investigate its sites and mechanisms of action, 11 adult male cynomolgus monkeys were castrated and 7 and 21 h later were pretreated with 20 mg progesterone s.c. (Prog, n = 3), or 5 mg dihydrotestosterone propionate s.c. (DHTP, n = 3) or oil vehicle (controls, n = 5). Twenty-four hours after castration, all males were injected i.v. with 5 mCi[3H]-MPA, and killed after 60 min. Left halves of the brains were processed for thaw-mount autoradiography to identify the neurons accumulating radioactivity, and right halves were analyzed by high performance liquid chromatography (HPLC) to measure the uptake of [3H]-MPA in nuclear fractions. In males pretreated with oil, there were labeled neurons in the ventromedial nucleus (n.), arcuate n., medial preoptic n. and anterior hypothalamic area. In progesterone-pretreated males, labeling was reduced by 84-100% compared with controls (p < 0.001), but in DHTP-pretreated males there was no effect, and labeling was not significantly different from control levels. Nuclear concentrations of [3H]-MPA measured by HPLC in controls were highest in the hypothalamus, amygdala, preoptic area and pituitary gland. Pretreatments with progesterone reduced the nuclear concentrations of [3H]-MPA in hypothalamus, preoptic area and pituitary gland by 82-95% compared with controls (p < 0.05), but DHTP pretreatments had no effect. Progesterone pretreatments did not reduce concentrations of [3H]MPA in blood or in tissue supernatants, and the blockade of labeling appeared to be limited to nuclear uptake mechanisms. Results indicated that MPA was bound predominantly to progestin and not androgen receptors in neuronal nuclei, suggesting that the effects of MPA in the brain of the male primate may be mediated by progestin-target neurons.