A Selective Androgen Receptor Modulator Enhances Male-Directed Sexual Preference, Proceptive Behavior, and Lordosis Behavior in Sexually Experienced, But Not Sexually Naive, Female Rats

Abstract

Androgens influence many aspects of reproductive behavior, including sexual preference of females for males. In oophorectomized women with sexual desire disorder, testosterone patches improve libido, but their use is limited because of adverse side effects. Selective androgen receptor modulators offer an improved safety profile for both sexes: enhancing libido and muscle and bone growth in a manner similar to steroidal androgens but with fewer adverse effects, such as hirsutism, acne, and prostate growth. The current study investigated the action of a novel selective androgen receptor modulator (LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one]) on male-directed sexual preference, proceptivity, and lordosis behavior of female rats. LGD-3303 is a nonsteroidal, nonaromatizable, highly selective ligand for the androgen receptor and effectively crosses the blood-brain barrier. Gonadectomized female rats were treated with LGD-3303 (3–30 mg/kg) or vehicle by daily oral gavage. Results showed that LGD-3303 treatment enhanced sexual preference of females for males but only if females had previous sexual experience. This occurred after 1 or 7 d of treatment. In contrast, preference for males was inhibited by LGD-3303 treatments of sexually naive females. The LGD-3303 increase in male preference was blocked by pretreatment with the androgen receptor antagonist flutamide. LGD-3303 treatment increased lordosis and proceptivity behaviors in ovariectomized females primed with suboptimal doses of estradiol benzoate plus progesterone. These data support the concept that LGD-3303 can stimulate aspects of female sexual behavior and may serve as a potential therapeutic for women with sexual desire disorders.