Endocrine modulation of stimulant use: bidirectional interactions within the hypothalamic-pituitary-gonadal axis

Stimulant use disorders are chronic relapsing conditions that differentially affect men and women. Growing evidence has demonstrated that endocrine systems play critical, bidirectional roles in regulating vulnerability to drug use, escalation, withdrawal, and relapse, particularly for women. In the current review we discuss the bidirectional relation between gonadal hormones; focusing on estradiol (E₂), progesterone (P₄), and testosterone (T); and stimulant rewards and reinforcement; focusing on cocaine, amphetamine, and methamphetamine. Most research to date has focused on cocaine and less so on amphetamine or methamphetamine. Similarly, most research has been conducted with rodents and less so with nonhuman primates and humans. Collectively, the literature supports stimulant misuse as an endocrine disorder, particularly for females, emerging from reciprocal interactions between neural and hormone systems. The reciprocal relation between gonadal hormones and stimulant rewards and reinforcement is, for the most part, reliable and robust in female rodents; however, the relation is somewhat mixed with female nonhuman primates and women. These mixed results likely are a result of the wide within- and between-subject variability in menstrual cycles (i.e., duration) and levels of ovarian hormones (e.g., E₂ and P₄ levels) in female nonhuman primates and women. Additionally, it is impossible to determine complete menstrual cycles prior to stimulant exposure in women as it is in female rats or nonhuman primates, though determination of menstrual cycles prior to stimulant exposure with female nonhuman primates is sparse. Female rodents, on the other hand, have much less variability in estrous cycles and corresponding E₂ and P₄ levels, and complete estrous cycles and hormone levels are easily obtainable prior to stimulant exposure. Finally, while the reciprocal relation between gonadal hormones and stimulants in males and men has been studied, the relation appears to be less reliably implicated in stimulant rewards and reinforcement compared with females, women, and ovarian hormones. Recognizing the hypothalamic-pituitary-gonadal (HPG) axis, including effects of stimulants on gonadal hormones and vice versa, is critical for developing individualized pharmacotherapies for stimulant misuse, particularly for women, and for understanding sex-specific stimulant-misuse phenotypes.