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Endocrine modulation of stimulant use: bidirectional interactions within the hypothalamic-pituitary-gonadal axis
Sally L Huskinson1,2,3, Amy S Kohtz1,2,3
1Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States.
Frontiers in Behavioral Neuroscience
|June 22, 2026
Summary
Gonadal hormones, like estradiol, progesterone, and testosterone, interact with stimulant use disorders. This relationship is more pronounced in females, suggesting stimulant misuse may be an endocrine disorder, especially in women.
Area of Science:
- Neuroendocrinology
- Addiction Science
- Pharmacology
Background:
- Stimulant use disorders are chronic, relapsing conditions with sex-specific differences.
- Endocrine systems, particularly gonadal hormones, play a critical role in drug vulnerability, escalation, withdrawal, and relapse.
- Existing research highlights bidirectional interactions between gonadal hormones and stimulant reinforcement.
Purpose of the Study:
- To review the bidirectional relationship between gonadal hormones (estradiol, progesterone, testosterone) and stimulant rewards/reinforcement (cocaine, amphetamine, methamphetamine).
- To examine sex differences in the influence of gonadal hormones on stimulant use disorders.
- To highlight the implications for developing individualized pharmacotherapies for stimulant misuse.
Main Methods:
- Literature review focusing on studies examining gonadal hormones and stimulant use.
- Analysis of research involving rodents, nonhuman primates, and humans.
- Comparison of findings across different stimulant types (cocaine, amphetamine, methamphetamine).
Main Results:
- The relationship between gonadal hormones and stimulant reinforcement is robust in female rodents but mixed in female nonhuman primates and women.
- Variability in menstrual cycles and ovarian hormone levels contributes to mixed results in primates and humans.
- The influence of gonadal hormones on stimulant reinforcement appears less consistent in males compared to females.
Conclusions:
- Stimulant misuse can be viewed as an endocrine disorder, particularly in females, due to reciprocal interactions between neural and hormone systems.
- Understanding the hypothalamic-pituitary-gonadal (HPG) axis is crucial for sex-specific treatment of stimulant use disorders.
- Individualized pharmacotherapies for stimulant misuse, especially for women, require consideration of these hormonal interactions.
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