Hormones and the nervous system are constantly in conversation, with a dynamic relationship that is foundational to human physiology. Referred to as the endocrine system, hormones exist in a network, and they are produced by various glands throughout the body. Hormones not only regulate physiological processes like growth, metabolism, and reproduction, but they also exert profound effects on the central and peripheral nervous systems. One of the key ways they influence neural function is through modulation of neurotransmitters—chemical messengers such as serotonin, dopamine, gamma-aminobutyric acid (GABA), and norepinephrine that contribute to mood.

Hormones and How They Affect Brain Function

Estrogen

Estrogens, primarily estradiol, are steroid hormones that influence a wide array of brain functions. Estrogen receptors are present at distinct regions of the brain associated with mood, cognition, and memory, such as the hippocampus and prefrontal cortex. Estrogens modulate neurotransmission through several mechanisms. They upregulate serotonin synthesis by increasing the activity of tryptophan hydroxylase, a key enzyme involved in serotonin production. In addition, estrogens inhibit monoamine oxidase (MAO) to limit the degradation of serotonin and other monoamines, allowing them to stay present for longer. They also enhance dopaminergic activity by influencing dopamine receptor density and neurotransmitter release.  These neurotransmitters are crucial in regulating mood, emotional well-being, motivation, reward, and pleasure, and the link between them poses estrogen as a key player in mental health.

Evidence from randomized controlled trials (RCTs) supports these mechanisms. A notable trial by Schmidt et al. in 2000 demonstrated that estrogen replacement therapy in perimenopausal women significantly reduced depressive symptoms compared to placebo, suggesting a serotonergic and dopaminergic basis for its antidepressant effects [1]. Another influential review by Sherwin in 1988 reported improved cognitive performance and mood in postmenopausal women receiving estrogen therapy [2]. These results support the view that estrogens act as neuromodulators with potential protective effects against mood disorders, particularly during hormonally vulnerable life stages.

Progesterone

Progesterone, another key sex hormone, also plays a significant role in brain function, primarily through its metabolite allopregnanolone, which influences the GABA receptors.  GABA is the major inhibitory neurotransmitter receptor in the brain, inducing a sedative effect. By enhancing GABA transmission, progesterone can elicit relaxation, improving sleep and decreasing anxiety.

Several RCTs have explored these effects. In a study by Freeman et al. in 1995, the administration of progesterone to women with premenstrual syndrome (PMS) led to a reduction in emotional and somatic symptoms, effects attributed in part to its influence on GABA receptors [3]. More recently, research into postpartum depression has highlighted the therapeutic role of allopregnanolone. A randomized controlled trial by Schiller et al. found that brexanolone, a synthetic formulation of allopregnanolone, produced rapid and significant improvements in mood among postpartum women [4]. These findings underscore the relevance of progesterone’s neuromodulatory properties in the context of mood and anxiety disorders, although not all trials have demonstrated uniform benefits.

Cortisol

Cortisol, the body’s primary glucocorticoid, is secreted in response to stress via the hypothalamic-pituitary-adrenal (HPA) axis and has complex interactions with neurotransmitter systems. Chronic stress and sustained elevations in cortisol are associated with dysregulation of serotonin, dopamine, and norepinephrine pathways. Specifically, cortisol can downregulate serotonin receptor expression, reduce dopamine signaling, and alter norepinephrine transmission, leading to depression, withdrawal, and an inability to experience pleasure, especially when cortisol elevation is sustained over extended periods of stress.

RCTs studying the effects of pharmacologically altering cortisol levels have provided insight into these relationships. Pariante et al. conducted a study in 2004 in which metyrapone, a cortisol synthesis inhibitor, was administered alongside antidepressants. Participants receiving the combination demonstrated improved mood outcomes compared to those receiving antidepressants alone [5]. This suggests that reducing cortisol levels may enhance monoamine neurotransmission and improve depressive symptoms. Similarly, RCTs using the dexamethasone suppression test have shown that individuals with depression who fail to suppress cortisol production tend to have poorer treatment outcomes, reinforcing the role of cortisol in mood regulation.

Testosterone

Testosterone, the principal androgen, also influences neurochemistry, particularly through influencing dopamine. It increases dopamine synthesis and receptor sensitivity in mesolimbic pathways, which are central to motivation, reward processing, and mood regulation. These effects may explain the role of testosterone in sexual behavior, assertiveness, and energy levels.

Several randomized trials have explored testosterone’s antidepressant and cognitive effects, particularly in hypogonadal men. A meta-analysis by Zarrouf et al. in 2009 reported that testosterone supplementation yielded moderate improvements in depressive symptoms [6]. One of the included studies, conducted by Seidman et al. in 2001, found that testosterone treatment significantly enhanced mood and libido [7]. However, in men with normal testosterone levels—the benefits were minimal or absent, suggesting that testosterone’s neuromodulatory impact is most evident in the context of correcting deficiency.

Oxytocin

Oxytocin, a neuropeptide synthesized in the hypothalamus, is widely recognized for its role in social bonding, trust, and emotional recognition. It modulates dopamine release in the mesolimbic reward system and influences serotonin activity in the amygdala, a brain region central to fear and emotional memory.

RCTs investigating the effects of intranasal oxytocin have shown promising results in enhancing social cognition. For instance, participants often exhibit increased trust, empathy, and emotional recognition following oxytocin administration. MacDonald et al. in 2011 conducted a meta-analysis of these studies and concluded that oxytocin has a significant impact on social-emotional processing [8]. In individuals with autism spectrum disorder, oxytocin improved social interaction and reduced repetitive behaviors.

Understanding the Relationship is Critical 

The interrelationship between endogenous hormones and neurotransmitters is critical to understanding the neurobiological underpinnings of mood, cognition, and behavior. Evidence from randomized controlled trials supports the neuromodulatory roles of estrogens, progesterone, testosterone, cortisol, insulin, and oxytocin, each influencing specific neurotransmitter systems through distinct mechanisms. While it is important to recognize these relationships, we must also consider individual variability and hormonal changes across life transitions such as menopause, pregnancy, and postpartum. The impactful connection between hormonal and mental health cannot be underestimated in clinical practice.

References

1. Schmidt PJ, et al. (2000). Estrogen replacement in perimenopausal depression: A RCT. Am J Obstet Gynecol.
2. Sherwin BB. (1988). Estrogen and cognitive function in postmenopausal women. Arch Intern Med.
3. Freeman EW, et al. (1995). Progesterone in PMS: A RCT. JAMA.
4. Schiller CE, et al. (2016). Brexanolone for postpartum depression: A RCT. Lancet.
5. Pariante CM, et al. (2004). Metyrapone and antidepressant efficacy: A RCT. Biol Psychiatry.
6. Zarrouf FA, et al. (2009). Testosterone and depression: A meta-analysis. J Psychiatr Pract.
7. Seidman SN, et al. (2001). Testosterone and depression in aging men: A RCT. Am J Psychiatry.
8. MacDonald K, et al. (2011). Oxytocin and social cognition: A meta-analysis. Neurosci Biobehav Rev.