Can Estrogen Blockers Cause Anxiety in Men?
Yes, estrogen blockers (anti-androgens and aromatase inhibitors) can cause anxiety and mood disturbances in men, though the evidence is primarily derived from cancer treatment contexts where these medications are used for androgen deprivation therapy in prostate cancer. The relationship between estrogen modulation and anxiety is complex and bidirectional, depending on which estrogen receptor subtypes are affected.
Evidence from Clinical Guidelines
Cancer Treatment Context
The NCCN guidelines explicitly recognize that medications affecting sex hormones—including selective serotonin reuptake inhibitors, beta-blockers, depression, and anxiety—can impact male sexual and mental health in men treated for cancer 1. While this guideline focuses on sexual dysfunction, it acknowledges the broader psychological impact of hormonal manipulation.
In the context of androgen deprivation therapy for prostate cancer (which includes estrogen-blocking mechanisms), cognitive and mood effects have been documented, though results are mixed 1. The cognitive impairment literature suggests that blocking estrogen synthesis or receptor binding may reduce neuroprotective effects, as estrogen receptors mediate antioxidant effects and enhance neuroplasticity through brain-derived neurotrophic factor (BDNF) pathways 1.
Mood Disturbances in Hormonal Therapy
Mood disturbances are specifically listed as adverse events in patients receiving tamoxifen (an estrogen blocker), with 19% of patients experiencing mood disturbances compared to 18% in control groups 2. While this data comes from breast cancer patients, the mechanism is relevant to men receiving similar estrogen-blocking therapy. Depression was reported in 13% of patients receiving anastrozole (an aromatase inhibitor) versus 12% receiving tamoxifen 2.
Mechanistic Understanding
Estrogen Receptor Subtypes and Anxiety
The relationship between estrogen blockade and anxiety depends critically on which estrogen receptor subtype is affected 3, 4, 5:
ERα (Estrogen Receptor Alpha): Generally has anxiogenic (anxiety-producing) effects. Blocking this receptor might theoretically reduce anxiety 3, 5.
ERβ (Estrogen Receptor Beta): Has anxiolytic (anxiety-reducing) effects. Blocking ERβ would be expected to increase anxiety-like behaviors 4, 5, 6.
Research demonstrates that ERβ agonists significantly decrease anxiety-related behaviors in animal models, while ERα agonists increase anxiogenic behaviors 5.
Sex-Specific Considerations
Male-specific data shows that genetic absence of ERβ in male mice was associated with decreased sucrose preference following stress, suggesting susceptibility for development of anhedonia and stress-related mood disturbances 7. This indicates that blocking estrogen receptors in males may predispose to anxiety and depression-like states, particularly under stress.
Estrogen's Neuroprotective Role
Estrogen provides multiple neuroprotective mechanisms that, when blocked, could contribute to anxiety 1:
- Antioxidant effects reducing mitochondrial damage
- Stimulation of dendritic spine production
- Enhancement of neuroplasticity via BDNF pathways, particularly in the prefrontal cortex
When estrogen blockers reduce these protective effects, vulnerability to mood disturbances including anxiety may increase 1.
Clinical Context: Transgender Medicine
In transgender medicine, the evidence provides an important counterpoint: feminizing hormone therapy (which includes estrogen administration and anti-androgens) is associated with improved mental health outcomes, including decreased depression and anxiety 1. Three studies reported decreased depression and anxiety levels following hormone treatment 1. This suggests that the anxiety risk from estrogen blockers may be context-dependent—occurring when estrogen activity is reduced below physiological needs rather than when it's modulated for gender affirmation.
Practical Clinical Implications
Risk Assessment
When prescribing estrogen blockers to men, clinicians should:
- Screen for pre-existing mood disorders, as individuals with psychiatric history may have increased sensitivity to estrogen fluctuations 8
- Monitor closely during the first weeks of treatment for signs of mood destabilization 8
- Recognize that mood disturbances are associated with estrogen withdrawal, fluctuations, and sustained deficiencies 8
Common Pitfalls
- Assuming all estrogen modulation has the same effect: The specific mechanism (receptor blockade vs. synthesis inhibition) and which receptor subtypes are affected determines the anxiety risk 3, 4, 5
- Ignoring baseline mental health: Patients with pre-existing anxiety or depression are at higher risk for mood destabilization with hormonal changes 1, 8
- Failing to distinguish between acute withdrawal effects and chronic steady-state effects: Anxiety may be more pronounced during initiation or dose changes 8
Monitoring Strategy
For men receiving estrogen blockers (particularly in prostate cancer treatment):
- Obtain baseline mental health assessment including validated anxiety screening tools 1
- Review medical history for conditions associated with mood disorders including depression, diabetes, and hypertension 1
- Monitor for mood changes, particularly depression and anxiety symptoms, at regular intervals 2
- Consider that 13-19% of patients may experience mood disturbances based on cancer treatment data 2
Strength of Evidence Considerations
The direct evidence linking estrogen blockers to anxiety specifically in men is limited, as most clinical data comes from:
- Cancer treatment populations (primarily prostate and breast cancer) 1, 2
- Preclinical animal models demonstrating receptor-specific effects 3, 4, 5, 7
- Transgender medicine showing improved mood with estrogen administration (the inverse scenario) 1
The mechanistic evidence strongly supports that blocking estrogen receptors, particularly ERβ, can increase anxiety-like behaviors, and clinical data from cancer populations confirms mood disturbances as a recognized adverse effect 2, 3, 4, 5.