“Boosting testosterone makes me anxious.” Here’s why.

Testosterone supplementation (topical or injection) has been shown to have strong anti-depressant and anti-anxiety effects.

However, some people do respond the opposite, where they get anxious as they optimize their testosterone. Why is that?

Testosterone via DHT and other 5-alpha-reduced steroids such as androsterone has strong anti-anxiety effects.

A few mechanisms include:

• Estrogen receptor beta (ERβ) activation. ERβ activation has anti-anxiety effects and selectively blocking ERβ in animals prevents these anti-anxiety effects (R, R).
  • 2 DHT metabolites, namely 3α and 3β-diol (which are converted from DHT by 3α-HSD3 and 3α-HSD respectively) are ERβ agonists.
    • 3α-diol has approximately 0.07% and 0.3% of the affinity of estradiol at the ERα and ERβ, respectively.
    • 3β-diol has approximately 3% and 7% of the affinity of estradiol at the ERα and ERβ, respectively.
• GABA activation.
  • 3α-diol, but not 3β-diol, has a strong affinity for the GABA receptor (R). Blocking the conversion of DHT to 3alpha-diol in the hippocampus can prevent the anti-anxiety effects of testosterone (R).
  • Androsterone, the 5-alpha-reductase metabolite of DHEA, is also a strong GABA agonist and has anti-anxiety effects. Supplementing testosterone can also increase androsterone.
• Androgen receptor activation and blocking the AR prevents the anti-anxiety effects of DHT (R).
• Lower CRH (R). CRH is released in the hypothalamus, to stimulate the pituitary to release ACTH, which stimulates the adrenals to release cortisol. CRH is involved in producing a number of anxiety- and depression-like symptoms.

Related article

• How to increase DHT
• Foods that will increase DHT
• Foods to avoid that can lower DHT

What is really the culprit?

If testosterone, DHT and its metabolites are anti-anxiety, what is then causing the anxiety?

Estrogen.

Estrogen is created from testosterone via aromatase. Aromatase can be upregulated due to a variety of reasons such as excess adipose tissue, nutrient deficiencies, inflammation, hyperinsulinemia, etc.

Apart from general estrogen levels, the expression of the estrogen receptors also matters. Someone can have normal estrogen, but be hypersensitive to it and it can cause problems.

ERα has a generally anxiogenic effect, whereas ERβ has a generally anxiolytic effect. The G-protein-coupled estrogen receptor known as GPR30, which has been found to both increase and decrease anxiety-like behavior (R).

Activation of GPR30 by estrogen appears to play a significant role in the pathophysiology of anxiety disorders (R). The concentration of GPR30 in serum is higher in patients with anxiety than in the controls (R). In animals, GPR30 knockout displays reduced anxiety (R).

In boys, elevated estradiol was associated with elevated depression and anxiety scores (R). Higher cortisol levels strengthened the depression association with estradiol in boys.

A few mechanisms of how estrogen contributes to anxiety

Estrogen has been shown to contribute to anxiety by:

• Lowering the serotonin receptor 5-HT1A in the paraventricular nucleus (PVN).
• Increasing 5-HT1A in the amygdala. 5-HT1A receptor activation in the amygdala might mediate long-term potentiation within the amygdala through the inhibition of GABA release (R).
• Increasing 5-HT2A.
• Promotes glutamate release and prevents its breakdown and potentiates glutamate signaling with NMDA and kainate receptors (R, R, R). Too much glutamate contributes to anxiety and that’s why anti-glutamate compounds, like zinc, magnesium, theanine, etc., have anti-anxiety effects.
• Direct activation of the glutamate receptors even in the absence of estrogen. The membrane-associated ERα and ERβ functionally couple to various group I and II metabotropic glutamate receptors (mGluRs) (R).
• Promoting CRH release, which promotes the whole stress/cortisol cascade.

Summary

If you get anxiety from testosterone, have your estrogen and DHT checked. A good place for estrogen to be is around 20-25pg/ml. I like to see DHT in the upper range of normal.

If those are in check, then take a look at your diet. Do you perhaps have nutritional deficiencies? Are you getting enough magnesium and zinc?

The fat-soluble vitamins and minerals namely zinc, selenium and magnesium are very important for lowering aromatase. White button mushrooms are good aromatase inhibitors. The B vitamins are needed for proper estrogen detox in the liver.

Related articles:

• How to inhibit aromatase
• How to block the estrogen receptors
• How to enhance estrogen detox
• Food that will lower estrogen