We have had data about how exogenous testosterone can decrease upstream neurosteroids. I am sure that decrease is worse at higher T doses.
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Allopregnanolone is one of the most important neurosteroids involved in mood. It is dependent on 5 alpha reductase.
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I searched on perplexity:
The effect of supraphysiologic testosterone on allopregnanolone levels in men is complex and involves several interrelated mechanisms:
## Neurosteroid Biosynthesis
Supraphysiologic testosterone administration can lead to changes in neurosteroid biosynthesis, particularly affecting allopregnanolone levels:
1. **Decreased Allopregnanolone**: Long-term administration of high doses of testosterone has been associated with a decrease in brain allopregnanolone content[1][4]. This reduction is likely due to the down-regulation of neurosteroid biosynthesis pathways.
2. **5α-reductase Expression**: Testosterone administration can cause a decrease in the expression of 5α-reductase type I mRNA, which is a key enzyme in the biosynthesis of allopregnanolone[1][4]. This decrease in enzyme expression contributes to the reduced allopregnanolone levels.
## Behavioral Effects
The changes in allopregnanolone levels due to supraphysiologic testosterone can have significant behavioral implications:
1. **Aggression**: The decrease in brain allopregnanolone content has been associated with increased aggressive behavior[1][4]. This may partly explain the phenomenon of "steroid rage" observed in some individuals using anabolic-androgenic steroids.
2. **Mood Alterations**: Allopregnanolone is a potent modulator of GABA<sub>A</sub> receptors, and its reduction can lead to changes in mood, potentially contributing to irritability and anxiety[3].
## Compensatory Mechanisms
The body may attempt to compensate for the effects of supraphysiologic testosterone:
1. **Androgen Backdoor Pathway**: Allopregnanolone is an intermediate in an androgen backdoor pathway from progesterone to dihydrotestosterone[3]. This pathway may be affected by supraphysiologic testosterone levels, potentially altering allopregnanolone production.
2. **Intratumoral Testosterone**: In the context of prostate cancer, long-term androgen deprivation therapy can lead to similar or even higher intratumoral testosterone levels compared to pre-castrate levels[2]. This suggests complex regulatory mechanisms that may also influence allopregnanolone synthesis.
## Clinical Implications
Understanding the relationship between supraphysiologic testosterone and allopregnanolone has important clinical implications:
1. **Cognitive Function**: Both testosterone and allopregnanolone play roles in cognitive function. Alterations in their levels may impact cognitive performance in older men[6].
2. **Sexual Function**: Changes in neurosteroid levels, including allopregnanolone, can affect sexual function. The neurosteroid androsterone, which is related to allopregnanolone in the steroid biosynthesis pathway, has been correlated with sexual interest in men[7].
3. **Prostate Cancer Treatment**: Supraphysiological testosterone therapy has shown potential in treating certain cases of enzalutamide-resistant prostate cancer[8]. The effects on allopregnanolone in this context warrant further investigation.
In conclusion, supraphysiologic testosterone administration in men can lead to a decrease in allopregnanolone levels through down-regulation of neurosteroid biosynthesis pathways. This change can have significant effects on behavior, mood, and potentially cognitive function. However, the body's compensatory mechanisms and the complex interplay between different steroid hormones make this relationship nuanced and context-dependent.
Citations:
[1] Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior - PubMed
[2] https://erc.bioscientifica.com/view/journals/erc/24/11/ERC-17-0155.xml
[3] Allopregnanolone - Wikipedia
[4] Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior - PMC
[5] Effects of Progesterone and Testosterone on Cocaine Self-Administration and Cocaine Discrimination by Female Rhesus Monkeys - Neuropsychopharmacology
[6] Frontiers | An Updated Review: Androgens and Cognitive Impairment in Older Men
[7] https://jamanetwork.com/journals/jamapsychiatry/fullarticle/209516
[8] https://www.europeanurology.com/article/S0302-2838(19)30449-X/fulltext
