5α-reductase is important for corticoid modulation and HPA axis feedback

Diokine

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The hypothalamic-pituitary-adrenal (HPA) axis is the fundamental stress handling system. The hypothalamus interprets information regarding challenges to homeostasis; the pituitary encodes solutions to challenges into metastable configurations, and the adrenals supply the products needed to maintain these states. This forms in essence an analog stress rectification circuit, with both positive and negative feedback. The rate of corticoid metabolism and clearance is a critical factor in maintaining proper adaptation to stress, and these factors differ between the sexes. 5α-reductase, commonly known as the enzyme responsible for the conversion of testosterone (TST) to di-hydro-testosterone (DHT,) is important in maintaining proper feedback in the HPA axis, and peripherally is involved in metabolizing and clearing cortisol.

When cortisol binds to glucocorticoid receptors in the hippocampus, corticotrophin releasing hormone (CRH) is synthesized in the hypothalamus, to act on the pituitary gland to release adrenocorticotropic hormone (ACTH) and increase HPA activity to prepare the body for stress. This is an example of positive feedback. When cortisol binds to receptors in the hypothalamus, a negative feedback loop is established and secretion of CRH is inhibited. The stress rectification capacity of the HPA axis depends on a proper balance of positive and negative feedback.

Chronic stress is progressively handled in the developing system, developing into a pattern of activity in the HPA axis that follows an ultradian rhythm, or rhythmic pulsing situated around a circadian rhythm, or 24 hour period of activity (R) Acute stress represents a perturbation in these rhythms, which requires a sufficient response to maintain physiological processes. HPA axis activity must be maintained in an optimal range, excessive activity and chronically elevated cortisol has been associated with metabolic syndrome and cardiovascular disease, while low levels may contribute to physiological frailty and increased risk of sudden death. Chronic activation of the HPA axis, or activation beyond physiological thresholds, can progress to “burn out,” representing a critically reduced capacity and presenting as learned helplessness or severe depression.

Androgens like testosterone (TST) have been modeled in the context of the HPA axis, and their action serves to reduce the response of the adrenals to HPA axis stimulation, functioning as a “damper” on the amplitude of reactions (R) This damper has the effect of limiting the response to stress through reduced ACTH and cortisol. In male rats, removal of the gonads increases the activity of the HPA axis and response to ACTH, increasing reaction to stress. Injections of TST or DHT reduce the ACTH and cortisol reaction to stress, showing a similar reaction to intact male rats. Treatment of mice with Finasteride, a 5α-reductase inhibitor, prevents the conversion of TST to DHT and exhibits the same effect on HPA axis reactivity as removal of the gonads. The effects of TST but not DHT could be blocked by injection of Finasteride into the central nervous system, indicating a crucial role for DHT in managing stress reactions (R)

DHT in this context is important in modulating the ACTH response to stress. Inhibiting 5α-reductase and reducing DHT has the effect of increasing the amplitude of stress reactions. This increases the tendency towards perturbation and greatly amplifies reactions to stress. This increased reactivity quickly leads to “burn-out,” and has been shown in mice to reduce response to all kinds of stimulation, mimicking depression or learned helplessness (R) 5α-reductase is also present in the liver and is involved in the metabolism and clearance of cortisol. Disruption of type 1 5α-reductase in mice caused a reduction in clearance of cortisol by eight times (R) Type 2 5α-reductase is less involved in cortisol maintenance, though it does play a role. Finasteride is predominantly a type 2 inhibitor, though some type 1 inhibition may occur. Reductions in the metabolism of cortisol may impair HPA axis activity through positive feedback via increased cortisol levels, contributing to dysfunctional stress responses.

In conclusion, HPA axis activity is a critically important factor in health and wellbeing. Disruption in 5α-reductase can increase the reactivity towards stress, initially presenting as emotional instability and increased tendency towards perturbation. This increased reactivity leads to excessive cortisol which reduces the response of the HPA axis to stress, reducing ACTH and possibly progressing to adrenal insufficiency. This increased reactivity can also progress to HPA axis depression, which would represent an inability to handle stress. This inability to handle stress represents a significant impact to quality of life and satisfaction in the face of challenge.



Developmental origins of the human hypothalamic-pituitary-adrenal axis

Kinetic modelling of testosterone-related differences in the hypothalamic–pituitary–adrenal axis response to stress

Central 5-alpha reduction of testosterone is required for testosterone's inhibition of the hypothalamo-pituitary-adrenal axis response to restraint stress in adult male rats

The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli

Relative adrenal insufficiency in mice deficient in 5α-reductase 1
 

Vileplume

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So if a person is under chronic stress and throws off the HPA axis rhythms, this could lead to a reduction in 5a-reductase activity, which could then inhibit the conversion of testosterone to DHT. Am I understanding this correctly?

If the above is the case, would this person see elevated testosterone in their bloodwork?

Asking because I’ve experienced years of stress and have testosterone that’s above the reference range, but I have a poor libido anyway.
 

haidut

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Treatment of mice with Finasteride, a 5α-reductase inhibitor, prevents the conversion of TST to DHT and exhibits the same effect on HPA axis reactivity as removal of the gonads. The effects of TST but not DHT could be blocked by injection of Finasteride into the central nervous system, indicating a crucial role for DHT in managing stress reactions

The bolded portion from the quote above is especially telling. Basically, taking finasteride has the same stress-amplifying effects as castration. I really hope the class-action lawsuits by PFS sufferers against the finasteride/dutasteride makers are allowed to proceed and result in some sort of injunction on the sales, as those drugs are pure poison.
 

FitnessMike

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So if a person is under chronic stress and throws off the HPA axis rhythms, this could lead to a reduction in 5a-reductase activity, which could then inhibit the conversion of testosterone to DHT. Am I understanding this correctly?

If the above is the case, would this person see elevated testosterone in their bloodwork?

Asking because I’ve experienced years of stress and have testosterone that’s above the reference range, but I have a poor libido anyway.
Me too i have got blood testosterone sometimes above norm/very high despite my sleep/thyroid problems.
 

Diokine

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@Vileplume

I think high testosterone and low libido might be related to challenges in rectifying stress in a suitable or satisfying direction. The actions of the androgens serve to damp the amplitude of stress reactions in the HPA-axis, in essence allowing you to digest stress more effectively. But if this doesn't move you towards something that you perceive as beneficial or meaningful, the continued damping can act to severely reduce reactivity of the HPA-axis. Reactivity in the proper context is very important for synthesizing solutions to challenges. Excessive reactivity can cause traumatic psychological injury, but critically reduced reactivity can lead to a hopeless situation.

Role of HPA and the HPG-axis interaction in testosterone-mediated learned helpless behavior

The present study investigates the influence of androgen on the behavioral phenotype and explores how it interacts with HPA-axis genes. Gonadectomized (GDX) rats and GDX rats treated with testosterone propionate (T) were tested for learned helplessness (LH) behavior and compared with tested controls (TC).

Unlike GDX rats, T-group exhibited significantly higher LH score when compared to any other group.

Altogether, the present study reveals an increased susceptibility to depression-like behavior due to chronic supraphysiological level of androgen via HPA axis inhibition.
 

FitnessMike

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DHT in this context is important in modulating the ACTH response to stress. Inhibiting 5α-reductase and reducing DHT has the effect of increasing the amplitude of stress reactions.
I maybe should stop taking nettle root extract then, even though it blocks only few % of the enzyme i believe, that could also be the reason why my testosterone is high.
 

Andman

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Aug 1, 2017
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@Vileplume

I think high testosterone and low libido might be related to challenges in rectifying stress in a suitable or satisfying direction. The actions of the androgens serve to damp the amplitude of stress reactions in the HPA-axis, in essence allowing you to digest stress more effectively. But if this doesn't move you towards something that you perceive as beneficial or meaningful, the continued damping can act to severely reduce reactivity of the HPA-axis. Reactivity in the proper context is very important for synthesizing solutions to challenges. Excessive reactivity can cause traumatic psychological injury, but critically reduced reactivity can lead to a hopeless situation.

Role of HPA and the HPG-axis interaction in testosterone-mediated learned helpless behavior

man this is fascinating, thanks for sharing. one would think that the opposite would happen, namely the test treated rats being immune to learned helplessness
 

TheBeard

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I maybe should stop taking nettle root extract then, even though it blocks only few % of the enzyme i believe, that could also be the reason why my testosterone is high.

Nettle root and Fenugreek are just as bad as Finasteride.
 

FitnessMike

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Jan 18, 2020
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Nettle root and Fenugreek are just as bad as Finasteride.
Well, now when i know that DHT hair loss is a myth, i can stop taking it, but I was also taking it as its kidney tonic herb according to Chinese medicine.
 

Basufa

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Is there any idea of how to resolve this HPA axis insufficiency? I’ve found descriptions, but no suggestions to resolve it! GPs don’t know what to do either, it seems.
 

TheBeard

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Is there any idea of how to resolve this HPA axis insufficiency? I’ve found descriptions, but no suggestions to resolve it! GPs don’t know what to do either, it seems.

Once you've optimized your nutrient intake and sun exposure, you're only left with exogenous hormones if you're still low.
 
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