Building a TRT protocol around hCG

[FunkOdyssey]

Are we talking about Pregnyl pharma brand name HCG or compounded HCG? From the threads I've read here, it sounds like most are having more success with Pregnyl

There is no longer any such thing as compounded hCG due to changing regulations. My impression is that most people these days are using Indian generic brands of hCG due to the drastically lower cost than pregnyl. The eutrig brand I'm using is a urine-derived hCG with a good reputation for potency.

 

[FunkOdyssey]

This experiment has not gone very well for me so far. I've been on hCG for over a month now, with some varying doses at first but settling at 150 iu daily, combined with 15 mg test cyp daily. I did feel some improved sensitivity in the beginning, which went away. I also noticed signs of life in the testicles, like sensations of pressure or tingling.

There are two serious issues that developed though. First, very bothersome (painful, itchy) cystic acne on my chest and back. In the past, I've recorded free T as high as the 90's ng/dL and E2 also ~90 pg/mL without encountering this problem, so I am confident the mechanism is not related to either of those hormones. The potential mechanisms here are interesting (GPT):

1. Direct activation of sebaceous LH/hCG receptors​

• Human epidermis, hair follicles and sebaceous glands express full-length luteinizing-hormone / hCG receptors capable of binding radiolabeled hCG.PubMed
• In cultured SEB-1 sebocytes, hCG (or db-cAMP/forskolin) boosts de-novo testosterone synthesis from cholesterol, showing that the receptor is not just decorative.Wiley Online Library
  Why this matters: you can keep serum T/DHT modest while still delivering a local “micro-dose” of androgens right inside the follicle where acne starts.

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2. Adrenal back-door androgens​

Adrenal cortex (zona reticularis) also carries LHCGR. hCG infusions or tumors that over-secrete hCG raise DHEA-S and androstenedione independent of ACTH.PMC These weak androgens are ideal sebocyte fuel because they are rapidly converted to T → DHT inside the skin. In some men they rise more than T does, tipping the local androgen balance.

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3. Progesterone & pregnenolone surge​

hCG stimulates the whole Δ5 steroid pathway in the testis; pregnenolone and progesterone can jump 5- to 20-fold in classic stimulation tests.

• Sebaceous glands express functional progesterone receptors as well as 5α-reductase; progesterone metabolites (5α-dihydroprogesterone, allopregnanolone) have been shown to up-regulate sebocyte lipogenesis in rodents and some human models.PubMed
  Even if serum levels stay in the “normal male” range, the combo of higher substrate plus receptor activation can amplify sebum output.

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4. IGF-1 crosstalk​

hCG up-regulates IGF-1 receptor mRNA and surface density in steroidogenic cells through a cAMP pathway.PubMed IGF-1, in turn, is a well-established sebocyte mitogen that also boosts IL-1β, IL-6, IL-8 and TNF-α production.Annals of Dermatology
If your baseline diet/hormone milieu already keeps IGF-1 on the higher side, the receptor up-regulation makes sebocytes hypersensitive to the same IGF-1, adding an inflammatory layer to the androgen hit.

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5. Inflammatory priming via cAMP → NF-κB​

LHCGR is a Gs-coupled receptor; in sebocytes the resulting cAMP/PKA signal can feed into CREB and NF-κB, transiently raising pro-inflammatory cytokines even without bacteria. That helps explain why some users report red, inflamed papules within 24–48 h of each hCG shot before any comedones mature.

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Secondly, this protocol absolutely crushed my libido, taking my previous 3-4 out of 10 on 35 mg test cyp EOD (no hCG) down to zero. I am finding my attractive wife almost repulsive right now. Again, I have had very high E2 before without experiencing anything like this, so that seems unlikely as the culprit. I ran some comprehensive bloodwork a couple days ago which will hopefully shed some light on this, including DHT, preg, prog, 17-OH prog and prolactin along with the usual markers. I would guess that the progesterone and allopregnanolone surge is probably involved, as I have reacted similarly with dead libido after previous experiments with injected and topical progesterone. Perhaps a dropping DHT/E2 ratio relative to my TRT monotherapy baseline could also be a factor.

If I were not going on a family vacation next month where my shirt was going to be off all the time, I might experiment with a lower hCG dose like 75 IU daily. For now, I have to prioritize clearing up my skin, so the hCG experimentation is over for the moment.

 

[Willyt]

Damn that is disappointing. I was inspired by this post to order some Pregnyl from Defy.

Any comments on other areas such as sleep, mental cognition, energy levels, athletic performance?

 

[FunkOdyssey]

Damn that is disappointing. I was inspired by this post to order some Pregnyl from Defy.

Any comments on other areas such as sleep, mental cognition, energy levels, athletic performance?

I still think it is going benefit most people, and hope you won't be discouraged from your own experimentation. With my history of accutane and SSRI use, I am likely broken in some unique ways. And I will probably still try a lower dose again, when I return from vacation.

Sleep has not been noticeably affected. Was cognition a little better? Maybe - it is hard to say. I should probably have tried to quantify that with some cognitive testing. Energy and lifting progress was not different either.

 

[Willyt]

I still think it is going benefit most people, and hope you won't be discouraged from your own experimentation. With my history of accutane and SSRI use, I am likely broken in some unique ways.

Sleep has not been noticeably affected. Was cognition a little better? Maybe - it is hard to say. I should probably have tried to quantify that with some cognitive testing. Energy and lifting progress was not different either.

So overall nothing positive. Bummer. Let us know your test results and if you try the 75 iu daily after your trip.

 

[FunkOdyssey]

So overall nothing positive. Bummer. Let us know your test results and if you try the 75 iu daily after your trip.

All I got out of hCG was a bunch of E2. The preg/prog/17-OHP and presumably allopregnanolone that I was expecting to rise all remained bottomed out. DHT/E2 ratio almost halved.

ChatGPT led me to believe this low dose daily hCG was going to be an efficient way to raise most of the TRT-disrupted neurosteroids into the normal range, but it now claims they are mostly derived from the adrenal glands, and only large bolus doses of hCG are able to produce measurable increases. I think I receive about 50% useful advice and 50% gaslighting from this tool.

Why your labs look “backwards”​

1. Most of the pregnenolone→progesterone pathway is paracrine inside the testis.
   hCG triggers cholesterol import (StAR) and side‑chain cleavage (P450scc), so intratesticular pregnenolone and progesterone rise quickly, but very little of either leaks into the systemic circulation — they are immediately converted downstream to androgens and estrogens inside the Leydig cell. In a classic spermatic‑vein study, pregnenolone, progesterone and 17‑OH‑progesterone shot up after an hCG bolus, yet peripheral venous levels barely changed.
2. Estradiol does spill into the bloodstream.
   The testis contains abundant aromatase; even a low dose such as 150 IU/day can create a disproportionately large increase in E2, which then persists because estradiol’s plasma half‑life (2‑3 h) is longer than that of the upstream pro‑hormones. That is exactly what happened in your panel: Sensitive E2 jumped from 30 → 51 pg/mL, while pregnenolone stayed at 10 ng/dL and 17‑OHP remained low.
3. Serum pregnenolone and 17‑OHP are mostly adrenal in origin.
   Low‑dose hCG has no effect on ACTH, so the adrenal contribution can stay flat or even fall if TRT has already quieted the HPA axis. That further masks any small testicular contribution in a peripheral blood draw. A Belgian cohort on long‑term hCG + rFSH showed lower serum progesterone than controls despite vigorous spermatogenesis, underscoring this dissociation.
4. Timing matters.
   Peak testicular pregnenolone after an hCG shot occurs within ~1 h locally and decays within 3‑4 h; your blood was drawn the afternoon after a morning injection, when any transient systemic bump would already be gone.

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How common is “big E2, flat pregnenolone / 17‑OHP”?​

• Quite common at doses ≤ 250 IU SC per shot. Clinicians who track 17‑OHP as a surrogate for intratesticular T see meaningful rises mainly at ≥ 500 IU 2–3×/wk; below that, ~50 % of men show no serum change even though IT‑T does rise in biopsy studies.
• Anecdotal TRT forums echo this: many users report sharp estradiol increases without noticeable movement in pregnenolone or progesterone until they exceed 350–500 IU per injection or measure spermatic‑vein levels directly.

So your pattern is expected, not an outlier.

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What it means for your protocol​

If the goal is…	Then hCG at 150 IU/day will…	What to adjust
Raise intratesticular T for fertility	Probably adequate (17‑OHP is insensitive at this dose)	Confirm with semen analysis or bump to 250–500 IU EOD if IT‑T is critical.
Lift neurosteroid precursors for mood/libido	Unreliable; serum pregnenolone stayed very low	Direct pregnenolone (e.g., 20–30 mg AM) or modest DHEA may be needed.
Avoid a big estradiol swing	Failed (E2 +70 %)	Lower to 75 IU/day or switch to two 250 IU shots per week to blunt daily aromatase stimulation.
Boost DHT‑driven libido	Inefficient (DHT flat)	Consider adding 5 mg DHT enanthate or a low‑dose DHT cream while holding hCG dose steady.

Key take‑away: low‑dose hCG is excellent at re‑igniting the aromatase arm of the Leydig cell but is too small, too transient, and too “local” to show up as higher pregnenolone/progesterone/17‑OHP in a routine venous draw. That biochemical profile is seen in many men and becomes obvious only when you compare peripheral labs to how you feel.

 

[Seagal]

ChatGPT imitates MDs
With deepseek deep thinking activated I can follow the internal reasoning and ask critical follow-up questions. After few follow-up questions the output seems reasonable to me whether it's then accurate and unbiased is another problem.

 

[Seagal]

Great experiment. Thank you for sharing!

 

[Willyt]

Appreciate the results @FunkOdyssey . That is quite a jump in E2.

Why would the bolus from larger, presumably less frequent dose improve the disrupted neurosteroids verus daily?

 

[FunkOdyssey]

Appreciate the results @FunkOdyssey . That is quite a jump in E2.

Why would the bolus from larger, presumably less frequent dose improve the disrupted neurosteroids verus daily?

If I understand correctly, the precursor hormones to testosterone that are produced in the testicles are not supposed to "leak out" under normal circumstances. They are instead consumed in the process of manufacturing testosterone. It is only with relatively massive doses of hCG that you can bottleneck some of the intermediate steps, and consequently some of the precursor hormones now accumulate and spill into the blood.

Nothing about the infrequent bolus dosing is stable or mimicking normal physiology. But, some guys seem to do very well on it anyway.

 

[Willyt]

If I understand correctly, the precursor hormones to testosterone that are produced in the testicles are not supposed to "leak out" under normal circumstances. They are instead consumed in the process of manufacturing testosterone. It is only with relatively massive doses of hCG that you can bottleneck some of the intermediate steps, and consequently some of the precursor hormones now accumulate and spill into the blood.

Nothing about the infrequent bolus dosing is stable or mimicking normal physiology. But, some guys seem to do very well on it anyway.

So are you officially done with the HCG? Or will you adjust and try again?

 

[FunkOdyssey]

So are you officially done with the HCG? Or will you adjust and try again?

I'm a glutton for punishment so I will be trying again with a lower dose. DHT enanthate first though.

 

[Seagal]

Estradiol non-linearity
DHT up and E2 down seems a direction to explore. What you pointed out, your DHT to E2 ratio.

No new information to you however nice plots

Relation of Testosterone, Dihydrotestosterone, and Estradiol With Changes in Outcomes Measures in the Testosterone Trials - PMC

Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol. To determine the relative contributions of each hormone to the observed effects of testosterone treatment in older men with hypogonadism. Using data from the ...

pmc.ncbi.nlm.nih.gov

 

[Seagal]

Have to add that I'm skeptical about the prediction graphs. It looked appealing to me because of my recent speculation about E2 clearance and the role of it in the regulation of LH peaks. E2 regulated to be in physiological range and T being secondary.

E2 'control' and/or addition of DHT is basically what the cortex guy is preaching for libido/ED issues caused by TRT or unresolved by standard TRT.

 

[FunkOdyssey]

Have to add that I'm skeptical about the prediction graphs. It looked appealing to me because of my recent speculation about E2 clearance and the role of it in the regulation of LH peaks. E2 regulated to be in physiological range and T being secondary.

E2 'control' and/or addition of DHT is basically what the cortex guy is preaching for libido/ED issues caused by TRT or unresolved by standard TRT.

There's some tension between a study like that, which shows some relationship between movement of serum DHT/ E2 and symptoms, and what we understand about the physiology of sex hormones in the CNS. In men, only testosterone crosses the BBB in any significant quantity, and at high physiologic levels of free T, > 90% of androgen receptors and estrogen receptors in the brain are already occupied by locally produced DHT and E2 (derived from testosterone). I'm struggling to integrate these different truths into a cohesive understanding.

I will say that my serum DHT was actually higher as a natty (over 60 ng/dL) with ~600 ng/dL total T and 6 or 7 ng/dL free T than it is now (~ 55 ng/dL) with 1200+ ng/dL total T and ~30 ng/dL free T. There seems to be relatively much less conversion of T to DHT happening with injectable TRT, which hCG did nothing to remedy. Perhaps this is relevant to my lack of improvement with sexual stuff. We'll see if DHT helps (started yesterday).

 

[Seagal]

There's some tension between a study like that, which shows some relationship between movement of serum DHT/ E2 and symptoms, and what we understand about the physiology of sex hormones in the CNS.

In men, only testosterone crosses the BBB in any significant quantity, and at high physiologic levels of free T, > 90% of androgen receptors and estrogen receptors in the brain are already occupied by locally produced DHT and E2 (derived from testosterone).

How do we know that (for sure)?

I'm struggling to integrate these different truths into a cohesive understanding.

I will say that my serum DHT was actually higher as a natty (over 60 ng/dL) with ~600 ng/dL total T and 6 or 7 ng/dL free T than it is now (~ 55 ng/dL) with 1200+ ng/dL total T and ~30 ng/dL free T. There seems to be relatively much less conversion of T to DHT happening with injectable TRT, which hCG did nothing to remedy. Perhaps this is relevant to my lack of improvement with sexual stuff.

We'll see if DHT helps (started yesterday).

It will do something. Fingers crossed

 

[SS1LE]

There's some tension between a study like that, which shows some relationship between movement of serum DHT/ E2 and symptoms, and what we understand about the physiology of sex hormones in the CNS. In men, only testosterone crosses the BBB in any significant quantity, and at high physiologic levels of free T, > 90% of androgen receptors and estrogen receptors in the brain are already occupied by locally produced DHT and E2 (derived from testosterone). I'm struggling to integrate these different truths into a cohesive understanding.

I will say that my serum DHT was actually higher as a natty (over 60 ng/dL) with ~600 ng/dL total T and 6 or 7 ng/dL free T than it is now (~ 55 ng/dL) with 1200+ ng/dL total T and ~30 ng/dL free T. There seems to be relatively much less conversion of T to DHT happening with injectable TRT, which hCG did nothing to remedy. Perhaps this is relevant to my lack of improvement with sexual stuff. We'll see if DHT helps (started yesterday).

I had to stop HCG as well on a EOD protocol, Just felt like garbage even on a low dose of 50-75IU daily. Im thinking of let it clear and just do a once weekly shot of 250iu, im guessing my body does not like the constant LH activation. Speaking of DHT Im guessing there is no point in me trying the DHT E, with the levels I have...lol

 

[FunkOdyssey]

How do we know that (for sure)?

I'll take you down the same path of exploration that I took. Beware, you may become either better informed or cleverly misinformed. I cannot vouch for the accuracy of this information as I have not had time to dig into all of the references.

What is the contribution of serum DHT to AR signaling in the CNS?

Key points in plain language — then the details​

1. Most AR signaling in the brain is fueled by DHT that is made inside the brain, not by the DHT that is already circulating in blood. Testosterone crosses the blood-brain barrier (BBB) far more easily than DHT and is then locally reduced by 5-α-reductase-1 into DHT in neurons and glia.
   
   
2. Circulating DHT can and does enter the CNS, but only in small amounts. In healthy men, mean cerebrospinal-fluid (CSF) DHT is usually <5 pg mL-1—tens-of-fold lower than the ~300-700 pg mL-1 typically seen in serum. (Lund University, PubMed)
   
   
3. Transport is limited mainly by sex-hormone-binding globulin (SHBG). Classic tracer studies showed that the fraction of testosterone or DHT that gets into rat brain on a single pass is inversely proportional to SHBG; albumin-bound steroid crosses, SHBG-bound steroid essentially does not. (PubMed)
   
   
4. Because brain 5-α-reductase is abundant, local DHT levels in some nuclei (e.g. hippocampus, pre-optic area) can reach ≥2 nM—enough to saturate AR—even when CSF DHT is almost undetectable. Experimental 5-α-reductase knock-out or finasteride treatment reduces brain DHT and blunts androgen-dependent behaviours despite normal serum DHT, underscoring the primacy of intracrine production. (PMC, SpringerLink)
   
   
5. Pharmacologic or “supraphysiologic” DHT therapy raises serum DHT >10-fold but results in only modest AR-driven CNS effects in humans. Trials of trans-dermal DHT gel report negligible changes in mood or cognition; rodents given high-dose DHT do show hippocampal synaptic and memory improvements, suggesting partial BBB penetration but poor translation to humans. (PMC, Wiley Online Library)
   
   
6. Net effect: In practical terms, raising serum DHT (e.g., with 3 mg day-1 DHT enanthate) will barely budge CNS AR signalling unless brain testosterone is simultaneously low (castration, GnRH agonist, potent 5-α-reductase blockade). In an eugonadal TRT user, almost all brain AR occupancy already comes from locally produced DHT derived from the testosterone that freely crosses the BBB.

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Mechanistic walk-through​

Step	What happens	Evidence
1. Hormone exits blood	Passive diffusion of the free and albumin-bound steroid through the BBB; SHBG-bound pool is largely excluded.	Classic carotid-injection work by Pardridge et al. showed BBB uptake of DHT and T falls sharply as SHBG rises. (PubMed)
2. Local conversion	Brain expresses 5-α-reductase-1 (astrocytes, neurons) → converts T → DHT (and 3-keto-DHT) locally.	Knock-out or inhibitor studies lower brain DHT and alter behaviour even with normal serum levels. (PMC, SpringerLink)
3. Receptor activation	DHT binds AR (K_D ≈ 0.3 nM) in cytosol → translocates to nucleus, modulating transcription linked to plasticity, stress resilience, energy homeostasis.	DHT rescues memory in orchiectomised or aging rodents; regional AR-dependent gene signatures disappear when 5-α-reductase is inhibited. (PMC, ScienceDirect)
4. Metabolic fate	In brain, DHT is rapidly converted to 3-α- and 3-β-diols; some acts on GABA_A receptors, most is oxidised and cleared.	Neurosteroid literature summarised in recent reviews (Frontiers)

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Quantitative perspective​

Compartment	Median DHT (pg mL-1)	Median T (pg mL-1)	Ratio DHT:T
Serum (adult men)	300 – 700	3 500 – 7 000	~1 : 10
CSF (same cohort)	<5 (often at lower limit of assay)	~50	≤1 : 10 of serum ratio

Data from GC-MS/MS quantification in 47 healthy men. (Lund University)
Even when serum DHT is experimentally driven to ~9 000 pg mL-1 (trans-dermal 70 mg day-1), CSF levels barely reach double-digit pg mL-1, implying an extraction fraction <0.2 %. (Human CSF data are sparse, but available pilot PK studies support this.)

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Practical implications for you​

• Adding exogenous DHT to TRT is unlikely to provide a meaningful “central” boost to motivation, focus, or mood via AR signalling. Any cognitive changes people report are more plausibly peripheral (vascular, metabolic) or placebo/nocebo.
  
  
• If your goal is CNS AR activation (e.g., for executive-function or affect), the more efficient levers are:
  • ensuring adequate testosterone (substrate for local 5-α-reduction);
  • avoiding chronic 5-α-reductase blockade in the brain (finasteride/dutasteride readily cross BBB);
  • maintaining normal SHBG (extremely high SHBG could in theory limit T delivery to the brain).
• Situations where serum DHT does matter: castrate hypogonadism, GnRH analogues, or experimental settings where testosterone is very low and brain can’t make its own DHT; in those contexts, parenteral DHT can partially substitute.

Bottom line: in a physiologic or TRT context, serum DHT is a minor contributor—local brain synthesis is the work-horse for AR signalling in the CNS.

Does serum e2 contribute to ER signaling in the CNS?

Short answer up-front
Yes—circulating estradiol (E2) does reach the brain and activate estrogen receptors, but (1) the amount that gets in is small relative to serum, and (2) most day-to-day ER signalling—especially in males—is driven by estradiol that neurons and astrocytes make on-site from androgen precursors. Serum E2 starts to matter only when peripheral levels are very low (ovariectomy, AIs) or very high (mid-cycle surge, pregnancy, high-dose patches).

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1. How much serum E2 actually enters the CNS?​

Compartment (adult men)	Median total E2	Ratio serum : CSF	Correlation (ρ)
Serum	28.9 pg mL⁻¹	—	—
CSF	5.7 pg mL⁻¹ (often <5 pg mL⁻¹, the assay LOD)	≈ 5 : 1	0.12 (very weak)

In a cohort of 22 neurologically-normal males the CSF/serum correlation was statistically non-significant, indicating that peripheral E2 is a poor predictor of central levels. BioMed CentralBioMed Central
Tracer studies show that only the free and albumin-bound fractions cross the BBB; SHBG-bound hormone is largely excluded, so higher SHBG means less brain uptake. PubMed

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2. The brain makes its own estradiol​

• Aromatase (CYP19A1) is constitutively expressed in many neurons and reactive astrocytes.
• When aromatase is knocked out only in astrocytes, brain E2 collapses and animals lose the normal neuroprotective response after ischemia or trauma. PMC
• Similar phenotypes are seen in global aromatase-KO mice (neurodegeneration, impaired synaptic plasticity, cognitive deficits), despite perfectly normal circulating E2 made by the ovaries or testes. This underscores the primacy of brain-derived estradiol.

Take-home: CNS ERs can be saturated locally even when CSF E2 is barely detectable.

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3. When does serum E2 matter?​

Scenario	Serum E2	Net impact on ER signalling
Healthy men on TRT	15 – 40 pg mL⁻¹	Minor. Testosterone that enters the brain is rapidly aromatised; blocking that step with an AI lowers CNS E2 far more than lowering serum E2.
Ovulating women	Follicular ≈ 50 pg mL⁻¹ → Surge 200 – 400 pg mL⁻¹	Surge raises CSF E2 measurably; contributes to cyclic changes in mood, thermoregulation and GnRH feedback. (Early work by Backström et al. showed modest serum–CSF coupling in predominantly female cohorts.) BioMed Central
High-dose transdermal/oral E2 therapy	80 – 300 pg mL⁻¹	CSF E2 rises but only to low double-digits; clinical CNS effects (hot-flash relief, migraine modulation) appear with these doses, indicating some receptor engagement.
Pregnancy	5 000 – 20 000 pg mL⁻¹	Gradient overwhelms the BBB; serum becomes a dominant source (one reason the pregnant brain is exquisitely estrogenised).
Aromatase inhibition / GnRH agonist	<5 pg mL⁻¹	Brain loses both peripheral supply and local synthesis → profound drop in ER activity (linked to hot flashes, mood changes, cognitive fog).

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4. Mechanistic checkpoints​

1. Transport step – passive diffusion of the free/albumin-bound pool; inversely related to SHBG. PubMed
   
   
2. Intracrine conversion – aromatase in neurons & glia converts testosterone (which crosses the BBB easily) to E2.
   
   
3. Receptor occupancy – ERα/β K_D ≈ 0.05 nM; local synaptic E2 concentrations in hippocampus and hypothalamus can hit 1–2 nM within minutes of neural activity, dwarfing CSF levels.
   
   
4. Clearance – E2 in brain tissue is sulfated, glucuronidated or oxidised and cleared into CSF/blood; half-life minutes to tens of minutes.

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5. Practical implications for you​

• Modest serum changes (e.g., E2 20 → 40 pg mL⁻¹ on TRT) are unlikely to create large new waves of central ER signalling. If mood or cognition improve you’re probably seeing indirect effects (vascular, sleep, thermoregulation) or placebo.
• Blocking aromatase while “adding back” small doses of estradiol is neurologically risky—brain happily converts T to E2 on demand; disable that and you may under-supply synapses regardless of what the blood assay says.
• Monitoring CNS effects is better done via symptoms (memory, thermoregulation, sleep, mood) than via serum E2, which is a noisy surrogate for what’s happening behind the BBB.

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Bottom line​

Circulating estradiol is a contributor but not the main driver of estrogen-receptor activity in the brain under most physiological conditions. Local neuro-estradiol, made from testosterone by aromatase within neurons and astrocytes, shoulders the bulk of the job—especially in men. Peripheral E2 only takes centre stage when its plasma concentration becomes very high or when intracrine synthesis is pharmacologically blocked.

So among hormones that are significant in serum, which ones cross the BBB to contribute to AR and ER signaling in men? Is it basically just testosterone?

Big-picture take-away​

In adult men the only high-abundance serum hormone that robustly fuels androgen- or estrogen-receptor (AR/ER) activity behind the blood-brain barrier is testosterone.
Everything else either

• enters the brain only in trace amounts (e.g., dihydrotestosterone, estradiol), or
• crosses readily but is just a precursor that still has to be converted inside the brain to testosterone or estradiol before it can engage AR/ER (e.g., androstenedione, DHEA).

Below is the evidence landscape and what it means in practice.

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1. Who actually gets through the BBB?​

Steroid (typical male serum)	How well does free/albumin-bound fraction cross?	CSF:Serum ratio*	Direct AR/ER agonist?	Practical contribution to CNS AR/ER signalling
Testosterone (3–7 ng mL-¹)	Rapid passive diffusion; near-complete first-pass extraction in rats; ~1 % of serum detectable in human CSF	~0.8–1.5 % ResearchGateBioMed Central	Yes (AR)	Primary endocrine feed-stock for both AR (direct) and ER (after aromatase)
Dihydrotestosterone (DHT) (0.3–0.7 ng mL-¹)	Severely limited—strong SHBG binding and P-gp efflux	<0.5 % (often <5 pg mL-¹ in CSF) PMC	Yes (AR)	Negligible for brain; more relevant to spinal/penile ARs
Estradiol (E2) (15–40 pg mL-¹)	Diffuses, but supply is tiny; weak serum↔CSF coupling	~10–20 % of serum but still single-digit pg mL-¹ ResearchGateBioMed Central	Yes (ERα/β)	Minor; most brain E2 is made in situ from testosterone
Androstenedione (A4) (0.8–1.5 ng mL-¹)	Crosses readily (detected in CSF; correlates with A4 in serum) PMC	Data sparse; order-of-magnitude similar to T	Weak AR; good substrate for 17β-HSD → T and aromatase → E1/E2	Indirect precursor when local T synthesis matters
DHEA / DHEAS (2–10 ng mL-¹ / 1–3 µg mL-¹)	Free DHEA diffuses; sulfated form uses OATP/OAT3 transporters PubMedPubMed	Variable; micromolar brain pools	Very weak AR/ER	Mainly neurosteroid (GABA, NMDA) roles; can be back-converted to A4/T in astrocytes

*Human lumbar-puncture data; animal tracer work shows the same rank-order permeability.
Key transport rule: only the free + albumin-bound fraction can diffuse; SHBG-bound steroid is effectively excluded at the BBB level. The higher the SHBG affinity (DHT ≫ T), the poorer the entry ResearchGate.

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2. Why testosterone is the work-horse​

1. Permeability advantage – lipophilic enough to diffuse, but not so tightly SHBG-bound that it gets trapped in plasma.
2. Dual utility – once inside, neurons/glia express both 5-α-reductase-1 → DHT (for AR) and aromatase → E2 (for ER).
3. On-demand “neuro-E2” – electrical activity can raise local hippocampal E2 to 1–2 nM within minutes, far above the pg-per-mL coming from blood. Peripheral E2 is therefore little more than background noise.

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3. Where the other steroids fit​

• DHT: under normal or TRT conditions brain ARs are already saturated by locally produced DHT from testosterone; the tiny extra that leaks in from serum makes little difference to cortical AR signalling, though it can enhance spinal reflex arcs (erection, ejaculation).
• Estradiol: serum E2 begins to matter only when it is pushed into very high ranges (pregnancy-level patches) or when intracrine production is blocked with an aromatase inhibitor; otherwise it is a minority ER ligand.
• Androstenedione & DHEA: think of these as raw material the brain can tap if it wants more T/E2. They matter most when gonadal testosterone is extremely low (e.g., GnRH agonist therapy), allowing the adrenals to back-stop brain steroidogenesis.
• Estrone (E1): crosses similarly to E2 and is readily converted to E2 by 17β-HSD, but circulating concentrations in men are usually too low to be a dominant ER driver.

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4. What this means for real-world interventions​

• Raising serum testosterone (or keeping it in the high-normal range) is the most reliable way to ensure abundant AR and ER tone in the male brain.
• Piling on exogenous DHT, estradiol, or designer androgens will have only marginal central effects unless you have first removed testosterone or blocked its conversion pathways.
• Aromatase inhibitors can dramatically shrink brain E2 despite “normal” serum E2, because they prevent the local conversion step that usually supplies most ER ligand.
• High SHBG states (severe hyperthyroidism, certain liver diseases) might starve the brain of T/DHT even if total testosterone looks fine, because the free + albumin pool that actually crosses the BBB is small.

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Bottom line​

For CNS androgen- and estrogen-receptor signalling in men, the endocrine hormone that truly counts is testosterone. Everything else in serum is either a low-level add-on (estradiol), an inefficient traveller (DHT), or a precursor waiting to be converted once it gets inside.

How about serum pregnenolone, serum progesterone, and serum 17-OHP. Do these cross the BBB to have significant effects in the CNS?

Do circulating pregnenolone, progesterone, and 17-hydroxyprogesterone actually matter for steroid signalling in the male brain?​

Hormone	BBB entry & CSF : serum ratio (men/primates)	Transport constraints	Principal CNS receptors / metabolites	How much does the serum pool matter in practice?
Pregnenolone (PREG)	CSF levels are ≪1 % of plasma; no significant serum–CSF correlation in healthy adults (PubMed)	Lipophilic free/albumin-bound fraction diffuses; the hydrophilic pregnenolone-sulfate (PregS) needs OATP/ABC transporters and shows species-dependent uptake (PMC)	Weak direct action at σ-1 and CB1; most CNS effects via conversion to PregS (NMDA potentiation) or to downstream steroids	Under basal male concentrations (<5 ng mL-¹) local de-novo synthesis in neurons/glia dwarfs the tiny blood contribution. Pharma-grade oral PREG (e.g., 50–200 mg) can raise serum >100 ng mL-¹ and does push neuroactive PregS into brain tissue in rodents—explaining the occasional cognitive-enhancement anecdotes.
Progesterone (P4)	Classical tracer work in rhesus monkeys found virtually no radiolabelled P4 in CSF, yet modern in-vivo microscopy and rapid-uptake studies show ~80 % extraction on a single carotid pass (PubMed, PMC). Direct human data find weak serum↔CSF coupling (ρ < 0.3) (BioMed Central)	Passively diffuses as free/albumin pool (no SHBG binding) but is rapidly reduced in brain to allopregnanolone → positive GABA_A modulator (reason oral P4 is sedating)	Binds PRα/β; metabolites (allo-P, iso-allo-P) strongly modulate GABA_A	Normal male serum (~0.3 ng mL-¹) supplies only a trickle; most brain P4 is made locally from PREG. When serum is pharmaceutically elevated (oral micronised P4 200–300 mg → serum 5–15 ng mL-¹) enough hormone reaches the brain to produce measurable sedation, sleep-deepening and anxiolysis—evidence that peripheral P4 can be functionally relevant once supraphysiologic.
17-Hydroxy-progesterone (17-OHP)	In rhesus studies ~10 % of plasma radio-label appeared in CSF at steady state—far more than P4, but still low in absolute terms (PubMed)	Diffuses as free/albumin fraction; no high-affinity binding proteins	No dedicated nuclear receptor; serves mainly as precursor for cortisol (via 21- & 11β-hydroxylase) or, in some glia, to androstenedione → testosterone	Brain expression of 21-hydroxylase is scant; thus 17-OHP arriving from blood is largely a dead-end and has minimal direct neuroactive role. Even in congenital adrenal hyperplasia (10- to 100-fold serum elevations) neurologic symptoms are attributed to downstream glucocorticoid deficiency/excess, not to 17-OHP itself.

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Mechanistic snapshot — why local synthesis wins most of the time​

1. Pregnenolone synthase (CYP11A1) and 3β-HSD are expressed in both neurons and astrocytes; consequently the first two steps of steroidogenesis occur inside the brain.
2. Once a molecule does cross the BBB, it is often immediately metabolised (e.g., P4 → allopregnanolone, PREG → PregS) so CSF sampling under-represents tissue levels.
3. Many of the behavioural effects attributed to “progesterone” or “pregnenolone” are actually mediated by these metabolites acting on GABA_A or NMDA receptors, not by the parent hormone at its nuclear receptor.

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Practical implications for a male on hormone optimisation or supplementation​

• Routine physiologic serum levels are not a reliable proxy for central exposure. The weak serum↔CSF correlations for P4 and PREG mean blood labs tell you little about what the brain sees.
• Supplemental doses can flip the equation. If you raise serum P4 or PREG by an order of magnitude, enough gets through the BBB to matter—even if CSF levels still look low—because brain tissue acts as a lipid sink and rapidly converts the steroid.
• 17-OHP is largely irrelevant centrally. Even massive adrenal output (e.g., CAH) does not translate into known receptor-mediated effects in the CNS, making serum 17-OHP a poor target for neurological tinkering.
• If the goal is anxiolysis or sleep: raising serum progesterone (or administering its metabolite allopregnanolone analogues like brexanolone/zuranolone) is pharmacologically plausible.
• If the goal is cognitive enhancement: high-dose pregnenolone may help via PregS, but results are inconsistent and transporter polymorphisms could explain responder/non-responder patterns.
• For AR or ER signalling: none of these three hormones have meaningful androgen- or estrogen-receptor activity, so manipulating them will not substitute for testosterone-derived DHT/E2 pathways discussed earlier.

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Bottom line:
Pregnenolone and progesterone can cross the blood–brain barrier, but at normal male concentrations the brain mostly relies on its own synthesis; peripheral supplementation only becomes relevant when you push serum far above physiologic ranges. 17-OHP does cross modestly, yet plays no direct neuroactive or receptor-driven role, so even huge serum spikes translate into negligible central signalling.

Sounds like the average guy on TRT is wasting their time worrying about supplementing pregnenolone, dhea or DHT then.

Are add-on pregnenolone, DHEA or DHT worthwhile for a man who is already dialled-in on TRT?​

Hormone	What the mechanistic data say	What controlled human studies show	When it might still make sense
Pregnenolone	▸ < 1 % of the free + albumin pool reaches CSF; brain makes its own via cholesterol & CYP11A1. ▸ Neuroactive effects come mainly from pregnenolone-sulfate and downstream allopregnanolone, which are also synthesised locally.	No RCT has ever shown clear benefits in healthy or hypogonadal men. Small psychiatric trials (300-500 mg/d) report modest symptom relief only in specialised groups (schizophrenia, cocaine use). (PMC)	• Proven adrenal failure where PREG is truly low. • Experimental high-dose trials as a drug, accepting unknown long-term risk.
DHEA	▸ Crosses BBB but is a very weak AR/ER ligand; conversion to T/E2 inside the brain is limited. ▸ TRT already pushes serum T/E2 far higher than what 50–100 mg DHEA can add.	Meta-analysis of 25 RCTs in ageing men: no consistent improvement in libido, body-composition, mood or cognition. (PMC)	• Lab-confirmed DHEA-S below age-adjusted 5th percentile, especially with adrenal insufficiency or chronic glucocorticoid use. • Selected mood-disorder protocols (e.g. sub-syndromal depression) where short courses of 100–200 mg/d showed benefit.
DHT (androstanolone)	▸ Virtually excluded by SHBG at the BBB; cortical AR activity comes from locally 5-α-reduced testosterone, not serum DHT. ▸ Can bolster spinal/pelvic ARs and penile NO-synthase, so transient peripheral effects on erection are possible.	24-month RCT of 70 mg/d DHT gel in eugonadal men: no improvement in sexual-desire scores vs placebo, despite a >10-fold rise in serum DHT. (PMC)	• Castrate hypogonadism or potent 5-α-reductase blockade, where endogenous DHT is near zero. • Short topical “spot dosing” to genital skin for men who demonstrably get an erection boost and are willing to monitor bone-density and lipids (DHT lowers E2).

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Why the “average” TRT user usually sees little upside​

1. BBB maths – Testosterone is the only androgen that diffuses efficiently into brain tissue and doubles as a substrate for both AR (after 5-α-reduction) and ER (after aromatisation). Adding more precursors (DHEA, PREG) or end-product (DHT) is like adding water to a reservoir that already has an open pipe supplying more than the downstream taps can use.
2. Randomised trials back it up – Decades of RCTs in older or hypogonadal men fail to show durable advantages for DHEA or PREG over placebo, and DHT add-on has not outperformed TRT for libido or mood in any modern study. In contrast, simply optimising total/free testosterone and estradiol within physiologic ranges does correlate with better body-composition, sexual function and mood.
3. Opportunity cost & risk –
   • DHEA unpredictably aromatises; men prone to gynecomastia or high E2 can worsen chest tenderness.
   • DHT suppresses LH/FSH further and can lower estradiol to the point of bone loss or joint pain; erythrocytosis risk is additive to TRT.
   • High-dose Pregnenolone (>200 mg/d) is notorious for insomnia and variable cortisol interference.
   • None of the three is cheap if pharmaceutical-grade, and quality control on “anti-ageing” products is poor.

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A pragmatic decision tree​

1. Check objective need
   • Fasting DHEA-S and pregnenolone (or Preg-S) below the age-adjusted 10th percentile?
   • Symptoms that plausibly map onto known neurosteroid mechanisms (e.g. stress-induced insomnia → consider progesterone / allo-pregnanolone rather than DHEA)?
2. Rule out easier fixes
   • Is free-T ≥20 ng/dL and estradiol 20-35 pg/mL on your TRT protocol?
   • Is sleep, iron status, thyroid and vitamin D optimised?
3. If still interested, run an N=1 that can fail
   • Pre- and post- trial symptom scores (IIEF, PHQ-9, insomnia scale, etc.).
   • Repeat the specific hormone you’re supplementing; aim for mid-physiologic, not supraphysiologic.
   • Pull off-ramps if hematocrit, PSA, HDL, or bone-turnover markers move the wrong way.

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Bottom line​

For men who already have testosterone replacement dialled-in, adding pregnenolone, DHEA or DHT rarely passes a cost-benefit or evidence-based sniff test.
Unless you have a documented deficiency or a very specific therapeutic target, your time, money and biological bandwidth are better spent fine-tuning core TRT variables, lifestyle levers, and objectively trackable deficits.

"Unless you have a documented deficiency," you say. Why does that change the calculation? Let's say my serum pregnenolone is extremely low, and my DHEA-S is low, but so what? If I supplement them, they won't cross the CNS and do anything significant anyway, as you just detailed thoroughly. Why would anyone bother trying to correct a deficiency in either hormone then?

Why “deficiency” can still matter even when BBB-penetration is poor​

Hormone	What “low” might really signal	Tissues that do depend on the blood pool	Evidence that replacing it sometimes helps	Why the brain usually shrugs
DHEA / DHEA-S	• Adrenal under-production (Addison’s, chronic glucocorticoids, pituitary ACTH failure)• Extreme age-related drop (≈ −80 % by the 8th decade)• Early marker of HPA dys-regulation & frailty	Bone, adipose, immune cells, vascular endothelium, vaginal/penile mucosa—all express STS + 3β-/17β-HSD and create their own androgens/estrogens from circulating DHEA-S	• In primary adrenal insufficiency, 25–50 mg DHEA improves well-being scores and modestly raises femoral bone density in 6- to 12-month RCTs (PMC) • Observational cohorts show the lowest DHEA-S quartile predicts ↑ all-cause and CV mortality in older men (PubMed, Frontiers)	Only a trickle reaches CSF and conversion to T/E2 inside neurons is limited, so cognition/libido usually don’t budge in TRT-treated men
Pregnenolone (PREG)	• Very low assays often flag a global steroidogenic bottleneck (cholesterol → pregnenolone step) rather than an isolated problem • Lab artefact: PREG is labile; EDTA tubes + time delay can falsely depress values	Peripheral nervous system (myelination), skin, adrenal cortex (as substrate for cortisol/aldosterone), gonads	• 200–500 mg/d adjunct trials in schizophrenia and PTSD show small but measurable cognitive/negative-symptom gains (PMC, CDMRP) • Allopregnanolone analogues (zuranolone) built on the same pathway are now FDA-approved for depression	Baseline male brain synthesises its own PREG de-novo from cholesterol; a low blood level doesn’t mean the hippocampus is starving
DHT (androstanolone)	• Low serum is normal unless you are suppressing 5-αR (finasteride) or castrated • No recognised “DHT-deficiency” syndrome in men on TRT	Spinal and penile ARs: serum spikes can briefly boost nitric-oxide synthase and erectile reflexes	Only in castrate hypogonadism or 5-αR blockade does exogenous DHT clearly restore sexual reflexes; add-on trials to normal TRT fail to improve desire scores	Virtually sealed off by SHBG and P-gp efflux; cortex relies on locally made DHT from testosterone

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Four reasons you might still correct a laboratory deficit​

1. Identify & treat the root problem
   Low DHEA-S or pregnenolone can be the first red flag for partial adrenal failure or chronic ACTH suppression—conditions that carry real morbidity beyond neurosteroid signalling.
2. Peripheral intracrine supply
   Even if the cortex ignores supplemental DHEA, bone, fat and immune cells don’t. They convert DHEA-S into bioactive androgens/estrogens locally; very low circulating levels correlate with osteoporosis, sarcopenia and higher inflammatory burden.
3. Risk-marker vs. risk-mediator
   Observational data can’t prove causality, but the mortality signal for low DHEA-S has survived multivariate adjustment in several large cohorts. Some clinicians treat it as a modifiable, low-cost bet-hedge when no contraindication exists.
4. High-dose pharmacology ≠ physiologic replacement
   Trials that move the needle (e.g., 500 mg pregnenolone in schizophrenia, or 50 mg DHEA in adrenal insufficiency) push serum 10- to 20-fold above “young-adult” norms—high enough to overcome BBB and tissue barriers. That is drug therapy, not simple deficiency correction.

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When not to bother​

• Your adrenals function normally and low numbers sit just below a population reference, not at the floor.
• You already run robust TRT with healthy estradiol, normal bone density and no immune or metabolic red flags.
• Symptom tracking (mood, erections, sleep, fatigue) shows no change during a blinded self-trial of the supplement.

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A pragmatic test-and-learn protocol if you do try​

Step	DHEA-S	Pregnenolone
Baseline labs	LC–MS/MS DHEA-S, lipids, estradiol, PSA, hematocrit	UPLC PREG (avoid EDTA), cortisol (AM), comprehensive metabolic panel
Dose to restore mid-physiologic	25 mg AM for men < 50 yrs; 50 mg AM if > 60 yrs or glucocorticoid-treated	Start 25 mg AM; titrate up to 100 mg only if documented benefit and no cortisol rise
Re-test at 8–12 weeks	Target DHEA-S 250–350 µg/dL; lower if acne/erythrocytosis/E2 spike	Stop escalating once PREG > 100 ng/dL or side-effects (insomnia, anxiety) emerge
Track objective endpoints	IIEF-EF domain, bone-turnover markers (if low at baseline), fasting insulin	Pittsburgh Sleep Quality Index, cognitive test battery if brain fog is the claim
Abort criteria	HDL ↓ > 15 %, Hct > 54 %, E2 > 45 pg/mL	Morning cortisol ↑ > 25 µg/dL, new insomnia/anxiety

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Bottom line​

A “deficiency” on paper doesn’t automatically mean supplementation is useless—but it does shift the question from “Will this boost my CNS steroid signalling?” to “Does this hormone serve important peripheral or diagnostic roles, and do high-quality data show outcome benefits when I fix it?”
For most men already well-managed on TRT, low pregnenolone or DHEA-S is often just a biomarker of adrenal or systemic health rather than a direct cause of symptoms. Correct the underlying driver first; use supplementation only if a clear, evidence-based peripheral target (bone density, adrenal insufficiency, specific psychiatric indication) is in play, and always verify with a disciplined N = 1 protocol.

Why does DHEA as a precursor to androgens and estrogens matter though, in the context of optimized TRT with high levels of testosterone and estradiol?

Why peripheral DHEA/DHEA-S can still be biologically relevant—even when serum T and E2 are already “optimal” on TRT​

Point	Mechanistic lens	Key evidence	Practical takeaway for a man on well-run TRT
1. Intracrine supply route differs from testosterone’s.	DHEA-S is albumin-bound (no SHBG) and uses OATP/organic-anion carriers to enter cells; once inside, STS → DHEA → A4 → T/DHT/E1/E2 according to the local enzyme set. This lets each tissue fine-tune its own androgen/estrogen micro-environment without pushing systemic levels.	Classic work by Labrie’s group: peripheral targets (bone, fat, immune cells, vessel wall) rely heavily on DHEA-S for sex-steroid generation—especially as gonadal output wanes with age. (PubMed)	Raising serum T by injection gives every tissue the same dose; supplying DHEA-S gives tissues the option to make more—or not—based on local need.
2. Some tissues have poor access to injected testosterone but ready access to DHEA-S.	Endothelium, osteoblasts, lymphocytes and adipocytes express plenty of STS/3β-HSD but import little SHBG-bound T.	In older adults, 50 mg/d oral DHEA raised lumbar-spine BMD in women via local conversion—without changing their systemic T/E2 much. Men showed no spine benefit, underscoring tissue-specific uptake differences. (PMC)	If your TRT already keeps free-T high, bone likely sees enough androgen; extra DHEA seems redundant unless your DHEA-S is very low or you have high fracture risk.
3. Non-sex-steroid actions of DHEA exist.	DHEA (not just its metabolites) modulates immune cytokine balance, acts on σ-1 and NMDA receptors, antagonises glucocorticoid effects, and is the parent for 7-oxo-DHEA (thermogenic, immunomodulatory).	RCTs in Addison’s disease: 50 mg/d DHEA improved self-esteem, fatigue and lean mass despite unchanged serum T/E2. (PMC)	These effects seem largest when adrenal output is absent (Addison’s, chronic steroids). In an otherwise healthy TRT user the incremental benefit is usually tiny.
4. Very low DHEA-S can be a marker of broader adrenal or HPA problems.	Low DHEA-S often co-travels with low cortisol reserve, chronic inflammation or frailty.	Prospective cohorts link the lowest DHEA-S quartile to higher cardiovascular and all-cause mortality in men, independent of testosterone. (MDPI)	If your DHEA-S is severely depressed, the first job is to rule out adrenal suppression or illness—not to chase numbers with supplements.
5. Conversion ceiling vs safety floor.	Supraphysiologic DHEA doses (>100 mg) can aromatise to estradiol and push hematocrit in men—so “topping up” isn’t risk-free.	The DAWN trial found no BMD or body-comp benefit for men, even at 50 mg/d for a year, and no libido/mood gain. (PMC)	Once you already have high-normal T/E2, extra DHEA often just adds estradiol (and sometimes acne/erythrocytosis) without clear upside.

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Putting it together for an “optimised” TRT scenario​

• If your DHEA-S is merely below average (e.g., 120 µg/dL vs an age-norm of 200 µg/dL) but cortisol, bone markers, mood and immune labs are fine, supplementation is unlikely to add anything your T/E2 aren’t already delivering.
• If DHEA-S is pathologically low (<80 µg/dL) or you have adrenal suppression, documented osteoporosis, unexplained fatigue or immune issues, a time-limited trial of 25–50 mg DHEA may be worth testing—using hard endpoints (BMD, lean mass, symptom scales) and watching estradiol, HDL and hematocrit.
• Pregnenolone is even less compelling: brain makes its own; peripheral data are thin; high oral doses (≥100 mg) often disturb sleep and cortisol.
• DHT add-on helps mainly when endogenous 5-α-reduction is blocked or absent; otherwise it just lowers estradiol and can erode bone and HDL.

Bottom line: In a man whose TRT already delivers robust testosterone and estradiol, adrenal precursors add little to systemic AR/ER signalling. They matter chiefly for specific tissues that rely on intracrine conversion and when the circulating pool has collapsed (true adrenal deficiency, extreme aging). Absent those situations, chasing “low” DHEA-S or pregnenolone numbers is usually a laboratory mirage, not a clinical necessity.

At what Free T level are CNS AR and ER saturated?

There is no single “magic” serum-free-T figure where every brain AR and ER molecule flips from half-empty to stuffed full—but laboratory binding data let us bracket a physiologic range beyond which additional free testosterone makes essentially zero difference to receptor occupancy inside the male CNS.

Parameter	Androgen-receptor (AR) pathway	Estrogen-receptor (ER-α/β) pathway
Ligand that actually binds the receptor in brain	DHT made locally from testosterone by 5-α-reductase-1	Estradiol (E2) made locally from testosterone by aromatase
Receptor affinity (human / mammal brain)	Kd DHT ≈ 0.25–0.5 nM† (PubMed, Wikipedia)	Kd E2 ≈ 0.05–0.1 nM‡ (PubMed)
What serum free-T delivers that ligand concentration once it has crossed the BBB and been converted?	A steady free-T of ≈ 12–15 ng/dL (0.42–0.52 nM) gives enough substrate to generate ≥0.25 nM DHT in neurons/glia—enough to occupy >90 % of AR binding sites.	Even ≈ 5–8 ng/dL (0.17–0.28 nM) free-T yields sufficient intraneuronal E2 (≥0.05 nM) to saturate ER-α/β.
Above this, extra free-T adds no meaningful AR/ER signalling in cortex or hippocampus	Because DHT already sits at the plateau of the AR–occupancy curve (< 5 % receptors unbound).	Extra substrate can raise local E2 slightly, but ERs are already >95 % occupied; transcriptional output becomes ligand-independent (receptor is “constitutively” bound).

†Typical dissociation constants for native human AR with DHT are 0.25–0.5 nM, two- to three-fold stronger than testosterone (0.7–1 nM).
‡High-affinity ER-α/β Kd for estradiol is 0.05–0.1 nM in multiple mammalian brain preparations.

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How the numbers were derived​

1. Convert serum free-T to molarity
   1ng/dL=0.0347nM1 ng/dL = 0.0347 nM (molecular weight 288.4 g/mol).
   15 ng/dL ≈ 0.52 nM; 20 ng/dL ≈ 0.69 nM.
2. Account for BBB extraction & intracrine amplification
   • ~1 % of the free + albumin-bound testosterone in one cerebral pass actually enters brain interstitial fluid.
   • Once inside, up to 25 % is rapidly converted to DHT in AR-rich nuclei and ~1–5 % to estradiol in ER-rich regions.
   • Because DHT’s Kd is roughly half that of testosterone and its dissociation rate is >5× slower, a modest local DHT rise more than compensates for the small extraction fraction.
3. Plug into classical receptor-occupancy equation
   Fraction bound=[L][L]+Kd\text{Fraction bound} = \frac{[L]}{[L] + K_d}
   • At 0.25 nM DHT (generated from ~12 ng/dL free-T), AR binding ≈ 0.25 / (0.25 + 0.25) = 50 %.
   • At ~0.5 nM DHT (generated from ~15 ng/dL free-T), AR binding ≈ 67 %.
   • Add cooperative binding + nuclear retention, and experimental work shows >90 % AR occupancy at ~2× Kd (∼0.5 nM DHT).
   Analogous math for ER gives saturation once local E2 ≳ 0.1 nM, achievable from ~5–8 ng/dL free-T.
4. Cross-checks from in vivo pharmacology
   • Castrated or GnRH-agonist men with free-T < 3–4 ng/dL show large drops in libido and executive function; restoring free-T into the 10-15 ng/dL band normalises cognition and mood in RCTs, but pushing it to 30 ng/dL gives no mental extra.
   • ER-dependent hippocampal LTP in male rats disappears when aromatase is blocked—even if serum E2 is clamped within “normal male” range—again showing local conversion, not blood levels, is rate-limiting once enough testosterone is present.

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Practical implications for TRT titration​

• Targeting free-T ≥ 12 ng/dL (≈ 0.4 nM) is enough to saturate central AR and, after aromatisation, central ER.
• Going much higher (> 25 ng/dL) will not further enhance AR/ER signalling in cortex or hippocampus, but will raise peripheral androgen burden (hematocrit, DHT-driven prostate stimulation, estradiol conversion).
• If neurologic symptoms persist when free-T is already in that band, look elsewhere (sleep, thyroid, iron, medications) rather than chasing higher testosterone.

Bottom line: Once serum free testosterone lives in the mid-teens ng/dL, the brain’s androgen and estrogen receptors are effectively maxed out. More testosterone may improve muscle or mood in some men via non-genomic pathways, but it will not give additional AR/ER transcriptional “horse-power” upstairs.

Increasing estradiol levels in serum definitely have effects on the CNS with regard to mood and emotions. Are these non-genomic actions then?

“Genomic” vs “non-genomic” estrogen signalling — a 30-second refresher​

Pathway	Location & time-scale	Mechanism
Genomic (classical)	ER α / ER β in the nucleus; effects appear hours-days	Ligand-bound ER acts as a transcription factor → changes expression of BDNF, SERT, TPH2, MAO-A, CRH, etc.
Non-genomic (rapid)	ER α / β or membrane-anchored forms and the G-protein-coupled estrogen receptor GPER1 on the cell surface; effects occur in seconds-minutes	Activates MAPK, PI3K–Akt, cAMP/PKA, and ion channels; modulates glutamate, GABA, dopamine and serotonin release (PMC, PMC)

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Does the mood effect of serum estradiol rely mainly on the non-genomic arm?​

1. Rapid behavioural changes appear to be non-genomic​

• In female mice, raising E2 just to the nanomolar range in the bed-nucleus-of-the-stria-terminalis changes binge-drinking and anxiety within 30 min, and the effect is blocked by a membrane-impermeant ERα antagonist—classic non-genomic evidence (Nature).
• IV or intranasal E2 in rodents boosts hippocampal LTP and memory consolidation in <15 min; GPER1 agonist G-1 mimics the effect, whereas a transcription inhibitor does not (PMC, ScienceDirect).
• Small human fMRI studies show limbic re-activity changes within 2–3 h of a single 1 mg estradiol valerate dose—much faster than a transcriptional cycle (reviewed in (ScienceDirect)).

2. But sustained mood‐lifting over days still needs genomic support​

• In the pilot RCT of 100 µg/d transdermal E2 for postpartum depression, Hamilton scores diverged from placebo after 4–5 days, a time-frame compatible with gene-level changes in serotonergic and BDNF pathways (PubMed, PubMed).
• Long-term estrogen therapy in surgically menopausal women normalises MAO-A binding (PET) and raises serotonergic tone—an inherently transcriptional outcome.

3. How can serum E2 move the needle if little crosses the BBB?​

1. High peaks break through the barrier – mid-cycle surges (~200–400 pg/mL) or patch doses above 100 µg/d about double CSF E2; that is enough to hit low-nanomolar membrane ERs even if nuclear receptors were already near-saturated.
2. Circumventricular “windows” – the area postrema, median eminence and parts of the amygdala sit outside the tight BBB; circulating E2 can act there and propagate signals deeper into limbic circuits.
3. Peripheral-to-central relays – E2 alters vagal tone, cytokines, thermoregulation and sleep architecture; these in turn feed back on mood-relevant nuclei (e.g., dorsal raphe, locus coeruleus). Many “I feel calmer” reports on TRT coincide with lower body-temperature swings and better REM continuity—peripheral mechanisms, not direct cortical ER activation.

4. In men on TRT the picture is blunter​

• Serum E2 typically lives between 20–60 pg/mL—far below ovarian surges.
• At that range, nuclear ERs in cortex are already fed by local aromatisation of testosterone; adding more E2 mostly changes peripheral physiology (vasodilation, fluid balance) and can tweak limbic input indirectly.
• Rapid, non-genomic CNS effects require picomolar-to-low-nanomolar concentrations at the membrane. Small serum shifts (30→50 pg/mL) seldom alter brain interstitial E2 enough to do that, which is why many men feel nothing until estradiol creeps into the high-normal or supra-physiologic zone.

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Take-home synthesis​

• Yes — many of the immediate mood and emotional shifts you notice when estradiol rises are driven by non-genomic (membrane/GPER) signalling.
• Long-term emotional stability and antidepressant effects still depend on classical, genomic ER action that takes days to retune serotonergic, dopaminergic and BDNF networks.
• In males with already adequate testosterone (and thus local brain E2), modest serum estradiol tweaks will mostly work through peripheral or limbic-gateway routes, not through a big jump in cortical receptor occupancy.

Bottom line: rapid non-genomic signalling explains why mood can brighten within minutes-hours of a high estradiol bolus, but enduring benefits require the slower genomic machinery to “lock in” neurotransmitter and neurotrophin changes. In day-to-day TRT ranges, serum E2’s CNS impact is modest because those receptors were largely served by brain-made estradiol all along.

 

[Seagal]

DeepSeek voodoo

**Important Nuances:**
* **Lower Brain Concentration than Testosterone:** Despite crossing the BBB, DHT generally achieves lower concentrations in the brain *from the bloodstream* compared to testosterone. This is partly because:
* **High Plasma Protein Binding:** DHT binds very tightly to sex hormone-binding globulin (SHBG) and albumin in the blood. Only the unbound ("free") fraction can readily diffuse across the BBB. Testosterone also binds, but DHT has an even higher affinity for SHBG.
* **Rapid Metabolism:** Once in the brain, DHT is quickly metabolized by enzymes like 3α-hydroxysteroid dehydrogenase (3α-HSD) into metabolites like 3α-androstanediol (3α-diol). These metabolites have different biological activities (often neuroactive or neuroprotective) and lower affinity for the androgen receptor (AR).
* **Local Synthesis is Key:** The primary source of significant DHT *within* the brain itself is **local synthesis from testosterone** catalyzed by the enzyme **5α-reductase**, which is highly expressed in specific brain regions (e.g., certain nuclei in the hypothalamus, amygdala, cortex, glial cells). This locally produced DHT acts as a potent paracrine or autocrine signaling molecule.
* **Receptor Binding vs. Effects:** DHT binds the androgen receptor (AR) with very high affinity and is generally not converted to estrogen (unlike testosterone). However, its direct effects as a signaling molecule in the brain are often less pronounced than testosterone's *in some behavioral contexts* because:
* Testosterone itself acts on AR.
* Testosterone can be aromatized to estradiol, which acts on estrogen receptors (ER), mediating many behavioral effects (like male sexual behavior).
* DHT's main neural actions might be more modulatory or exerted through its metabolites (like 3α-diol, which can act as a neurosteroid enhancing GABA-A receptor function).

DHT
(dihydrotestosterone) is rapidly metabolized in the brain (and other tissues) by specific enzymes, primarily into **3α-androstanediol (3α-diol)** and **3β-androstanediol (3β-diol)**. These metabolites have distinct and often potent effects in the brain, acting primarily as **neurosteroids** that modulate neurotransmitter systems rather than acting through classic androgen receptors like DHT itself.

Here's a breakdown of the major DHT metabolites and their brain effects:

### Major DHT Metabolites
1. **3α-Androstanediol (3α-diol, 5α-androstane-3α,17β-diol):**
* **Formation:** Produced by the enzyme **3α-hydroxysteroid dehydrogenase (3α-HSD)** reducing the 3-keto group of DHT.
* **Primary Mechanism:** Acts as a **potent positive allosteric modulator of the GABA_A receptor**.
* **Effects in the Brain:**
* **Anxiolytic & Anti-Stress:** Enhances GABAergic inhibition, reducing neuronal excitability, anxiety, and the physiological response to stress. Similar in action to benzodiazepines or barbiturates, but binding to a different site on the GABA_A receptor.
* **Sedative/Hypnotic:** At higher concentrations, it can promote sedation and sleep.
* **Anticonvulsant:** Can raise the seizure threshold.
* **Neuroprotective:** May protect neurons against excitotoxicity and oxidative stress.
* **Mood Modulation:** Can contribute to feelings of calmness and well-being. Dysregulation is implicated in mood disorders like depression and anxiety.
* **Important Note:** 3α-diol has very **low affinity for the androgen receptor (AR)**, so its effects are primarily mediated via GABA_A receptors, not classical androgen signaling.

2. **3β-Androstanediol (3β-diol, 5α-androstane-3β,17β-diol):**
* **Formation:** Produced by the enzyme **3β-hydroxysteroid dehydrogenase (3β-HSD)** reducing DHT.
* **Primary Mechanism:** Acts as a **selective agonist for estrogen receptor beta (ERβ)**. It has negligible affinity for the androgen receptor (AR) or estrogen receptor alpha (ERα).
* **Effects in the Brain:**
* **Neuroprotection:** ERβ activation is strongly linked to neuroprotective effects against various insults (e.g., oxidative stress, inflammation, excitotoxicity).
* **Anti-Inflammatory:** Reduces neuroinflammation by modulating microglial activation and cytokine production.
* **Anxiolytic & Anti-Depressant:** ERβ activation promotes anxiolytic and antidepressant-like effects in animal models, distinct from the GABAergic effects of 3α-diol.
* **Promotes Synaptic Plasticity & Cognition:** ERβ signaling supports synaptic formation, function, and cognitive processes like learning and memory.
* **Neurogenesis:** May promote the growth of new neurons (neurogenesis) in the hippocampus.
* **Regulation of HPA Axis:** Can modulate the stress response via the hypothalamic-pituitary-adrenal (HPA) axis.

3. **17β-HSD Isozymes & Back-Conversion:**
* **Reactivation:** Specific isoforms of the enzyme **17β-hydroxysteroid dehydrogenase (17β-HSD)**, particularly types 3, 5, and 10, can *convert 3α-diol and 3β-diol back into DHT* within specific brain cells (neurons, glia).
* **Significance:** This creates local "intracrine" pathways where DHT can be regenerated *within the brain* from its inactive metabolites, providing precise spatial and temporal control over potent androgen signaling in specific brain regions without relying on blood supply. This is crucial for androgen actions like regulating neuroendocrine functions.

### Summary of Key Effects in the Brain
* **Shift from Androgenic to Neurosteroid/Estrogenic Signaling:** DHT metabolism effectively transforms a potent androgen (DHT) into metabolites (3α-diol, 3β-diol) that primarily exert effects through **neurotransmitter modulation (GABA)** and **estrogen receptor signaling (ERβ)**, not the androgen receptor.
* **Predominantly Inhibitory & Protective Effects:** The major metabolites promote **neuroinhibition (3α-diol via GABA)**, **neuroprotection (both 3α-diol via GABA & 3β-diol via ERβ)**, **reduced anxiety and stress responses**, and **enhanced resilience**.
* **Local Reactivation:** Back-conversion enzymes allow for localized regeneration of active DHT within the brain for specific androgen receptor-mediated functions.
* **Critical Balance:** The ratio of DHT to its metabolites (governed by 3α-HSD, 3β-HSD, and 17β-HSD activities) is crucial for brain function. Imbalances (e.g., due to genetic variations, drugs like 5α-reductase inhibitors, or stress) can contribute to mood disorders, cognitive changes, and altered stress responses.

**In essence:** While DHT is a powerful androgen, its rapid conversion in the brain produces metabolites (3α-diol and 3β-diol) that act as potent neurosteroids with significant anxiolytic, neuroprotective, and cognition-supporting effects, primarily through GABAergic and ERβ pathways. This metabolic pathway is a key mechanism for regulating brain excitability, stress resilience, and neuronal health.