How to fix your low libido as a man.

It’s George.

Erectile dysfunction is quite a common issue in this day and age, with up to 1 in 4 men under 40 struggling with it.

Yet, ED signals deeper issues and imbalances in things such as:

• The cardiovascular system
• Neurotransmitters
• Hormones
• Oxidative stress
• Lifestyle pitfalls.

This is why it can even serve as an early biomarker for cardiovascular disease, because if the small helicine arteries cannot dilate due to endothelial dysfunction, the larger coronary arteries are likely next.

Now you can go ahead and choose to use phosphodiesterase-5 inhibitors like sildenafil (Viagra), tadalafil (Cialis) or vardenafil (Levitra).

But if these were enough:

• The discontinuation rates wouldn’t be so high
• Basic supplements wouldn’t outperform them
• The severity of the issue wouldn’t increase with time, turning more and more people who initially saw some improvement into non-responders

Am i saying that they are useless? Obviously not. Use your God-given brain that allows you to read these sentences.

Cialis can:

-Reduce all-cause mortality (34% reduction), myocardial infarction (27% reduction), stroke (34% reduction), venous thromboembolism (21% reduction), and dementia (32% reduction).

-Inhibit PRMT5.

-Help the prostate.

-Lower systolic and diastolic pressure.

-Lower HbA1c in people with T2D.

-Lower estrogen to some extent (improves testosterone:E2) and increase the number, expression and activity of androgen receptors.

-Lower inflammation.

So it’s not useless.

What i’m saying is that fixing ED is more complicated than “pop a pill” most of the time.

Now let’s begin this by understanding the physiology of erections.

Erections are a complex neurovascular process involving coordinated interactions between the nervous system, vascular structures, smooth muscle cells, certain hormones and molecular signaling pathways.

Now the penis comprises three cylindrical erectile bodies:

• Two corpora cavernosa: Paired dorsal structures responsible for most tumescence and rigidity.Each contains interconnected lacunar (sinusoidal) spaces lined by vascular endothelium and surrounded by trabecular smooth muscle.
• provides less rigidity to maintain urethral patency during ejaculation.Corpus spongiosum: Ventral structure encircling the urethra, expanding distally into the glanspenis.It

These are enveloped by the tunica albuginea, a dense bilayered fibrous sheath (inner circular, outer longitudinal fibers) that limits expansion and facilitates veno-occlusion.

Buck’s fascia surrounds the tunica, while dartos fascia covers the skin.

Blood supply derives from the internal pudendal artery, branching into cavernosal arteries (helicine arteries feed sinusoids) and dorsal arteries.

Venous drainage occurs via subtunical venules that compress during erection.

In the flaccid state, sinusoids are contracted, with high smooth muscle tone maintaining minimal blood volume (~20-50% capacity).

Now erections happen in sequential phases:

1. Flaccid phase: Low arterial inflow (~5-10 mL/min), unrestricted venous outflow. Intracavernosal pressure ~10-20 mmHg.
2. Latent/filling phase: Parasympathetic activation initiates relaxation; inflow increases rapidly.
3. Tumescence phase: Sinusoids fill, corpora expand, compressing subtunical venules → veno-occlusion. Pressure rises to ~80-100 mmHg (sysolic blood pressure equivalent).
4. Full erection phase: Equilibrium with sustained inflow matching minimal outflow.
5. Rigid erection phase: Somatic activation of bulbocavernosus and ischiocavernosus muscles (pelvic floor) compresses corpora roots, transiently elevating pressure >200 mmHg for maximal rigidity.
6. Detumescence phase: Sympathetic surge and cGMP hydrolysis contract smooth muscle, restoring outflow.

Note 1: Veno-occlusion is critical: Expanded sinusoids compress venules against the inextensible tunica, trapping blood like a “vascular tourniquet.”

Note 2: The bulbocavernosus reflex enhances rigidity.

So erections require balanced autonomic input:

• Parasympathetic (pro-erectile): Sacral (S2-S4) via pelvic splanchnic nerves and cavernous nerves.Releases acetylcholine (endothelium) and NO from NANC fibers.
• Sympathetic (anti-erectile): Thoracolumbar (T11-L2) via hypogastric nerves. Releases noradrenaline, promoting contraction.
• Somatic: Pudendal nerve (S2-S4) innervates pelvic floor muscles for the rigidity reflex.

There are also different types of erections.

We have:

• Reflexogenic: Tactile stimulation → dorsal penile nerve → spinal reflex arc (intact below brain level).
• Psychogenic: Visual/auditory/fantasy stimuli → limbic system (amygdala, hypothalamus) → thoracolumbar inhibition and sacral activation.
• Nocturnal (NPTR): During REM sleep, via reduced sympathetic tone.

Central integration involves dopamine (pro-erectile, via D1/D2 receptors in the paraventricular nucleus) and serotonin (generally inhibitory).

Excess sympathetic activity (stress, anxiety) elevates noradrenaline, activating α1-adrenergic receptors → calcium influx → contraction.

Parasympathetic dominance (relaxation) favors acetylcholine and NO.

When it comes to the molecular pathways, here’s a summary:

• Stimulation → nNOS (neural initiation) and eNOS (endothelial shear stress sustenance) produce NO.
• NO → soluble guanylate cyclase → cGMP ↑.
• cGMP activates protein kinase G (PKG) → phosphorylates: K⁺ channels (hyperpolarization). Myosin light chain phosphatase (dephosphorylates myosin → relaxation). IP3 receptor (reduced Ca²⁺ release).
• Intracellular Ca²⁺ ↓ → smooth muscle relaxation → inflow.

PDE5 hydrolyzes cGMP → termination. Inhibitors (sildenafil) prolong effects.

Alternative pathways include:

• Hydrogen sulfide (H₂S) from cystathionine γ-lyase (sulfur-rich foods enhance).
• Carbon monoxide (less dominant).

Pro-Contraction:

• Noradrenaline → α1 receptors → PLC → IP3 → Ca²⁺ release.
• Endothelin-1 (from endothelium, platelet LOX-1) → ET_A receptors → Ca²⁺ influx.
• RhoA/ROCK pathway (noradrenaline-activated; testosterone inhibits ROCK).

Low-dose aspirin for example reduces platelet-derived endothelin and testosterone antagonizes ROCK.

This is why TRT can sometimes improve erections even when NO levels are sufficient.

A summary of key hormonal influences includes:

• Testosterone/DHT: Upregulates nNOS/eNOS, maintains structural integrity, antagonizes ROCK.Low levels impair libido and NO production.
• Estrogen: Biphasic nature (low promotes NO while excess increases serotonin/prolactin/calcium, causing leakage).
• Stress Axis: Cortisol/adrenaline → sympathetic dominance, Ca²⁺ influx.
• Others: IGF-1 restores endothelial NO, high prolactin/serotonin inhibits it.

If these were too complicated, here’s a simplified explanation/summary.

An erection is basically your penis filling with blood and becoming hard when you’re aroused, either from a physical sensation, a visual, a thought or even during sleep.

Think of the penis like a sponge with three main tubes:

• Two big ones on top called corpora cavernosa (these fill with blood for hardness).
• One smaller one on the bottom called corpus spongiosum (surrounds the urethra for urine and semen).

These tubes are wrapped in a tough cover called the tunica albuginea (like a strong balloon skin that traps blood inside).

When it’s flaccid (soft), the sponge tubes are squeezed tight, with little blood inside.

Now your nervous system has two modes:

• Parasympathetic (”relax and enjoy” mode) → Turns on erection.
• Sympathetic (”fight or flight” mode, like stress) → Keeps it soft or makes it go down.

Here’s entire process summarized in phases:

1. Signal arrives → Nerves release a chemical called nitric oxide (NO) (like a “relax” message).
2. Muscles relax → The smooth muscles in the penis walls unwind. Blood rushes in through arteries.
3. Blood fills up → The sponge tubes expand like filling a balloon.
4. Blood gets trapped → The expanding tubes press veins shut against the tough cover (called veno-occlusion – like pinching the balloon’s neck so air/blood can’t escape).
5. Full hardness → Pressure builds high. Pelvic muscles squeeze extra for super rigidity during sex.

When it comes to nitric oxide:

• It triggers a chain: NO → makes cGMP (a relaxer chemical) → muscles relax → blood flows in.
• An enzyme called PDE5 breaks down cGMP to end the erection (that’s why pills like Viagra block PDE5 to keep it going longer).

Overall, common reasons for ED include:

• Stress → Too much sympathetic mode (adrenaline, cortisol) keeps muscles tight.
• Poor blood flow → From smoking, diabetes, or bad diet damaging vessels.
• Hormonal issues → Like low testosterone (reduces NO), low DHT, low E2.
• Other → Certain meds such as SSRIs, or nerve issues.
• Neurotransmitter imbalances (low dopamine + low oxytocin + high serotonin for example).

Erectile dysfunction quite often involves impaired nitric oxide (NO) signaling.

After all, vasculogenic erectile dysfunction is by far the most common organic type of erectile dysfunction.

In general, nitric oxide is the central non-adrenergic, non-cholinergic neurotransmitter responsible for initiating and maintaining penile erection.

Normally, as it was mentioned in the previous part, sexual stimulation activates parasympathetic neurons originating from the sacral spinal cord (S2–S4), traveling through the pelvic nerves and cavernous nerves to the penis.

These nerves release NO primarily from neuronal nitric oxide synthase (nNOS) located in nerve terminals within the corpora cavernosa.

Inside these cells, NO activates an enzyme called soluble guanylate cyclase, increasing levels of cyclic guanosine monophosphate (cGMP).

NO diffuses rapidly across cell membranes into adjacent smooth muscle cells of the penile arteries and trabeculae (the sponge-like tissue in the corpora cavernosa).

Inside smooth muscle cells, NO binds to and activates soluble guanylate cyclase (sGC), converting guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).

Then, elevated cGMP activates protein kinase G (PKG), which:

• Reduces intracellular calcium by inhibiting calcium influx and promoting sequestration into the sarcoplasmic reticulum.
• Opens potassium channels, leading to hyperpolarization and further reduction in calcium entry.
• Phosphorylates myosin light chain phosphatase, which causes dephosphorylation of myosin and further smooth muscle relaxation.

Now increased blood flow creates shear stress on endothelial cells lining the penile arteries and sinusoids.

This stimulates endothelial nitric oxide synthase (eNOS) to produce additional NO, amplifying the signal in a positive feedback loop.

Acetylcholine (from parasympathetic nerves) and other factors such as bradykinin also activate eNOS via receptor-mediated pathways.

This sustained NO production maintains high cGMP levels for full rigidity.

Then, when stimulation ceases:

• Sympathetic nerves release noradrenaline → vasoconstriction.
• Phosphodiesterase type 5 (PDE5) hydrolyzes cGMP to inactive GMP.
• Intracellular calcium rises → smooth muscle contraction → reduced inflow and increased outflow → flaccidity.

When it comes to how nitric oxide is produced, it’s synthesised in 2 main ways.

In the first one NO is synthesized from L-arginine + oxygen by NOS enzymes, requiring cofactors such as:

• NADPH (electron donor)
• Tetrahydrobiopterin (BH4) – critical for “coupling” NOS (ensures electrons go to NO production rather than superoxide).
• Flavins (FAD, FMN), heme and calcium-calmodulin (especially for nNOS/eNOS).

Note 1: Before you go and buy some L-arginine, realize that L-citrulline is actually more effective at raising blood arginine levels because the liver breaks down a large portion of ingested L-arginine before it reaches the bloodstream (L-citrulline bypasses this process and is later converted into arginine by the kidneys).

Note 2: Coupled NOS = NO + L-citrulline (good for endothelial function).

Note 3: Uncoupled NOS (low BH4, oxidative stress) = superoxide (O₂⁻) + H₂O₂ instead of NO (bad for endothelial function).

Note 4: All three NOS isoforms are present in penile tissue:

• nNOS: Nerve terminals + initiates erection.
• eNOS: Endothelium + sustains erection.
• iNOS: Induced during inflammation/injury + can produce excessive NO, contributing to priapism or dysfunction if chronic(*).

(*)iNOS, unlike constitutive eNOS/nNOS (Ca²⁺-dependent, low NO), is transcriptionally induced and Ca²⁺-independent, producing high, sustained NO (up to 1000x more) for hours/days.

High iNOS-derived NO overwhelms physiological regulation since:

• NO reacts rapidly with superoxide (O₂⁻) (from NADPH oxidase, mitochondria, or uncoupled eNOS) to form peroxynitrite (ONOO⁻) (a reactive nitrogen species (RNS)).
• Peroxynitrite causes lipid peroxidation, protein nitration, DNA damage, enzyme inactivation and is cytotoxic in general.

Some studies even link it to major depression.

In the second one, it’s created by nitrites, but too much (as seen in many studies, such as one at 400mg, which is often found in 70-100ml of beetroot juice) can increase carcinogenic nitroso compounds.

Now theoretically, if it’s a one time thing, you can get away with it if you pair it with some vitamin C.

But with frequent use, vitamin C is not able to undo the increase of carcinogenic nitroso compounds.

So in my opinion, it’s not worth it since citruline malate for example, will not have this effect and it’s also shown to actually improve athletic performance.

The main things that harm NO signaling (note: these factors often interconnect) can be found here:

https://fitandball.gumroad.com/l/zmaoz/aug53

Supplements to consider when it comes to supporting eNOS and nNOS.

Number 1: Whole food vitamin C + magnesium.

Number 2: Garlic extract.

You can also combine vitamin C and garlic

Number 3: Citruline malate + panax ginseng

Number 4: Methylated B complex

Number 5: Ginkgo biloba

Number 6: Thai black ginger

Now, since this part is basically about vasculogenic ED (ED that stems from problems with the blood vessels (an erection requires rapid inflow of arterial blood and effective trapping of that blood in the penile erectile tissue)) two other supplements that can help some people by inhibiting calcium deposition in arteries for example are:

Number 7: Nattokinase

Number 8: Vitamin K complex

Number 9: Agmatine sulfate

Number 10: Artichoke extract

And three lifestyle interventions that can be more effective than all of these supplements include:

-12-15K steps/day

-Sauna

-Optimizing your sleep

And if you want 5 foods you can add, try:

-Pomegranates

-Pickled ginger

-A quality cacao

-EVOO

-Blueberries

Now obviously, all these won’t work to their full extent if you do not focus on getting rid of the big offenders such as nicotine, which contributes significantly to ED through vasoconstriction, reduced nitric oxide (NO) bioavailability and endothelial dysfunction.

Nicotine for example binds to nicotinic acetylcholine receptors (nAChRs) on peripheral postganglionic sympathetic nerve endings and the adrenal medulla.

This triggers the release of catecholamines (mainly norepinephrine) from nerves and epinephrine from adrenals.

The first binds to α1-adrenergic receptors on vascular smooth muscle cells leading to calcium influx, muscle contraction and vasoconstriction.

Chronic nicotine usage also upregulates α1-receptors, amplifying the norepinephrine response.

It also upregulates endothelin-1 (ET-1) production/release from endothelial cells (a vasoconstrictor acting on ETA/ETB receptors) and impairs NO/prostacyclin (PGI2) pathways.

Now in case you are not aware of what vasoconstriction and vasodilation are, these two are opposite processes that control the diameter of your blood vessels such as arteries and arterioles regulating our blood pressure, body temperature and blood flow to organs for example.

If we think of our blood vessels as adjustable pipes, then vasoconstriction increases pressure and redirects flow, while vasodilation decreases pressure and boosts delivery.

Basically:

• Vasoconstriction: Smooth muscle contracts → vessel narrows (smaller lumen) → higher resistance to flow.
• Vasodilation: Smooth muscle relaxes → vessel widens (larger lumen) → lower resistance.

The contraction/relaxation is triggered by calcium ions (Ca²⁺) inside muscle cells:

• High Ca²⁺ → contraction
• Low Ca²⁺ → relaxation.

Overall, if you want to identify in general if something can contribute to vasculogenic erectile dysfunction, see if it can trigger vasoconstriction.

The main system that cause it include:

• Sympathetic nervous system (fight-or-flight)
• Norepinephrine/epinephrine
• Agiotensin II
• Vasopressin
• Endothelin-1
• Hypoxia
• Cortisol
• Adrenaline

Now erections are regulated by several neurotransmitters and neuropeptides in the penile tissue but also the central nervous system.

Neurotransmitters are chemical messengers released by neurons at synapses.

They directly excite or inhibit the target cell (whether that’s another neuron, a muscle or a gland) by binding to receptors and triggering rapid responses (within milliseconds).

So a neurotransmitter can excite the neuron, inhibit a message or adjust the communication at the synapse. Now neuromodulators are a bit different as they are not restricted to the synaptic cleft between two neurons, and so can affect large numbers of neurons at once. Neuromodulators therefore regulate populations of neurons, while also operating over a slower time course than excitatory and inhibitory transmitters.

Some molecules (like nitric oxide or certain peptides) can act as both, depending on context.

These (neurotransmitters and neuromodulators) operate at two levels:

• Central (brain and spinal cord): Initiating psychogenic/nocturnal erections via arousal, motivation and autonomic control.
• Peripheral (penile tissues): Executing tumescence by relaxing/contracting smooth muscle in the corpora cavernosa.

Psychogenic erections (from thoughts, sights, fantasies) and nocturnal ones involve the limbic system (amygdala, hypothalamus like paraventricular nucleus/PVN and medial preoptic area/MPOA) descending to spinal centers.

Now the pro-erectile (facilitatory) ones include:

• Dopamine
• Oxytocin
• Nitric oxide (NO)
• Glutamate
• Vasoactive intestinal polypeptide (VIP)
• Acetylcholine

The anti-erectile or mixed (inhibitory) ones include:

• Serotonin (5-HT)
• Noradrenaline
• GABA
• Opioids
• Endocannabinoids
• Endothelin-1
• Prolactin

The most common “combination” in ED for example is low dopamine + oxytocin that leads to reduced psychogenic drive and excess serotonin/prolactin that inhibits arousal.

Let’s start with dopamine (DA).

Dopamine is arguably the most important central neurotransmitter for facilitating sexual motivation, arousal, and penile erection.

It is synthesized from phenylalanine and tyrosine with the help of phenylalanine hydroxylase and tyrosine hydroxylase.

The steps are:

1. L-Phenylalanine → L-Tyrosine.This conversion is catalyzed by phenylalanine hydroxylase (PAH), primarily in the liver. PAH uses tetrahydrobiopterin (BH₄ (see previous parts on this series)) as a cofactor and adds a hydroxyl group to phenylalanine. Phenylalanine is an essential amino acid (must come from diet), while tyrosine is conditionally essential (can be synthesized from phenylalanine or obtained directly from diet/proteins).
2. L-Tyrosine → L-DOPA (L-3,4-dihydroxyphenylalanine). This is the rate-limiting step, catalyzed by tyrosine hydroxylase (TH) in dopaminergic neurons (e.g., in the brain and adrenal medulla). TH also requires BH₄, oxygen, and iron (Fe²⁺) as cofactors. TH is highly regulated (by feedback inhibition from dopamine and phosphorylation for example).
3. L-DOPA → Dopamine. Catalyzed by aromatic L-amino acid decarboxylase (AADC, also called DOPA decarboxylase), using pyridoxal phosphate as a cofactor.

Now dopamine is involved in motor control, the reinforcement of certain behaviors through reward, motivation, learning, concentration and sleep but when it comes to erections, it acts primarily in the brain to integrate psychogenic and reflexogenic stimuli, bridging libido with the consummatory phase (actual erection and copulation).

Unlike peripheral mechanisms such as NO-cGMP in penile tissue, dopamine’s effects are predominantly central, with key actions in hypothalamic and limbic areas.

It influences erection through three main systems:

• Incertohypothalamic system: Dopaminergic neurons from the A11-A14 groups project to the medial preoptic area (MPOA) and paraventricular nucleus (PVN) of the hypothalamus (the primary sites for pro-erectile DA action).
• Mesolimbic system: From ventral tegmental area (VTA) to nucleus accumbens (drives sexual motivation/reward).
• Nigrostriatal system: More for motor coordination during copulation.

In the PVN, DA activates oxytocinergic neurons projecting to the spinal cord (thoracolumbar and sacral levels), triggering parasympathetic outflow for erection.

The core pathway in the PVN are the following:

1. DA binds to receptors → increases intracellular Ca²⁺.
2. Activates neuronal nitric oxide synthase (nNOS) → produces NO.
3. NO (via cGMP-independent mechanisms, e.g., protein nitrosylation) activates oxytocinergic neurons.
4. Oxytocin release in spinal cord → pro-erectile parasympathetic signals → penile smooth muscle relaxation and tumescence.

This loop links DA to central NO and oxytocin, explaining why DA agonists induce erections even with NOS inhibitors peripherally.

Non-selective agonists like apomorphine for example, induce erections within 10-25 minutes (sublingually).

When it comes to the dopamine receptors we have 5 (D1, D2, D3, D4, D5 and potentially a D6 (some of the recent literature includes the D6 and some does not)).

They divide into D1-like (D1, D5: stimulate adenylate cyclase) and D2-like (D2, D3, D4: inhibit it).

Pro-erectile effects are mainly via D2-like receptors in the PVN.

Now, when it comes to supporting dopamine production and its receptors in general, the first things you have to do are to:

1. Provide bioavailable protein, retinol, zinc, P5P, B9, vitamin C, vitamin K, vitamin D and vitamin E.
2. Avoid overstimulation (D2 receptors specifically are susceptible to downregulation from overstimulation (this is why meditation is shown to increase their density)).
3. Get some sun and avoid too much artificial blue light since in some animal models its shown to lead to an up to 30% reduction of tyrosine hydroxylase-positive neurons in the substantia nigra.
4. Monitor stress and relax.
5. Don’t live a sedentary lifestyle (we are meant to move thought the day which is why even 10 minutes of exercise can increase the density of the D2 and D3 receptors in some cases).
6. If you can go and measure your prolactin, insulin and androgens (testosterone for example upregulates dopamine (DA) pathways, particularly in brain regions like the nigrostriatal system).

Then, once you’ve addressed these, the supplements that might help you specifically with libido, in case low dopamine plays a role in your case are (note: in case you are struggling with any condition that includes hypomania or in the case you are using an antipsychotic, do not add these without medical supervision):

• CDP-chole or uridine, both of which upregulate D2 receptor density/signaling
• Sulbutiamine also upregulates D2 receptor density/signaling
• Forskolin also upregulates D2 (and D1) but through cAMP elevation
• Rhodiola rosea + taurine that enhance dopamine receptor sensitivity (general, some D2 overlap).
• Mucuna Pruriens (velvet bean) that’s a natural L-DOPA source (do not use it for more than 3 days at a time (note: if the comedown from it is too strong, you may not have enough B6 in your system)).

So as always, pick the supplement that might also assist other goals you might have.

Other things can help when it comes to dopamine in general, but caffeine for example, which can impact D2 receptors, is a vasoconstrictor so it’s not ideal in the context we are talking about.

Now let’s move on to glutamate.

This is the brain’s primary excitatory neurotransmitter and even though in excess it’s toxic to neurons, it plays a crucial pro-erectile role centrally, particularly in integrating sexual stimuli and activating downstream pathways for penile tumescence.

The primary synthesis (~70-80% of neuronal glutamate) pathway is the glutamine-glutamate cycle.

Here’s a summary.

1. Glutamine → Glutamate (in neurons) Enzyme: Phosphate-activated glutaminase (PAG or GLS) Glutamine (from blood or astrocytes) enters neurons → PAG hydrolyzes it → glutamate + ammonia. This is the rate-limiting step for neurotransmitter glutamate replenishment.
2. Astrocytes provide glutamine: Astrocytes take up synaptic glutamate (via transporters like EAAT1/2) → convert to glutamine via glutamine synthetase (GS) (astrocyte-specific enzyme). Glutamine released → taken up by neurons → completes the cycle (prevents excitotoxicity and recycles nitrogen).

There’s also an alternative/de novo pathway (α-Ketoglutarate route (~20-30% of glutamate)), utlizied especially during development or high demand:

1. α-Ketoglutarate → Glutamate Enzyme: Glutamate dehydrogenase (GDH) (reversible) α-Ketoglutarate (TCA cycle intermediate) + NH₄⁺ + NADPH → glutamate. Or via transamination reactions: Enzymes: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) Example: α-Ketoglutarate + alanine → glutamate + pyruvate.

There are also some supporting pathways from ornithine for example, via ornithine aminotransferase (OAT) (→ pyrroline-5-carboxylate → glutamate (minor in brain)).

Note: Glutamate is not efficiently transported across the blood-brain barrier → almost all neurotransmitter glutamate is synthesized locally in the brain.

So its effects are mediated mainly through ionotropic receptors (NMDA, AMPA/kainate) in key hypothalamic/limbic areas, with NMDA receptors being the dominant player.

Glutamate release surges during sexual activity, facilitating arousal and erection via nitric oxide (NO) and oxytocin pathways.

For example it activates oxytocinergic neurons projecting to the spinal cord, it rises ~170% during mounting/intromission and ~300% at ejaculation.

A quick summary is basically the following:

1. Sexual stimuli → glutamate release in MPOA/PVN.
2. Glutamate binds primarily NMDA receptors (coupled to Ca²⁺ channels) on oxytocinergic neurons.
3. Ca²⁺ influx → activates neuronal NO synthase (nNOS) → NO production.
4. NO (via nitrosylation or other cGMP-independent paths) activates oxytocin release.
5. Oxytocin projections to spinal cord → parasympathetic activation → penile smooth muscle relaxation and erection.

Now it’s unlikely that you are struggling with low glutamate so we’ll move on to the next.

Even if you think (which is surprisingly common) that a particular GABA supplement or benzodiazepines led to low glutamate, this is not the case.

The opposite is often the case, where there’s a glutamate rebound/hyperactivity.

Moving on to oxytocin’s role in erections.

Oxytocin (OT), often called the “love hormone” for its roles in bonding and social behavior, is a central facilitator of penile erection and male sexual function that acts as a neuropeptide neurotransmitter downstream of dopamine and glutamate, serving as a key “executor” in the brain-spinal-penile axis.

It is a nonapeptide hormone (meaning 9 amino acids) primarily synthesized in the magnocellular neurons of the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON).

Minor synthesis occurs in peripheral tissues such as the uterus, placenta and testes.

It forms via post-translational processing of a larger precursor protein (no simple amino acid assembly like neurotransmitters).

The 101 is:

1. Gene Expression: The human OXT gene (on chromosome 20) transcribes into mRNA.
2. Translation: Ribosomes produce prepro-oxytocin (prepro-oxyphysin), a ~125-amino-acid precursor with a signal peptide.
3. Signal Peptide Cleavage: In the endoplasmic reticulum, the signal peptide removes, yielding pro-oxytocin (~100 aa), which includes: Oxytocin sequence (N-terminal). Neurophysin I (carrier protein). Connecting peptide.
4. Packaging and Transport: Pro-oxytocin packages into vesicles, binds neurophysin I (protects/folds), and transports axonally to the posterior pituitary.
5. Maturation/Processing: During transport/in vesicles, enzymes cleave pro-oxytocin: Endopeptidases at basic residues (Lys-Arg). Carboxypeptidases remove basics. Final step: Peptidylglycine alpha-amidating monooxygenase (PAM) amidates C-terminal glycine (requires vitamin C/ascorbate as cofactor) → mature oxytocin (C-terminal amide, disulfide bond between cysteines 1 and 6).

Now while peripheral oxytocin (such as in the corpus cavernosum) may have minor or inhibitory effects, its pro-erectile action is overwhelmingly central, integrating arousal signals and triggering parasympathetic outflow for tumescence.

The primary site is the paraventricular nucleus (PVN) of the hypothalamus, where magnocellular and parvocellular oxytocinergic neurons reside.

• Oxytocinergic cell bodies in PVN project directly to the thoracolumbar and lumbosacral spinal cord (to preganglionic parasympathetic neurons and the spinal ejaculation generator/SEG in the lumbar region).
• Additional sites: Ventral tegmental area (VTA), hippocampus (ventral subiculum/CA1), posteromedial amygdala, bed nucleus of the stria terminalis (BNST).

The 101 of the molecular mechanism are the following:

1. Pro-erectile stimuli (dopamine, glutamate/NMDA) activate PVN oxytocinergic neurons.
2. Oxytocin receptor (OXTR) stimulation → Ca²⁺ influx → neuronal NO synthase (nNOS) activation → NO production (central, independent of peripheral cGMP in some paths).
3. Oxytocin release: Synaptically in the spinal cord → direct parasympathetic activation. Non-synaptically (volume transmission): Diffusion from axonal varicosities to nearby receptors (for example on gastrin-releasing peptide/GRP neurons in the lumbar SEG, which control ejaculation and rigidity reflexes).
4. Spinal oxytocin → enhanced NO in cavernous nerve → penile smooth muscle relaxation + veno-occlusion.

Important note: This is testosterone-dependent (castration abolishes central OT effects and testosterone/DHT/estradiol restore nNOS and OXTR expression).

Now you can support oxytocin through:

• Social bonding
• Aerobic exercise
• Music
• Sunlight (vitamin D for example activates oxytocin gene expression and production).
• Magnesium that sensitizes oxytocin receptors.
• Vitamin C that’a an essential cofactor for oxytocin synthesis

Other mentions (weaker evidence):

• Lactobacillus reuteri → Some strains increase oxytocin in animal models.
• Melatonin → Small doses may stimulate release.
• Intranasal sprays.

Moving on to acetylcholine.

Acetylcholine (ACh) is the primary neurotransmitter of the parasympathetic nervous system (pro-erectile).

It plays a key supportive role in penile tumescence, though its effects are largely modulatory and indirect (enhancing or facilitating the dominant nitric oxide (NO) pathway rather than directly driving relaxation).

It’s synthesized in cholinergic neurons through a single, straightforward enzymatic reaction from two precursors: acetyl coenzyme A (acetyl-CoA) and choline.

The reaction is: Choline + Acetyl-CoA → Acetylcholine + Coenzyme A

This is catalyzed by the enzyme choline acetyltransferase (ChAT), often considered the rate-limiting step in ACh production that is primarily located in the cytosol of cholinergic nerve terminals and is a specific marker for cholinergic neurons.

Acetylcholine receptors, also known as cholinergic receptors, are divided into two main classes based on their response to specific agonists: nicotinic (activated by nicotine) and muscarinic (activated by muscarine).

Nicotinic acetylcholine receptors (nAChRs) are ionotropic (ligand-gated ion channels) and pentameric (5 subunits around a central pore, allow Na⁺/K⁺/Ca²⁺ influx → rapid depolarization) found in neuromuscular junctions, autonomic ganglia and CNS.

Their subtypes are:

• Muscle-type (Nm): At neuromuscular junctions ((α1)₂β1δε adult form); mediates skeletal muscle contraction.
• Neuronal-type (Nn): In CNS/PNS; combinations of α2–α10 and β2–β4 subunits (for example, α4β2 is common in the brain with a high nicotine affinity).

Muscarinic acetylcholine receptors (mAChRs) are G-protein coupled receptors with 7 transmembrane domains found in the CNS (mainly in the hippocampus, cortex), parasympathetic targets (heart, smooth muscle, glands), and some sympathetic (sweat glands).

Their subtypes are:

• Odd (M1, M3, M5): Gq-coupled → PLC → IP3/Ca²⁺ ↑ (excitatory).
• Even (M2, M4): Gi/o-coupled → adenylate cyclase ↓ → cAMP ↓ (inhibitory).

In penile erection, ACh has a supportive pro-erectile role primarily via muscarinic receptors.

Ch is released from parasympathetic postganglionic nerves (cavernous nerves, originating S2-S4) into the corpus cavernosum.

Basically:

• Muscarinic receptors (primarily M2/M3 on endothelium): ACh binds → activates endothelial NO synthase (eNOS) → NO release → diffuses to smooth muscle → cGMP → relaxation. This is endothelium-dependent and amplifies shear-stress-induced NO during filling. Intracavernous ACh injections induce erections in animal models (dose-dependent, atropine-sensitive).
• Nicotinic receptors (on nitrergic nerve terminals): Higher ACh/nicotine levels potentiate neurogenic NO release (presynaptic facilitation).
• Cholinergic nerves co-localize with nNOS/VIP, ACh may inhibit noradrenaline release (presynaptic M receptors on adrenergic terminals) or directly modulate NANC transmission.
• Atropine (muscarinic blocker) partially reduces neurogenic relaxation but does not abolish it.

Two support acetylcholine basically eat choline-rich foods and B5-rich foods (beef liver, eggs, salmon etc).

You can also consider huperzine A or bacopa since they inhibit ACh breakdown.

Now ACTH/MSH peptides, α-MSH, hexarelin and histamine (via H2)are lesser-known but potent pro-erectile facilitators.

Melanocortins are a family of peptide hormones derived from pro-opiomelanocortin (POMC) cleavage in the hypothalamus (arcuate nucleus) and pituitary.

Key pro-erectile members include α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH), sharing the core sequence His-Phe-Arg-Trp.

But let’s back up for a moment?

What’s POMC?

POMC is a precursor polypeptide primarily produced in the pituitary gland, the skin and the hypothalamus.

I like to call it a “master precursor” even though it’s incorrect because it gets cleaved into crucial peptides like a-MSH, ACTH, CLIP, Gamma-MSH and beta-endorphin by enzymes like prohormone convertases (PC1/3 and PC2).

Its expression and upregulation is influenced by a variety of physiological, environmental and molecular factors one of them being: UV light exposure (especially UVB (280–320 nm)) that stimulates POMC expression in keratinocytes and melanocytes in the skin (up to 30% increase).

When UVB light penetrates the skin, it causes DNA damage in keratinocytes, activating the tumor suppressor protein p53 and UVA (320–400 nm) activates photoreceptors like neuropsin (OPN5) which further enhances POMC expression.

So melanocortins are peptides cleaved from pro-opiomelanocortin (POMC) in the arcuate nucleus/hypothalamus.

The key pro-erectile ones are: α-MSH and ACTH (share core sequence His-Phe-Arg-Trp).

a-MSH is expressed mainly in the hypothalamic arcuate nucleus and nucleus tractus solitarius of the brainstem and stimulates melanocytes to produce eumelanin, inhibits pro-inflammatory cytokines such as IL-6, TNF-alpha, improves our libido (melanotan I and II Synthetic analogs of α-MSH), regulates our appetite, and supports our immune system and brain. In order to support these focus on:

-Morning sunlight exposure (10–30 minutes).

-Managing stress (it can reduce alpha-MSH production by 25% in animal models)

-Minimizing blue light at night.

-Cold exposure (in mice it can increases POMC expression by even 25%).

-Managing stress to prevent ACTH dominance.

-Supporting nutrition with tyrosine, vitamin C, zinc and copper in order to enhance prohormone convertase activity

When it comes to vasoactive intestinal polypeptide (VIP), it is a 28-amino-acid neuropeptide widely distributed in the nervous system and gastrointestinal tract.

In penile erection, VIP acts as a supportive pro-erectile neurotransmitter/neuromodulator, primarily at the peripheral level.

Its production follows the classic pathway for neuropeptides: gene expression → pre-pro-protein synthesis → proteolytic processing → mature peptide.

Here’s the 101:

1. Gene and transcription

• Encoded by the VIP gene on human chromosome 6q25.
• The gene also encodes peptide histidine isoleucine (PHI) or peptide histidine methionine (PHM) in humans (a related 27-amino-acid peptide co-produced with VIP).
• Transcription occurs primarily in neurons (cholinergic/parasympathetic, sensory) and some immune cells such as mast cells and lymphocytes.
• Regulated by neuronal activity, growth factors such as NGF and cytokines.

2. Translation and initial processing

• Translated as a pre-pro-VIP precursor (~170 amino acids).
• Pre-sequence (signal peptide) is cleaved in the endoplasmic reticulum → pro-VIP (~150 amino acids).
• Pro-VIP contains: N-terminal signal PHM/PHI sequence Connecting peptide VIP sequence C-terminal extension

3. Post-Translational Processing

In secretory vesicles:

• Prohormone convertases (PC1/3 and PC2, common in neurons) cleave at dibasic sites (Lys-Arg or Arg-Arg).
• VIP and PHM are excised as separate peptides.
• C-terminal glycine on pre-VIP is used by peptidylglycine α-amidating monooxygenase (PAM) → amidation of VIP’s C-terminus (essential for bioactivity).
• Final mature VIP sequence: His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂.

4. Storage and release

• Packaged into large dense-core vesicles (co-stored with acetylcholine and nNOS in parasympathetic nerves).
• Released by high-frequency neuronal stimulation (Ca²⁺-dependent exocytosis).
• In penile tissue: Released from cavernous nerve terminals upon parasympathetic activation.

Ao VIP binds VPAC1 and VPAC2 receptors (Gs-coupled GPCRs) on cavernosal smooth muscle → adenylate cyclase activation → cAMP ↑ → PKA → hyperpolarization (K⁺ channels), reduced Ca²⁺ sensitivity, myosin dephosphorylation → relaxation.

• Primary effect: Enhances veno-occlusion (traps blood) more than arterial inflow.
• Synergizes with NO (cGMP pathway); some independence (not blocked by NOS inhibitors).
• In hypogonadal models (low testosterone), VIP effects stronger due to VPAC2 upregulation.

Nov 1: Androgens (testosterone) upregulate VIP expression/content in penile nerves.

Note 2: Diabetes decreases VIP nerve density/content.

Note 3: When it comes to using VIP, you have to test your inflamattory markers first since it can lead to T-cell exhaustion and also, there’s no evidence that it’s quite effective when it comes to ED. So most likely, lowering inflammation and relaxing will do more for you.

Now two peptides that can help you are PT-141 and BPC-157.

We have discussed these in the peptide series but here’s the 101 for both.

PT-141, also known as bremelanotide, is a cyclic heptapeptide and an active metabolite of Melanotan II.

Its chemical structure is: Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH.

It acts as a non-selective agonist of melanocortin receptors (primarily MC3R and MC4R, with some activity at MC1R, MC3R, MC4R, and MC5R.

Originally developed from research on α-melanocyte-stimulating hormone (α-MSH) analogs for sunless tanning, it was found to induce sexual arousal as a side effect.

Primary approved use:

• FDA-approved (since June 2019) under the brand name Vyleesi for the treatment of generalized acquired hypoactive sexual desire disorder (HSDD) in premenopausal women, where the low desire is not due to medical, psychiatric, relationship, or substance-related issues.
• Administered as a subcutaneous autoinjector (1.75 mg dose) at least 45 minutes before anticipated sexual activity.

Off-label and investigational uses:

• Broad off-label use in men for erectile dysfunction (ED), particularly in PDE5 inhibitor (Viagra, Cialis) non-responders and for low libido.
• Potential benefits in both sexes for psychogenic or mixed-origin sexual dysfunction, where vascular treatments fall short.

Mechanisms of action.

Unlike PDE5 inhibitors that enhance penile blood flow via peripheral nitric oxide pathways, PT-141 acts centrally in the brain:

• Primarily agonizes MC4R (and MC3R) in hypothalamic regions, triggering neural circuits for sexual motivation and arousal.
• Enhances dopamine release in key areas (e.g., medial preoptic area), boosting desire, mood, and sexual confidence.
• Indirectly increases genital blood flow through CNS effects, without direct vascular action.
• May improve subjective arousal, orgasm intensity, and overall sexual satisfaction by modulating pleasure/reward pathways.

This central mechanism makes it effective for desire-driven issues, even when vascular health is intact.

Core benefits:

• Significantly increases sexual desire and arousal in approved (women) and off-label (men/women) populations.
• Restores erectile function in difficult cases, including PDE5 non-responders (synergistic when combined).
• Elevates mood, reduces performance anxiety and intensifies pleasurable sensations/orgasms via dopaminergic effects.
• Works regardless of underlying vascular limitations; valuable for psychological, hormonal, or stress-related low libido.

Administration:

• FDA-approved: Vyleesi subcutaneous autoinjector (thigh or abdomen).
• Research/off-label: Often supplied as lyophilized powder (10 mg vials) reconstituted with bacteriostatic water for subcutaneous injection; some compounding pharmacies offer nasal sprays (though intranasal was discontinued early due to BP variability).

Potential risks:

• Most common: Nausea (40%, often worst on first dose; may require anti-nausea meds like ondansetron), flushing (20%), headache (11%), injection site reactions (13%), transient blood pressure increase (systolic ~6 mmHg, diastolic ~3 mmHg), fatigue, dizziness.
• Hyperpigmentation: Focal skin darkening (face, gums, breasts) – rare at recommended dosing (<8/month), but occurs in >1/3 with daily/high-frequency use; may be permanent in some cases, higher risk in darker skin tones.
• Cardiovascular: Contraindicated in uncontrolled hypertension or significant heart disease.
• Other: Vomiting, nasal congestion (if nasal form), no alcohol interaction (unlike flibanserin).
• Long-term data limited: No fertility issues in animal studies, modest weight loss noted in some trials (via MC4R appetite effects).
• Drug interactions: Slows gastric emptying, reducing oral absorption of some meds (naltrexone, indomethacin).

Now BPC-157, is derived from a protein found in human gastric juice and has the following 15 amino acid sequence: Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val

Primary uses (based on preclinical and limited human data):

• Accelerated healing of common gym/overuse injuries, such as elbow tendinitis, tendon/ligament tears, muscle strains, and post-surgical recovery.
• Gastrointestinal tract protection and repair (ulcers, inflammatory bowel conditions, leaky gut).
• Neuroprotection and potential nerve regeneration.
• Support for chronic joint/connective tissue disorders (osteoarthritis-like models).
• Cardiovascular benefits (improved blood flow, endothelial protection).
• Liver protection in toxin-induced damage models.
• Ongoing research areas: Spinal cord injury regeneration, corneal healing, and interstitial cystitis/bladder pain.

Other areas such as spinal cord regeneration, are under ongoing research.

The main mechanisms of action include:

• Upregulates vascular endothelial growth factor (VEGF) expression (a protein that promotes new blood vessel formation) by activating the VEGF receptor 2 (VEGFR2) pathway that triggers the Akt-eNOS pathway, which increases production of nitric oxide (NO) in the blood vessel walls, resulting in enhanced tissue perfusion, aiding repair of muscles, tendons, ligaments and even bones since without adequate blood supply, injured tissues cannot heal properly.
• Stimulates fibroblast proliferation and collagen deposition (which is also crucial for healing the gut lining).
• Protects and repairs gastrointestinal mucosa by modulating tight junction proteins.
• Downregulates Nos2 and Nfkb and thus reduces inflammatory responses.
• Downregulates pro-inflammatory cytokines such as TNF-α, IL-6 and upregulates anti-inflammatory pathways.
• Influences serotonin and dopamine systems in the gut-brain axis and it may promote nerve regeneration via growth factor pathways (JAK2 signaling).
• Activates focal adhesion kinase (FAK)-paxillin complexes that move cells into the damaged areas to begin rebuilding tissue and early growth response gene 1 (Egr-1) is also activated (involved in cell growth, survival and blood vessel formation).

Administration Forms:

• Oral: Highly stable in human gastric juice (>24 hours intact), making it effective for gut-focused issues (IBD models, ulcers).
• Injectable (subcutaneous, intramuscular, or intra-articular): Preferred for localized tissue repair (near injury site) due to direct delivery and potentially higher local concentrations.

Potential risks:

• Angiogenesis promotion could potentially exacerbate undiagnosed tumors.
• Modulating tissue growth and repair mechanisms can ALWAYS, no matter the COMPOUND, negatively affect some autoimmune cases.
• It’s also banned by WADA.

Now since we are talking about the topic of neurotransmitters and neuromodulators, i thought that it would be a good idea to mention neurotropic factors as well.

You shouldn’t worry about these most likely unless you are struggling with diabetes or a TBI, but here’s the 101.

These are proteins that act as growth factors, supporting the formation of new neural connections (synaptic plasticity), the growth of new neurons (neurogenesis), and the repair of damaged neural tissue.

There are three key ones that it’s a good idea to be familiar with:

1. Brain-derived neurotrophic factor (BDNF)

This one is the most abundant neurotrophin in the brain, being primarily expressed in the hippocampus, cortex and basal ganglia.

It is essential for consolidating memories and enhancing cognitive flexibility, mood regulation (low BDNF levels are linked to depression and anxiety and reduced BDNF in individuals with major depressive disorder is very common), increases dendritic spine density, protects neurons from oxidative stress, inflammation and apoptosis, it reduces beta-amyloid toxicity and supports dopaminergic neurons which are the primary mechanisms behind how it protects us against Alzheimer’s and Parkinson’s.

2. Glial-derived neurotrophic factor (GDNF)

GDNF is primarily produced by glial cells and is critical for the survival and function of dopaminergic neurons, particularly in the substantia nigra.

It modulates reward circuits in the ventral tegmental area, influencing addiction behaviors (higher levels = less addiction), plays a key role in motor control, axonal growth, protects dopaminergic neurons from oxidative stress and also interacts with NCAM (neural cell adhesion molecule) to support neural repair.

3. Nerve growth factor (NGF)

NGF is critical for the growth, maintenance, and survival of sensory and sympathetic neurons, particularly in the peripheral nervous system (PNS), supports cholinergic neurons in the basal forebrain (it also enhances acetylcholine release in it), cognitive functions like attention and memory, protects neurons from oxidative stress and inflammation, regulates sensory neuron function in the PNS, modulates stress

All of these show significant promise in treating erectile dysfunction (ED), especially in cases related to nerve damage (neurogenic ED), by promoting the regeneration and survival of cavernous nerves crucial for erections, improving blood flow, and enhancing neuronal function through pathways like PI3/Akt and JAK/STAT.

Some tools that you can keep in mind for supporting these are:

• Curcumin (boosts BDNF and NGF)
• Lion’s mane (increases NGF and BDNF)
• Magnesium (BDNF)
• NAC (BDNF)
• Bacopa (Increases BDNF and NGF)
• PQQ (enhances BDNF and NGF)
• Ubiquinol (BDNF, GDNF)
• Semax (boosts BDNF and NGF)
• Huperzine A (enhances NGF and BDNF)
• Saffron (boosts BDNF and NGF)

Now you can go here and read more about the rest of neurotransmitters:

https://healthlibrary.substack.com/archive

Moving on to hormones since one of the main things that impacts erections is obviously hormones.

Low testosterone and DHEA-S levels for example (the storage form of DHEA) not only increase the risk but are also significantly lower in men with ED compared to controls.

There are 11 hormones that can impact libido quite a lot so let’s dive deeper into them.

Number 1: Pregnenolone.

Now pregnenolone is often referred to as the “Mother Hormone” and is a steroid hormone produced mainly in the adrenal glands, but also in the brain, gonads, skin and even retina.

Its chemical name is 3beta-hydroxypregn-5-en-20-one, a 21-carbon delta-5 steroid with a hydroxyl group at position 3 and a ketone at position 20.

Why is it referred to as the mother hormone?

Because it is the single molecule from which every steroid hormone in the human body is ultimately derived.

Now here’s how pregnenolone is synthesized.

Once again, everything begins with cholesterol.

The rate-limiting step is the transport of cholesterol from the outer to the inner mitochondrial membrane, a process mediated by the Steroidogenic Acute Regulatory protein (StAR (gene STARD1)).

Once inside the mitochondrion, the side-chain cleavage enzyme CYP11A1 (P450scc) removes six carbons from cholesterol using three molecules of oxygen and three NADPH to yield pregnenolone and isocaproaldehyde.From pregnenolone, two major branches diverge:

1. Δ5 pathway:Pregnenolone → 17α-hydroxypregnenolone (via CYP17A1 17α-hydroxylase activity) → DHEA (via CYP17A1 17,20-lyase activity, strongly stimulated by cytochrome b5).
2. Δ4 pathway:Pregnenolone → progesterone (via 3β-hydroxysteroid dehydrogenase, HSD3B2) → 17α-hydroxyprogesterone → androstenedione → testosterone, or further to cortisol and aldosterone.

In the brain and peripheral nerves, pregnenolone is rapidly reduced by 5α-reductase type 1 and then 3α-hydroxysteroid dehydrogenase to form allopregnanolone and pregnanolone, two of the most potent positive allosteric modulators of GABA-A receptors known.

If we are healthy (and young), we synthesize roughly 35–50 mg of pregnenolone per day.

Surprisingly, the brain produces almost as much de novo as the adrenal glands (15–20 mg/day each), with smaller contributions from gonads, skin, retina, and placenta during pregnancy.

Brain synthesis is largely independent of peripheral cholesterol pools and continues even in Addison’s disease.

Acute regulation is handled by ACTH and LH, which phosphorylate StAR within minutes.

Chronic regulation depends on the orphan nuclear receptors SF-1 (stimulatory) and DAX-1 (inhibitory), as well as local cytokines, insulin, and IGF-1.

Pregnenolone affects erections both through direct neurosteroid effects but also indirect hormonal precursor roles.

For example:

• It acts as a positive allosteric modulator of NMDA receptors → enhances glutamate signaling (pro-erectile in PVN).
• While pregnenolone sulfate and allopregnanolone are among the most abundant neurosteroids in human cerebrospinal fluid and they potentiate both synaptic and extrasynaptic GABA-A receptors (especially δ-subunit-containing receptors), producing benzodiazepine-like anxiolysis WITHOUT tolerance. Pregnenolone is also a GABA-A antagonist → reduces excessive inhibitory tone Excess GABA suppresses erection (as discussed).
• Preserves nitrergic nerves, reduces inflammation/oxidative stress in brain/penile tissue.
• Is converted to pretty much all hormones.
• In diabetes and ageing models, it can reduce fibrosis/apoptosis in the cavernosum.

Now aging causes a 60–70 % decline by age 75 through reduced StAR and CYP11A1 expression.

Also, chronic stress diverts pregnenolone toward cortisol at the expense of DHEA and progesterone (“pregnenolone steal” is an oversimplification, but the ratio shift is real (chronic stress dysregulates the hypothalamic-pituitary-adrenal (HPA) axis, leading to imbalances where cortisol rises while pregnenolone, DHEA, or other downstream hormones decline)).

Because it sits at the very top of the cascade, pregnenolone is shunted toward whichever downstream hormone is most needed.

Then, statins, severe caloric restriction, hypothyroidism, sleep deprivation, long-term SSRI use, and high-dose opioid therapy all lower levels significantly.

So before supplementing with pregnenolone (if you choose to supplement, start with a dose as little as 10mg and increase the dose only after 10-14 days if you don’t notice anything)) go and test your free and sulfated levels.

Then, if your levels come back low, address the negative factors that were just mentioned.

Now if you choose to supplement and experience insomnia, irritability, headache, or oily skin and even scalp hair shedding, stop.

If you, on the other hand experience:

-Improved resilience to stress, less anxiety, and depression

-Improved sleep quality

-Improved memory recall

-Improved libido

-Improved energy levels

and your blood work is fine, then you are using the right dose.

Number 2: DHEA

When it comes to dehydroepiandrosterone (DHEA), it is an androgen that primarily functions as a prohormone produced primarily by the adrenal glands (specifically in the zona reticularis (the innermost layer of the adrenal cortex)), with smaller amounts synthesized in the gonads (ovaries and testes) and brain.

It plays a role in various physiological functions such as:

• Enhancing insulin sensitivity by upregulating glucose transporter 4 (GLUT4) expression in adipocytes and skeletal muscle, plus modulating leptin signaling.
• Promoting fat breakdown by stimulating lipolysis in adipose tissue.
• Supporting energy expenditure by enhancing mitochondrial function and thermogenesis, increasing RMR (resting metabolic rate).
• Increasing eNOS expression/activity.
• Promoting osteoblast proliferation and inhibiting osteoclast activity.
• Contributing to the production of allopregnanolone, a neurosteroid that modulates GABA receptors, promoting stress resilience and mood stability.
• Enhancing thyroid hormone activity by improving thyroid receptor sensitivity and supporting T3/T4 conversion.
• Acting as a cortisol antagonist by inhibiting 11β-HSD1.
• Modulating estrogen levels through its conversion to estrone and estradiol.
• Enhancing dopamine synthesis and release.
• Promoting synaptic plasticity and supporting neurogenesis.
• Enhancing T-cell proliferation and natural killer (NK) cell activity

So as you can tell, low levels will impact our libido.

DHEA exists in two forms in the body:

• DHEA: The free form, which is biologically active.
• DHEA-S (DHEA sulfate): A more stable, sulfated form that serves as a reservoir for DHEA and is more commonly measured in blood tests due to its longer half-life.

Now for DHEA to be synthesized, cholesterol is converted into pregnenolone by the enzyme P450scc (cholesterol side-chain cleavage enzyme) in the mitochondria of adrenal cells.

Pregnenolone is then converted to 17α-hydroxypregnenolone by the enzyme 17α-hydroxylase and 17α-hydroxypregnenolone is then transformed into DHEA by the enzyme 17,20-lyase.

It is regulated by adrenocorticotropic hormone (ACTH) from the pituitary gland, which stimulates the adrenal glands.

First consider the following natural ways of boosting DHEA before supplementing with DHEA:

Number 1: Upregulating StAR.

This is a protein that facilitates the transport of cholesterol from the outer to the inner mitochondrial membrane in steroidogenic cells such as the adrenal glands or gonads.

This is the rate-limiting step in steroid hormone synthesis, including DHEA.

In order to do this, avoid herbicides such as glyphosate that are now known to have a negative impact on it.

Consider consuming cholesterol rich foods, chrysin rich food such as quality raw honey, COX-2 inhibitors such as glycine, vitamin E and apigenin rich foods such as chamomile, things that can reduce DAX-1 such as chamomile once again, selenium, retinol and vitamin K2.

Number 2: Lower stress/manage cortisol.

Under stress, the adrenal glands prioritize cortisol production, diverting pregnenolone away from DHEA synthesis.

This can lead to high cortisol and low DHEA levels, a common pattern in chronic stress or HPA axis dysregulation.

For starters in regards to these, go to bed since just one night of sleep deprivation increases cortisol by 21% (and even 50% in some cases), don’t skip breakfast, get sunlight and enough B5, C, zinc, magnesium, sodium and potassium (B5 for example is needed to make coenzyme A and under stress, the adrenal glands dumb A LOT of vitamin C).

Number 3: Fix your circadian rhythm.

All hormones follow a circadian pattern and DHEA is not different.

Number 4: Shilajit and royal jelly use.

Shilajit can boost DHEA by 30% in the span of 3 months and royal jelly increases its conversion to DHEA-S.

Number 5: MR-10

After 2-3 months test again.

If your levels are still low you can consider (if you are over 45):

-5mg of DHEA and 10mg of pregnenolone for a month

-10-15mg of DHEA and 20-30mg of pregnenolone if the previous dose does not work.

But once again: DO NOT, start using them without any bloodwork.

Now if you want to learn how to address everything else, go here and just follow the lessons:

https://fitandball.gumroad.com/l/zmaoz/aug53

-George