The Erectile Response & Raging Boners
Updated: Mar 31, 2021
I often get this question on my discord server: Why PDE5 inhibitors such as Viagra, Cialis, and Levitra DO NOT work for some people despite supplementing nitric oxide donors such as L-citrulline/L-arginine?
This question cannot have a single all-encompassing answer. The erectile mechanisms are numerous and pathways, complex. In order to address your problem, it's crucial that you arm yourself with sufficient knowledge on the matter at hand (your stronger hand).
And this is exactly what this article is about. Let's dive in!
Disclaimer: The [Simply Explained] series of articles are simplified for the layman and may contain crude humor and casual language.
Table of contents:
1. Brief Overview of Penile Anatomy
2. Brief Overview of Penile Neuroanatomy
3. Central Control of Erectile Function
4. My Answer to the Question
5. Final Remarks
1. Brief Overview of Penile Anatomy
This is an article for the layman so I'll keep it simple and get to the point.
The bare essentials you need to know about penile anatomy: the internal pudendal artery, the corpora cavernosa (CC), its smooth muscles and artery, and finally, the neuroanatomy of erectile function.
A: The internal pudendal artery:
When blood rushes into your penis, you get an erection which depends on the sum of in-flow resistance from the feeder vasculatures of the penis versus the venous outflow. This artery is the most important since it contributes 70% of the total vascular resistance [1].
As the in-flow resistance is ramped up, the cavernosal sinusoids become engorged, leading to penile lengthening and tumescence.
Under normal circumstances, erections are maintained because the engorging sinusoids compress the exiting venules and veins, leading to passive limitation of venous outflow [2].
The internal pudendal artery gives off several branches. The most important branch for erectile function is, perhaps, the artery to the corpus cavernosum (aka deep penile cavernosal artery) [3].
B: The corpora cavernosa (CC):
The two CC function as vascular 'tanks' that are blood-filled during an erection, giving girth and structure to the erected penis.
It gets its blood supply mainly from the aforementioned deep penile cavernosal artery. It's important to note that the glans of the penis gets its blood supply from the deep dorsal artery instead, which is another branch of the internal pudendal artery [4].
C- The cavernous smooth muscles (CSM) are critical for the physiological role of the CC as vascular tanks or capacitors. The CSM control the vascular events leading to an erection and constitute approximately 40-50% of tissue cross-sectional area [1] [5].
As human males age, they keep losing those smooth muscles due to apoptosis (programmed cell death). Apoptosis and autophagy are modulated by androgens. As such, androgen deprivation, or reduction due to aging, leads to structural changes of the CC [6].
2. Brief Overview of Penile Neuroanatomy
I know that neuroanatomy can get boring fast. But you are so sick of PSSD that you are gonna read it anyway, right? right? I have faith in you!
A- Autonomic Pathways:
These are divided into sympathetic and parasympathetic innervation of the penis. The pathways start at the level of spinal segments, making it in part a reflex process.
- Sympathetic: originates from the 11th thoracic to the 2nd lumbar spinal
segments. Stimulation of this thoracolumbar sympathetic pathway is triggers detumescence (no erection).
- Parasympathetic: originates from the 2nd sacral to 4th sacral spinal segments. Stimulation of this sacral parasympathetic pathway triggers tumescence (yes erection).
This means that the sacral parasympathetic input is responsible for tumescence and the thoracolumbar sympathetic pathway is responsible for detumescence [5].
BUT WAIT, THERE'S MORE!
Remember when I said this is in part a reflex process?
This is called a reflexogenic erection: an erection that occurs solely due to direct penile stimulation or when you have a full bladder. The brain has no control over this. It's purely a spinal reflex [7].
There are two other types of erections, one called a psychogenic erection: an erection that occurs only when you think lewd thoughts or from lewd audiovisual stimuli [7].
The other is the nocturnal erection: an erection that occurs mostly during REM sleep, which is triggered within the pontine reticular formation (pons of the brainstem) [7].
In spinal cord injury, many patients with sacral spinal cord injury retain psychogenic erectile ability but NOT reflexogenic erections. Psychogenic erections are enough to involve lengthening and swelling of the penis but rigidity is insufficient [7] [5].
No psychogenic erection occurs in patients with lesions above T9 [5].
B- Somatic Pathways:
Somatosensory pathways also play a role in the erectile response. This is called the bulbocavernosus reflex and it depends on the intensity and nature of genital stimulation [5].
Contraction of the ischiocavernosus muscles produces the rigid-erection phase [5] [9]. Rhythmic contraction of the bulbocavernosus muscle is what makes you ejaculate [5].
This is a spinal reflex, by the way (sacral, S2 to S4).
C- Neurotransmitters & molecules involved in these spinal reflexes
- Sympathetic pathways & anti-erectile pathways:
a) Norepinephrine release.
b) Endotelin-1 (ET-1) release -> ET receptors -> Rho-kinase pathway.
c) Phospholipase C (PLC) pathway: NE/Ang II/ET-1 -> PLC -> IP3 & DAG -> intracellular Ca+2 release.
d) Activation of estrogen receptors.
- Parasympathetic pathways & pro-erectile pathways:
a) Acetylcholine release -> eNOS -> NO release.
b) NO/cGMP pathway: NO --> GS --> cGMP -> PKG -> decreases intracellular Ca2+ AND blocks RhoA migration avoiding Rho-kinase pathway activation which is potently anti-erectile.
c) PGE1 -> cAMP -> PKA -> decreases intracellular Ca2+.
d) Phosphatidylinositol 3-kinase pathway -> Akt -> eNOS -> NO.
e) Nitric oxide from non-adrenergic non-cholinergic nerves (NANC).
f) Androgens maintaining the erectile response of the cavernous nerve, nerve fibers and myelin sheath structure. Androgens also regulate the expression and activity of NOS isoforms in the corpus cavernosum and modulating PDE5 activity.
- Somatosensory pathways (pro-erectile): Acetylcholine and nitric oxide* * This pathway utilizes NOS. As such, the dorsal nerve of the penis is a mixed autonomic plus somatosensory nerve [8].
You finally made it! You are a goddamn weapon and I'm proud of you, son.
Or that's what you thought I'd say..
WE AIN'T DONE YET, MAGGOT! Do you understand?
Bullshit! I can't hear you! [10]
3. Central Control of Erectile Function
Erections result from both the increased activity of spinal parasympathetic pathways and reduced activity of sympathetic pathways.
It's time to learn what role brain centers play in all of this.
But before we proceed, you have to know a very important bit of information:
Central control of the erectile response is still poorly understood in humans and most data is obtained from neurotransmitter-induced reflex-erection in lab animals and PET/fMRI scans of human subjects. Human sexual functions are generally much more complex and less predictable.
A- SEROTONIN:
The raphe-to-spinal projections are serotonergic with receptors subtypes 5HT1A, 5HT1B, 5HT2A and 5HT2C (formerly known as 5HT1C) present [11].
5HT1A receptor: Anti-erectile, both pre-synaptically and post-synaptically [12] [13] [14] [15].
5HT1B receptor: Anti-erectile similarly to 5HT1A receptors [12] [16].
5HT2A receptor: Data on its effect on erection is insufficient [17] [21].
5HT2C receptor: Pro-erectile. Directly opposes the anti-erectile effect of 5HT1A receptor, but might be following an inverted U-shaped curve [18] [19][22][23]. Chronic activation might by anti-sexual though inhibition of melanocortin MC4 receptors by 5HT2C and 5HT2A agonism [20].
Other serotonin receptor subtypes play minor roles in the erectile response.
B- DOPAMINE:
Dopamine plays a critical role in psychogenic erections, and sexual functions in general, within the medial preoptic area (mPOA), the supraoptic nucleus (SON), and the paraventricular nucleus (PVN) [24] [25].
All dopamine receptors (D1, D2, D3, D4, D5) are pro-erectile [25] [24] [26].
However, it interacts with oxytocin and nitric oxide to trigger this pro-erectile effect [27] [28]. Nothing wrong with being a team player.
C- EPINEPHRINE & NOREPINEPHRINE:
Alpha-adrenergic receptors are anti-erectile [29]. Peripherally, androgens maintain erectile function is by reducing the alpha 1-adrenergic responsiveness of the cavernosal smooth muscle [36].
But when it comes to beta-adrenergic receptors, it's not as straight-forward as that.
Non-selective beta-blockers are known to induce erectile dysfunction [30].
Beta-1 adrenergic antagonist (Bisoprolol) doesn't have a clear effect on erectile function but might lower testosterone synthesis indirectly [34][35].
Beta-2 adrenergic agonist (Salbutamol) is used to terminate intraoperative penile erection [31].
Beta-3 adrenergic agonists are pro-erectile and are under investigation as novel treatment for erectile dysfunction [32] [33].
D- OXYTOCIN-NITRIC OXIDE:
The medial preoptic area (mPOA) sends projections to the paraventricular nucleus (PVN). The PVN is very rich in oxytocin neurons that are critical for the erectile function [11].
The oxytocin neurons of the PVN project to the hippocampus, medulla oblongata and spinal cord.
The PVN neurons are activated by sexual stimuli leading to release of dopamine, glutamate (NMDAR->NOS pathway), hexarelin analogue peptides, nitric oxide, or oxytocin [37] [38]. They are inhibited by GABA, opioids, and endocannabinoids [37].
When these neurons are activated, neuronal nitric oxide synthase (nNOS) starts synthesizing nitric oxide (NO). This NO leads to activation of oxytocin neurons projecting to extra-hypothalamic regions such as the hippocampus and the spinal cord [39].
This spinal activation ultimately leads to enhanced penile nitric oxide neurotransmission, triggering a raging erection [39].
E- SEX HORMONES:
Peripherally, we learned earlier that androgens are crucial for maintaining the erectile response of the cavernous nerve, nerve fibers and myelin sheath structure, leading to a more potent erectile capacity [43].
They also maintain smooth muscles of the CC by modulating apoptosis and autophagy, as well as regulating the expression and activity of NOS isoforms in the corpus cavernosum and modulating PDE5 activity [41] [42].
Centrally, stimulation of the mPOA leading to an erection (via projection to PVN) is a testosterone-dependent process [40]. Dihydrotestosterone (DHT) and estradiol (E2) maintain androgen receptor mRNA expression within the mPOA [44] [45].
For more in-depth info regarding sex hormone modulation of the mPOA and the limbic system, please refer to my article:
On sexual desire systems and loss of libido [Part 1]
4. My Answer to the Question
Q: Why PDE5 inhibitors such as Viagra, Cialis, and Levitra DO NOT work for some people despite supplementing nitric oxide donors such as L-citrulline/L-arginine?
A:
Because pumping it up full of nitric oxide is far from the only requirement needed for having a boner.
You need solid structural integrity and healthy vasculatures. You need optimally-functional central and peripheral nerves, structurally speaking. You need a fine balance of neurotransmitters. You need functional sex hormone receptors with the right ratio of densities. You need a healthy balance of the sympathetic and parasympathetic outflow.
Just to name a few.
5. Final Remarks
Now that you have a general idea on how complex this shit is, a good first step is identifying which type of erectile dysfunction you are suffering from and pin-pointing the problem.
Here's a simple classification of male erectile dysfunction:
Thanks for making it to the end of the article. You are a goddamn weapon and I'm proud of you, son!