Testosterone is not the end all, be all when it comes to libido.
More correctly, exogenous testosterone (TRT).
We’ve all been indoctrinated that testosterone is essential for libido.
And it’s true that testosterone is needed, but about a 4th of people on TRT are non-responders.
When testosterone fails
Have you ever tried all kinds of testo-boosters, dopamine boosters, etc., but still no major uptick in libido? Maybe an uptick initially, but then it just goes back to normal again.
And the same happens with testosterone injections.
Although 75% of the people experience an uptick in libido and sexual function after starting testosterone, which then usually plateaus after 3 months, but about 25% of the people taking testosterone doesn’t (R, R).
And actually, a lot of guys have told me that after about a year or 2 after on TRT, everything went back to the way it was before starting TRT. As if they never even started.
Why testosterone and testo-boosters fail
There are quite a few reasons why it might fail, but here is the link.
And this is why some aphrodisiacs promote libido without modifying your hormones or neurotransmitters.
Here are some more evidence
After adjusting for age, we observed a higher prevalence of ED [erectile dysfunction] (IIEF-15-erectile function domain score <26) (18.3% versus 0%; P = 0.006) and PE [premature ejaculation] (PEDT score >8) (12.9% versus 4.1%; P = 0.036) in males of infertile couples compared with fertile men.
The ED prevalence increases as a function of semen quality impairment severity even after adjusting for confounders (age, CDS, MHQ and NIH-CPSI total score), despite similar hormonal, glyco-metabolic and penile vascular status. Compared to fertile men, all three groups of males with couple infertility showed a poorer erectile function, associated with an overall psychopathological burden (MHQ total score), particularly with somatized anxiety (MHQ-S). Azoospermic men showed the worst erectile function and general health.
In addition, azoospermic men reported higher PE prevalence and lower sexual desire and orgasmic function when compared to fertile men (all P < 0.05), all of which were related to psychopathological symptomsReference
This could be why testosterone supplementation could do nothing for libido, since it reduces fertility, by lowering FSH (R). Not all patients with ED and a low testosterone level have an improvement in erectile function when treated with exogenous androgens (R).
Another reason why testosterone injections don’t always work is because an excess is converted to estrogen.
And serum estradiol levels are negatively correlated with penile rigidity. Estrogen promotes nitric oxide production and together they promote vascular weakness and leakage (R).
In a lot of cases with older people, testosterone might improve sexual desire, however other parameters of sexual function including erectile function remain unaffected by the treatment (R).
A few reasons why testo-boosters fail
- They don’t restore Leydig cell function. Some experimental evidence suggests that aging induces a Leydig cell dysfunction (R).
- They don’t protect against endotoxin-induced inflammation.
- They don’t specifically upregulate the rate-limited enzyme, StAR, which is necessary for transporting cholesterol into the mitochondria.
- They don’t restore neurological health
- They don’t improve vascular health
Here’s what to use instead
Our stack will consist of:
Vitamin K2 (MK-4)
Vitamin K and testosterone
There are multiple animal studies showing that vitamin K (only MK-4) boosts testosterone production by increasing StAR, which is the rate-limited step in transporting cholesterol into the mitochondria for conversion to pregnenolone.
In this study, rats were given 75mg/kg MK-4 for 5 weeks and their testosterone increased significantly. MK-4 is the predominant vitamin K form present in the testes.
The MK-4 increases protein kinase A (PKA) signaling, which stimulates the steroidogenic acute regulatory protein (StAR) to transport cholesterol from the outer to the inner mitochondria. Furthermore, MK-4 increases CYP11A activity and also its mRNA gene expression. CYP11A is the enzyme that converts cholesterol into pregnenolone (the first steroid).
The increase in testosterone is independent of LH secretion as LH remains unchanged with vitamin K2 administration.
As the study concluded: “expression of CYP11A, the rate-limiting enzyme in steroidogenesis, and phosphorylation levels of protein kinase A (PKA) and the cAMP response element-binding protein were all stimulated by the presence of MK-4” (R).
Although that’s a really big dose used in the rat study, direct testicular application of vitamin K2 could spot specific increase local concentrations of vitamin K, thus exerting the same effects are oral doses of vitamin K. Oral absorption of vitamin K is very low, and then the liver and all other tissue in the body get their share, so only a small amount reaches the testes.
Also, vitamin K is important for the post-translation of Gla proteins in various tissues, including the testes and is directly involved in steroidogenesis. The mRNA of steroidogenic genes is low in vitamin K deficient tissue.
Furthermore, vitamin K2 increases osteocalcin, which acts on Leydig cells of the testis to stimulate testosterone biosynthesis and therefore affect male fertility. More on osteocalcin here and how to boost it.
Vitamin K boost dopamine and lowers serotonin
Serotonin is a major inhibitor of testosterone production and it correlates very well with prolactin. Prolactin is well known for inhibiting libido and fertility.
Dopamine on the other hand promotes libido and sexual function.
Vitamin K2 and other quinones (such as beta-lapachone, emodin, PQQ, etc) enhance serotonin uptake (by redox modification) and increase dopamine levels, by inhibiting MAO-B (R, R, discussed in this thread).
Vitamin K2 lowers estradiol
As mentioned earlier, estrogen causes vascular dysfunction and contributes to sexual dysfunction. Vitamin K2 can actually lower estradiol.
This study found that vitamin K2 binds to 17beta-HSD4, a key enzyme that regulates important redox reactions at the C17 position of steroid hormones, converting estradiol (E2) to estrone (E1).
We found in the present study that vitamin K2 decreased E2:E1 ratio and inhibited the amount of ERa-DNA binding in a dose-dependentReference
manner, although the precise relationship between the binding and functional modulation of vitamin K2 by 17h-HSD4 remains to be elucidated. These results may provide new knowledge of the linkage
between vitamin K and estrogen function.
Vitamin K2 improves mitochondrial function
Improves mitochondrial function. a study in Drosophila proposes vitamin K2 as a promising compound to treat mitochondrial pathology. In this study, MK4 can act as a mitochondrial electron carrier, like ubiquinone, facilitating ATP production, rescuing mitochondrial defects and restoring its function. Vitamin K2 combined with vitamin C supported ETC function and ATP production, thus improving glucose oxidation and lowers lactate and we all know by now how essential proper energy metabolism is in the testes for testosterone production (R).
Few additional benefits of vitamin K2. Vitamin K2:
- Improves neurological health (R). Neural damage is a major reason why people get erectile dysfunction, and it can be caused by excess gut issues, excess iron, PUFA accumulation, etc.
- Inhibits 12-lipoxygenase (12-LOX) and protects against oxidative stress in the testes (R).
- Lowers concentrations of inflammatory markers in vivo, and exerts an anti-inflammatory role by suppressing nuclear factor κB (NF-κB) signal transduction (R).
- Inhibits endotoxin increased inflammation (R).
- After LPS treatment, plasma testosterone levels were significantly reduced in the vitamin K-free diet group compared with the control diet group. Testicular mRNA and protein levels of Cyp11a, a rate-limiting enzyme in steroidogenesis, corresponded to plasma testosterone levels. However, plasma luteinizing hormone levels were unaffected by diet and LPS. Phosphorylated nuclear factor κB p65 in the testis was significantly increased in the LPS-treated, vitamin K-free diet group compared with control. These results indicate that dietary vitamin K affects testicular vitamin K levels and ameliorates the LPS-induced reduction in testicular testosterone synthesis. Testicular vitamin K might facilitate the inhibition of inflammation signal transduction and maintain steady levels of testosterone (R).
- Inhibits lipid peroxidation (R).
- Promotes sperm maturation. “Vitamin-K-dependent γ-glutamyl carboxylase (GGCX) and matrix Gla protein (MGP) were essential in extracellular calcium signaling of the intercellular communication required for epididymal sperm maturation” (R).
After my evening shower, I apply 5 drops of Kuinone (which gives me 10mg K2) on my scrotum and then read a book for 30 minutes just so that it can be absorbed completely.
Similar to vitamin K2, taurine has been shown to increase testosterone synthesis. Taurine concentrates in the testes and declines with aging. Low taurine can lead to low testosterone and supplementing taurine has been shown to increase GnRH, LH and testosterone and enhance sexual function (R, R).
One of the possible mechanisms of how taurine lowers cholesterol is by increasing cholesterol uptake in the testes and increased androgen synthesis (R).
Taurine has also been shown to improve sperm quality and function by elevating mitochondrial energy metabolism. Taurine has also been shown to be an excellent testes protectant.
Taurine protects epididymal epithelium structure, improves secretion activity, and maintains intraluminal microenvironment homeostasis. Finally, the present results showed taurine effectively increased cauda epididymal SOD, GSH and γ-GT levels in model rats, reduced ROS and MDA production, suggesting epididymal antioxidant ability of asthenospermia rats could be elevated by taurine treatment.Reference
Any dose between 500mg or 5g daily should do the trick (to replenish testicular taurine levels over time), depending on your protein intake and tolerance to the taurine. Some people get tired from taurine whereas others feel alert and awake. This could be because low-dose taurine potentiates the effect of stimulants such as caffeine (e.g. Red Bull), whereas bigger doses would oppose it.
I use 2-3g before bed in my pre-bed smoothie/shake, which is about 2-3hours apart from when I apply the other supplements since timing doesn’t matter. I’ve also dissolved some taurine in water and applied that to my scrotum for direct absorption. One reason why I wanted to try it out is that taurine is also a skin penetration enhancer, so should allow more vitamin K2 to be absorbed. However, the solution in water made my skin feel wet as if nothing absorbed even after 30 minutes, so I haven’t tried it again with water. Oral should be good enough.
If you remember, taurine is also a part of my boner stack, which can be supercharged with things like cordyceps and so on.
Few know this but thyroid function is essential for testosterone production. It’s like this low-key info similar to how gut health influences testicular function.
Thyroid hormones stimulate Leydig cell steroidogenesis. Thyroid hormones cause proliferation of the cytoplasmic organelle peroxisome and stimulate the production of steroidogenic acute regulatory protein (StAR) and StAR mRNA in Leydig cells; both peroxisomes and StAR are linked with the transport of cholesterol, the obligatory intermediate in steroid hormone biosynthesis, into mitochondria (R).
Hyperthyroid also 1) increases androgen receptors, 2) increases IGF-1 and IGFBP-4, 3) decreases estrogen receptors, 4) inhibits the aromatase and 5) decreases androgen binding proteins.
T3 directly increases Leydig cell LH (luteinizing hormone) receptor numbers and mRNA levels of steroidogenic enzymes and steroidogenic acute regulatory protein. It stimulates basal and LH-induced secretion of progesterone, testosterone, and estradiol by Leydig cells. Steroidogenic factor-1 (regulates the transcription of StAR) acts as a mediator for T3-induced Leydig cell steroidogenesis (R).
When the testes are damaged (by oxidative stress for e.g.), thyroid hormones help to repair the damage by generating new (differentiation) Leydig cells (R).
In this rat study, the Leydig cell number per testis in hyperthyroid rats was twice as those of controls at Day 21 (R).
Although proper thyroid function will ensure optimal testicular function, topical application of thyroid hormones could have a more potent effect than oral thyroid, since the testes express thyroid hormone receptors.
A small dose of 1-3mcg dose of T3 and/or 3-6mcg T4 once daily should suffice to potently stimulate testosterone production. I usually apply 1 drop Tyromix first, before I apply the Kuinone, but it doesn’t really matter which one is first.
It’s important that it’s isolated thyroid hormone and not NDT, since you stomach has to digest it first to release the thyroid hormones, so topical won’t work so well.
Effects I’ve noticed so far
- Increase in libido. No the kind of libido where you want to lose your mind, but rather “I want to make love to you” oxytocin kind of libido.
- Bigger testicular size (fuller)
- More endurance. Not that super-sensitive-“I’m going to explode if I stop just 1 millisecond too late”.
- Full sexual recovery before 24 hours
- Repeated strong stiffs (day after day) without ‘tiring’.
- Longer flaccid hang. Not that it was a problem before, but it’s definitely noticeable.
5 of the latest reviews
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