NAD+ for testosterone; an indispensable cofactor?

NAD is well known as an important compound (nucleotide) to prevent aging.

Many supplements are designed to boost NAD maximally, such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), etc.

Can these supplements also boost testosterone?

Let’s find out!

Steroidogenic enzymes use NAD

At least 3 steroidogenic enzymes use NAD. This includes CYP450scc (cholesterol side chain cleavage enzyme), 3β-HSD and 17β-HSD3.

CYP450scc is the enzyme that converts progesterone to pregnenolone and uses NADPH as a cofactor (R). Boosting NAD levels will help with NADPH creation.

3β-HSD uses NAD as a cofactor. Low NAD can lead to low 3β-HSD activity and low steroids (in the tear duct for example and cause dry eyes) (R).

17β-HSD3, which converts androstenedione to testosterone (activation) preferentially uses NADP as a cofactor (NADP is created from NAD). On the flip side, 17β-HSD2 which converts testosterone to androstenedione (inactivation) uses NAD as a cofactor.

Furthermore, 5alpha reductase also uses NADPH as a cofactor.

Evidence that NAD can boost testosterone

Since at least 3 of the steroidogenic enzymes use NAD as a cofactor, you’d think that more is better, or that low NAD can lead to low testosterone.

Aging is associated with a continuous decline of blood and tissue NAD levels, as well as a decline in testicular functions (R).

This study found that NAD levels decline with aging and this leads to reduced mitochondrial function, increased ROS production and low testosterone (R).

BPA, NAD and testosterone

We all know about BPA by now; an endocrine-disrupting plastic that lowers testosterone. It lowers testosterone by inhibiting the steroidogenic enzymes 3β-HSD, CYP17A1 and 17β-HSD3.

BPA competes with NAD as a cofactor at various steroidogenic enzymes, such as 3β-HSD (R). Thus preventing proper conversion.

🥤BPA on testosterone, libido and erections and how to detox BPA

Niacin supplementation on testosterone

Supplementing rats with “low dose” niacin (800mg/kg; human equivalent dose of 130mg/kg HED hence 13g for a 100kg guy) almost doubled testosterone.

In the testes of diabetic rats, it reduced oxidative stress, increased antioxidant status, increased testicular size and improved some histological parameters (R).

HC = healthy control. DC = diabetic control. NL = low dose niacin group. NH = high dose niacin group.

But this doesn’t mean that niacin increased testosterone due to an increase in NAD. Niacin acts on the HCA2 receptors and the presence of mRNA for these receptors is found in the testicular tissue of rats.

So the boost could be via NAD and/or acting on the HCA2 receptor.

Niacinamide on testosterone

Supplementing rats with niacinamide reduced ROS (reactive oxygen species), increased ATP production and restored LH, FSH and testosterone levels (R).

As you can see in this graph in the tweet, the increase in LH, FSH and testosterone correlates with the increase in NAD.

There is a possible correlation with NAD levels of testosterone.

According to this study, niacinamide increased testosterone, likely by increasing NAD levels.
The dose was quite large, at roughly 6g for a 100kg guy. pic.twitter.com/DGivumgj8k

— Hans Amato (@HansAmato) July 8, 2023

The ideal niacinamide dose was 400mg/kg, translating to 64.86mg/kg for a human (6486.49mg for a 100kg person). Yes close to 6g of niacinamide is a high dose.

Depleting NAD on testosterone

In this study, they used mice that can’t create their own B3 from tryptophan (making them reliant on dietary niacin) and then gave them a B3 deficient diet as well (R).

As you can imagine, this tanked their NAD levels.

Compared to the group that got B3, both groups had the same level of testosterone. Depleting NAD didn’t lower testosterone, at least in this study.

However, the NAD-depleted mice’s testicles shrunk and they became infertile over time.

What happened was retinol started to build up. Retinol is extremely important for fertility and needs to be converted to retinal and retinoic acid by retinol dehydrogenase (NAD-dependent) and aldehyde dehydrogenases (NADP+ dependent).

So you still need optimal NAD for optimal testicular health.

Summary

NAD is used as a cofactor for steroidogenic enzymes to create testosterone. Niacin and niacinamide, which boost NAD levels, have been shown to increase testosterone in rodents.

However, on the flip side, depleting NAD didn’t lower testosterone.

Low NAD is mostly due to increased oxidative stress that increases with age and not a lack of dietary tryptophan and vitamin B3 (R).

Thus, to prevent NAD from decreasing:

• Eat a low-inflammatory diet
• Eat a nutrient-dense diet rich in zinc, selenium, magnesium, manganese, etc, that helps to reduce reactive oxygen species.
• Avoid toxins that cause oxidative stress (heavy metals, plastics, pesticides, xenoestrogens, etc.)
• Prevent NAD catabolism by blocking CD38 with apigenin (R, R) (apigenin can also boost testosterone)
  • Niacinamide also inhibits PARP and CD38, thus sparing NAD.

A good stack to boost NAD is to take niacinamide and apigenin together.