Dr. Rhonda Patrick: What would be the best method to get you to a more normal range? Maybe you are not someone who is totally hypogonadal, but you have low-T symptoms, lower testosterone, and symptoms. You are aging. You are a 50-year-old man or something. What would be the ideal delivery method that would get you those benefits but lower the risk profile?

Derek: Before we enter that subtopic, I do want to clarify one thing. If somebody takes an amount of testosterone that puts them at the high-normal end of the reference range, but it is something they tolerated in youth and their body was capable of handling, which is true for a lot of people, they will probably be fine if they do it responsibly. They need to understand what they are taking, know how to monitor biomarkers, be lean and healthy, have a good diet and lifestyle, and be aware of the risks. All of that should be overseen with education and rigor. The need for oversight decreases as you dial in the protocol. After that, you are living your life, and you know what to expect from your blood work and how it affects everything.

You will probably be fine, but it is not zero risk. That is what people need to accept if they want to push to that level. It is never going to be risk-free. I can also say with certainty that if you are hypogonadal, you are going to be healthier replacing testosterone to physiologic levels than staying hypogonadal. You are almost certainly in cardiotoxic, neurotoxic, and poor-quality-of-life territory if you are at hypogonadal levels.

It is worth being cautious and aware of all this, but do not dissuade yourself from fixing your levels. It is critical that you have adequate hormone production, similar to women in menopause. The benefit outweighs the risk essentially every time. You just have to be responsible about your approach.

Dr. Rhonda Patrick: Especially if you are monitoring biomarkers. I would love to talk about some of those in a minute, but that is the key too, right? Monitoring?

Derek: Yeah. Circling back to administration and the ideal way to go about it, I can say immediately that I would not do pellets. I would probably not do AndroGel if you are male. If you are female, it is a bit different, which we can get into.

The creams from compounding pharmacies are probably the only tolerable option that you can apply scrotally to get the ideal absorption and pharmacokinetic profile that would reflect something more natural. On paper, that is arguably the best way to go about it. It is just not necessarily something everyone wants to do. It works well, gets you to good levels, looks physiologic, and reflects the pulsatile, diurnal nature of normal testosterone secretion.

It is also converting locally in the area where you would be producing it. There is a local effect through 5-alpha reduction in the skin. That is why monitoring DHT and some of these other things can be important, but that is a more nuanced discussion. In general, scrotal cream is reliable, produces a favorable outcome, and a lot of guys will be happy with that method.

The other method worth considering, and the typical one that most guys use, is injection. It is usually more predictable in terms of what you get out of it. Adherence is easier because you do not have to inject daily. You can also modulate its release pattern through the ester. You will typically get prescribed the longest-lasting ester. Testosterone cypionate has a half-life of about 8 to 10 days, depending on individual biochemistry and how you cleave the ester.

You can also change the way it absorbs by injecting subcutaneously into abdominal fat or other subcutaneous fat, versus intramuscularly, where it will be absorbed and assimilated more quickly. You can extend the effect and make blood levels more stable. It is fairly easy to adhere to a TRT protocol with microinjections on a relatively frequent basis. Every other day is quite stable. A lot of guys inject subcutaneously, and it works well. It maintains a stable hormone-concentration curve and is predictable. You just have to be aware of how hard you are pushing it and what that does to your risk profile.

Another promising route is oral testosterone undecanoate in a patented, lymphatically absorbed format. I believe there are three: Tlando, Jatenzo, and Kyzatrex. They have made a lymphatically absorbed testosterone undecanoate that you can swallow. In the past, they would have had to make an oral steroid hepatotoxic for it to pass through the liver during first-pass metabolism and reach a meaningful level in circulation. They would have added a 17-alpha-alkylated group, making it a terrible oral steroid for you.

This does not have the same level of stress. It is not stress-free as far as I know, but it can provide meaningful replacement of total testosterone into the mid-to-high range, depending on the person. It is likely to provide symptom relief for guys who are hypogonadal and can be sustainable because you are just taking a pill. Some people prefer that. It is expensive and a newer method of administration, but it is promising.

Most guys still use injections or cream. Another method is intranasal testosterone. You have probably heard of its potential use for hypoactive sexual desire disorder in women. For men, it is a different medium that may avoid stimulating erythropoiesis because its effect is so acute. Unfortunately, it is an unsustainable daily treatment. It may be acceptable for an on-demand libido boost in a woman, but I do not think a man would want to use something intranasally multiple times a day. Even if it seems interesting at first, the novelty would probably fade after a month or two.

A lot of guys are excited when they start testosterone injections because it feels like a significant thing. A year later, it is just, "I have to do my injection." The method you can adhere to most sustainably, that is safest, and that achieves the desired symptom relief is the one you should stick to.

With cream, transference is an obvious concern. If you have children or pets, you have to consider what you might rub it onto and maintain careful hygiene. Cases of transference have been reported. I did a video about a father who accidentally transferred residue to his child without realizing it, even after he thought he had cleaned it off. His child started to become masculinized from the testosterone residue.

Dr. Rhonda Patrick: Wow.

Derek: Yeah, it is crazy. Their levels are so low that any significant amount will push things in a direction that can cause problems. An injection is clean and done in the bathroom. You do not have to worry about whether your hands are fully clean or whether somebody will get into it. Accidentally getting into a multidose vial is unlikely.

Dr. Rhonda Patrick: Right.

Derek: There are logistical advantages to these administration methods that should not be understated. I think the three most viable are scrotal cream, intramuscular or subcutaneous injection if you want to extend the effect, and perhaps oral testosterone undecanoate. I want to see more literature as it evolves.

Dr. Rhonda Patrick: Right. The oral route is a newer option. When it comes to injections, it sounds like more frequent subcutaneous injections are less likely to produce a supraphysiologic peak than one intramuscular injection each week, because the effect is spread out. Compliance may be better with once-weekly injections, but twice a week, three times a week, or every other day may appeal to people who are concerned about risk. If someone already has a family history of cardiovascular disease or stroke, they may be more motivated to lower the risk of potential side effects.

Derek: Yeah.

Dr. Rhonda Patrick: What about fertility in men who want to reproduce? We have to talk about that too.

Derek: One rule of thumb makes this easier to understand. The closer something is to what you would naturally make if you had healthy, functioning testes producing testosterone, the less impact it should have from unintended consequences of hormone spikes. Normally, you would release testosterone in pulses and flows multiple times a day. The more stable you can make it with smaller administrations spread throughout the week, the more stable everything will be. As a consequence, there will be fewer spikes into territory that is not representative of physiologic levels.

Daily administration is typically the way to go. Cream will be at least twice a day. For injections, there are diminishing returns between every day and every other day, but you can spread the effect out. It's...