#180 – AMA #28: All things testosterone and testosterone replacement therapy

“There were countless other studies to look at, but they all basically point in the same direction, which is testosterone replacement therapy improves lean mass, reduces fat mass, improves strength.” —Peter Attia

Read Time 44 minutes

In this “Ask Me Anything” (AMA) episode, Peter and Bob discuss all things related to testosterone: what happens when testosterone levels are low, and the potential benefits and risks of testosterone replacement therapy (TRT). They explain the physiology of testosterone, how it works, and how its level changes over the course of a person’s life. They have a detailed discussion about existing literature, which reveals vast potential structural, functional, and metabolic benefits of testosterone replacement therapy. They also take a very close look at potential risks of this therapy, with a focus on the controversial effects on cardiovascular disease and prostate cancer.

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AMA #28 Sneak Peak

We discuss:

  • A primer on the hormone testosterone and how it influences gene expression [3:30];
  • How the body naturally regulates testosterone levels [11:30];
  • The defining threshold for “low testosterone,” how low T impacts men, and why free testosterone is the most important metric [16:15];
  • When it makes sense to treat low testosterone [26:00];
  • The structural and metabolic benefits of testosterone replacement therapy [29:15];  
  • Body composition changes with TRT [45:30];
  • Changes in bone mineral density with TRT [48:15];
  • The metabolic impact of TRT: glucose, insulin, triglycerides, and more [52:30];
  • A study investigating testosterone replacement therapy for prevention or reversal of type 2 diabetes [59:30];
  • The impact of TRT on metabolic parameters and body composition—A study comparing results from continuous vs. interrupted treatment [1:07:15];  
  • The controversy over TRT and cardiovascular disease [1:21:45];
  • Two flawed studies that shaped perceptions of risks associated with TRT [1:44:15];
  • The controversy over TRT and prostate cancer [1:56:45];
  • Other potential risks with testosterone replacement therapy [2:02:15]; and 
  • More


A primer on the hormone testosterone and how it influences gene expression [3:30]


  • Testosterone is a steroid hormone
  • It’s derived from the cholesterol family and it is synthesized in a number of steps
  • What’s really important is that it exerts its effect through binding to an androgen receptor
  • Because it is a hydrophobic molecule, it basically makes its way into the cell easily—meaning it doesn’t require a channel or a receptor on the cell membrane to make its way inside
  • Cholesterol can’t make its way through the bloodstream the way glucose can or the way electrolytes can; for example, sodium & potassium (because electrolytes are soluble in water, they’re therefore soluble in the bloodstream (plasma), and they don’t need a chaperone or carrier proteins)
  • But cholesterol does need carrier proteins (lipoproteins)
  • Similarly, testosterone needs to be bound primarily to carrier proteins

Two dominant carrier proteins for testosterone:

  • 1) One is called sex hormone-binding globulin or SHBG 
  • 2) The other is albumin
  • SHBG is responsible for about two-thirds of the carrying capacity, whereas albumin is about one-third
  • what’s important is knowing that it’s only the unbound portion of testosterone that is able to actually exert the biological influence
  • “We pay very special attention to how much testosterone is “free,” and free is defined as the testosterone that is neither bound to SHBG or albumin”
  • whereas there’s another term that many people who have had a blood test may notice, something called bioavailable testosterone
    • that’s the portion that is unbound to SHBG, but remains bound to albumin or is free
  • In other words, free testosterone, which is a tiny amount, it’s typically 1% to 3% of total testosterone, is that which is completely unbound
  • whereas bioavailable includes that tiny fraction plus the much larger fraction that is bound to albumin
  • From a clinical standpoint, symptoms track more with free testosterone than bioavailable
  • But honestly, they’re close enough in terms of their prediction of what’s going on that if you’re using a lab that relies on one versus the other, it’s probably okay.
  • The lab that Peter uses looks at total testosterone, of course, but free testosterone, and it’s really the free number that Peter is paying most attention to

How testosterone works [9:15]

  • It makes its way into the cell, and then it binds to an androgen receptor (this receptor is outside of the nucleus)
  • It undergoes this conformational change, and it causes things called heat shock proteins to be dislocated
  • Heat shock proteins get transported into the cell, and then something called the dimerization takes place 
  • Dimerization is a fancy way of saying a new molecule is created by the fusion—and it doesn’t have to be covalent, it can be non-covalent—but fusion of two molecules that look very much alike
  • This androgen receptor dimer now makes its way into the nucleus and binds with something called a hormone response element, which is what actually turns on and off gene transcription
  • Effectively, testosterone is up or downregulating genes that are responsible for a number of things—the most obvious of these are the anabolic or growth characteristics

Another important hormone worth mentioning is dihydrotestosterone (DHT)

  • DHT is about three to six times more powerful than testosterone—meaning a greater binding affinity for the androgen receptor
  • DHT is something that is converted from testosterone using an enzyme called 5-alpha reductase
  • We could go a lot deeper into it, but I’m not sure it really adds much value to the clinical questions that we’re going to want to get to

{end of show notes preview}

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  1. Superb review! Thanks.
    Some of the studies discussed don’t describe the patient population in terms of their baseline testosterone levels. What are your thoughts on T replacement in men with normal/upper normal (for age) T/free T levels?
    For that matter, given the huge between-person variability, should normal levels be based on a person’s own levels at younger ages (if one had that info available)? And given the inevitable age related decline in levels, should all men, at some point, be using supplemental testosterone? be on testosterone supplementation?

  2. Early in the podcast, it is mentioned that continued use of TRT can affect your body’s ability to produce its own hormones and pre-cursors. Later you mention testicular atrophy occurs at 2 years of continuous use. What I missed and am interested in is any studies identifying the best cycling strategy to do TRT without shutting down my body’s own systems.

  3. Would be useful to include some of the ancillary drugs used in combination with trt such as hcg and ai’s. Would be interested in their long term health effects on the same topics you have discussed above.

  4. please clarify the statement about PVCs “pre-ventricular contraction, so PVCs, are very common. They usually result from magnesium insufficiency. So you can usually just give somebody magnesium and those will go away.” I would say PAC’s are very common, but not PVC’s.
    What is the evidence for Magnesium insufficiency?
    It would have also been helpful to at least mention DHEA endogenous relationships and wide spread use of supplements.

  5. Thank you guys for another informative Q&A, could you please comment on how prolonged fasting and time restricting eating influences on testosterone levels

  6. Regarding the observational study discussed and some of the results not being what one might expect…….I would argue it must primarily be the fat loss (and a little from the increase in muscle mass). Add 5-10 pounds of muscle and take 25-30 pounds of fat off any over fat male with a BMI of 30 or above and I would pretty much expect some or all of those findings.

  7. As a clarification, The study by WITTERT, et al, used a different sort of testosterone, one called TESTOSTERONE UNDECANOATE.

    The dosing of Undecanoate is unique–i.e. every 2 weeks–because ITS HALF-LIFE IS THREE WEEKS IN LENGTH.

    Hence the seemingly unusual intervals between repeat doses are not unintentional. It would be likely that the nadir of serum testosterone levels would not be so undulant even despite these long dosing intervals, once a target serum level is reached.

  8. My question is a practical one. Peter, in your clinical practice, have you treated quite a few middle aged men complaining of low libido, and if so have you seen patterns of interventions that seem to help across men (ideas that come to mind are sauna, cold plunge, supplementation, weight lifting, etc)? Curious to know the specifics (if sauna/cold how frequently, what kind of supplementation, the need to cycle supplements or not, etc.). Thanks.

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