#180 - AMA #28: All things testosterone and testosterone replacement therapy
In this AMA, Peter Attia and Bob Kaplan discuss testosterone, its physiology, epidemiology, and the benefits and risks of testosterone replacement therapy (TRT), with a focus on cardiovascular disease and prostate cancer. They aim to clarify misinformation surrounding TRT in men.
Deep Dive Analysis
7 Topic Outline
Introduction to Testosterone and Testosterone Replacement Therapy (TRT)
Physiology of Testosterone: Synthesis and Mechanism of Action
Testosterone Transport in Blood: Carrier Proteins and Bioavailability
The Role and Potency of Dihydrotestosterone (DHT)
Macro-Level Regulation of Testosterone: The Hypothalamic-Pituitary-Gonadal Axis
Clinical Interpretation of LH, FSH, and Testosterone Levels
Defining Low Testosterone: Total vs. Free Testosterone
7 Key Concepts
Testosterone
Testosterone is a steroid hormone derived from cholesterol. It is a hydrophobic molecule that easily diffuses into cells and exerts its effects by binding to an androgen receptor, which then influences gene transcription to regulate anabolic and growth characteristics.
Sex Hormone Binding Globulin (SHBG)
SHBG is a dominant carrier protein that binds testosterone in the bloodstream, responsible for about two-thirds of its carrying capacity. Testosterone bound to SHBG is generally not biologically active.
Albumin
Albumin is another carrier protein that binds testosterone in the bloodstream, responsible for about one-third of its carrying capacity. Testosterone bound to albumin is considered part of bioavailable testosterone.
Free Testosterone
Free testosterone is the portion of testosterone that is completely unbound to carrier proteins like SHBG or albumin. This tiny fraction, typically 1-3% of total testosterone, is the biologically active form that can enter cells and exert influence.
Bioavailable Testosterone
Bioavailable testosterone includes the free testosterone fraction plus the portion of testosterone that is bound to albumin. It is considered a measure of testosterone that is available for biological activity, though free testosterone is often seen as a more direct indicator of symptoms.
Dihydrotestosterone (DHT)
DHT is a hormone converted from testosterone by the enzyme 5-alpha reductase. It is significantly more powerful than testosterone, having a greater binding affinity for the androgen receptor.
Hypothalamic-Pituitary-Gonadal (HPG) Axis
The HPG axis is a feedback loop that regulates testosterone production. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) to the pituitary, which then releases luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to the testes, stimulating testosterone production.
6 Questions Answered
Testosterone is a steroid hormone derived from cholesterol that diffuses into cells and binds to an androgen receptor, leading to the up or down-regulation of genes responsible for anabolic and growth characteristics.
Testosterone is primarily carried by two proteins: Sex Hormone Binding Globulin (SHBG), which carries about two-thirds, and albumin, which carries about one-third. Only the unbound portion is biologically active.
Free testosterone is the tiny fraction of testosterone completely unbound to any carrier protein, while bioavailable testosterone includes this free fraction plus the portion bound to albumin, but not SHBG.
The hypothalamus releases GnRH, stimulating the pituitary to release LH and FSH, which then act on the testes to produce testosterone. This process is a feedback loop, where high testosterone inhibits LH/FSH production and low testosterone ramps it up.
This combination typically indicates a problem originating in the testes, as the brain is sending strong signals (high LH/FSH) but the testes are not producing adequate testosterone.
This combination usually points to a central problem in the brain's signaling pathway (hypothalamus or pituitary), often seen in situations of sleep deprivation or high stress (hypercortisolemia).
8 Actionable Insights
1. Improve Sleep, Reduce Stress
If you have low testosterone combined with inappropriately low LH and FSH, prioritize improving sleep and reducing stress (hypercortisolemia), as these are common causes for this central issue.
2. Identify Low T Cause
When considering treatment for low testosterone, differentiate between testicular causes (high LH/FSH, low T) and central causes (low LH/FSH, low T), because treatment strategies are highly dependent on this distinction.
3. Focus on Free Testosterone
When assessing testosterone levels, pay special attention to ‘free testosterone’ numbers from lab tests, as symptoms tend to track more closely with this biologically active form compared to total or bioavailable testosterone.
4. Learn About Hormones
Get smart on the topic of testosterone and hormone replacement therapy (HRT) for both men and women, as there is a lot of misinformation out there.
5. Consult Healthcare Professionals
Do not disregard or delay in obtaining professional medical advice for any medical condition you have, and always seek the assistance of your healthcare professionals for such conditions.
6. Understand Exogenous T Risks
Be aware that if a person takes exogenous testosterone for long enough, their body will likely lose the ability to make its own testosterone, becoming a permanent issue.
7. Anticipate Male Testosterone Decline
Understand that males will experience a decline in testosterone levels, akin to female menopause, and be prepared to consider if any intervention should be done about it.
8. Watch Video for Data
For AMA episodes that present a lot of data, graphs, and figures, watch the video version of the podcast to gain a deeper and clearer understanding of the detailed information presented.
3 Key Quotes
almost everyone at some point in the course of their life will get to a point where their levels get to a level that is defined as low.
Peter Attia
it's only the unbound portion of testosterone that is able to actually exert the biological influence.
Peter Attia
DHT is anywhere from, oh, I don't know. I think it's about three to six times more powerful than testosterone.
Peter Attia