#256 ‒ The endocrine system: exploring thyroid, adrenal, and sex hormones | Peter Attia, M.D.

Read Time 27 minutes

In this special episode of The Drive, Peter provides a comprehensive overview of the various endocrine systems: the thyroid system, the adrenal system, and the sex hormone system (for both men and women). He walks through the basic biology and the feedback cycles that regulate the production of these hormones and discusses the various options for the treatment of hormone deficiencies. In addition, Peter delves into hormone replacement therapy (HRT), providing nuanced insights into its appropriate usage and the clinical approach he adopts when working with patients. 

Peter supplements these explanations with whiteboard illustrations. For a more complete understanding, we highly recommend watching these videos over just listening. The videos can be found on our YouTube channel or on the show notes page.


We discuss:

  • The thyroid system [2:15];
  • The adrenal system [15:45];
  • The female sex hormone system [27:00];
  • The male sex hormone system [40:00]; and
  • More.


View the clips from each section:

The thyroid system:

The adrenal system:

The female sex hormone stystem:

The male sex hormone system:

Show notes preview below:

The thyroid system [2:15]

Figure 1. Hormones that stimulate the thyroid, hormones produced by the thyroid and their inhibitory effects

  • The thyroid gland sits in front of your larynx
    • You can actually feel it
    • It’s shaped like a shield
  • The thyroid is regulated directly via a hormone called TSH
  • TSH is produced by the anterior portion of the pituitary gland
  • TSH tells the thyroid gland to make T4 and T3
  • The pituitary gland is regulated upstream by the hypothalamus, which stimulates it via a hormone called TRH (we’ll come back to this)
  • The thyroid gland makes mostly T4 and a little bit of T3
  • The numbers 3 and 4 refer to the number of iodines in the molecule
    • T4 has 4 iodines
    • T3 has 3 iodines
    • The difference has to do with their biologic activity

All of the thyroid-promoting functions are controlled by the active version, which is T3 

  • T3 keeps you warm, aids in metabolism, controls things like the brittleness of your nails, your hair, bowel function, all sorts of things
  • T4 is the inactive version of the hormone

Most of what comes out of the thyroid is T4, inactive 

  • It’s not entirely clear what the ratio is between these, but it’s directionally about 4:1 or 5:1 [T4:T3]
    • Peter imagines that virtually everything the thyroid is producing is T4

T4 needs to be converted into an active hormone in the body, and that’s where the enzymes called deiodinases come in 

  • Deiodinases remove one of the iodines from T4 to create T3 (T3 is the active hormone)
  • The story gets a little bit more complicated because there are different types of deiodinases, but the three most relevant are D1, D2, and D3
  • D1 and D2 are quite similar in that they both convert T4 into T3; what’s different is where they do it
    • D1 is extracellular, it’s on the cell membrane facing outward
    • D2 is on the membrane of the endoplasmic reticulum and it’s facing internal to the cytosol
    • Put that aside for a moment and just keep in mind that D1 and D2 both convert T4 into the active hormone T3, and T3 is the one that has all of the positive effects of thyroid hormone
  • D3 is different in that D3 takes T4 and makes something called reverse T3
  • Reverse T3 is very similar to T3 except for a very important difference, which is it doesn’t activate the receptor that T3 activates
    • It occupies the receptor without activating it
    • In effect, you can think of reverse T3 as anti-T3; it basically blocks the effects of T3
  • It sounds like a very bad idea to have reverse T3 floating around, and unfortunately in the modern world it often is
    • Reverse T3 usually is a sign of inflammation, illness or things of that nature
    • The reason it probably exists is to cope with shortage of nutrients
      • When nutrients are scarce, when you need to slow down metabolism, one of the first things that the body does is it increases the production of reverse T3 to block the effects of T3

One of the things Peter used to notice when fasting 

  • When fasting for a week at a time, he would check his blood pre and post
  • He was surprised at how much his thyroid function deteriorated during that period of time
    • How much much his free T3 and reverse T3 changed 
  • The ratio of free T3: reverse T3 might go from 0.25 (normal) to 0.05 or less in a 5-7 day fast
    • About half of that was due to the reduction in T3, and the majority was due to the increase in reverse T3

The body is going to regulate these three enzymes in response to various physiologic circumstances, and that’s effectively at the cellular level how the body is controlling thyroid function 

Evaluating thyroid function 

  • This creates a bit of a problem when you want to evaluate a patient for their thyroid status because the traditional way to think about a patient’s thyroid status is just to look at their TSH
  • On the surface this makes sense because if everything is working perfectly, the TSH should give you the answer
    • If the TSH is very high, there must not be much T3 around because it would be inhibiting TSH [refer to figure above]
    • If TSH is very, very low, you would be getting a lot of inhibition from these things [on the figure above], and you would be in a hyperthyroid state 
  • But the reality of it is you can sometimes have a normal TSH and still have the symptoms of hypothyroidism
    • For example, you have very high amounts of reverse T3 and very low amounts of T3, in other words, if your T4 is being preferentially shunted into reverse T3 instead of T3, you might feel like you have the symptoms of hypothyroidism
      • You could be cold, your metabolism might be slow, you’d have difficulty sleeping
      • If it were really extreme, your nails might even get brittle, you’d be constipated
      • These sorts of unfortunately nonspecific symptoms which make it difficult to make such a diagnosis at times

Where does this matter when it comes to how we treat hypothyroidism?  

To be clear, hypothyroidism is far more common than hyperthyroidism 

  • Peter is not going to talk about hyperthyroidism, he’s going to talk about hypo
  • The standard treatment for hypothyroidism is to give T4
    • We give a synthetic version of this hormone, the inactive thyroid hormone, and we do that with the knowledge that most patients will convert that T4 into T3 (via D1 and D2)
    • The T3 will go on to have all the biologic effects, and it will also suppress TRH and TSH, and the body will come back into line
  • For example, if a patient shows up and they have the classic symptoms of hypothyroidism and their TSH is elevated (for example, at 6-7), you might give them 75 mg of T4
    • And you might expect to come back and see that TSH at 2-3 and them feeling better
    • Many times it works out that way, but unfortunately it doesn’t always work out that way
  • Sometimes you give a patient T4 and they start to feel worse, and sometimes their TSH actually improves
    • And the reason it improves is T4 does have some inhibition of TSH (not as much as T3, but some)

{end of show notes preview}

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  1. Top. Isso mesmo. Mas na prática é bem complicado, pois me aprece que os exames são bem variáveis e um ia para outro

  2. Love the information. I have been treated for primary adrenal insufficiency for the past 13 years and take hydrocortisone and fludrocortisone. I was diagnosed using an ITT and later an ACTH stimulation test. I always have wondered how much they didn’t know when diagnosing me and if there were anyway to not be life dependent on pills. At this stage, do you think I could get adrenal function back by using some of the measures you are referring to? I have used licorice root in the past when I did not have access to fludrocortisone on a trip overseas. It was very helpful!

  3. Is there any good data on natural testosterone rebound after ceasing long-term use of exogenous TRT? My understanding was that men tend to go back pre-TRT levels of T if they stop TRT, it just might take a year or two.

  4. This was a great episode. If you could do more white board discussions that would be really helpful. Another thing that would be helpful in regards to understanding these hormones is how they interplay with one another. For instance you talked about giving progesterone to relieve severe PMS symptoms. You also mentioned that progesterone stimulates the body to move cortisol towards the inactive form cortisone. Would you be concerned about creating low cortisol levels through supplementation with progesterone or even in the case of HRT in postmenopausal women?
    Thanks! Love your podcast!

  5. Thanks for this episode! I’d like to hear more of the lifestyle protocols to target the hormones Dr. Attia covers.

    Ive been dealing w low T3 w “normal” TSH (2-2.5) and T4. I’m on Liothyronine but I would really like to understand what causes this. Are there lifestyle changes I can make? I’ve been told to eat in the morning and not fast. Does this mean someone like me can never take advantage of the benefits of intermittent fasting or time based eating?
    Also, Dr. Attia pointed out his T3 levels would drop after a fast. How did he recoup from that?

    And is it actually bad to have low T3 if the symptoms aren’t bothersome?

    Also i do trend low on cortisol so I will look into that additional testing. Again though covering those specific lifestyle changes would be great!

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