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

KEYPOINTS

• 01

  The thyroid mostly makes inactive T4, which has to be converted to active T3

  The hypothalamus releases TRH, which drives the pituitary to release TSH, which drives the thyroid to make mostly T4 (four iodines) and a little T3 (three). T3 does the work: keeping you warm, supporting metabolism, and maintaining hair, nails and bowel function. Deiodinase enzymes D1 and D2 remove an iodine to turn T4 into T3. D3 turns T4 into reverse T3, which Peter describes as 'anti-T3' because it blocks T3's effects.

• 02

  Reverse T3 rises sharply in some states, including fasting

  Peter says his free T3 to reverse T3 ratio can fall from a normal of about 0.25 to 0.05 or below in a 5–7-day fast. He measured this before and after week-long fasts, and most of the drop came from rising reverse T3. Insulin resistance and low-grade inflammation can also shift conversion toward reverse T3, down-regulating D1 and D2 and up-regulating D3.

• 03

  Why some patients feel worse on standard T4 therapy

  The textbook approach is to give a patient with a TSH of 6–7 about 75 µg of T4 and expect TSH to fall to 2–3 and symptoms to improve. Often that works. But if conversion is skewed, the extra T4 just becomes more reverse T3, so TSH looks better while the patient feels worse. For them Peter adds T3 directly, bypassing the faulty conversion step.

• 04

  How Peter gives T3

  Standard immediate-release T3 (Cytomel) is hard for many patients to tolerate. He prefers compounded controlled-release T3, typically 10–30 µg, taken in the morning so it lasts through the day and fades by evening. Desiccated thyroid contains both hormones at a fixed ratio (about 4.2 units of T4 to 1 of T3), which suits some people. He usually prescribes T4 and T3 separately so each can be adjusted.

• 05

  Test more than TSH when symptoms are present

  He orders TSH, free T4, free T3 and reverse T3 to infer what the deiodinases are doing. If TSH, T3 and T4 are normal and the patient has no symptoms, he skips reverse T3.

• 06

  Measure free cortisol and its metabolites over the day in urine

  Most cortisol in the blood is bound to proteins, and only the free fraction acts. Peter uses the four-sample DUTCH urine test, which captures free cortisol and cortisone across 24 hours plus their breakdown products (alpha- and beta-tetrahydrocortisol, tetrahydrocortisone). Those breakdown products show total adrenal output, which a blood test can't. The healthy pattern peaks a couple of hours after waking and is low at bedtime.

• 07

  'Adrenal fatigue' is mostly a misnomer

  People who feel run down may have low free cortisol, but when total metabolized output is counted, most have ample production. The problem is often the enzyme 11β-HSD, which converts between active cortisol and inactive cortisone. Insulin resistance, obesity, inflammation, low thyroid function and leptin resistance push toward cortisol. Steroid use, hyperthyroidism, progesterone, PCOS and supplements like curcumin push toward cortisone. Peter calls lifestyle management the key fix.

• 08

  Perimenopause shows up in day 3–5 FSH before periods stop

  In a 28-day cycle, estradiol rises in the follicular phase, LH surges to trigger ovulation around day 14, and progesterone peaks around day 21 before falling and triggering menstruation. As ovarian output falls, the brain drives FSH and LH higher. An early-cycle FSH creeping above about 10–12 is the 'canary in the coal mine'. FSH above about 25–40, with very low estradiol, confirms menopause, and FSH can exceed 50 years later.

• 09

  Start hormone therapy during the transition, not years after

  Peter doesn't wait until a woman has flat-line estradiol and very high FSH. He starts a year or two before that point, giving enough estradiol to keep FSH around 20–30. The aim is not maximal estrogen but control of hot flashes, night sweats and vaginal atrophy, and above all protection of cardiovascular and bone health. For severe PMS in women who still cycle, he uses about 50 mg of oral progesterone from day 21 to day 28, or for the full 14 days after ovulation.

• 10

  Low testosterone isn't diagnosed from a number alone

  Only about 1–3% of testosterone is free, and the rest is bound to SHBG or albumin. A small fraction becomes DHT, which is 2–10 times more potent, and less than 1% becomes estrogen. Androgen receptor numbers vary between people, so a man at the 30th percentile may or may not have symptoms caused by low testosterone. In trials, testosterone improves insulin resistance and mood, but Peter remains cautious.