#256 ‒ The endocrine system: exploring thyroid, adrenal, and sex hormones | Peter Attia, M.D.
In this special episode, Dr. Peter Attia provides a comprehensive overview of the thyroid, adrenal, and sex hormone systems for both men and women. He explains their basic biology, feedback cycles, and discusses various treatment options for hormone deficiencies, emphasizing the importance of watching the accompanying videos for full understanding.
Deep Dive Analysis
11 Topic Outline
Introduction to Endocrine Systems Overview
The Thyroid System: Basic Biology and Regulation
Thyroid Hormone Conversion: T4, T3, and Reverse T3
Evaluating Thyroid Status and Hypothyroidism Treatment Approaches
The Adrenal System: Cortisol Measurement and Metabolism
Understanding Adrenal Output and Addressing Cortisol Imbalances
The Female Reproductive System: Menstrual Cycle Hormones
Perimenopause, Menopause, and Female Hormone Replacement Therapy
The Male Sex Hormone System: Testosterone Production and Regulation
Testosterone Metabolism: DHT and Estradiol Conversion
Diagnosing and Treating Low Testosterone (TRT)
10 Key Concepts
T4 (Thyroxine)
The inactive version of thyroid hormone, containing four iodine atoms. It is mostly produced by the thyroid gland and needs to be converted into T3 to exert its biological effects.
T3 (Triiodothyronine)
The active version of thyroid hormone, containing three iodine atoms. It is responsible for all thyroid-promoting functions like metabolism, warmth, and hair/nail health.
Deiodinases
Enzymes (D1, D2, D3) that convert T4 into either active T3 or inactive reverse T3 by removing iodine atoms. D1 and D2 produce T3, while D3 produces reverse T3.
Reverse T3 (rT3)
A form of thyroid hormone similar to T3 but inactive, as it occupies the T3 receptor without activating it, effectively blocking T3's effects. Its production increases during inflammation, illness, or nutrient scarcity to slow metabolism.
Free Cortisol
The unbound, biologically active form of cortisol that exerts its effects in the body. Unlike total cortisol measured in blood tests, free cortisol levels, typically assessed via saliva or urine, provide a more accurate picture of adrenal function.
Cortisol Metabolites
Breakdown products of cortisol and cortisone (e.g., alpha/beta tetrahydrocortisol, tetrahydrocortisone). Their sum total, measured in tests like the Dutch test, indicates the overall adrenal output, which is crucial for understanding adrenal function beyond just free cortisol levels.
11-beta-HSD (Hydroxysteroid Dehydrogenase)
An enzyme that interconverts active cortisol and inactive cortisone. Its activity and direction of conversion are influenced by factors like insulin resistance, obesity, inflammation, and thyroid function, impacting the availability of active cortisol.
Sex Hormone Binding Globulin (SHBG)
A carrier protein that binds to testosterone (and other sex hormones), making most of it inactive. Only the small percentage of testosterone that remains unbound (free testosterone) is biologically active.
Dihydrotestosterone (DHT)
A potent androgen produced from testosterone by the enzyme 5-alpha reductase. DHT has a much higher binding affinity for the androgen receptor than testosterone, making it significantly more potent in its effects.
Aromatase
An enzyme that converts testosterone into estradiol (estrogen). This conversion is important for men's mood, body composition, and bone mineral density, and its activity can be influenced by genetics, insulin resistance, and obesity.
9 Questions Answered
The hypothalamus releases TRH, stimulating the pituitary to release TSH, which then tells the thyroid gland to produce mostly inactive T4 and a small amount of active T3.
A normal TSH can occur if the body is preferentially shunting T4 into inactive reverse T3 instead of active T3, often due to inflammation or insulin resistance, leading to symptoms despite seemingly normal TSH.
Blood tests for total cortisol are unhelpful; instead, free cortisol and its metabolites, measured via saliva or urine tests (like the Dutch test), provide a comprehensive picture of adrenal output and rhythm.
'Adrenal fatigue' is a common term for feeling lousy due to low cortisol, but the adrenal glands are rarely truly fatigued; often, low free cortisol is due to excessive degradation or conversion to inactive cortisone, not insufficient production.
PMS symptoms, particularly mood alterations, are likely driven by the profound and rapid drop in progesterone levels during the end of the luteal phase (days 21-28). A low dose of progesterone (e.g., 50mg orally) taken from day 21 to 28 can blunt this withdrawal and ameliorate symptoms.
Yes, women have testosterone, and surprisingly, even at peak estradiol levels during ovulation, a woman typically has five to ten times more testosterone in her body than estradiol, though its fluctuations during the cycle are minor.
As a woman approaches perimenopause, a rising FSH level (especially above 10-12) during a day 3-5 blood test, coupled with potentially low estradiol, serves as a 'canary in the coal mine' indicating she is getting closer to menopause.
When exogenous testosterone is administered, it creates a potent negative feedback loop that shuts down the body's natural production of GnRH, LH, and FSH, causing endogenous testosterone production to cease.
No, estradiol is important for men's mood, body composition, and bone health, so it's generally not recommended to suppress it unless levels are excessively high (e.g., >50-60) or causing symptoms like gynecomastia.
23 Actionable Insights
1. Prioritize Lifestyle for Adrenal Health
Address underlying issues like obesity, insulin resistance, leptin resistance, and inflammation to improve adrenal function, especially if free cortisol is low but metabolites are ample, as lifestyle management is key.
2. Request Comprehensive Thyroid Panel
If experiencing symptoms of hypothyroidism, request a full thyroid panel including TSH, free T4, free T3, and reverse T3, as TSH alone is often insufficient for accurate diagnosis.
3. Initiate HRT in Perimenopause
For women, consider initiating hormone replacement therapy (HRT) during perimenopause, 1-2 years before full menopause, rather than waiting for complete hormone decline, to manage symptoms and support long-term health.
4. Treat PMS with Progesterone
To ameliorate significant PMS symptoms caused by progesterone withdrawal, take a low dose of oral progesterone (approximately 50mg) daily for seven days, starting around day 21 of a regular cycle.
5. Use Phosphatidylserine for Sleep
To suppress evening cortisol production and facilitate sleep, especially for jet lag or time zone adjustments, take 400-600 milligrams of phosphatidylserine.
6. Consider T3 for Hypothyroidism
If standard T4 treatment for hypothyroidism is ineffective or causes worsening symptoms due to conversion issues, consider using T3 (e.g., compounded control-release T3) to bypass the body’s conversion process.
7. Take Control-Release T3 in Morning
If prescribed compounded control-release T3, take it generally in the morning to ensure its potency is reduced by evening, improving tolerance and mimicking natural rhythms.
8. Prioritize Symptoms in Thyroid Treatment
When treating hypothyroidism, prioritize fixing the patient’s symptoms and overall well-being over solely optimizing lab numbers, using whatever treatment approach proves effective.
9. Manage Missed T4 Doses
If you miss a dose of T4 (levothyroxine), simply take it the next day and do not double up, as T4 has a long half-life and a single missed dose is not critical.
10. Be Consistent with T3 Doses
Due to its much shorter half-life compared to T4, it is important to consistently take T3 medication as prescribed to maintain stable levels and therapeutic effects.
11. Avoid Glucocorticoids for Low Cortisol
Do not use hydrocortisone, prednisone, or other glucocorticoid replacements for general low free cortisol symptoms; reserve these treatments for severe distress or conditions like Addisonian crisis.
12. Use Urine/Saliva for Cortisol
To accurately assess adrenal function, use a urine or saliva test (like the Dutch test) to measure free cortisol and its metabolites, as blood tests for total cortisol are unhelpful.
13. TRT: Symptoms & Low Free T
Only consider testosterone replacement therapy (TRT) if there is a clear symptomatic case for low testosterone (e.g., low libido, low mood, difficulty building muscle) and free testosterone levels are relatively low (below the 50th percentile).
14. Trial TRT for 8-12 Weeks
If initiating TRT, conduct a trial for 8 to 12 weeks to assess both biochemical improvement and, more importantly, the resolution of symptoms.
15. Discontinue TRT if No Symptom Relief
If symptoms do not improve after an 8-12 week trial of TRT, even if testosterone levels normalize, discontinue the treatment unless it’s for a specific reason like bone health.
16. TRT for Bone Health
For men with osteopenia or osteoporosis, use TRT to achieve high testosterone and estradiol levels, combined with heavy training, to increase or maintain bone mineral density, even if other symptoms are not present.
17. Caution with Clomid for Men
Be cautious about using Clomid (clomiphene) to increase testosterone, as it blocks estrogen receptors in the brain, which can negatively impact mood and may not improve symptoms despite raising testosterone levels.
18. Avoid Anastrozole Unless Necessary
Generally avoid using anastrozole to lower estradiol during TRT unless levels are excessively high (e.g., >50-60) or causing symptoms, as estrogen is beneficial for men’s bone health and mood.
19. Understand TRT Hair Loss Risk
Be aware that testosterone replacement therapy can accelerate hair loss in susceptible individuals due to increased conversion to dihydrotestosterone (DHT).
20. Overweight Men: Higher Estrogen Risk
Overweight men on TRT may convert more testosterone to estradiol due to higher aromatase activity in adipose tissue, potentially leading to higher estrogen levels.
21. Exogenous Testosterone Shuts Production
Understand that taking exogenous testosterone will shut down the body’s natural testosterone production, potentially permanently within one to two years.
22. Understand Female Luteal Phase
Gain an understanding of the profound physiological changes and hormone withdrawal women experience during the end of the luteal phase to foster empathy for those struggling with PMS.
23. Watch Podcast Video Series
For a much deeper understanding of the thyroid, adrenal, and sex hormone systems, watch the accompanying video series, as visual aids provide significant clarity.
8 Key Quotes
A picture says a thousand words.
Peter Attia
If the thyroid's producing T4, which is inactive, it needs to be converted into an active hormone in the body. And that's where these enzymes called deiodinases come in.
Peter Attia
In other words, 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.
Peter Attia
But the reality of it is, you can sometimes have a normal TSH and still have the symptoms of hypothyroidism.
Peter Attia
A woman has, even at peak estradiol level, which is during ovulation, a woman has five to ten times more testosterone in her body than she does estradiol.
Peter Attia
Men don't have an equivalent of this. We don't have a scenario whereby we're having a tenfold reduction in a major sex hormone that occurs over the course of a week.
Peter Attia
I think too many people are being given testosterone and they probably don't need it because they're just being treated on their total testosterone level without necessarily considering these other factors, such as free testosterone.
Peter Attia
For most men, we care about the symptoms more than we care about the numbers. And if we don't fix the symptoms, we take it off.
Peter Attia
3 Protocols
Managing PMS Symptoms (Progesterone Withdrawal)
Peter Attia- Identify a fairly regular menstrual cycle and approximate ovulation day.
- Starting about 7 days after ovulation (around day 21 of a 28-day cycle), take a low dose of progesterone.
- Administer 50 milligrams of oral progesterone daily.
- Continue taking progesterone for 7 days, until the start of the period.
Suppressing Evening Cortisol to Aid Sleep
Peter Attia- Take 400 to 600 milligrams of phosphatidylserine.
- Administer in the evening to drop cortisol levels.
Initiating Testosterone Replacement Therapy (TRT)
Peter Attia- Confirm a biochemical case (free testosterone relatively low, at least below 50th percentile).
- Confirm a symptomatic case (patient experiences common low T symptoms).
- Ensure patient understands the risks and benefits of TRT.
- Administer TRT for a trial period of 8 to 12 weeks.
- Re-evaluate biochemical issues (e.g., free T from 30th to 80th percentile).
- Assess symptom improvement; if no improvement, discontinue TRT (unless the primary goal is bone health).