# Estrogen-serotonin axis

Category: Theories & Frameworks

Also known as: estrogen-serotonin, serotonin-estrogen

Estrogen and serotonin form a self-amplifying, pathological positive feedback loop that Ray Peat identified as central to the field of sickness. Estrogen activates the enzyme tryptophan hydroxylase, which converts tryptophan into serotonin, while simultaneously inhibiting…

11 passages · 3 authors · 2011–2020 · Most-cited: [Ray Peat](https://bioenergeticoracle.com/md/voices/ray-peat/index.md)

Canonical page: https://bioenergeticoracle.com/concepts/estrogen-serotonin-axis

## Synthesis

**Estrogen** and **serotonin** form a self-amplifying, pathological positive feedback loop that Ray Peat identified as central to the *field of sickness*. [Source 11] Estrogen activates the enzyme **tryptophan hydroxylase**, which converts tryptophan into serotonin, while simultaneously inhibiting **monoamine oxidase type A (MAO-A)**, the primary route for serotonin's breakdown. [Source 1, 7, 8] Conversely, serotonin is one of the most potent known inducers of the enzyme **aromatase**, which synthesizes estrogen. [Source 6, 11] This bilateral stimulation means that when one hormone becomes dominant, the other is inevitably elevated, creating a vicious cycle that is difficult to break. [Source 2, 11]

Peat argued that this axis is fundamentally a stress cascade. Estrogen's basic effect is to shift metabolism away from glucose oxidation toward fat oxidation, a defensive mechanism that, under chronic stress, becomes destructive. [Source 6] Serotonin acts as a terminal mediator of this stress process, activating the pituitary to release ACTH, which drives the adrenal cortex to produce **cortisol** in a dose-dependent manner. [Source 4, 7, 8] This entire system is further amplified by **polyunsaturated fatty acids (PUFA)**, which specifically release tryptophan to enter cells and produce more serotonin; the serotonin then activates enzymes that convert PUFA into inflammatory prostaglandins. [Source 1] The convergence of these signals overworks the adrenal cortex and promotes tissue breakdown. [Source 1, 6]

The gut is the primary site of this interaction, as roughly 95% of the body's serotonin is produced in the intestine, with the largest concentration around the appendix. [Source 3] Intestinal irritation, often driven by bacterial **endotoxin**, triggers serotonin release. [Source 1, 9] Peat correlated this gut-derived serotonin with the systemic effects of estrogen, noting that both are anti-thyroid factors. [Source 3] Roddy has written that serotonin, estrogen, and endotoxin form a unified axis, and that serotonin's role in torpor and hibernation works in the opposite direction of thyroid hormone by inhibiting mitochondrial respiration and inducing mitochondrial swelling, an effect reversed by ATP. [Source 7, 8] Dinkov has elaborated that serotonin, being a more ancient hormone, holds a higher role in the stress cascade, and that taking a serotonin antagonist tends to calm the entire system. [Source 11]

Peat consistently refuted the drug industry's framing of serotonin as the "hormone of bliss," calling it instead a basic inflammatory signal essential for processes like blood clotting, spasms, and osteoporosis. [Source 4, 6] He noted that the disease carcinoid tumor, which produces massive serotonin, was historically identified by flushing, psychiatric symptoms, and degeneration of the right side of the heart. [Source 2, 6] The entire preeclampsia syndrome is centered on high serotonin, and it acts as a demyelinating factor and a direct cause of bone loss, effects that are increased by estrogen and prolactin and corrected by **progesterone** and **thyroid**. [Source 2, 5] Dinkov has confirmed that estrogen, prolactin, and serotonin are all part of the "field of sickness," and that selective serotonin reuptake inhibitors increase prolactin, contributing to osteoporosis. [Source 10]

The axis is opposed by protective factors that support oxidative metabolism. **Aspirin**, **thyroid**, and **fructose** work in similar ways to antagonize serotonin, with aspirin alone capable of curing pulmonary artery hypertension in animal models. [Source 5] Progesterone inhibits tryptophan hydroxylase, directly opposing estrogen's induction of the enzyme, and both progesterone and thyroid increase the intestine's ability to absorb sugars quickly, preventing the bacterial overgrowth that drives endotoxin and serotonin production. [Source 1, 9, 11] Peat emphasized that the perception of unavoidable stress activates the hypothalamic CRH, which is promoted by serotonin and estrogen, while progesterone and androgens decrease its activity. [Source 9] The ability to act with defensive meaning, rather than withdrawing into helplessness, prevents the excessive production of serotonin and its downstream consequences. [Source 9]

## People also ask

### How does estrogen increase serotonin levels in the body?

Estrogen activates tryptophan hydroxylase, the enzyme that converts tryptophan into serotonin, while simultaneously inhibiting MAO-A, the enzyme that breaks serotonin down.

### Why is the gut considered central to the estrogen-serotonin feedback loop?

Roughly 95% of the body's serotonin is produced in the intestine, and intestinal irritation from bacterial endotoxin triggers serotonin release, which Peat correlated with estrogen's systemic anti-thyroid effects.

### What substances does Peat identify as opposing the estrogen-serotonin axis?

Progesterone inhibits tryptophan hydroxylase to oppose estrogen's induction of the enzyme, while aspirin, thyroid, and fructose antagonize serotonin, and both progesterone and thyroid help prevent the bacterial overgrowth that drives endotoxin and serotonin production.

## Related concepts

- [SIBO](https://bioenergeticoracle.com/md/concepts/sibo/index.md)
- [Biotin](https://bioenergeticoracle.com/md/concepts/biotin/index.md)
- [Cellular respiration](https://bioenergeticoracle.com/md/concepts/cellular-respiration/index.md)
- [Chronic Fatigue Syndrome](https://bioenergeticoracle.com/md/concepts/chronic-fatigue-syndrome/index.md)
- [Diphenhydramine](https://bioenergeticoracle.com/md/concepts/diphenhydramine/index.md)
- [Endotoxin (Lipopolysaccharide, LPS)](https://bioenergeticoracle.com/md/concepts/endotoxin-lipopolysaccharide-lps/index.md)

## Cited passages

Passage numbers match the `[Source N]` markers in the synthesis above.

### Source 1 — EastWest Healing Serotonin and Endotoxin

Ray Peat · Interview · Aug 24, 2011 · http://l-i-g-h-t.com/files/east-west-serotonin-and-endotoxin.mp4

> ## Estrogen, Cortisol, and PUFA
>
> **Josh Rubin:** What other hormones does serotonin synthesize with? What is its correlation with estrogen?
>
> **Ray Peat:** Estrogen activates the enzyme that turns tryptophan into serotonin. It is inhibited by progesterone. The route *out* of serotonin—monoamine oxidase type A—is inhibited by estrogen, so it doesn't break down serotonin. So, the "in" route is increased by estrogen and the "out" route is decreased by estrogen. In our lab, we saw that estrogen treatment would cause animals to enlarge their adrenal cortex, activate it, and then the adrenal cortex would start bleeding and dying. The mechanism is that stress increases serotonin; serotonin increases the release factor that drives the pituitary hormone, which drives the adrenal cortex. So stress, acting through estrogen or serotonin, ends up overworking your adrenal cortex.
>
> **Josh Rubin:** This is dangerous because a lot of women are on SSRIs and synthetic estrogens.
>
> **Ray Peat:** That's where the polyunsaturated fatty acids (PUFA) come in too. They are specifically effective at releasing tryptophan to enter the brain or other cells to produce more serotonin. The serotonin activates the enzymes that convert PUFA into prostaglandins, which are executors of the inflammatory process.

### Source 2 — Ask the Herb Doctor: Hormone Replacement Therapy

Ray Peat · Interview · Apr 20, 2013 · http://l-i-g-h-t.com/files/herb-doctors-hormone-replacement-therapy-60-mins.mp4

> ## HRT, Prolactin, and Serotonin
>
> **Andrew Murray:** Give me your opinion of HRT's effects and why it was eventually taken out—or rather, why there was a backlash against it.
>
> **Ray Peat:** The industry succeeded so greatly in turning science completely upside down in the case of estrogen that it took a lot of other hormones with it. Progesterone was suppressed and ignored because it would cure the things that estrogen was claimed to cure but actually caused. Prolactin had many toxic effects that were well recognized. But since estrogen increases prolactin, there was great pressure not to think about the fact that prolactin causes bone loss and contributes to osteoporosis. Serotonin is another thing that has been strongly influenced by this inverted interpretation. Estrogen increases exposure to serotonin. Serotonin is one of the means by which estrogen increases prolactin. Serotonin does many of the harmful things that estrogen and prolactin do, including being a direct cause of bone loss. People who take the fluoxetine (Prozac) type of antidepressants are seen to have a lot of premature bone loss because of the excess exposure to serotonin. Serotonin is, in a way, a co-factor for estrogen. Estrogen increases prolactin or serotonin systemically, and serotonin in turn increases the production of estrogen. So when one gets out of control, they both tend to become dominant.

### Source 3 — EastWest Healing Serotonin and Endotoxin

Ray Peat · Interview · Aug 24, 2011 · http://l-i-g-h-t.com/files/east-west-serotonin-and-endotoxin.mp4

> ## The Role of Serotonin
>
> **Ray Peat:** Roughly 95% of it is produced in the intestine. The biggest concentration in the digestive system is in or around the appendix. Part of how I got interested in the pattern of thyroid, estrogen, and serotonin was when I was about nine years old, I started becoming nearsighted and occasionally had migraine headaches. I noticed that things I ate would tend to bring on the headaches. I saw that nearsightedness was much more common among girls, especially starting around puberty, and several of the nearsighted girls I knew had migraines. I started thinking about what I had in common with girls in puberty, and it was the thyroid question. Estrogen and serotonin happen to be anti-thyroid factors. If you are borderline for thyroid function, you are very susceptible to excesses and imbalances in estrogen and serotonin.

### Source 4 — Ask the Herb Doctor: Progesterone vs Estrogen, Listener Questions (Part 2)

Ray Peat · Interview · May 18, 2018

> ## Critiquing the Swedish Study: Serotonin and Depression
>
> **Andrew Murray:** I want to go over the article by Professor Inger Sundström Poromaa regarding progesterone. She claims progesterone causes PMS and depression. She writes that estrogen increases brain serotonin, "the hormone most associated with happiness," while progesterone can have a depressing effect. Dr. Peat, what do you think about the claim that serotonin is a happiness signal?
>
> **Ray Peat:** To be polite, I think it's very, very silly. Everything there is confused and backwards. Serotonin is essential for inflammation, osteoporosis, cancer, blood clotting, and spasms. It is right there with histamine as the most intense, acute local inflammatory signal. In the brain, the inflammatory process of serotonin turns on the whole stress system that activates ACTH and cortisol. Estrogen activates that serotonin-dependent pathway and directly activates the adrenal glands to produce cortisol. Estrogen is a basic stress hormone. Serotonin is a terminal mediator of that stress process.
>
> **Andrew Murray:** She also cites research by Torbjörn Bäckström claiming progesterone metabolites (like allopregnanolone) bind to the GABA-A receptor and cause "the blues," similar to alcohol or sleeping pills.

### Source 5 — EastWest Healing Serotonin and Endotoxin

Ray Peat · Interview · Aug 24, 2011 · http://l-i-g-h-t.com/files/east-west-serotonin-and-endotoxin.mp4

> **Ray Peat:** 40 years ago someone identified increased serotonin as a demyelinating factor as well as blood vessel leakiness factor released by platelets that concentrate around the plaques in multiple sclerosis for example, and all of those are increased by high estrogen, high prolactin and tend to be corrected by progesterone and thyroid. But all of the stuff that has been known very clearly demonstrated 30, 40, 50 years ago, the drug science culture manages to get everyone to forget.

### Source 6 — Hot Flashes Night Sweats the Relationship to Stress KMUD Her

Ray Peat · Interview · 2012

> **Andrew Murray:** Pharmaceutical representatives are some of the best paid salesmen/ saleswomen. They are convincing doctors of a very unsafe practice, unfortunately. Because they’re such good sales people.
>
> **Andrew Murray:** The relationship between serotonin and body temperature regulation (or aberration in temperature), and the misconception about serotonin, or 5-HTP, or melatonin being good for you, which is completely bogus... Would you please bring the relationship between the night sweats and estrogen and serotonin?
>
> **Ray Peat:** Fifty years ago, a similar thing happened with the drug industry and government in relation to serotonin. The disease “carcinoid tumor”, an intestinal tumor that produces serotonin, was being studied just when serotonin was discovered to be both a brain and an intestinal hormone (but mostly the latter). The drug industry, with [it’s] psychoactive chemicals, wanted for various reasons (which my newsletters talked about) to create this idea that serotonin was the “hormone of bliss” (they called it). It was something to be raised to create well-being. But still, the carcinoid study was identifying it as a stress-related hormone that caused flushing. One of the basic signs of having that intestinal disease was frequent flushing, as well as psychiatric symptoms. One of the effects of serotonin is to activate the stress hormones, (the cortisol system) and to activate aromatase (the enzyme that makes estrogen). But estrogen also releases and activates the production of serotonin. And so, it can become a vicious circle: one of stress, flushing, tissue break down under the influence of cortisol, and so on.

### Source 7 — A Bioenergetic View of Bacterial Endotoxin: Poisoning From The Inside Out

Danny Roddy · Article · Jun 23, 2013

> Estrogen increases the synthesis of serotonin by activating the tryptophan hydroxylase enzyme (Hiroi, et al. 2006), which is also increased by the "essential fatty acids" (McNamara R, et al. 2008).
>
> Serotonin acts on the pituitary to release ACTH (Martin C, 1985) and increases cortisol in a dose-dependent manner (Lefebvre H, et al., 1992).
>
> Serotonin is involved in the biology of torpor and hibernation, which works in the opposite direction of thyroid hormone (or adapting to a high altitude). Hans Selye found that administering thyroid hormone to hibernating animals woke them up (Selye H, 1947). In addition, inhibiting serotonin synthesis stops hibernation altogether (Spafford and Pengelley 1971).
>
> Hibernation likely occurs due to serotonin's inhibition of mitochondrial respiration (Assouline-Cohen et al. 1998; Koren-Schwartzer N, et al. 1994). One study found that serotonin induced swelling in mitochondria (Watanabe et al. 1969) and that ATP reversed the swelling, suggesting that serotonin and ATP are acting in opposite directions.
>
> Whereas thyroid increases carbon dioxide levels, serotonin, histamine and estrogen activates carbonic anhydrase, an enzyme that breaks down carbon dioxide (Vullo D, et al., 2007; Barnett D, et al., 2008). Research suggests that those with low thyroid have higher levels of serotonin (Henley, et al., 1997, 1998; Neckers and Sze, 1976; Schwark W, et al., 1975). Carbonic anhydrase inhibitors have been researched for their various anti-cancer effects (Supuran C, et al., 2000; 2000; 2001).
>
> A Logical Diet
>
> I have empathy for those with long standing digestive problems. Similar to those with "weak adrenals" there is so much conflicting information that 'giving up' is a viable option. Additionally, "the experts" often engage in egregious fear mongering that usually results in the systematic reduction of 'healthy' foodstuffs in hopes of finding "the trigger."

### Source 8 — A Bioenergetic View of Bacterial Endotoxin: Poisoning From The Inside Out

Danny Roddy · Article · Jun 23, 2013

> Similar to those with "weak adrenals" there is so much conflicting information that 'giving up' is a viable option. Additionally, "the experts" often engage in egregious fear mongering that usually results in the systematic reduction of 'healthy' foodstuffs in hopes of finding "the trigger."
>
> Throughout the last several articles I've detailed ideas to easily (and inexpensively) influence the estrogen-serotonin-endotoxin axis, so I won't rehash them here.
>
> [references]
>
> Something for a future article is calcium's influence on estrogen, serotonin, prolactin, and endotoxin. Similar to fructose, I think calcium's somewhat negative reputation is undeserved, and when evaluated objectively may be one of the easiest therapies to support mood, libido, cognition, and digestive resilience.
>
> [references]

### Source 9 — Endotoxin, stress, depression: Serotonin, starches, fatty acids, and antidotes

Ray Peat · Article · 2011

> The interplay between the state of the intestine and the assessed state of the stressful situation determines whether the individual will withdraw (often with its incontinence of the bowel and bladder) or persist and struggle to adapt.
>
> Defensive aggression is probably a response intermediate between fearful giving up and confident achievement. When a rat is restrained, held down on its back, it quickly develops ulcers, but if it has a stick to bite, it is very resistant to the formation of the ulcers. The ability to do something with a defensive meaning prevents the excessive production of serotonin and its consequences, such as increased production of cortisol and other stress hormones, and disturbance of circulation and energy production. Endotoxin and prostaglandins activate these same systems, and progesterone and aspirin are among the protective factors that can oppose those effects.
>
> When physical and mental activity are intensified to meet an adaptive crisis, the adrenergic sympathetic nervous system optimizes muscular energy production, but inhibits the digestive system. In the state of anxious-helpless withdrawal, the parasympathetic and serotonergic systems demobilize the active neuroskeletomuscular systems, and activate the bladder, intestine and stomach, tending to empty the contents by causing diarrhea, vomiting, and urination. Serotonin reduces energy production in muscles; this is probably related to the muscular dystrophy it produced in Selye's experiments, and the myopathy produced by tryptophan (Castot et al., 1991). Antiserotonin drugs are used for controlling diarrhea and vomiting, and some of them are protective against ulcers (Ramesh et al., 2009).
>
> Chronically elevated cortisol is commonly seen in depressed people, but giving a supplement of cortisol is effective in relieving depression. Both cortisol and the pituitary corticotropic hormone that stimulates its production, ACTH, have some antidepressant effects, and they inhibit the hypothalamic corticotropin release hormone, CRH. CRH is more directly associated with depression than cortisol is, and it by itself activates many inflammatory processes, including the release of histamine, cytokines, and nitric oxide. CRH is promoted in the hypothalamus (and in many other tissues) by inflammation, endotoxin, serotonin, interleukins, and prostaglandins, but also by the perception of unavoidable difficulties.

### Source 10 — A Bioenergetic View of Osteoporosis [Generative Energy #25]

Danny Roddy · Interview · Mar 24, 2016 · https://www.youtube.com/watch?v=8wAlMUFN1g0

> **Danny Roddy:** We started with estrogen and then we talked a little bit about prolactin. And then I want to talk about serotonin too. And the known fact that serotonin reuptake inhibitors, antidepressants, increase prolactin and can lead to osteoporosis. So can you talk about how these three things could be linked in an easy, maybe an easy to understand manner, referring to estrogen, prolactin and serotonin?

### Source 11 — Thermo Diet Podcast Episode 39 - Georgi Dinkov

Georgi Dinkov · Interview · Jul 19, 2020 · https://www.youtube.com/watch?v=11N-wEMl_Ks

> **Thermo Diet:** Wow. Now, is there a relationship between serotonin and estrogen? And in the relationship, which one typically comes first?
>
> **Georgi Dinkov:** Actually, there is a bilateral relationship. Both of them stimulate each other's synthesis. Now, I mentioned progesterone being an inhibitor of the enzyme tryptophan hydroxylase, which synthesizes serotonin, right? Well, you would expect if things work, you know, logically you expect something that acts the opposite way of estrogen, which is, sorry, progesterone, which is estrogen in the body. You expect this to have an opposite effect, in other words, to activate tryptophan hydroxylase, and there are multiple studies published on the topic demonstrating that estrogen is one of the most potent endogenous inducers of the enzyme tryptophan hydroxylase. Conversely, serotonin is one of the most potent known inducers of the enzyme aromatase. So if you have more serotonin, you will be producing more estrogen. If you have more estrogen, you'll be producing even more serotonin. So it forms a positive feedback loop. And that's why many people find it so hard to break out of this vicious cycle of stress, of chronic stress, because often it's many more than one of the stress materials that is elevated. So some people will say, oh, I'm taking, let's say, an aromatase inhibitor and my estrogen is not low, but I still don't feel well. Well, because the estrogen ramped up the production of serotonin, nitric oxide. growth hormone, and a number of different mediators of stress. So it's like basically you kind of have to address all of them at the same time. In my experience, taking a serotonin antagonist actually tends to calm down the entire system because it does seem like serotonin being a more ancient hormone, a more ancient neurotransmitter, it has a higher role in the cascade of things in terms of controlling the overall health of the organism. So if you have to choose which one of the two you need to address first, I would probably go with serotonin, but they're both promoting each other's effects and synthesis.

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