Thyrotropin-releasing hormone (TRH), the Master Regulator of the Thyroid Axis (HPT), and 15 Factors that Increase or Decrease TRH Levels

Thyrotropin-releasing hormone (TRH) is a hormone produced in the hypothalamus. It controls thyroid hormone production and also has several other important roles in the body. Read this post to learn more about the roles of TRH, as well as 15 factors that increase and decrease TRH levels.

Introduction: Thyrotropin-Releasing Hormone (TRH)

Thyrotropin-releasing hormone (TRH) was originally found in the hypothalamus of the brain (R).

It is found widely in the brain and is considered a neurotransmitter (R).

TRH controls (R):

  • energy balance (homeostasis)
  • eating patterns
  • thermogenesis (heat production)
  • autonomic regulation (the unconscious control of vital bodily functions)


The hypothalamus, pituitary, and the thyroid gland (also called the hypothalamic-pituitary-thyroid or HPT axis) controls T4 levels (R).

These three glands release the following hormones: TRH (Hypothalamus) -> TSH (Pituitary) -> T4 (Thyroid) (R).

If there is too little of the thyroid hormones in the bloodstream, the hypothalamus will signal the pituitary gland (via TRH) to produce TSH for the thyroid to release more T4.

Hypothyroidism that is caused by low TRH is called hypothalamic hypothyroidism, or central hypothyroidism.

Reference Range of TRH

Normal Range of TRH is 5 – 25 U/ml.

TRH: The Good

1) TRH Reduces Anxiety

Rats treated with TRH showed less anxiety in stressful situations, so TRH may help with anxiety (R).

2) TRH Improves Learning and Memory


TRH is widely found in the brains of mammals and is considered a neurotransmitter (R)

Whether TRH has a positive or neutral effect on cognitive function is still debated.

A rat model of Alzheimer’s showed no beneficial effects of TRH in learning and memory (R).

However, many other studies have found TRH to enhance learning and reduce memory impairment (R).

In rabbits, chronically high levels of TRH delayed the process of forgetting and improved learning (R).

TRH improved memory in patients with Alzheimer’s, schizophrenia, and alcoholism (R).

TRH and similar hormones are promising in the treatment of depression and brain degeneration diseases (R).

3) TRH is an Antidepressant

Generally, TRH is an antidepressant (R).

Depressed patients do not produce as much TSH in response to TRH; the response can be increased by an anti-depressant (R).

Hypothyroidism (not enough TRH response) is found in people with major depression (R).

Depressed patients have decreased TRH gene expression in the hypothalamus of the brain (R).

In mice, TRH functions by activating two receptors – TRH-R1 and TRH-R2, the latter of which is not found in humans. Activation of these receptors initiates a number of effects in the brain. Mice lacking TRH receptor type 1 (TRH-R1) are more depressed and anxious. These mice exhibited hypothyroidism. (R).

Mice lacking TRH receptor type 2 (TRH-R2) have no thyroid abnormalities, with regular development and growth. However, female mice were slightly more depressed but less anxious than male mice (R)

4) TRH May Be Linked to Weight Loss

TRH suppresses appetite (R).

Hungry rats injected with TRH ate less food (R).

Generally, the presence of a healthy dopamine can reduce eating for pleasure, which helps with weight loss (R).

Hungry rats injected with TRH had more dopamine (R).

Fasting and food restriction decreased TRH, which stimulated appetite (R).

TRH injections reduce food and water intake in both fed and food-restricted animals (R).

Animal studies show that TRH stimulates the production of dopamine (R).

5) TRH Increases Arousal

An injection of TRH effects arousal and feeding centers of the brain, causing wakefulness and loss of appetite by activating orexin neurons (RR2).

6) TRH May Help with High Blood Sugar and Diabetes

TRH is also made in the pancreas. It inhibits amylase secretion and increases glucagon secretion from the pancreas (R).

Genetically modified mice that lack TRH have elevated blood sugar (hyperglycemia) (R).

Injection of TRH combats elevated blood sugar in hyperglycemic mice, by reducing damage and stimulating regeneration of insulin-producing cells in the pancreas (R).

7) TRH Stimulates Healthy Stomach Secretions


In the brain, TRH acts through the vagus nerve to increase stomach acid, pepsin, and serotonin, blood flow in the gut lining, and contraction (R, R2).

8) TRH Stimulates Prolactin Secretion

Secretion of TRH can also stimulate the release of prolactin, another hormone from the pituitary gland (R).

Potential Side Effects of TRH

1) TRH Can Induce Stomach Ulcer

Administration of TRH through the vagus nerves can induce stomach ulcer and erosion of the stomach lining (R, R2).

2) Administration of TRH May Cause Bleeding Tumors in the Pituitary

A rare side effect of TRH injection during pituitary function tests is apoplexy (loss of consciousness) because large doses of TRH injection can cause hemorrhagic pituitary adenoma (bleeding tumors in the pituitary). The adenoma can cause abnormal pituitary functions and vision changes (R). However, this only happens with TRH administration at very high doses under medical supervision.

Factors that Increase TRH

1) Low Thyroid Hormones Increase TRH

If there is too little of the thyroid hormones in the bloodstream, the hypothalamus will signal the pituitary gland (via TRH) to produce TSH for the thyroid to release more T3 and T4.

Once there is enough of these hormones, the hypothalamus will be signaled to stop the release of TRH and the cascade of actions to increase T3 and T4.

High free T4 and free T3 levels can signal the pituitary to adjust TSH and TRH levels (R), so, conversely, low free T4 and free T3 levels can increase TRH levels.

2) Estrogen (Estradiol) Increases TRH

E2 decreases the effects of ghrelin on the hypothalamus, which also reduces the activity of agouti and neuropeptide Y. This increases levels of TRH in rats (R).

In menopausal mice, feeding estrogen (E2) increases TRH and thyroid hormone levels (R).

3) Cold Exposure Increases TRH


Cold exposure increases TRH (RR2R3,R4R5).

4) Sauna Increases TRH

TSH is released by TRH, so when TSH is increased, it’s an indicator that TRH is also increased.

A 30-minute stay in sauna in people with a healthy thyroid resulted in an increase in plasma TSH (R).

5) Exercise Increases TRH

Mild exercise increases TSH, T4, T3 and Free T3 (R).

Exercise performed at the anaerobic threshold (70% of maximum heart rate) caused the most prominent increase in the amount of any hormone values (R).

TSH continued to rise in a dose dependent manner (R).

6) Forskolin

Forskolin can increase TSH, T3, and T4 (R).


LLLT is also incredible at stimulating the thyroid and reducing local inflammation.  Indeed, clinical trials have shown benefit for autoimmune thyroiditis (R).

8) Lithium and Valproate Increase TRH Levels and TRH Receptors

Lithium Increases TRH production (R).

Lithium increases TSH response to TRH (R)

Valproate and lithium increases levels of TRH receptors in the brain (R).


Inhibiting Sirt1 Increases TRH

In diet-induced obese rats, inhibiting Sirt1 increases TRH level. Read this post to learn about how to inhibit Sirt1.

This effect is through circadian rhythm, by changing POMC and a-MSH levels, (R).

Ketamine Increases TRH Levels

In rats, administration of ketamine (an antidepressant and anesthesia) increases TRH levels in most regions of the brain and the body (R).

Electroconvulsive Therapy Increases TRH Levels

Electroconvulsive therapy is a treatment for treatment-resistant depression. In rats, electroconvulsive therapy increases TRH levels, which correlates well with the reduction in depressive symptoms (R).

Factors that Decrease TRH

1) High Thyroid Hormones Decrease TRH

High Free T4 and Free T3 levels can signal the pituitary to adjust TSH and TRH levels (R).

T4 increases production of pyroglutamyl peptidase II, an enzyme that degrades TRH in the hypothalamus (R).

2) Stress and High Cortisol Can Reduce TRH Levels

Cortisol can inhibit the HPT axis by reducing TRH levels at the hypothalamus (R, R2).

However, in cell-based studies, cortisol can stimulate TRH production (R).

3) Inflammation Reduces TRH Levels


In rats, injection of LPS (a bacterial toxin) suppresses production of TRH, TSH, and T3 levels, while increasing CRH and cortisol levels. However, blocking the CRH and cortisol increase does not prevent the reduction in TRH and TSH levels due to LPS-induced inflammation (R).

High dose of LPS injection in rats reduced TRH levels within 2 hours (R).

Chronic inflammation in mice reduces TRH production in mice and rabbits (R, R2).

Injection of IL-1, TNF, and IFN-gamma either in the blood or the brain results in a fall of plasma TSH levels in rats. This may be because TNF reduces TRH production in rat hypothalamus (R, R2, R3).

However, IL-6 stimulated TRH release from rat hypothalamus in one cell-based study, but had no effects in another (R, R2).

4) Orexin Reduces TRH Levels

Injection of orexin-A in rats inhibits TRH release from the hypothalamus, leading to a reduction in TSH levels but no change in thyroid hormone levels (R).

5) Adipokine Signaling Suppresses TRH Production

NPY suppresses TRH production (R).

Ghrelin may inhibit HPT axis activity by increasing Agouti or NPY.

Ghrelin blocks GABA release from Agouti or NPY neurons of the hypothalamus, which decreases TRH levels (R).

6) Leptin Resistance Reduces TRH

Leptin-resistant humans have signs of hypothalamic hypothyroidism (hypothyroidism due to starvation) with low T4 and normal TSH (R).

A leptin analog increase FT3 and FT4 in leptin-deficient children, and reverse decreased T3 and T4 levels in people with low-calorie diet (R, R2).

High leptin levels in newborn rats can lead to persistently elevated leptin levels, leptin resistance, and hypothyroidism in their hypothalamus at 30 days of age and at adulthood. In these animals, acute cold at 30 days old restore normal leptin levels and leptin sensitivity in the hypothalamus. In addition, cold exposure further increased thyroid hormones (R).

In rats, administration of high dose of leptin reduces TRH levels within 30 minutes by causing leptin resistance (R).

This is because leptin (and cold exposure) stimulates TRH levels, so leptin resistance reduces TRH levels, and restoring leptin sensitivity increases thyroid hormones.

7) Fasting and Starvation Reduce TRH

Fasting reduces leptin and therefore reduces HPT activity by reducing TRH, TSH production, T3, T4, and liver enzymes that convert T4 to T3 (R).

However, leptin administration does not reverse changes in thyroid hormone levels in acute fasting (R).

8) Chemotherapy May Reduce TRH

Some acute lymphoblastic leukemia patients treated with chemotherapy alone may develop central hypothyroidism, which could be treated by TRH infusion (R).



  • Tissues that control the TRH release or HPT axis, Source:
  • TRH is created by the paraventricular nucleus, a nerve cell cluster in the hypothalamus (R).
  • Thyrotropin-releasing hormone (TRH) is a 3-amino acid peptide synthesized in the hypothalamus. TRH binds to the receptors in the pituitary cells, causing them to release the thyroid stimulating hormone (TSH), which then stimulates T4 production (R).
  • The hormone is released into the blood surrounding the pituitary gland (R).
  • TRH lasts for only two minutes and travels less than one inch before it’s broken down (R).
  • Pyroglutamyl peptidase II is the enzyme that deactivates TRH in the tanycytes of the hypothalamus. In the serum, this enzyme is called thyroliberinase (R).
  • In rats, administration of TRH in the pancreas induced various types of gene expressions, such as G-protein coupled receptors (GPCR) and signal transduction related genes (GPCR kinase 4, transducin beta subunit 5, arrestin beta1, MAPK3, MAPK5, c-Src kinase, PKCs, PI3 kinase), growth factors (PDGF-B, IGF-2, IL-18, IGF-1, IL-2, IL-6, endothelin-1) and apoptotic factors (Bcl2, BAD, Bax).
  • Thyroid hormone receptor regulates transcription of Trh mRHA (R).
  • Factors that activate TRH expression include Leptin (through the Ob-Rb receptor and phosphorylation of Stat3), a-MSH, noradrenaline, PKA, BDNF, ERK phosphorylation of CREB (R).
  • pCREB and cortisol binding to Trh promoter inhibits TRH transcription (R).
Genes that Control TRH Production in the Hypothalamus, Source
Genes that Control TRH Production in the Hypothalamus, Source

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