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.
What is Thyrotropin-Releasing Hormone (TRH)?
Thyrotropin-releasing hormone (TRH) was originally found in the hypothalamus of the brain .
It is found widely in the brain and is considered a neurotransmitter .
TRH controls :
- 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 .
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) Reduces Anxiety
Rats treated with TRH showed less anxiety in stressful situations, so TRH may help with anxiety .
2) Improves Learning and Memory
TRH is widely found in the brains of mammals and is considered a neurotransmitter .
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 .
However, many other studies have found TRH to enhance learning and reduce memory impairment .
In rabbits, chronically high levels of TRH delayed the process of forgetting and improved learning .
TRH improved memory in patients with Alzheimer’s, schizophrenia, and alcoholism .
TRH and similar hormones are promising in the treatment of depression and brain degeneration diseases .
3) Is an Antidepressant
Generally, TRH is an antidepressant .
Depressed patients do not produce as much TSH in response to TRH; the response can be increased by an anti-depressant .
Hypothyroidism (not enough TRH response) is found in people with major depression .
Depressed patients have decreased TRH gene expression in the hypothalamus of the brain .
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 .
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 .
4) May Be Linked to Weight Loss
TRH suppresses appetite .
Hungry rats injected with TRH ate less food .
Hungry rats injected with TRH had more dopamine .
Fasting and food restriction decreased TRH, which stimulated appetite .
TRH injections reduce food and water intake in both fed and food-restricted animals .
Animal studies show that TRH stimulates the production of dopamine .
5) Increases Arousal
An injection of TRH effects arousal and feeding centers of the brain, causing wakefulness and loss of appetite by activating orexin neurons [R, 12].
6) 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 .
Genetically modified mice that lack TRH have elevated blood sugar (hyperglycemia) .
Injection of TRH combats elevated blood sugar in hyperglycemic mice, by reducing damage and stimulating regeneration of insulin-producing cells in the pancreas .
7) Stimulates Healthy Stomach Secretions
8) 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) Can Induce Stomach Ulcer
2) 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 . However, this only happens with TRH administration at very high doses under medical supervision.
Factors that Increase TRH
1) Low Thyroid Hormones
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)
3) Cold Exposure
In rats, exposure to 4 degrees C or 39 degrees F increased TRH release by twofold in the first 15 minutes.
Therefore, you want to expose yourself to acute cold by going outside in the winter or taking cold showers.
TSH is released by TRH, so when TSH is increased, it’s an indicator that TRH is also increased.
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).
8) Lithium and Valproate
It increases TSH response to TRH 
Valproate and lithium increase levels of TRH receptors in the brain .
Inhibiting Sirt1 Increases TRH
In diet-induced obese rats, inhibiting Sirt1 increases TRH level. Read this post to learn about how to inhibit Sirt1.
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 .
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 .
Factors that Decrease TRH
1) High Thyroid Hormones
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 .
2) Stress and High Cortisol
However, in cell-based studies, cortisol can stimulate TRH production .
In rats, injection of LPS (a bacterial toxin) suppresses the 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 .
High dose of LPS injection in rats reduced TRH levels within 2 hours .
5) Adipokine Signaling
Ghrelin may inhibit HPT axis activity by increasing Agouti or NPY.
6) Leptin Resistance
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. Additionally, cold exposure further increased thyroid hormones .
In rats, administration of a high dose of leptin reduces TRH levels within 30 minutes by causing leptin resistance .
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
Some acute lymphoblastic leukemia patients treated with chemotherapy alone may develop central hypothyroidism, which could be treated by TRH infusion .
- Tissues that control the TRH release or HPT axis .
- 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 .
- 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, PKC, 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 .
- 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 .
- pCREB and cortisol binding to Trh promoter inhibit TRH transcription .
Irregular Thyroid Hormone Levels?
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