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Thyrotropin-Releasing Hormone (TRH) Roles & Regulation

Written by Aleksa Ristic, MS (Pharmacy) | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Aleksa Ristic, MS (Pharmacy) | Last updated:

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Thyroid hormones

Thyrotropin-releasing hormone (TRH) is a hormone produced in the hypothalamus. It controls thyroid hormone secretion and has important roles in metabolism, cognition, mental health, and more. This post reveals lesser-known roles of TRH, along with 13 factors that increase or decrease its levels.

What is Thyrotropin-Releasing Hormone (TRH)?

Thyrotropin-releasing hormone (TRH) is a hormone produced in the hypothalamus. It stimulates the release of TSH, which then increases thyroid hormones. Thus, TRH controls [1]:

  • 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 [2].

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

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

Normal Range of TRH is 5-25 U/ml, but it may depend on the lab.

Roles of TRH in Health & Disease

1) Learning and Memory

TRH is widely found in the brains of mammals and is considered a neurotransmitter [3].

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 [4].

However, other studies have found TRH to enhance learning and reduce memory impairment [3].

In rabbits, chronically high levels of TRH improved learning and memory [3].

TRH and similar hormones are promising research agents in the treatment of brain degeneration, but the clinical evidence is lacking [1].

2) Mental Health

Depressed patients do not produce as much TSH in response to TRH and have decreased TRH gene expression in the hypothalamus. Hypothyroidism is found in many patients with major depression [5, 6].

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 [7].

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 [7].

Rats treated with TRH showed less anxiety in stressful situations [8].

3) Appetite Control

TRH may suppress appetite. Both fed and food-restricted animals ate less food when injected with TRH [9].

Generally, the presence of healthy dopamine levels can reduce eating for pleasure, which helps with weight loss. Hungry rats injected with TRH had more dopamine [10, 9].

4) Blood Sugar Control

TRH is also made in the pancreas. It inhibits amylase secretion and increases glucagon secretion from the pancreas [11].

Genetically modified mice that lack TRH have elevated blood sugar (hyperglycemia) [12].

Injection of TRH combats elevated blood sugar in hyperglycemic mice, by reducing damage and stimulating regeneration of insulin-producing cells in the pancreas [12].

5) Digestion

In the brain, TRH acts through the vagus nerve to increase stomach acid, pepsin, and serotonin, blood flow in the gut lining, and contraction [13, 14].

6) Prolactin Secretion

The secretion of TRH can also stimulate the release of prolactin, another hormone from the pituitary gland [15].

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 [16].

Once there is enough of these hormones, they signal the hypothalamus and pituitary to stop this cascade of actions and drop T3 and T4 levels.

2) Estrogen (Estradiol)

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 [17].

In menopausal mice, feeding estrogen (E2) increased TRH and thyroid hormone levels [18].

3) Cold Exposure

Cold exposure increases TRH, according to preclinical research. In rats, exposure to 4 degrees C or 39 degrees F increased TRH release by twofold in the first 15 minutes [19, 20, 21, 22].

4) Drugs

Lithium increases the TRH production and the response of TSH to TRH [23, 24].

Valproate and lithium increase levels of TRH receptors in the brain [25].

In rats, administration of ketamine (anesthetic) increases TRH levels in most regions of the brain and the body [26].

5) Other

Inhibiting Sirt1

In diet-induced obese rats, inhibiting Sirt1 increased TRH level. Read this post to learn about the factors that inhibit Sirt1.

This effect is possibly mediated through circadian rhythm, by changing POMC and a-MSH levels [27].

Electroconvulsive Therapy

Electroconvulsive therapy is a treatment for treatment-resistant depression. In rats, electroconvulsive therapy increased TRH levels, which correlated well with the reduction in depressive symptoms [28].

Genes that Control TRH Production in the Hypothalamus, Source https://www.ncbi.nlm.nih.gov/pubmed/27515033

Factors that Decrease TRH

1) High Thyroid Hormones

High Free T4 and Free T3 levels can signal the pituitary and hypothalamus to adjust TSH and TRH levels.

T4 increases the production of pyroglutamyl peptidase II, an enzyme that degrades TRH in the hypothalamus [29].

2) Stress and High Cortisol

Cortisol can inhibit the HPT axis by reducing TRH levels at the hypothalamus [30, 31].

However, in cell-based experiments, cortisol stimulated TRH production [31].

3) Inflammation

In rats, injection of LPS (a bacterial toxin) suppresses the production of TRH, TSH, and T3 levels, while increasing CRH and cortisol levels [32].

A high dose of LPS injection in rats reduced TRH levels within 2 hours [33].

Chronic inflammation in mice reduces TRH production in mice and rabbits [34, 35].

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 [36, 37, 38].

4) Orexin

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 [39].

5) Adipokine Signaling

NPY suppresses TRH production [40].

Ghrelin blocks GABA release from Agouti or NPY neurons of the hypothalamus, which decreases TRH levels [41].

6) Leptin Resistance

Leptin-resistant humans have signs of hypothalamic hypothyroidism (hypothyroidism due to how TRH) with low T4 and normal TSH [42].

A leptin analog increased FT3 and FT4 in leptin-deficient children, and reversed low T3 and T4 levels in people on a low-calorie diet [42, 43].

High leptin levels in newborn rats can lead to leptin resistance and low TRH at 30 days of age and at adulthood. In these animals, acute cold exposure at 30 days old restores normal leptin levels and leptin sensitivity in the hypothalamus. Additionally, cold exposure further increased thyroid hormones [44].

In rats, the administration of a high dose of leptin reduces TRH levels within 30 minutes by causing leptin resistance [45].

7) Fasting and Starvation

Fasting reduces leptin levels, TRH & TSH production, and liver enzymes that convert T4 to T3 [46].

However, leptin administration does not reverse changes in thyroid hormone levels in acute fasting [47].

8) Chemotherapy

Some acute lymphoblastic leukemia patients treated with chemotherapy alone may develop central hypothyroidism, which can be treated with TRH infusion [48].

About the Author

Aleksa Ristic

Aleksa Ristic

MS (Pharmacy)
Aleksa received his MS in Pharmacy from the University of Belgrade, his master thesis focusing on protein sources in plant-based diets. 
Aleksa is passionate about herbal pharmacy, nutrition, and functional medicine. He found a way to merge his two biggest passions—writing and health—and use them for noble purposes. His mission is to bridge the gap between science and everyday life, helping readers improve their health and feel better.

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