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].
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].
