Overview
TRH (Thyrotropin-Releasing Hormone), also known by names such as protirelin and thyroliberin, is a naturally occurring tripeptide hormone originally identified in the hypothalamus, where it plays a central role in regulating the thyroid axis by signaling the pituitary gland to release thyroid-stimulating hormone. It belongs to the category of hypothalamic releasing hormones and is one of the smallest known hormones in the human body. Beyond its classical role in thyroid regulation, research has explored TRH's presence and activity in extrahypothalamic brain regions, where it is studied in relation to appetite regulation, mood-related pathways, and neurological signaling. The synthetic form of TRH shares the same molecular structure as its naturally occurring counterpart and is used in laboratory research settings to investigate these diverse biological mechanisms. All research involving TRH is conducted for scientific study purposes only and is not intended for human use or consumption.
Research & Bioactivity
Researchers have studied TRH (Thyrotropin-Releasing Hormone), a tripeptide neuropeptide with the molecular formula C16H22N6O4, primarily in relation to its classical role in regulating the hypothalamic-pituitary-thyroid axis, where it stimulates the release of thyroid-stimulating hormone from the pituitary gland. Beyond this endocrine function, research has investigated TRH's activity in extrahypothalamic brain regions, with animal model studies examining its involvement in feeding behavior, including observations of reduced food intake in fasted rats following TRH administration into specific brain nuclei such as the nucleus accumbens. Studies have also examined distinct populations of TRH-expressing neurons in hypothalamic regions including the paraventricular nucleus, dorsomedial hypothalamus, and medial preoptic area, with findings suggesting roles in energy expenditure regulation. In vitro and in vivo research has further explored TRH's potential connections to anxiolytic and antiepileptic effects, as well as its relationship to serotonergic neuron activity in the context of mood-related neurological research. Additionally, researchers have studied the broader implications of disrupted TRH signaling pathways in conditions involving thyroid hormone resistance, contributing to an evolving understanding of how this neuropeptide participates in complex endocrine and neurological systems.
Published Research
Effects of SSRIs on the spatial transcriptome of dorsal raphe serotonin neurons.
Henningson C, Mlost J, Pollak Dorocic I — 2026
The serotonin system is the main therapeutic target for selective serotonin reuptake inhibitors (SSRIs) in treating depression, yet the mechanism of action of SSRIs remains incompletely understood. To investigate the molecular and transcriptional effects of SSRI administration on serotonin neurons, we performed spatial transcriptomics, a spatially resolved RNA-sequencing method in intact brain tissue. Mouse brain sections containing the dorsal raphe nucleus and adjacent midbrain structures were analyzed, revealing six distinct serotonergic subpopulations with unique molecular signatures and spatial distributions. Both acute and chronic fluoxetine treatment induced a large number of changes in gene expression in the dorsal raphe nucleus. Notably, Htr1a expression increased following acute treatment but decreased after chronic administration, supporting previous findings on serotonin transporter blockade effects on 5-HT1A autoreceptors. Gene enrichment and network analysis identified key pathways modulated by SSRI administration, including Ras, MAPK and cAMP signaling pathways as well as pathways involved in axonal guidance. Additionally, we observed treatment-dependent opposing transcriptional changes in neuropeptides, particularly Thyrotropin-releasing hormone (Trh) and Prodynorphin (Pdyn), with distinct spatial localization within the dorsal raphe nucleus. Collectively, our transcriptomic and in situ hybridization analyses reveal spatial and cell-type-specific heterogeneity in SSRI action within the dorsal raphe nucleus, providing new insights into the molecular basis of SSRI treatment effects.
Type-1 thyrotropin-releasing hormone receptor in the nucleus accumbens participates in the anorectic effect of the stimulation of central nucleus of the amygdala.
Hernández-Bustamante I, Soberanes-Chávez P, Simón-Arceo K, Magdaleno-Madrigal VM, Espitia-Bautista E, et al. — 2026
Thyrotropin-releasing hormone (TRH) is a hypothalamic neuropeptide that directs the thyroid axis function. Beyond this classical role, TRH is also synthesized in extrahypothalamic brain regions, where it is implicated with anorectic, anxiolytic and antiepileptic effects. Its anorectic role is supported by the reduced food intake of fasted rats when refed, after TRH is injected into their nucleus accumbens (NAc). The central nucleus of the amygdala (CeA) contains TRHergic cells, and its electrical stimulation (ES) induces a hypophagic effect on rats and transsynaptic changes in TRH content in the NAc and other brain regions. Since the G-protein-coupled type-1-TRH receptor is expressed in the NAc, we evaluated its participation in ES-amygdala-induced feeding regulation by using the electrical amygdaloid kindling model and by injecting antisense oligonucleotides (ASO) against type-1 TRH receptor (TRH-R1) in the NAc of rats. Male Wistar rats with an implanted electrode in CeA received daily ES (1 s, 60 Hz, 1 ms pulses) for seven days; then, fasted 48-h and on day 10, receiving a last ES, and refed for 2 h. Amygdala TRH mRNA expression was analyzed by in situ hybridization, while accumbal pro-TRH content by Western blot and immunohistochemistry. Amygdalar stimulation increased TRH mRNA in CeA, cortical amygdala and medial amygdalar nucleus; pro-TRH content increased in shell of NAc. Importantly, intra-NAc shell administration of ASO targeting TRH-R1, reversed the reduced food intake induced by CeA stimulation. These findings support the functional role of TRH-R1 in the NAc for the CeA electrical stimulation-induced hypophagia observed in re-fed fasted rats.
Thyroid hormone resistance beta and autoimmune thyroid disease - a family case study highlighting diagnostic and therapeutic challenges.
Đukić M, Kovačević Z, Tomšić KZ, Muzurović E — 2026
BACKGROUND: Resistance to thyroid hormone (RTH) is a rare endocrine disorder, most commonly caused by mutations in the thyroid hormone receptor β (TRβ) gene, resulting in the RTH beta (RTHβ) subtype. In contrast, autoimmune thyroid disease (AITD) is common. The coexistence of RTHβ with AITD has not been fully clarified. Here, we describe a family in which RTHβ coexists with AITD, highlighting the complex interplay between these disorders. CASE PRESENTATION: A 45-year-old woman, previously for years treated for hyperthyroidism, presented after a decade-long gap in follow-up, reporting palpitations and fatigue. Laboratory evaluation revealed elevated free thyroxine (fT4 34 pmol/L) and free triiodothyronine (fT3 11.8 pmol/L) with inappropriately normal thyroid-stimulating hormone (TSH 1.87 µIU/mL). Thyroid antibodies, anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) were positive, while TSH receptor antibodies (TRAb) was negative. Thyroid ultrasound demonstrated a mildly enlarged gland with clinically insignificant nodules, and Tc-99 m scintigraphy showed normally functioning tissue. Pituitary MRI was normal. The thyrotropin-releasing hormone (TRH) stimulation test demonstrated an exaggerated TSH response, consistent with RTHβ. Genetic testing confirmed a heterozygous pathogenic thyroid hormone receptor β THRB variant. Further evaluation of the patient’s family and genetic testing confirmed RTHβ in her daughter and sister, both of whom also had coexisting AITD. CONCLUSIONS: The clinical phenotype of RTHβ is highly variable, ranging from asymptomatic individuals to features of hypo- or hyperthyroidism. Variable tissue responsiveness underlies the overlapping features of thyroid hormone excess and deficiency seen in RTHβ. Coexisting primary hypothyroidism due to AITD can further complicate the clinical course, creating diagnostic and therapeutic challenges. This overlap presents unique challenges in diagnosis and management, often leading to diagnostic uncertainty and therapeutic difficulties. Management should be patient-centred, emphasising individual assessment, multidisciplinary collaboration, and long-term follow-up to optimise outcomes and quality of life.
Thyrotropin-releasing hormone neurons of different hypothalamic nuclei increase energy expenditure.
Constantinescu A, Chandrasekar A, Kleindienst L, Höhne L, Da Silva Lima N, et al. — 2026
Several neuronal populations in the hypothalamus and brainstem express thyrotropin-releasing hormone (TRH). While TRH neurons in the paraventricular nucleus (PVN) regulate the thyroid axis, the roles of other TRH-producing neurons remain largely unknown. Here we investigate the role of TRH neurons in the PVN, the dorsomedial hypothalamus (DMH), the medial preoptic area (MPA), and the rostral raphe pallidus (RPa) for metabolism in mice. Selective activation of these populations using chemogenetics in mice revealed that TRH neurons of the hypothalamus increase food intake and influence energy homeostasis in different ways. Specifically, TRH neurons in the PVN and DMH enhance brown adipose tissue activity via a polysynaptic circuit, while MPA-located neurons increase locomotor activity and maintain cold tolerance. These effects were independent of the thyroid axis, demonstrating that TRH neurons have distinct, subtype-specific ways to increase energy expenditure beyond regulating the thyroid axis in mice.
Impact of pituitary pars intermedia dysfunction on inflammation within the equine reproductive tract of the mare.
Howard J, Hamner I, Crook RA, Elliott C, Carnevale E, et al. — 2026
INTRODUCTION: Pituitary pars intermedia dysfunction (PPID) is an age-related endocrinopathy associated with elevated systemic inflammation, and specifically an upregulation of interleukin-8 (IL-8). It is unknown if PPID in concomitant with reproductive tract inflammation. This is a pertinent question, as chronic inflammation of the endometrium and ovary would impede fertility. Therefore, the objective of this study was to evaluate the impact of PPID on the reproductive tract of the mare. METHODS: PPID was diagnosed via thyrotropin releasing-hormone (TRH) stimulation test, where PPID was diagnosed as ACTH>120 pg/mL post-stimulation, and controls were diagnosed as ACTH<60 pg/mL. In the first study, seven PPID mares and four age-matched control mares had endometrial biopsies taken when in diestrus. In the second study, seven PPID mares and ten age-matched control mares had follicular fluid aspirated from preovulatory follicles using transvaginal aspirations. Analysis included qPCR analysis of select targets associated with endometrial inflammation in addition to immunochemistry for leukocytes. Finally, immunoassay was used to assess the production of systemic and follicular fluid cytokines. Statistics were performed using SAS 9.4®. The impact of PPID on the expression of transcripts, production of cytokines, and number of leukocytes was evaluated using an unequal variances t-test. The correlation between ACTH and number of leukocytes was assessed using a Pearson's correlation test. Significance was set to < 0.05, with trends noted at < 0.1. RESULTS: Only endometrial IL-8 was found to increase in expression in the PPID population ( = 0.02). There was a positive correlation between ACTH and the endometrial expression of IL-8 ( < 0.001; R = 0.80). A weak correlation was also noted between ACTH and expression of ( = 0.04; R = 0.41) and ( < 0.01; R = 0.63). PPID mares had more endometrial leukocytes than control animals ( = 0.03), which was also positively correlated with ACTH ( = 0.03; R = 0.47). An increase in IL-8 was also noted in the follicular fluid ( < 0.01) of PPID mares. DISCUSSION: The systemic inflammation previously reported in the PPID animal was also observed within the reproductive tract of the mare, and this was found as both expression and production of pro-inflammatory cytokines in addition to presence of leukocytes. Furthermore, this inflammation was noted within the uterus in addition to the preovulatory follicle. Future research is warranted to determine if this increase in inflammation of the reproductive tract is detrimental to the fertility of PPID mares.