General Description

Clinical studies suggest that thyrotropin-releasing hormone (TRH) holds promise in treating various epileptic syndromes, particularly intractable forms like West syndrome and Lennox-Gastaut syndrome. Though lacking placebo-controlled trials, TRH add-on studies and case reports show significant seizure reduction, with some achieving complete seizure control. Thyrotropin-releasing hormone exhibits a favorable safety profile, with infrequent and mild adverse effects. Long-term studies show no thyroid axis disturbances. Despite challenges in administration and metabolism, Thyrotropin-releasing hormone's safety and efficacy warrant further investigation as an adjunctive therapy for severe epilepsy. Additional controlled trials are needed to determine optimal dosages and treatment approaches.

Figure 1. Thyrotropin-releasing hormone

Clinical Studies

Clinical studies on thyrotropin-releasing hormone have shown promising results in the treatment of various types of epilepsy, particularly intractable epilepsies like West syndrome, Lennox-Gastaut syndrome, and other refractory epileptic syndromes. While there haven't been any placebo-controlled, double-blind trials on TRH for epilepsy, numerous add-on studies and case reports have provided valuable insights into its potential antiepileptic role. In these studies, patients treated with TRH were closely monitored using video-electroencephalogram (EEG) to accurately classify seizures and assess treatment efficacy. Results indicated that TRH treatment led to complete seizure control in a significant proportion of patients, with some achieving seizure freedom. Moreover, TRH-tartrate showed fewer side effects compared to other medications like Cortrosyn-z. For instance, one study demonstrated that over half of the patients with infantile spasms became seizure-free after Thyrotropin-releasing hormone treatment. Another study on West syndrome patients found that a portion of them became seizure-free, while others experienced a reduction in seizure frequency. Interestingly, TRH seemed less effective in patients previously treated with adrenocorticotropic hormone. Furthermore, dose-response studies revealed that there was no clear difference in efficacy between low and high doses of Thyrotropin-releasing hormone. However, a notable percentage of patients across both dose groups showed marked to moderate improvement in seizure frequency. Overall, these clinical studies suggest that Thyrotropin-releasing hormone may be beneficial in treating infantile spasms and Lennox-Gastaut syndrome, particularly for atypical absence seizures. While there's limited data on its effectiveness for partial seizures, further controlled studies with varying dosages and treatment approaches in larger patient populations are needed to determine the specific seizure syndromes most responsive to TRH therapy. ¹

Safety

Thyrotropin-releasing hormone and its analogs have exhibited a favorable safety profile in various clinical studies across different patient populations. These studies have utilized diverse administration routes, including intrathecal, intravenous (IV), intramuscular, subcutaneous, or parenteral methods, for conditions such as amyotrophic lateral sclerosis, senile dementia, premature labor risk, and intractable epilepsy. Adverse effects associated with Thyrotropin-releasing hormone administration have been infrequent and transient, typically including mild symptoms such as urinary retention, irritability, sleepiness, mild hypertension, tachycardia, appetite loss, nausea and vomiting, sweating, shivering, and sensations of cold and warmth. Notably, long-term follow-up studies on prenatal Thyrotropin-releasing hormone exposure in children showed normal thyroid function in all cases, indicating no adverse effects on the hypothalamo-pituitary-thyroid axis. In a recent dementia trial, only a small proportion (2.8%) of TRH-treated patients discontinued treatment due to adverse effects, which was not significantly different from the placebo group. Furthermore, there have been no reports of morbidity or mortality directly linked to TRH use, highlighting its overall safety profile. Although the optimal route of administration for Thyrotropin-releasing hormone remains uncertain due to its poor blood-brain barrier penetration and rapid metabolism in various tissues, including the central nervous system, efforts have been made to develop metabolically stable analogs with improved transport across the blood-brain barrier and enhanced bioavailability in the central nervous system. Despite these challenges, the accumulating evidence supports the continued investigation of TRH as a potential adjunctive treatment for severe medically refractory epilepsy. In conclusion, the available data suggest that Thyrotropin-releasing hormone and its analogs are generally safe when used across a wide age range, from prenatal exposure to elderly patients. Further research is warranted to optimize administration methods and explore the full therapeutic potential of TRH in epilepsy and other neurological disorders. ²

Reference

1. Kubek MJ, Garg BP. Thyrotropin-releasing hormone in the treatment of intractable epilepsy. Pediatr Neurol. 2002;26(1):9-17.

2. Takeuchi Y. TRH (Protirelin): Role in the treatment of epilepsy. CNS Drugs. 1996; 6: 341-350.