TRH (Protirelin)

What TRH is and how it works

TRH is produced in the hypothalamus and reaches the anterior pituitary via the portal vessels. There it triggers the release of thyrotropin (TSH), which in turn stimulates the thyroid; in healthy people, prolactin rises at the same time. After an injection into a vein, TRH peaks within 2 to 5 minutes, TSH after 20 to 30 minutes. The tripeptide is rapidly broken down in blood and tissue; its serum half-life is about 3 to 6.5 minutes.

In addition, effects on drive and mood are attributed to TRH. However, it passes poorly from the blood into the brain, which is why one research group gave it to people with depression directly into the spinal canal. How the mood effect comes about has not been clarified.

What the studies show

Cochrane review on lung maturation, 2013

15 trials with more than 4,600 women tested TRH in addition to corticosteroids before threatened preterm birth. TRH reduced neither mortality up to discharge (RR 1.05) nor respiratory distress syndrome (RR 1.05) or chronic lung disease (RR 1.01). The infants needed respiratory support more often (RR 1.16) and more often had a low Apgar score at 5 minutes (RR 1.48). The mothers suffered more often from nausea, vomiting, light-headedness, urge to urinate and facial flushing.

ACTOBAT, Lancet 1995, and the North American trial, NEJM 1998

In the Australian trial with 1,234 women, respiratory distress syndrome even occurred slightly more often under TRH (relative risk 1.17), as did the need for ventilation (1.15). In the North American trial with 996 women, respiratory distress syndrome (66 versus 65 percent), death after 28 days (11 percent each) and chronic lung disease were on a par.

Depression: TRH into the spinal canal, 1997

Eight medication-free patients with treatment-resistant depression received, double-blind, TRH once and a sham puncture once, one week apart. Five of eight responded, defined as a halving of the depression score, and suicidality fell markedly.

Bipolar depression: nocturnal infusion, 2005

20 patients with bipolar depression received TRH or saline into a vein at midnight. Within 24 hours, 60 percent under TRH and 10 percent under saline halved their depression score; on average it fell by 52 versus 12 percent. Observation lasted 48 hours; mania scores rose slightly.

Tolerance with repeated administration, 1997

In two patients with bipolar depression, TRH worked both intravenously and in the spinal canal. With repeated intravenous administration the effect waned; via the spinal canal both responded again. These are individual observations.

Fatigue in cancer, 2012, and ALS, 1986

In a pilot crossover study with 8 cancer patients, energy and fatigue scores improved after TRH. In ALS, neither single infusions nor daily injections over 3 months showed a benefit in 25 patients.

Where the data stop

• Mood and drive in healthy people. All mood data come from patients with depression or cancer, from studies with 2 to 20 participants and observation over hours to days. There are no data for healthy people.
• Lasting effect. The effects were short-lived, and a waning effect with repeated intravenous administration has been described. In the depression studies analyzed here, TRH was given only once or a few times.
• Other routes of administration. The positive mood findings concern infusions and administration into the spinal canal under clinical conditions; they cannot be transferred to other routes of administration.
• ALS. Neither single infusions nor daily injections over 3 months brought a measurable benefit.

Status, approval and legal

In Germany, TRH Ferring 0.2 mg/ml solution for injection is approved (approval September 1, 1998, renewed August 4, 2015) and prescription-only. The sole indication is the TRH test in thyroid and pituitary diagnostics; for this, the summary of product characteristics specifies for adults as a rule a single dose of 200 µg into a vein, with a repetition no earlier than after 14 days. Use against depression, fatigue or as a stimulant is off-label and not supported by evidence. Protirelin is not listed by name on the WADA list 2026; the catch-all class S0 does not apply because it is approved as a medicine.

Safety

Even a single intravenous dose triggers typical complaints for 1 to 3 minutes: a feeling of heat, nausea, urge to urinate, mild headache, light-headedness, flushing and abnormal sensations in the abdominal and pelvic area. Occasionally blood pressure and pulse rise; rarely, TRH triggers seizures in people predisposed to them and asthma attacks in people with asthma. In large pituitary tumors, tumor enlargement and bleeding have been described in temporal association. Contraindications include acute myocardial infarction, unstable angina pectoris, increased seizure susceptibility and pronounced bronchial obstruction. In the pregnancy trials, the infants more often had low Apgar scores and more often needed respiratory support. For repeated or continuous use in healthy people there are no data.

Sources

• Summary of product characteristics (Fachinformation) TRH Ferring 0.2 mg/ml solution for injection (as of 08/2015) – indication, dosage, side effects
• Crowther CA et al., Cochrane 2013 – TRH in addition to corticosteroids before preterm birth, 15 trials
• ACTOBAT Study Group, Lancet 1995 – TRH before preterm birth, 1,234 women
• Ballard RA et al., N Engl J Med 1998 – TRH before preterm birth, 996 women
• Marangell LB et al., Arch Gen Psychiatry 1997 – intrathecal TRH in treatment-resistant depression
• Szuba MP et al., J Clin Psychopharmacol 2005 – nocturnal TRH infusion in bipolar depression
• Callahan AM et al., Biol Psychiatry 1997 – intravenous and intrathecal TRH, tolerance
• Kamath J et al., Support Care Cancer 2012 – TRH in cancer-related fatigue
• Mitsumoto H et al., Neurology 1986 – TRH in ALS
• NADA, WADA Prohibited List 2026 (informational German translation)