PROTIRELIN

Fetal Risk Summary

Protirelin is a synthetic tripeptide that is thought to be structurally identical to naturally occurring thyrotropin-releasing hormone (TRH). TRH stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the pituitary.

Reproduction studies in rats and rabbits at doses 6 and 1.5 times, respectively, the human dose have shown an increased number of resorptions in rabbits, but not in rats (1).

The published experience in human pregnancy for this agent is restricted to studies evaluating its role, in combination with corticosteroids, in the acceleration of fetal lung maturity. No reports describing the use in human pregnancy of only TRH, either for fetal lung maturation or for diagnostic assessment of thyroid function, have been located.

Several research studies have demonstrated that cord blood levels of liothyronine (T3) and levothyroxine (T4) are lower, and TSH levels are higher, in infants with respiratory distress syndrome (RDS) when compared with healthy matched controls without clinical evidence of lung immaturity (2,3,4 and 5). Moreover, a 1975 publication reported a higher incidence of RDS in premature infants with congenital hypothyroidism (6). In studies of animals and humans, when T3 or T4 was administered directly to the fetus, or in experiments involving fetal lung cultures, significant increases were measured in the synthesis of phosphatidylcholine, a major constituent of lung surfactant (2,7,8,9,10 and 11). Combining thyroid hormones with corticosteroids, such as dexamethasone, produced an additive effect on phosphatidylcholine synthesis that was greater than that produced by either agent alone (7,8,9,10 and 11). These data suggest that the thyroid hormones act at different receptors in the fetal lung than those stimulated by corticosteroids (6,7,8,9,10 and 11).

In contrast to T3, T4, and TSH, which either do not cross the human placenta or cross in negligible amounts, TRH is rapidly transferred across the animal and human placenta to the fetus and stimulates fetal TSH, T3, and T4 (2,12,13). Research published in 1991 indicated that the fetal pituitary is capable of responding to TRH with an increase in TSH by at least the 25th week of gestation (13). Moreover, the fetal response to TRH is much greater than the maternal response, which may be caused by lower concentrations of fetal thyroid hormone and resulting reduced negative feedback on the pituitary (13). It is these characteristics that have stimulated research on the use of TRH for fetal lung maturation.

In fetal rabbits, the maternal administration of TRH enhanced functional and morphologic fetal lung maturation (12). The first human study comparing the use of TRH and corticosteroids with corticosteroids alone was published in 1989 (5). In this study, 248 women who were at risk for delivery before 34 weeks' gestation and who had a lecithin:sphingomyelin (L:S) ratio less than 2.0 (maturity defined as an L:S ratio 2.0 or greater) were randomized into a study group (N=119) or controls (N=129). Mothers in the study group were treated with TRH (400 µg IV every 8 hours for 6 doses) plus betamethasone (12 mg IM every 24 hours for 2 doses). Control patients received the betamethasone doses only. Infants delivered from the study group within 1 week of therapy had a greater increase in L:S ratio, fewer respirator days, and a lower incidence of bronchopulmonary dysplasia, indicating that the combination of TRH with betamethasone was superior to betamethasone alone (5). Adverse effects occurred in 35% of the study group mothers, consisting of nausea, flushing, hot flashes, and palpitations, all resolving within 20 minutes (5). No adverse fetal or newborn effects were observed, a finding similar to other studies (2,12).

Breast Feeding Summary

Three nursing women, 5–6 weeks postpartum, were treated with 1–300 µg of TRH (14). Doses of 1–2 µg produced no significant change in maternal TSH or prolactin. When the doses were increased to 6–300 µg, significant increases in both TSH and prolactin were measured. Suckling alone produced a much greater effect on serum prolactin than did TRH, but had no effect on serum TSH levels.

Administration of TRH will increase maternal levels of T3 and T4, and both hormones are excreted into breast milk in low concentrations (see Liothyronine and Levothyroxine).

References

1. Product information. Thyrel TRH. Ferring Pharmaceuticals, 2000.
2. Moya FR, Gross I. Prevention of respiratory distress syndrome. Semin Perinatol 1988;12:348–58.
3. Cuestas RA, Lindall A, Engel RR. Low thyroid hormones and respiratory-distress syndrome of the newborn. Studies on cord blood. N Engl J Med 1976;295:297–302.
4. Klein AH, Foley B, Foley TP, MacDonald HM, Fisher DA. Thyroid function studies in cord blood from premature infants with and without RDS. J Pediatr 1981;98:818–20.
5. Morales WJ, O'Brien WF, Angel JL, Knuppel RA, Sawai S. Fetal lung maturation: the combined use of corticosteroids and thyrotropin-releasing hormone. Obstet Gynecol 1989;73:111–6.
6. Smith DW, Klein AM, Henderson JR, Myrianthopoulos NC. Congenital hypothyroidism–signs and symptoms in the newborn period. J Pediatr 1975;87:958–62.
7. Gross I, Wilson CM. Fetal lung in organ culture. IV. Supra-additive hormone interactions. J Appl Physiol 1982;52:1420–5.
8. Gonzales LK, Ballard PL. Glucocorticoid and thyroid hormone stimulation of phosphatidylcholine (PC) synthesis in cultured human fetal lung (abstract). Pediatr Res 1984;18:310A.
9. Gross I, Dynia DW, Wilson CM, Ingleson LD, Gewolb IH, Rooney SA. Glucocorticoid-thyroid hormone interactions in fetal rat lung. Pediatr Res 1984;18:191–6.
10. Ballard PL, Hovey ML, Gonzales LK. Thyroid hormone stimulation of phosphatidylcholine synthesis in cultured fetal rabbit lung. J Clin Invest 1984;74:898–905.
11. Warburton D, Parton L, Buckley S, Cosico L, Enns G, Saluna T. Combined effects of corticosteroid, thyroid hormones, and b-agonist on surfactant, pulmonary mechanics, and b-receptor binding in fetal lamb lung. Pediatr Res 1988;24:166–70.
12. Devaskar U, Nitta K, Szewczyk K, Sadiq HF, deMello D. Transplacental stimulation of functional and morphologic fetal rabbit lung maturation: effect of thyrotropin-releasing hormone. Am J Obstet Gynecol 1987;157:460–4.
13. Thorpe-Beeston JG, Nicolaides KH, Snijders RJM, Butler J, McGregor AM. Fetal thyroid-stimulating hormone response to maternal administration of thyrotropin-releasing hormone. Am J Obstet Gynecol 1991;164:1244–5.
14. Gautvik KM, Weintraub BD, Graeber CT, Maloof F, Zuckerman JE, Tashjian AH Jr. Serum prolactin and TSH: effects of nursing and pyroGlu-His-ProNH2 administration in postpartum women. J Clin Endocrinol Metab 1973;36:135–9.