Review Article
Thyrotropin-Releasing Hormone: A Powerful Tripeptide With Diverse Effects in Horses

https://doi.org/10.1016/j.jevs.2017.08.020Get rights and content

Highlights

  • Thyrotropin-releasing hormone was the first trophic “factor” from the hypothalamus to be isolated and identified chemically.

  • Thyrotropin-releasing hormone is a known regulator of thyroid-stimulating hormone production and secretion in the adenohypophysis with the structure (pyro)Glu-His-Pro-NH2.

  • Thyrotropin-releasing hormone also has stimulatory effects on secretion of prolactin, adrenocorticotropin, and melanocyte-stimulating hormone from the adenohypophysis.

  • Thyrotropin-releasing hormone in some way inhibits the normal growth hormone (GH) response to various GH secretagogues but does not have any effect on secretion of luteinizing hormone or follicle-stimulating hormone.

  • This diversity of effects has been extensively applied in research as well as in clinical settings in diagnostic tests for thyroid dysfunctions and pituitary pars intermedia dysfunction.

Abstract

Thyrotropin-releasing hormone (TRH) was the first trophic “factor” from the hypothalamus to be isolated and identified chemically. It was known to have a stimulatory effect on thyroid-stimulating hormone (TSH) production and secretion by cells within the adenohypothesis, and its structure was revealed to be a modified tripeptide: (pyro)Glu-His-Pro-NH2. Intravenous or intramuscular injection of TRH to horses results in an immediate rise in plasma TSH concentrations, as would be expected. However, it is now known that TRH has consistent effects on four of the other five cell types in the equine adenohypophysis as well. Administration of TRH to horses stimulates not only plasma TSH concentrations, but also plasma prolactin, adrenocorticotropic hormone, and melanocyte-stimulating hormone concentrations. In contrast, administration of TRH simultaneously or within 1 hour before administration of secretagogues for growth hormone (GH) greatly reduces the GH response to the secretagogues. To date, TRH has not been reported to have positive or inhibitory effects on the release of luteinizing hormone or follicle-stimulating hormone from gonadotropes. Whether the noted effects of TRH on cells other than the thyrotropes are physiologic or pharmacologic is not clear. Regardless, a significant clinical utility has developed for the use of TRH in diagnosing thyroid gland disease as well as pituitary pars intermedia dysfunction in horses.

Introduction

Thyrotropin-releasing hormone (TRH) was the first hypothalamic factor to be isolated and chemically identified as a peptide hormone [1]. Two groups working independently in the United States [2], [3] reported in 1969 the structure to be a tripeptide: (pyro)Glu-His-Pro-NH2. The “pyro” prefix before the glutamic acid designator indicates that the amino end of the peptide forms a cyclic ring with the glutamic acid side chain carboxyl group and hence does not have a chemically active amino group like most peptides. This latter characteristic was the last to be deciphered and likely led to the extended period of time that it took for the scientists to finally match chemical structure of TRH to its biological activity [4], [5], [6].

Extensive research has been performed and reported on the biological activity of TRH in various species. The purpose of this review is to concentrate on what is specifically known for the horse regarding TRH activity and how that knowledge has been applied in research and clinical settings in the horse industry. For such a small molecule, TRH has an amazing diversity of effects on hypophyseal hormones in addition to the expected effects on thyroid-stimulating hormone (TSH).

Section snippets

TRH and TSH

The first reported use of TRH to stimulate TSH in equine research was by Thompson et al [7] in 1983. Daily treatment with 100 μg of TRH was used as a means to potentially stimulate plasma prolactin (PRL) concentrations in seasonally anovulatory mares. Plasma concentrations of TSH were measured around the first injection of TRH (or vehicle; administered intramuscularly) in treated and control mares, and TSH concentrations were found to increase in the first 30 minutes after TRH injection, peak

TRH and PRL

Perhaps the greatest amount of information regarding hormonal responses to TRH in horses is that concerning PRL. Johnson [23] and Johnson and Becker [24] were the first to describe the stimulatory effect of TRH on plasma PRL concentrations in horses. Johnson [23] reported that PRL response in mares to TRH was greater in June compared to January. He further demonstrated that increasing daily light exposure from 8 to 16 hours per day increased the PRL response to TRH, thus confirming the

TRH and Adrenocorticotropic Hormone

The first reported use of TRH in an equine clinical setting not involving the thyroid gland was by Beech and Garcia [19], who compared the cortisol responses of normal horses to those of horses with pituitary adenomas. As described by Beech [35] herself in her presentation on diagnosis of PPID in 2011, there was no readily available assay for the measurement of adrenocorticotropic hormone (ACTH) when she and Garcia reported their first study [19], thus cortisol response was used. With the

TRH and Alpha-Melanocyte-Stimulating Hormone (MSH)

Alpha-melanocyte-stimulating hormone (MSH) is a hormone that has gained notoriety due to its production and secretion by the intermediate lobe of the pituitary gland and its hypersecretion in horses with PPID. Accordingly, much of the literature on TRH and MSH overlaps with that for TRH and ACTH. Both ACTH and MSH are derived from the larger, preprohormone, pro-opiomelanocortin (POMC), which is found in both corticotropes in the distal lobe of the adenohypophysis as well as in melanotropes of

TRH and Growth Hormone

Growth hormone (GH) in horses, if similar to other species that have been well characterized, is under dual positive and negative control by the hypothalamus. Growth hormone–releasing hormone (GHRH) is believed to be the positive, trophic peptide affecting the somatotropes in the adenohypophysis, whereas GH-inhibiting hormone, more commonly referred to as somatostatin, is the inhibitory peptide. Supposedly, they are secreted by hypothalamic neurons in a somewhat temporally back-and-forth manner

TRH and Gonadotropins

Horses produce and secrete two distinct gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from adenohypophyseal gonadotropes. Like in other species, horses have three types of gonadotropes [59]: those that contain secretory granules that stain for LH only, those that contain secretory granules that stain for FSH only, and those that contain secretory granules that stain for both gonadotropins. Except for the differential immunocytochemical staining for the

Summary and Conclusions

The hormones of the equine adenohypophyseal distal and intermediate lobes, their known hypothalamic control hormones, and the effects of TRH and other stimuli on their secretion are presented in Table 1. Four of the six known cell types are affected positively by TRH administration, and a fifth, the somatotropes, are affected negatively. The gonadotrope is the only cell type not affected by TRH, which in a way indicates that the other stimulatory effects are not just casual interactions of

References (64)

  • E. Diez de Castro et al.

    Influence of feeding status, time of the day, and season on baseline adrenocorticotropic hormone and the response to thyrotropin releasing hormone-stimulation test in healthy horses

    Domest Anim Endocrinol

    (2014)
  • D. McFarlane et al.

    Alpha-melanocyte stimulating hormone release in response to thyrotropin releasing hormone in healthy horses, horses with pituitary pars intermedia dysfunction and equine pars intermedia explants

    Domest Anim Endocrinol

    (2006)
  • D. McFarlane

    Equine pituitary pars intermedia dysfunction

    Vet Clin North Am Equine Pract

    (2011)
  • S.M. Gray et al.

    High glycemic and insulinemic responses to meals affect plasma growth hormone secretory characteristics in Quarter Horse weanlings

    Domest Anim Endocrinol

    (2013)
  • D. Gourdji

    Multihormonal regulation of the pituitary gland binding and secretory responses to hypothalamic neuropeptides in rat GH pituitary strains in culture

    Neurochem Int

    (1985)
  • M.E. Hadley et al.

    Endocrinology

    (2007)
  • R. Burgus et al.

    Molecular structure of the hypothalamic hyophysiotropic TRH factor of ovine origin: mass spectrometry demonstration of the PCA-His-Pro-NH2 sequence

    C R Hebd Seances Acad Sci D

    (1969)
  • N. Wade et al.

    The years in the wilderness

    Science

    (1978)
  • N. Wade et al.

    The three-lap race to Stockholm

    Science

    (1978)
  • N. Wade et al.

    A Race spurred by rivalry

    Science

    (1978)
  • D.L. Thompson et al.

    Effects of melatonin and thyrotropin releasing hormone on mares during the nonbreeding season

    J Anim Sci

    (1983)
  • L.R. Gentry et al.

    Treatment of seasonally anovulatory mares with thyrotropin releasing hormone and (or) gonadotropin releasing hormone analog

    J Anim Sci

    (2002)
  • H.E. Pruett et al.

    Thyrotropin releasing hormone interactions with growth hormone secretion in horses

    J Anim Sci

    (2003)
  • J.A. Cartmill et al.

    Endocrine responses in mares and geldings with high body condition scores grouped by high vs. low resting leptin concentrations

    J Anim Sci

    (2003)
  • N. Arana Valencia et al.

    Changes in plasma melanocyte-stimulating hormone, ACTH, prolactin, GH, LH, FSH, and thyroid-stimulating hormone in response to injection of sulpiride, thyrotropin-releasing hormone, or vehicle in insulin-sensitive and -insensitive mares

    Domest Anim Endocrinol

    (2013)
  • B.A. Breuhaus

    Thyroid-stimulating hormone in adult euthyroid and hypothyroid horses

    J Vet Intern Med

    (2002)
  • P.J. Johnson et al.

    Effects of propylthiouracil and bromocryptine on serum concentrations of thyrotrophin and thyroid hormones in normal female horses

    Equine Vet J

    (2003)
  • C.S. Sommardahl et al.

    Effects of oral administration of levothyroxine sodium on serum concentrations of thyroid gland hormones and responses to injections of thyrotropin-releasing hormone in healthy adult mares

    Am J Vet Res

    (2005)
  • B.A. Breuhaus

    Thyroid function in anhidrotic horses

    J Vet Intern Med

    (2009)
  • B.A. Breuhaus

    Thyroid function and dysfunction in term and premature equine neonates

    J Vet Intern Med

    (2014)
  • J. Beech et al.

    Hormonal response to thyrotropin-releasing hormone in healthy horses and in horses with pituitary adenoma

    Am J Vet Res

    (1985)
  • C.D. Lothrop et al.

    Equine thyroid function assessment with the thyrotropin-releasing hormone response test

    Am J Vet Res

    (1986)
  • Cited by (3)

    • Plasma prolactin, thyroid-stimulating hormone, melanocyte-stimulating hormone, and adrenocorticotropin responses to thyrotropin-releasing hormone in mares treated with detomidine and butorphanol

      2021, Domestic Animal Endocrinology
      Citation Excerpt :

      Differentiation between these 2 possibilities could possibly be obtained from in vitro studies with isolated hypophyseal tissue. Given that prolactin- and MSH-secreting cells are both primarily regulated by tonic suppression by dopamine [19,20], albeit from different sets of neuronal pathways [19,20], it is interesting to note the differential effects of DET on the secretion of the 2 hormones after TRH. First, unstimulated (pre-TRH) MSH concentrations were increased by DET and DET/BUT, whereas prolactin concentrations were not affected in the first 10 min after treatment.

    • Melanocyte-Stimulating Hormone Response to Exercise, Twitching, Epinephrine Injection, Substance P Injection, and Prostaglandin-F <inf>2α</inf> Administration in Mares

      2019, Journal of Equine Veterinary Science
      Citation Excerpt :

      Given that we have reported a greater MSH secretory response after sulpiride or TRH injection in insulin insensitive mares compared to sensitive mares [13], we compared insulin sensitivity estimates [19], which are relative consistent over time, from other trials to the MSH and ACTH responses in the five experiments herein and found basically no correlation overall. As mentioned in the Introduction, we previously suggested [9] that MSH was a good candidate for a stress-stimulated hormone in horses because of similarities with prolactin, GH, and ACTH in its regulation and factors that cause its release. Production and secretion of MSH in the intermediate lobe of the pituitary gland is tonically suppressed by dopaminergic input arising from the periventricular hypothalamic dopaminergic and tuberohypophyseal dopaminergic neural pathways [20,21].

    Approved for publication by the Director of the Louisiana Agricultural Experiment Station as manuscript number 2017-230-31384.

    Animal welfare/ethical statement: No animals were used in the generation of this review article.

    Conflict of interest statement: The authors declare no conflicts of interest.

    View full text