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Chapter 9 Growth Hormone and Secretagogues

DEFINITION/OVERVIEW

 Growth hormone (GH) is a protein hormone that is produced in the pituitary gland and is essential to normal growth, development, and overall health of animals.

 Recombinant GH, growth hormone‐releasing peptides, or small molecule drugs capable of stimulating the release of GH have been developed or approved as pharmaceutical agents.

 Cases may be a result of accidental or illicit use in performance horses.

ETIOLOGY/PATHOPHYSIOLOGY

 There are no FDA‐approved GH formulations approved for use in the horse. There are no peptide or small molecule mimetics of GH approved by the FDA for use in the horse.

 There are many compounds that are currently undergoing pre‐clinical development or clinical trials.

 Illicit formulations of GH and its mimetics are readily available on the internet, primarily directed towards body builders and other performance athletes.

 The prevalence of use is unknown, and administrations may be unreported to practitioners due to illicit use.

Mechanism of Action

 Natural production:Hormone produced in the anterior pituitary gland which is under the control of either GH stimulatory hormone (+) or somatostatin (–) produced in the hypothalamus.Following release into systemic circulation, GH binds to GH receptors found on target cells.GH has several effects, both directly acting on target tissues and via downstream mediators such as insulin‐like growth factor 1 (IGF‐1).GH increases muscle, bone, and organ growth and increased cellular protein synthesis and intracellular lipolysis.

 Recombinant GH:Synthetically produced to mimic the effects of naturally produced GH.FDA has approved recombinant GHs for both human and bovine versions.Equine recombinant GH was developed in the late 1990s and marketed in Australia.

 GH‐releasing peptides:Synthetically produced to mimic the effects of GH‐releasing hormone binding to either the GH‐releasing hormone receptor or the GH secretagogue receptor.These may also act as mimetics to the natural hormone ghrelin.Examples include hexarelin, sermorelin, hexarelin, tesamorelin, GHRP 2, GHRP 6, CJC‐1295, CJC‐1295‐DAC.

 Small molecule mimetics:Small molecule drugs synthesized to mimic the effects of GH‐releasing peptides.Examples include Ibutamorelin and Anamorelin.

Toxicokinetics

 Little is known about onset of action or duration of toxicity for GH.

 Recombinant GH:Typical routes of administration are SC or IM injection (8 μg/kg daily) as oral bioavailability is minimal.Variable pharmacokinetics depending on dose/route with Cmax ~ 4 hours post‐dose, ~2 hours terminal half‐life. Cleared by proteolytic digestion and urinary excretion.

 GH‐releasing peptides – limited pharmacokinetic information in the horse:Typically dosed via SC or IM administration as oral bioavailability is < 1% for most compounds.Rapid half‐lives < 1 hour except for CJC‐1295‐DAC due to the presence of the drug affinity complex which increases binding to free thiols in blood.Cleared by proteolytic digestion and urinary excretion.

 Small molecule mimetics – limited pharmacokinetic information in the horse:Oral bioavailability is good (> 50%), distribution, metabolism and excretion are not well characterized.

Toxicity

 Acute – injection site reaction and muscle stiffness. Potential pyrexia. Overdose can result in hypoglycemia followed by hyperglycemia and fluid retention. Acute effects are not fully understood in the horse.

 Chronic – acromegaly and gigantism noted in humans and other species. Chronic effects are unknown in the horse.

Systems Affected

 Cardiovascular – cardiomegaly, hypo/hypertension.

 Endocrine/metabolic – hypopituitarism, hypothyroidism, disturbances in maintenance of blood glucose levels.

 Gastrointestinal – potential for increased feed and fluid intake.

 Hemic/lymphatic/immune – injection site reactions, potential neutralizing antibody formation.

 Musculoskeletal – potential for increased muscle mass and weight gain, stimulation of skeletal growth. Potential for increased osteoarthritis.

 Renal/urologic – fluid retention.

 Reproductive – potential for mammary stimulation at high doses.

 Skin/exocrine – injection site reactions, excessive sweating.

SIGNALMENT/HISTORY

Potential for increased illicit use in performance horses.

Risk Factors

 Higher potential for use in performance horses

 Incomplete medical records and failure to disclose administrations by owners/trainers.

Historical Findings

 History of use of GH substances. Owner or trainer may be reluctant to disclose.

 History of use of other performance‐enhancing drugs with similar desired effects such as anabolic steroids, selective androgen receptor modulators and beta‐agonists.

 Performance supplement use.

CLINICAL FEATURES

 Clinical exam may not suggest exposure.

DIFFERENTIAL DIAGNOSIS

 Administration of other pharmaceutical agents such as anabolic steroids.

 Stimulation of hypothalamic–pituitary axis by other environmental or pharmaceutical agents.

 Evaluate for pituitary gland disorders or neoplasms.

 Administration of IGF‐1.

DIAGNOSTICS

 IGF1 levels can be determined from blood samples.

 Hyperglycemia or hypoglycemia depending upon time course.

 Detection of parent compounds (GH or its secretagogues) is not a routine clinical diagnostic test.

 Potential to send samples to specialized laboratories for LC‐MS testing.

THERAPEUTICS

 Objectives of treatment are to prevent further exposure to compounds and provide symptomatic treatments.

Detoxification

 No well‐characterized treatment strategies. Detoxification strategy based upon reducing potential for exposure.

Antidotes

 Somatostatin analogs (octreotide and lareotide) have strong suppression on GH production.

Appropriate Health Care

 Monitor blood glucose levels.

 CBC and biochemistry panel to evaluate hydration status and overall health.

 Evaluate thyroid and parathyroid levels.

 Potential for increased urinary excretion of inorganic phosphorus and calcium.

 Hepatic function panel to evaluate abnormal alkaline phosphatase.

 Evaluate for elevated IGF‐1 in blood sample.

Precautions/Interactions

 Decreased insulin sensitivity and glucose intolerance.

 Avoid co‐administration with CYP450 substrates.

 Decreased efficacy of corticosteroids.

COMMENTS

Client Education

 Educate client on the potential for exposure from performance‐enhancing supplements marketed on the internet.

Prevention/Avoidance

 Remove compounds from the environment.

Possible Complications

 Contaminants or adulterants found in supplements.

 Unknown exposure to other related compounds.

Expected Course and Prognosis

 Compounds are relatively quickly eliminated following administration.

 Effects are time‐ and dose‐dependent, with lower dosages and duration of exposure having better prognosis.

Abbreviations

See Appendix 1 for a complete list.

Suggested Reading

1 Sigalos JT, Patuszak AW. The safety and efficacy of growth hormone secretagogues. Sex Med Rev 2018; 6:45–53.

2 Anderson LJ, Tamayose JM, Garcia JM. Use of growth hormone, IGF‐I, and insulin for anabolic purpose: pharmacological basis, methods of detection, and adverse effects. Mol Cell Endocrinol 2018; 464:65–74.

3 Bailly‐Chouriberry L, Pinel G, Garcia P, et al. Identification of recombinant equine growth hormone in horse plasma by LC‐MS/MS: A confirmatory analysis in doping control. Anal Chem 2008; 80(21):8340–8347.

Author: Benjamin C. Moeller, PhD, DABT

Consulting Editor: Dionne Benson, DVM, JD