Growth Hormone: The Goldilocks Principle
An overview of GH, and the impact of GH replacement
April 2015
Volume 6, Issue 2

The Endocrine Society Clinical Practice Guideline on Diagnosis and Treatment of Growth Hormone Deficiency in Adults

J Clin Endocrinol Metab. 2011;96(6):1587-1609

The 2011 update to The Endocrine Society Clinical Practice Guideline on the evaluation and treatment of growth hormone deficiency (GHD) in adults offers recommendations on the definition and diagnosis of GHD, weighs the risks and benefits of growth hormone (GH) replacement, and offers recommendations on individualizing treatment. Below is a summary of key recommendations.

Definition and Evaluation of GHD in Adults
In adults, the causes of GHD are divided into 3 subgroups:

  1. Childhood GHD (ie, organic or idiopathic)
  2. GHD secondary to structural lesions or trauma
  3. Idiopathic adult-onset GHD
  • Adults with childhood-onset GHD should be re-evaluated for GHD after achieving full adult height, unless they have known mutations, embryopathic lesions causing multiple hormone deficits, or irreversible structural lesions/damage.
  • Evaluation of acquired GHD should be conducted in adults with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, head trauma, or evidence of other pituitary hormone deficiencies. Pituitary adenoma or surgery and/or radiotherapy treatment to treat pituitary adenomas are the most common cause of GHD in adults.
  • Idiopathic adult-onset GHD is rare and GH stimulation testing should be conducted twice before making a diagnosis given the high rate of false-positive results to a single GH stimulation test in this group.

Diagnosis of GHD in Adults

  • The insulin tolerance test (ITT) and the growth-hormone-releasing hormone (GHRH)-arginine test are recommended for the diagnosis of GHD.
  • GHRH-arginine testing may be misleading in adults with recent hypothalamic causes of suspected GHD (eg, radiation therapy).
  • Dynamic testing is required for diagnosis of GHD in adults with normal IGF-I levels.
  • A low IGF-I level in patients without catabolic conditions (eg, diabetes, liver disease, and oral estrogen therapy) is a strong predictor of GHD and indicates the need for GH stimulation testing. Furthermore, it can be used to help differentiate true GHD in adults with blunted GH level due to overweight/obesity; in obesity, GH levels may be lower IGF-1 levels may be elevated.
  • Deficiencies in ≥3 pituitary axes are a strong predictor of GHD and dynamic testing is optional in this context (though may be required for reimbursement).

Benefits of GH Treatment in GH-Deficient Adults

  • Improves body composition, skeletal integrity, exercise capacity, and quality of life.
  • Improves cardiovascular outcomes endothelial function, inflammatory cardiovascular biomarkers, lipoprotein metabolism, carotid intima-media thickness (IMT), and aspects of myocardial function.
  • An effect on mortality has not yet been proven.

Side Effects and Risks of GHD Treatment

  • Increases insulin resistance.
  • Contraindicated in people with active malignancy.
  • Dosages of anti-diabetic medications taken concomitantly may need to be adjusted.
  • Thyroid and adrenal function should be monitored during GHD treatment.

Treatment Recommendations

  • Treatment should be individualized, starting with a low dose and titrating upwards according to clinical response, emergence of side effects, and IGF-I levels.
  • Gender, estrogen status, and age should be taken into consideration when individualizing treatment.
  • Patients should be monitored every 1 to 2 months during dose titration and every 6 months thereafter to assess for treatment response, emergence of side effects, IGF-I levels, and other parameters of GH response.
  • Patients with childhood-onset GHD that is found to persist into adulthood should continue GH therapy.

Commentary

Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in neuroendocrinology and reproductive endocrinology. She is the Director of the NYU Langone Medical Center Pituitary Center in New York, NY, as well as an Attending in Medicine at Massachusetts General Hospital, Boston, MA.

This 2011 update to the 2006 Endocrine Society stance on the evaluation of, and treatment for adult growth hormone deficiency (AGHD) provides guidelines for diagnosis, the role of treatment, and appropriate monitoring. In addition, evidence to support the guidelines is summarized. The article also discusses those patients who were treated with GH as children, addressing when to re-test and when to treat that particular cohort.

The article also may serve as a useful practical guide for clinicians deciding when and how to test for GHD, and ties monitoring recommendations to evidence of the impact of GH in different areas of the body (eg, bone, cardiovascular). Available diagnostic tests are discussed with recommended prioritization and interpretations. For example, while the ITT is referred to as the gold standard for diagnosis of GHD, given the potential contraindications and need for careful monitoring during administration, GHRH-arginine stimulation is recommended as one first-line option (unless a hypothalamic cause is suspected). The glucagon stimulation test is recommended as an alternate to GHRH-arginine stimulation testing when the latter is not available; as discussed in the Introduction to this issue of EndoScan, as of July 2008, recombinant GHRH was no longer commercially available in the United States. The potential for future use of ghrelin-mimetic GH secretagogues in diagnosing GHD is mentioned. Since the publication of the guidelines, at least one such option concluded phase 3 trials, with an NDA submitted to the FDA (NDA not approved in present form).1

The article also alludes to the impact of body mass index (BMI) on thresholds used in dynamic testing; we later review a recent article by Dichtel and colleagues suggesting new glucagon stimulation testing cutoffs in obese patients.

While the focus of this EndoScan is adults (children will be discussed in a future EndoScan), the article touches on two important factors for endocrinologists: 1) the need to retest GH in cases in which a congenital GHD is not present, underscoring that not all children for whom GHR is indicated and approved will meet criteria for adult GHD and replacement, and 2) the importance of continuing GH replacement (GHR) in some patients who received it as children (as well as particular considerations in monitoring and treating this cohort).

Discussion of the potential benefits (and risks) of GHR in adults, and reference to the related evidence, is particularly useful in understanding why it is important to consider testing and replacement in addition to offering guidance for appropriate monitoring.

Reference
1. Garcia JM, Swerdloff R, Wang C, et al. Macimorelin (AEZS-130)-stimulated growth hormone (GH) test: validation of a novel oral stimulation test for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. 2013;98(6):2422-2429.

Next Article:
Long-term GH Treatment Improves Exercise and Cardiac Performance in Patients with Chronic Heart Failure and Low Peak GH Levels
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