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Neuroendocrine and Pituitary
Tumor Clinical Center (NEPTCC) Bulletin

Winter 2018/2019 | Volume 24, Issue 2

Macimorelin as a Diagnostic Test for Adult GH Deficiency


The evaluation for growth hormone deficiency (GHD) is an important step in the management of adults with known or suspected pituitary disorders. Growth hormone (GH) replacement has been shown to have positive effects on body composition, muscle mass, bone density, liver health and quality of life (1). However, GH replacement is an expensive therapy and carries the burden of daily injections for patients. Thus, accurate diagnostic testing is critical to identifying patients with true GHD who may benefit from GH replacement.

The insulin tolerance test (ITT) is considered the gold standard test for the diagnosis of adult GHD. However, this test requires induction of hypoglycemia and is thus contraindicated in the elderly, those with seizure disorders or cardiovascular disease. Growth hormone releasing hormone (GHRH)-arginine testing was previously available in the United States for testing of GHD, which offered an alternative testing procedure with established cut-offs stratified by body mass index (2). However, GHRH was withdrawn from the U.S. market in 2008, although it is still available in other markets. Glucagon stimulation testing has remained as a viable alternative to the ITT in the U.S., however, it requires an IM injection, 3-4 hours of testing time and can cause nausea and vomiting (1,3-5).

Macimorelin, a ghrelin analog, is a GH secretagogue that can be administered as an oral solution. Piccoli et al. established that oral administration of macimorelin led to rapid absorption and a substantial peak in GH levels in 36 healthy male volunteers between 50-75 minutes later with no adverse events (6). A subsequent study by Garcia et al. established that a GH cutoff of 2.7 ng/mL on oral macimorelin testing had 82% sensitivity and 92% specificity for the diagnosis of GHD in a population of 50 individuals with adult onset GHD versus controls matched for age, BMI, sex and estrogen status. This study was initially designed to compare the efficacy of macimorelin versus GHRH-arginine, however, the full protocol could not be completed once GHRH was withdrawal from the U.S. market (7).

More recently, Garcia et al. performed a randomized, open-label, two-way crossover trial to compare macimorelin with the standard ITT for diagnosis of adult GHD (8). They studied 139 adults age 18-65 years, including adults at risk for GHD as well as controls. The individuals at risk for GHD were subdivided into three categories based on their pituitary disease and other hormone deficits, including (A) high likelihood (n=38), (B) moderate likelihood (n=37) and (C) low likelihood of GHD (n=39).  A fourth group (D) of controls (n=25) with no pituitary disorders were studied and matched to group A (high likelihood of GHD) for sex, age, BMI and estrogen status. Notable exclusions for all groups included age >65 years old, uncontrolled diabetes mellitus (hemoglobin A1C >8.0%) and extreme obesity (BMI >40 kg/m2).

These individuals were randomized with regards to the order of the ITT and macimorelin testing. The ITT was performed per standard protocol with serum sampling for GH and glucose at 15, 30, 45, 60, 90 and 120 minutes after the administration of insulin. Macimorelin testing involved a dose of 0.5 mg/kg administered as an oral solution within a 30-minute window with serum sampling for GH at 30, 45, 60 and 90 minutes after administration.

In the current study, authors first compared the agreement between the results of macimorelin testing and the ITT. The predefined cutoffs were 5.1 ng/mL for the ITT and 2.8 ng/mL for the macimorelin test based on prior literature (5,7). Thus, the macimorelin test with a cutoff of 2.8 ng/mL and ITT with a cutoff of 5.1 ng/mL had a 95% negative agreement and 74% positive agreement, which translated to a low risk of macimorelin overdiagnosing GHD but the possibility of underdiagnosis of GHD when compared to the gold standard ITT. A post-hoc analysis was completed using 5.1 ng/mL for both the macimorelin test and ITT, which demonstrated a similar negative agreement of 94% and improved positive agreement of 82%. Thus, using the higher cutoff for the macimorelin test led to fewer missed cases of GHD (fewer instances of underdiagnosis) with a similarly low rate of overdiagnosis when using the ITT as a gold standard.

In receiver operator curve analysis of subjects with presumed GHD (Group A / true GHD) and controls with no pituitary disorders (Group D / true controls), the a priori cutoff of 2.8 ng/mL was determined to have a sensitivity of 87% and specificity of 96% for the diagnosis of GHD, indicating that some cases of GHD would likely be missed using this cutoff. When the cutoff was increased to 5.1 ng/mL (identical to the traditional ITT cutoff), the sensitivity of the macimorelin test improved to 92% with unchanged specificity of 96%.

This study demonstrated that macimorelin testing was practical, with only one (0.6%, total n=154) non-evaluable test versus 27 (17%, total n=157) non-evaluable ITTs, mainly due to lack of achieved hypoglycemia for the latter test. Additionally, the reproducibility of the macimorelin testing was demonstrated to be 94% in a substudy of 33 patients. No serious adverse events were reported with either the ITT or macimorelin. Non-serious adverse events occurred much more frequently in the ITT versus macimorelin (761 events in 157 patients versus 77 events in 154 patients, respectively). The mild-to-moderate side effects reported with macimorelin included dysgeusia (4.5%), fatigue (3.2%), headache (2.6%) and nausea (2.6%). These were compared to those side effects most common with the ITT, including somnolence and hyperhidrosis (3.2% each), asthenia (2.5%), hunger (1.9%), nervousness (1.3%) and tremor (0.6%). Additionally, QTc prolongation on EKG was less frequent and generally milder in the macimorelin tests versus ITT. However, there do not appear to be good data regarding the use of macimorelin in patients already on QTc prolonging medications, and the authors of this study indicate that this could be an area of future investigation.

Finally, in the 2013 study, Garcia et al. demonstrated that peak GH levels after macimorelin were inversely associated with BMI in controls (R=-0.37, P=0.01) (7). Multiple studies from our group and others have demonstrated that peak-stimulated GH with glucagon stimulation is lower in overweight and obese individuals compared to normal-weight controls (3,9). Given that the vast majority of subjects in this study (70%) had a BMI of <30 kg/m2, this particular study is does not allow detailed evaluation of BMI-stratified peak-stimulated GH cutoffs.

In summary, macimorelin is a new option for GH stimulation testing that is orally administered, 90 minutes in length, reproducible, well tolerated and has published cutoffs with high sensitivity and specificity based on a population of adult patients with a BMI <30 kg/m2. Further study will be needed to determine the effectiveness of this test in children, adults >65 years old and patients with hemoglobin A1C >8.0%.


1. Molitch ME, et al. J Clin Endocrinol Metab. 2011;96(6):1587-609.

2. Maccario M, et al. J Clin Endocrinol Invest. 1999;22(6):424-9.

3. Hamrahian AH, et al. Pituitary. 2016;19(3):332-41.

4. Yuen KC. ISRN endocrinol. 2011;2011:608056.

5. Biller BM, et al. J Clin Endocrinol Metab. 2002;87(5):2067-79.

6. Piccoli F, et al. J Clin Endocrinol Metab. 2007;92(5):1814-20.

7. Garcia JM, et al. J Clin Endocrinol Metab. 2013;98(6):2422-9.

8. Garcia JM, et al. J Clin Endocrinol Metab. 2018;103(8):3083-93.

9. Dichtel LE, et al. J Clin Endocrinol Metab. 2014;99(12):4712-9