Jeff Craven

The Endocrine Society Clinical Practice Guidelines for evaluation and treatment of adult growth hormone deficiency (AGHD), published in 2011, are the latest authority on how to evaluate and treat patients with the disease. 

How will your answers match up with the Endocrine Society Task Force’s recommendations for AGHD treatment? Test your knowledge in this 6-question quiz.

1. Patients with childhood-onset growth hormone deficiency (GHD) should be retested for AGHD if they reach adult height and display which of the following:

 Embryopathic lesions responsible for hormone deficits
	

 Irreversible structural lesions/damage
	

Please click here for answer and next question.

Multiple studies have reported that GHD in children that is a result of embryopathic lesions, genetic mutations, and damage to the hypothalamic-pituitary axis does not revert to normal growth hormone status when transitioning to adulthood.

2. Clinicians should use 2 growth hormone stimulation tests to diagnose patients suspected of idiopathic AGHD.

Idiopathic AGHD is a rare diagnosis and growth hormone stimulation tests have a high false positive rate, so clinicians should use 2 tests to confirm diagnosis. Low insulin growth factor-1 (IGF-I) is also an indicator of a correct diagnosis of idiopathic AGHD.

3. A patient with a low IGF-I level and without which of the following conditions should receive growth hormone stimulation testing to diagnose AGHD:

Low IGF-I levels can be indicative of AGHD provided a patient does not have a blunted response to growth hormone as a result of increased oral estrogen such as seen in cases of a liver disease, poorly controlled diabetes, and during administration of oral estrogen therapy.

4. Provocative testing for AGHD is optional if a patient has one or more deficiencies present in pituitary axes.

The Endocrine Society guidelines state that deficiencies in 3 or more pituitary axes “strongly suggests” the presence of GHD, and provocative testing may be unnecessary. One study revealed that deficiencies in 3 pituitary axes together with an IGF-1 level of <84 ng/mL was equally predictive of disease as proactive growth hormone testing.

5. Patients with GHD who have an abnormal dual-energy X-ray absorptiometry (DXA) scan should receive a repeat measurement at which of the following time points:

DXA measurements should be repeated every 2 years in patients with abnormal results, and the guidelines note that testing should be done “expeditiously” for patients transitioning from childhood to adulthood in whom growth hormone therapy has been stopped.

6. Dosing of growth hormone should be based on body weight, with fixed doses of sequential growth hormone administered beginning at 4 µg/kg, 8 µg/kg and 12 µg/kg per day.

Although dosing of growth hormone for adults was initially adopted from pediatric practice, researchers soon learned that fixed doses were supraphysiological and associated with side effects of AGHD such as joint stiffness, arthralgias, paresthesias, peripheral edema, and myalgias.

Endocrine Society, Molitch ME, Clemmons DR, et al. 

Evaluation and treatment of adult growth hormone deficiency: An endocrine society clinical practice guideline

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

Articles

True or false? Clinicians should use 2 growth hormone stimulation tests to diagnose patients suspected of idiopathic AGHD. Answer plus 5 more.

AGHD Endocrine Society Guidelines: A 6-question Quiz

Patients with adult growth hormone deficiency (AGHD) who receive early and sustained growth hormone replacement (GHR) therapy are likely to benefit from improved quality of life and reduced disease-related economic burden, but studies have yet to examine the direct cost or caregiver burden of the disease, according to a recent literature review published in Current Medical Research and Opinion.

“Despite a wealth of information on the efficacy and safety of treatments for GHD, only a small number of studies reported on the humanistic and economic burden, and none reported data on the direct costs or caregiver burden of the disease-making it difficult to build a full and accurate picture of the impact of AGHD,” Jane Loftus, from Pfizer Ltd in Surrey, United Kingdom, and colleagues wrote in their review.

Although the researchers found significant evidence of the positive impact of regular treatment for individuals with AGHD, they noted there were only 14 studies between January 2006 and July 2016 that met inclusion criteria of studying the humanistic and economic burden of AGHD. Of these, 7 studies were 5-years-old, and no study had looked at the economic burden associated with AGHD since 2014.

Seven studies used the Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) instrument, which measured health-related QoL (HR-QoL) outcomes such as cognitive function, emotional functioning, social functioning, motivation, sleep, and physical impact. In 4 studies, HR-QoL was significantly impaired in AGHD patients at baseline compared with the general population as measured by QoL-AGHDA scores and 5 studies showed worse HR-QoL in women compared with men.

Energy, vitality most consistently impaired 


	
	The negative impact on HR-QoL of untreated AGHD was underscored in 2 of the studies reviewed. Researchers found memory and concentration domains are most impaired, followed by tiredness, self-confidence, tenseness, and socialization issues. In one study, 91% of AGHD patients reported energy and vitality were the domains most consistently affected, and other patients frequently reported symptoms of anxiety, social isolation, and depressed mood.

Eight studies examined the effect of GHR therapy on HR-QoL, with results showing an improvement in QoL-AGHDA scores of 2.3 and 5.3 points. The QoL-AGHDA scale includes 25 statements responded to with “Yes” or “No.” A score can range from 0 to 25 with higher scores indicating poor QoL. In 2 studies, issues that were least impaired improved first such as socialization issues, tenseness, and self-confidence, while tiredness, and memory and concentration were among the last symptoms to improve.

Short-term improvement in QoL was seen in 4 studies, with tiredness, memory and concentration improving after 1 year; results tended to plateau after the first year and in the long-term, improvement was dependent upon factors such as European origin, lack of depression history, lower body mass index, and no impaired vision at baseline.

… results tended to plateau after the first year and in the long-term, improvement was dependent upon factors such as European origin, lack of depression history, lower body mass index, and no impaired vision at baseline.

With regard to the health economic impact of AGHD treatment, economic burden was associated with “productivity losses related to the disease” such as lower working capacity related to days off for sickness and a higher unemployment rate. After successful GHR therapy, patient productivity is substantially improved and so economic loss is reduced. Specific improvements noted in one study after 12 months of GHR therapy included increased physical activity and decreased need for assistance with activities of daily living; these measures correlated with improved Qol, as measured by QoL-AGHDA, and a reduction in the number of sick days from work, visits to a doctor, hospital stays, and use of healthcare resources.

The authors conclude that the results of their review underscore the need for additional research that will help optimize patient management and outcomes, particularly given the increasing need to better manage health care resources.

  Loftus J, Camacho-Hubner C, Hey-Hadavi J, et al. 

Targeted literature review of the humanistic and economic burden of adult growth hormone deficiency.

Adult growth hormone deficiency treatment is safe and effective, but who is tracking the social and economic impact, reviewers ask?

Social, Economic Impact of AGHD Treatment Demands Study, Review Finds 

As clinicians and researchers continue to advance their understanding of adult growth hormone deficiency (AGHD), knowing who is at risk for developing AGHD and how they will respond to therapy grows ever more important.

 at risk for AGHD? What are the recommended diagnostic tools? How does growth hormone replacement therapy (GHRT) affect patients? Take our 6-question quiz on a few facts and some emerging evidence.

1. Patients should be tested for AGHD if there is evidence of hypothalamic-pituitary disease or related trauma, and in instances where there is an intention to treat with growth hormone.

Click here for answer and next question. 

Not all patients with reduced growth hormone or insulin growth factor-1 (IGF-1) are candidates for AGHD testing, such as elderly individuals or those patients with excess visceral adipose tissue, and so should not be subjected to diagnostic procedures.

2. Recent studies have found that AGHD  has resulted from involvement in popular sports including which of the following:

Research has shed light on an increasing prevalence of disorders unrelated to pituitary adenomas or their treatment, including traumatic brain injury and head trauma related to sports such as ice hockey, boxing, kickboxing, football, soccer, and rugby.

3. Arginine, clonidine and L-dopa, used to diagnose GHD in children, are valid for diagnosing AGHD.

The current Endocrine Society clinical practice guidelines do not recommend these biochemical tools for diagnosis of AGHD. The clinical guidelines recommend the insulin tolerance test (ITT) as a preferred diagnostic tool and where it is not available or contraindicated, the glucagon stimulation test can be used. 

4. What is the validated cut-off value for peak GH response in the insulin tolerance test (ITT) for a biochemical diagnosis of severe AGHD (assuming no influence from factors such as age, GH secretion type, and body mass index)?

Clinical guidelines state a valid cut-off value for peak GHD response to the ITT for a diagnosis of AGHD is <3 µg/L.

5. As is the case with GH treatment in children, replacement GH doses in adults are calculated on the basis of body weight.

GH replacement dose calculated for adults based on body weight has led to a high frequency of adverse side effects, related primarily to fluid retention (eg, paresthesias, joint stiffness, myalgia). Instead, initiation in adults is with low doses followed by gradual uptitration to reach normal IGF-1 levels.

6. Which of the following is/are known health benefits of GHRT in AGHD?

GHRT is known to improve exercise capacity and cardiovascular risk markers such as diastolic blood pressure and total cholesterol; GHRT has also been shown to increase bone mass and lean body mass.

 F1000Res. 2017; doi:10.12688/f1000research.12057.1.
 

Molitch ME, Clemmons DR, Malozowski S, et al. 

Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline.

 J Clin Endocrinol Metab. 2011;96:1587–609. 10.1210/jc.2011-0179

Find out what you know about the facts and some emerging evidence.

Adult GH Deficiency: Quick 6-question Quiz 

Researchers recently evaluated the use of a score that measures the impact growth hormone replacement therapy (GHRT) has on clinical factors associated with adult growth hormone deficiency (AGHD) and found the score was clinically different in patients who did not receive replacement therapy, according to a recent prospective, multicenter proof-of-concept study.

The Growth hormone deficiency and Efficacy of Treatment (GET) score was developed by incorporating a weighted score into six clinical factors associated with (AGHD):

• Health-related quality of life (40%)
• Bone mineral density (20%)
• Waist circumference (10%)
• Body fat mass (10%)
• Low-density lipoprotein (LDL) cholesterol (10%)
• Disease-related days off of work (10%)

“The newly developed GET score appeared to be a suitable instrument to summarize the features of AGHD and evaluate the pleiotropic response to GH substitution therapy in an integrated way,” Peter H. Kann, MD, PhD, from the Division of Endocrinology & Diabetology at Philipp’s University Marburg in Marburg, Germany, and colleagues wrote in their study. “We suggest the GET score as a tool for clinical studies rather than for routine clinical practice.”

To test the GET score, the researchers analyzed 106 patients who were treatment-naÃ¯ve at baseline; of these, 53 men and 31 women received GHRT according to their physician’s usual clinical practice, while 13 men and 9 women did not receive GHRT. The baseline average for GET was 51.66 ± 20.48 points and baseline scores were similar between untreated and treated groups as well as by gender.

 GET-associated SF-36 scores improved for women (4.64 ± 24.14) and men (0.96 ± 14.42) in the physical functioning, physical role functioning (women: 5.36 ± 25.66; men: 1.92 ± 30.4) and emotional role functioning (women: 12.05 ± 26.00; 1.39 ± 20.17) components of the score.

âº Women in the study had a decrease of 30.00 ± 63.44 days in disease-related days off work, while there was no significant change in men.

âº There was an decrease in waist circumference among women (–2.86 ± 5.15 cm) and men (–1.23 ± 7.55 cm) in the GHRT group from baseline compared with an increase in waistline among women (2.67 ± 5.28 cm) and men (3.86 ± 4.84 cm) in the control group.

âº Women saw a 0.85% ± 1.06% increase and men saw a 3.46% ± 3.07%   in body fat in the control group compared with a decrease of body fat among women (−2.29% ± 4.14%) and men (−1.93% ± 4.52%) in the GHRT group.

âº From baseline, there was a slight increase in LDL cholesterol among patients in the control and a slight decrease in the GHRT group.

âº The authors noted a small number of patients underwent dual-energy X-ray absorptiometry to measure bone mineral density and there were small fluctuations throughout the study period that did not meaningfully change from baseline.

One major limitation of the study was the significant number of patients (75 of 106 patients) who did not receive a GET score from their baseline because of lack of data. “This was surprising since the score was designed so that a GET score could be calculated with a total weighting of variables of only 70%, to account for potential missing data in a real-world setting,” the authors wrote.

Dr. Kann and colleagues noted future studies in a larger patient population with longer follow-up could overcome some of the limitations encoutered in this proof-of-concept study.

 Kann PH, Bergmann S, Bidlingmaier M, et al. 

Design of the Growth hormone deficiency and Efficacy of Treatment (GET) score and non-interventional proof of concept study.

The new score was developed by incorporating a weighted score into 6 clinical facgtors associated with AGHD.

Novel Score Identifies Efficacy of Replacement Therapy in AGHD Patients 

Source: Brod, M, Beck, JF, HÃ¸jbjerre, L, et al. Assessing the impact of growth hormone deficiency in adults: interpreting change of the treatment-related impact measure-Adult Growth Hormone Deficiency (TRIM-AGHD). Pharmacoecon Open. 2018. https://doi.org/10.1007/s41669-018-0082-3

Slideshows

TRIM-AGHD was found in this study to be highly responsive to patient-reported response to treatment in adults naïve to GH therapy.

The TRIM-AGHD: Measuring Response to Treatment 

The novel growth hormone derivative somapacitan taken once-weekly was associated with similar mean insulin-like growth factor (IGF) 1 scores compared with once-daily Norditropin in patients with adult growth hormone deficiency (AGHD), according to results from a 26-week trial published in the European Journal of Endocrinology.

“Although daily GH is administered with the use of fine needles which minimize pain, some patients still find a daily regimen burdensome, particularly because treatment may last for several years or even be lifelong,” Gudmundur Johannsson, MD, PhD, from the University of GÃ¶teborg and Sahlgrenska University Hospital in GÃ¶teborg, Sweden, and colleagues wrote in their study.

Dr. Johannsson and his colleagues performed a randomized, controlled phase 3 trial of 92 patients from 26 centers in 6 countries with AGHD. Patients were between 18- and 79-years-old and received once-daily GH for a minimum of 6 months before being randomized to receive once-weekly somapacitan (61 patients), which is a novel reversible albumin-binding GH derivative, or once-daily Norditropin (31 patients). Each group was titrated for 8 weeks to achieve normal IGF-1 standard deviation score (SDS) values prior to administration of somapacitan or Norditropin. Patients in the somapacitan group received a starting dose of 1.5 mg per week followed by mean 1.96 mg per week for 18 weeks; in the Norditropin group, the mean dose was 0.20 mg per day.

The researchers said more than 1,500 injections occurred in the somapacitan group with no clinically significant injection site reactions. Regarding satisfaction, the mean score for convenience as reported by patients in the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) increased by 15.3 points to 83.8 from a baseline of 68.3 compared with an increase of 3.0 points to 75.8 from a baseline of 71.7 in the TSQM-9 (P = .0171), which indicated patients believed somapacitan was more convenient than Norditropin.

There were 3 patients each in the somapacitan (4.9%) and Norditropin (9.7%) groups who withdrew from the trial. In both groups, IGF-1 SDS were between mean 0 and 2 during the trial, with values of mean 0.22 SDS in the somapacitan group and 0.35 SDS in the Norditropin at the end of the trial. With regard to adverse events, 86.9% of patients in the somapacitan and 67.7% of patients in Norditropin groups reported events such as nasopharyngitis, fatigue, and headache; there was 1 case of hematoma after the third dose and 1 case of bruising after the second dose, researchers noted.

Researchers noted a potential limitation in the trial-that body composition changes, quality of life, and other clinical outcomes were not measurements of efficacy since patients were already receiving GH therapy prior to trial enrollment.

“On the other hand, study strengths lie in the fact that it was a randomized trial in which somapacitan was compared head-to-head with hGH in AGHD patients already using daily GH replacement treatment,” the authors concluded. “Thus, the current study adds important data for patients who will switch from daily to weekly therapy.”

 Johannsson G, Feldt-Rasmussen U, HÃ¥konsson IH et al. S

afety and convenience of once-weekly somapacitan in adult GH deficiency: a 26-week randomized, controlled trial. 

The once-weekly novel growth hormone derivative was favored over once-daily hGH in this head-to-head trial that evaluated treatment satisfaction.