Risk of Growth Hormone Deficiency Rises In Survivors of Childhood Cancers

Seeking better overall care, as the prevalence of cancer survivorship grows in the pediatric population, so may the risk for late effect growth hormone deficiency, particularly among those receiving radiation.

With Jad G. Sfeir, MD, and Mark Molitch, MD

Growth hormone deficiency (GHD) is a rare cause of short stature in childhood, with a prevalence of about 1 in 4000 people in the United States.1,2 As such, the diagnosis of GHD remains challenging in both the general pediatric and adult population, owing to the absence of a true gold standard for diagnosis.2,3

While childhood cancers remain relatively rare with 15,270 cases annually,4 it behooves endocrinologists and primary care practitioners to anticipate that GHD is a late effect of radiation therapy among childhood cancer survivors,5 according to findings of a paper published in the Journal of Clinical Endocrinology and Metabolism.

Children and adolescents need better diagnostic tools to catch growth hormone deficiency.Growth hormone deficiency is more likely to arise in young adults who were treated with radiation for childhood cancers.

This will assure a more proactive approach to diagnosis, using the most advanced tools available, which will, in turn, assure better and earlier treatment for our patients,5 said lead author Jad G. Sfeir, MD, FACP, assistant professor of medicine at the Mayo College of Medicine in Rochester, Minnesota.

Limitations of Current Diagnostic Techniques for GHD 

Currently, the diagnosis of growth hormone deficiency is made based on auxology and clinical judgment, with supporting evidence from biochemical and neuroradiological studies.1-3 Yet the limitations of growth hormone provocation tests, considered the mainstay of diagnostic assessment, are well-known.

In particular, the diagnostic tools are poorly reproducible, 1-3 as:

  • The measured GH concentration can vary significantly with stimulation test and different GH assays.
  • Test results are influenced by body composition, nutritional status, and pubertal status.
  • There is limited evidence for the cut-off values used to distinguish between GH deficiency and non-GH deficiency.

There are also controversies and questions regarding the use of adjunct biochemical markers, including insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3). 1-3Low serum levels of IGF-1 or IGFBP-3 are suggestive of GHD in adults, but normal levels of IGF1 do not exclude the diagnosis.5

While these tests do not appear to have diagnostic value when used in isolation, they appear more efficacious when combined with other tests.5 For example, pituitary magnetic resonance imaging (MRI) appears useful to inform a diagnosis of growth hormone deficiency, as pituitary abnormalities have been linked with an increased risk for GHD, persisting into adulthood.1,3 While the insulin tolerance test (ITT) is considered a gold standard diagnostic test of GHD in adults, it may not be viable owing to its increased risk for potentiating hypoglycemia and seizures.6

Ability to Detect Growth Hormone Deficiency  in Children and Adolescents

Advances in the treatment of childhood cancers have led to improved survival rates, which in turn, has elevated the risk of late-onset complications–or late effects–of the cancer treatments, particularly as a result of radiation therapy.5 The lifetime prevalence of endocrine late effects in this population is estimated at 50% with hypothalamic/pituitary (HP) irradiation is a primary risk factor. Growth hormone deficiency is the most common, and often sole, endocrine late effect following radiation treatment for pediatric cancer.5

In an interview with EndocrineWeb, Dr. Sfeir indicated that there has been very limited research regarding the best diagnostic tool to identify GHD in cases of childhood cancer.

Assessing Functional Detection of Growth Hormone Deficiency after Pediatric Cancer

Towards this end, Dr. Sfeir and colleagues performed a systematic review of studies regarding the diagnosis of GHD in CCSs, in combination with IGF-1 or IGFBP-3 measurements compared with GH dynamic testing.[Sfeir 2018]

This review encompassed 15 studies evaluating diagnostic tools to identify growth hormone deficiency—eight involving insulin-like growth factor-1 (IGF-1) and seven utilizing insulin-like growth factor binding protein-3 (IGFBP-3)—with more than 475 patients enrolled overall. In effect, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy, alone or when used in combination.5

As Dr. Sfeir said, “in addition to the lack of both a gold standard diagnostic test and a control group, they could not ‘objectively evaluate the performance of a certain test when the study methodology is not set out to do so (in a limited number of studies);… the studies spanned 3 decades and in the face of a rapidly changing technology, particularly in laboratory medicine, this limits the homogeneity of the studies.’”

“Dynamic tests remained the most accurate in identifying patients with GHD,” Dr. Sfeir told EndocrineWeb, while the insulin tolerance test (ITT) seems to be the most accepted reference test, alone or in combination with arginine.5 “However, each institution had its own protocols for dynamic testing, and local experience and expertise remains key in the absence of a gold standard.”

“The newest Endocrine Society Clinical Practice Guideline,7 which was released at the same time as this systematic review, also emphasizes the importance of life-long screening in this population,” he said. The Endocrine Society guideline recommends against relying solely on IGF-1, GHRH alone or in combination with arginine, or spontaneous growth hormone secretion in the diagnosis of GHD in this population, and recommends for the use of the same provocative tests that are used in the non-cancer population to diagnose GHD.[Sklar 2018]

“The best laboratory test to diagnose growth hormone deficiency has yet to be identified,” said Dr. Sfeir. “Ultimately, the systemic review demonstrated the importance of the physician’s clinical judgment in suspecting GHD and using tools (such as GF levels or provocative tests) only to confirm the diagnosis. The study highlights the need for further clinical studies in this population.”

Going Forward: Stepping Up Surveillance of Growth Hormone Deficiency

“Most pediatric cancer patients are followed throughout their life in a dedicated, long-term surveillance program with appropriate referrals,” Mark Molitch, MD, Martha Leland Sherwin Professor of Endocrinology in the Division of Endocrinology, Metabolism & Molecular Medicine at Northwestern University Feinberg School of Medicine in Chicago, Illinois, told EndocrineWeb.

Although it is uncommon for endocrinologic concerns to arise in between patients’ yearly visits that may necessitate seeking care from community-based endocrinologists, it is certainly important for all practitioners to be cognizant of the risks of endocrine late effects, including GHD as well as other endocrine diseases.

Dr. Molitch cited evidence from a Danish population-based cohort study that followed more than 32,500 adolescent and young-adult cancer survivors for a median of 10 years.8 In this study, the investigators found a statistically significant increased relative risk of endocrine disease among cancer survivors, with greatest risks for testicular or ovarian hypofunction and pituitary hypofunction. Other common endocrine disorders observed in this cohort included hypothyroidism and diabetes.8

 “When considered along with the review study by Sfeir and colleagues,5 all endocrinologists need to be familiar with the endocrine risks that may arise among childhood cancer survivors,” Dr. Molitch said.

Dr. Sfeir emphasized that over the next few decades, “the number of children treated for cancer and surviving will increase significantly given the myriad of existing and anticipated medical advances.”

“As these pediatric patients progress through adulthood, we will encounter them in all practice settings and hopefully have a better appreciation for the long-term endocrine consequences of cancer treatment, particularly HP radiation,” he said. “It thus becomes important for us as practicing endocrinologists to closely follow these patients, whether clinically or through continued enrollment in national registries and research.” 

Continue Reading:
Causes of Child Onset Growth Hormone Deficiency Impact Adult Mortality and Socio-Economic Status
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