Dr. Maya Lodish, pediatric endocrinologist
National Institute of Child Health and Human Development
National Institutes of Health, Bethesda, MD
Survivors of childhood brain tumors are at an especially high risk for damage to the endocrine system. The endocrine system is comprised of glands and hormones that help to control specific functions of the body, such as metabolism, growth, puberty and reproduction. Glands of the endocrine system include the pituitary, hypothalamus, thyroid, adrenals, pancreas, ovaries, and testes. Data from the Childhood Cancer Survivor Study has shown that endocrine disturbances occur in 43% of childhood brain tumor survivors (1), as self-reported by patients; other studies have found rates ranging from 50%-70% (2,3). Characteristics of the malignancy itself, in addition to characteristics of the treatment received (i.e. surgery, radiation, chemotherapy), influence the risk of developing long-term endocrine side effects.
In this article, we will focus on one of the possible late-effects seen in childhood brain tumor survivors called hypopituitarism. In this disorder, the pituitary gland fails to produce one or more hormones. The pituitary is a small gland located at the base of the brain that releases hormones with important functions in the body, including growth, regulation of blood pressure, and reproduction. Hypopituitarism may sometimes develop suddenly; however, more often the symptoms develop gradually, even years after treatment is complete. There is a strong correlation between the total radiation dose and the development of pituitary hormone deficiencies. The exact symptoms of hypopituitarism depend on which hormones are affected, and many of the deficiencies may be treated successfully with hormone replacement. We will briefly touch upon each of the hormone deficiencies involved in hypopituitarism, including growth hormone deficiency, hypothyroidism, adrenal insufficiency, hypogonadism, and diabetes insipidus.
Growth hormone deficiency
Children who receive radiation to the brain or have neurosurgery are at risk for growth hormone deficiency from damage to the part of the brain that controls growth. Growth hormone is made by the pituitary gland in the brain, and as its name suggests, growth hormone is necessary to help children grow. In addition, growth hormone helps to maintain bone health, cardiovascular health, and muscle strength. Children with growth hormone deficiency will have slowing of their growth, which can be seen on a growth chart by downward crossing of percentiles. A good rule of thumb is to make sure that all childhood cancer survivors have their height measured every 6 months until they have completed growing. If there are signs of poor growth, an x-ray of the wrist called a bone age x-ray should be performed, as well as a blood test to measure insulin-like growth factor -1 (IGF-1) and your child’s doctor should investigate other possible causes of poor growth. If growth hormone deficiency is suspected, a pediatric endocrinologist may need to perform a special type of blood test called a growth hormone stimulation test. Treatment for proven growth hormone deficiency involves daily sub-cutaneous injections of synthetic growth hormone, which is prescribed by a pediatric endocrinologist.
Adrenal Insufficiency
Certain survivors of pediatric brain tumors who have received high doses of cranial radiation (> 40 Gy) or who have had surgical removal of the pituitary gland are at risk for the development of central adrenal insufficiency. Central adrenal insufficiency is caused by a deficiency of one of the pituitary hormones called adrenocorticotrophic hormone, or ACTH, that acts to stimulate the adrenal glands to make a hormone called cortisol. The pituitary gland needs to be functioning properly in order to send the ACTH signal to the adrenal glands for the body to make enough cortisol. Cortisol is an important hormone for helping the body respond to physical stress by regulating blood pressure and blood sugar. Symptoms of adrenal insufficiency may include weakness, fatigue, poor appetite, low blood sugar, nausea, or vomiting. For patients who have had high doses of cranial radiation, a morning cortisol level is a blood test that should be performed once per year to screen for central adrenal insufficiency. Often this test cannot rule out the disorder, and more specific tests may need to be performed by an endocrinologist to evaluate the problem. If central adrenal insufficiency is diagnosed, individuals are treated with hydro-cortisone replacement therapy, and specific recommendations are made for increasing the dose during times of increased physical stress such as surgery or illness.
Hypothyroidism
The thyroid gland is located in the neck and makes thyroid hormone, which is important for growth, neurological development, and control of metabolism. The pituitary gland controls the release of thyroid hormone through the release of thyroid-stimulating hormone (TSH); damage to the pituitary leading to low levels of TSH may cause an underactive thyroid gland (hypothyroidism). After a childhood brain tumor, damage to the thyroid gland directly from radiation to the neck or radiation to the brain may lead to hypothyroidism. This may not develop for years after treatment is complete, which is a reason that follow-up is important to detect and treat a thyroid hormone deficiency early. Possible symptoms of hypothyroidism may include increased tiredness, constipation, weakness, feeling cold all of the time, slow growth, weight gain, and dry skin. A yearly checkup to monitor growth in children who are childhood brain tumor survivors should include measurement of thyroid function tests. If diagnosed, central hypothyroidism can be easily treated with administration of a daily dose of oral thyroid hormone. Treatment of hypothyroidism is crucial to optimize growth, cognition, and pubertal development.
Hypogonadism
The gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), are made by the pituitary gland and control the production of hormones by the testes and ovaries. When survivors of a brain tumor do not have adequate amounts of these pituitary hormones, problems with progression of puberty and fertility can result. When boys enter puberty, the pituitary gland releases FSH and LH that signal the testicles to begin producing testosterone and sperm. Testosterone leads to voice changes, growth of the penis and testes, muscle development, and increased body hair. All children should be evaluated by their doctor for development through puberty with a yearly check-up that includes a puberty exam and hormone levels (LH, FSH, testosterone). The normal age ranges for pubertal onset are between 9 and 14 years for boys, and between 8 to 13 years in girls. If a boy is lagging behind his peers, he may need help to go through puberty by having testosterone prescribed by an endocrinologist. Testosterone is important for muscle strength as well as body fat, libido, and erectile function. When the pituitary gland is damaged, low levels of LH and FSH may result. When this happens, males will need to take testosterone replacement, usually given as a monthly injection up until puberty is complete and then as either a patch or gel. It is sometimes possible for men with central hypogonadism to have fertility function restored with the help of hormone treatments given by a fertility specialist. In girls, radiation therapy that affects the pituitary may also lead to low levels of LH and FSH. Both of these hormones are necessary for proper function of the ovaries. In girls, LH and FSH stimulate the ovaries to produce estrogen and progesterone, as well as to develop eggs and ovulate. A yearly check-up in survivors of childhood brain tumors should include careful evaluation of progression through puberty, and blood tests for hormone levels including LH, FSH, and estradiol should be performed. Girls who have hypogonadism will need estrogen and progesterone replacement to progress through puberty. Estrogen is also important to help maintain healthy bones. These hormones should be given in slowly increasing doses in order to mimic the normal progression through puberty.
Diabetes insipidus
The pituitary gland releases anti-diuretic hormone, or ADH, that manages water balance in your body by regulating urine production. If the pituitary does not release enough ADH, the patient will have excess thirst and urination, a condition known as diabetes insipidus. This is usually clinically diagnosed and verified by measurement of a blood and urine sample in the morning while fasting to see that the urine is inappropriately dilute and the blood is inappropriately concentrated. Diabetes insipidus is not caused from radiation damage to the pituitary gland but only from direct pituitary/hypothalamic damage due to surgery or tumor. Diabetes insipidus is treated with desmopressin, a synthetic version of ADH that is taken in pill form or as a nasal spray.
The endocrine system is particularly vulnerable to long-term side effects associated with brain tumors and their therapies. The early detection and treatment of potential problems that may arise as a result of a childhood brain tumor is crucial. Many of the endocrine related side effects are treatable, and early intervention may increase quality of life by limiting the impact of these complications on the patient’s health. With the knowledge that survivors of childhood brain tumors are at significantly increased risk for several adverse endocrine late effects, lifetime medical surveillance and follow up is critical, especially as some of the treatment-related complications may occur many years after therapy.
1. Gurney JG, Kadan-Lottick NS, Packer RJ, et al. Endocrine and cardiovascular late effects among adult survivors of child-hood brain tumors: Childhood Cancer Survivor Study. Cancer 2003;97:663-73.
2. Shalitin S, Gal M, Goshen Y, et al. Endocrine Outcome in Long-Term Survivors of Childhood Brain Tumors. Horm.Res. Paediatr. 2011 Jun 17. [Epub ahead of print]
3. Cohen LE. Endocrine late effects of cancer treatment. Endocrinol. Metab. Clinic North Am. 2005 Sep;34(3):769-89, xi.
2012 Dr. Maya Lodish is a pediatric endocrinologist at the National Institute of Child Health and Human Development, at the National Institutes of Health in Bethesda, Maryland. She is an assistant clinical investigator in the unit on hormones of cancer, and her clinical research focuses on the endocrine-related care of pediatric cancer survivors. More information about her clinical research is available at:
http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2007-CH-0192.html