ENDOCRINE EXPLAINED

Growth in childhood follows a typical pattern: rapid growth from birth to two years, slower growth from toddlerhood through puberty, a rapid phase of growth called a growth spurt during puberty, and slower growth thereafter through the end of growth and a final height is reached. 

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In the first two years of life, a child's size may shift significantly from birthweight and length to a percentile that is consistent with their parents' sizes. This shift to a child's genetic potential is often referred to by pediatricians as a child "finding their curve."

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Thereafter, children usually follow a percentile through the onset of puberty. The amount of growth differs for each child, ranging from almost 2 inches to 3 1/2 inches per year, with shorter children growing less per year than the taller ones.

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The production of estrogen and testosterone causes an increase in the rate of growth, called a "growth spurt." Since normal puberty starts between 8-14 in most children, that is when we expect to see the start of a growth spurt, with an average growth spurt starting at about 10 in girls, and 12 1/2 in boys. Growth spurts vary, both in intensity and duration, but average about 3 1/2 inches per year, with shorter children typically having a slower peak growth velocity, and taller children with more rapid growth.

 

Growth commonly slows two years following the onset of the growth spurt, and is dependent upon how rapidly the skeleton matures in puberty. Growth is complete for most girls by 15 years, and for boys by 17 years.

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Physicians assess these patterns at a child's yearly check-up, when they follow the progression of a child's height and weight on a graph that plots each point by their chronological age, and is adjusted for sex. The charts have percentiles marked, with channels outlining ranges: 10-25th percentile vs. 75-90th percentile. This allows the physician to note if there is a trend showing declining or rising percentiles, and to determine if this is normal - within the range of one channel - or bears investigation. 

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More detailed information about children's puberty can be found here.

 

What is the definition of short stature? Short stature is when a child's height is significantly less than what would be expected. This means they are either particularly small for their family, or - if family members have significantly short stature - than significantly small for the general population. Officially, this means that a child's height is less than the 2.3rd percentile, OR is several inches shorter (at least 45 percentiles less) than the expected percentile in a tall family.

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If my child is short, should they take Growth Hormone? This is the big question so many have when then walk into my office. And the answer is: it depends. So, let's start by reviewing what growth hormone is, who is more likely to grow if they take GH, and what other factors may be playing a role in growth and a child's final height.

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What is Growth Hormone? Growth hormone (GH) is a protein hormone made in the pituitary gland that is one of the main ingredients that supports growth in children. It is also important for maintaining a normal - and not low - blood sugar, normal function of the liver and intestines, other pituitary hormones for energy and pubertal development, psychological brain health, muscle development and well-being. 

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What is GH used for? Most of the children who use growth hormone have a diagnosed growth hormone deficiency - mostly isolated, but others due to multiple pituitary hormone deficiencies. Others have short stature due to known causes, such as Turner syndrome, SHOX deficiency, Prader-Willi Syndrome, Noonan Syndrome, or geneticist-diagnosed growth hormone receptor mutation. GH is used for height growth in these conditions, chronic kidney disease, prevention of low blood sugar in infants, muscle growth in Prader-Willi syndrome, and for intestinal growth in those with Crohn's disease and short gut syndrome. 

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What is growth hormone deficiency? Growth hormone deficiency (GHD) means that someone does not make enough GH for normal body processes. GHD is defined as having a combination of multiple factors that can be caused by low GH. These include having most of the following to assure a correct diagnosis of GH deficiency: a history of low blood sugar in the newborn period, multiple pituitary hormone deficiencies, significant short stature, significantly slow growth, short predicted height for the family and/or for the general population, low IGF-1 levels, low GH on GH stimulation test, and no other explanation for these were found through their evaluation.

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Why does my child have GHD? Typically, children are born with GHD. In more significant deficiencies, a child may be born somewhat small, and has difficulty maintaining normal blood sugars in the newborn period. In these infants, growth further slows after the first 6-12 months of age. In the first few years, a child's height declines to a low percentile, either for the general population (less than 1.2 %), or for the family. Because children need so much more GH to grow once they start puberty, some children with a more mild isolated GH deficiency have an absent growth spurt, so are evaluated for declining height percentiles as their peers are rapidly growing. These deficiencies are often inherited, or may result from a pituitary gland formed in an ectopic, or atypical, location. Sometimes there is more than one pituitary hormone that is deficient, with replacement of multiple deficiencies allowing a child to grow and thrive.

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Otherwise, a child may have had a concussion, resulting in trauma to the pituitary. Since GH is the most frequent deficiency after brain trauma, a child's slow growth after TBI may be a clue that there is GHD - even years after the event. Rarely, a child may develop pressure on the pituitary causing destruction of the gland and its blood supply, due to a brain tumor, surgery or radiation therapy to treat a tumor, or inflammatory destruction of the pituitary. While these are rare, any sudden decline in growth warrants an urgent evaluation for these diagnoses so they can be addressed promptly.

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Last, there may be another condition that causes GHD. Hypothyroidism, elevated prolactin, sleep apnea, and medications can cause abnormal GH secretion.  As a result, many tests are evaluated before determining there is GHD.

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What is a Growth Hormone Stimulation test? GH is secreted by the pituitary gland at night, so checking a level in the blood during the day requires the use of medications that provoke GH to be secreted during a time that it can be evaluated. This is called a "Growth hormone stimulation test". Since GH is naturally secreted when blood sugar is very low, as part of the body's way to increase blood sugar to normal, testing is performed when a child has not yet had breakfast - in a fasting state. Medications used are Insulin, Glucagon, Arginine, Clonidine, and L-Dopa. GH levels in the blood are measured for up to 3 hours after medications are given, usually checked every 30 minutes. If all levels are less than a certain amount, usually less than 10 mcg/L, it is consistent with a diagnosis of GHD.

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The first - and "gold standard" - stimulus is a rapid insulin infusion that reduces blood sugar to a low level. After insulin is given, blood sugar is measured every few minutes - or if the person develops signs or symptoms of low blood sugar. Blood is drawn to measure the level of GH at the time of the low blood sugar. Side effects include the unpleasant sensations of low blood sugar, including anxiety, hunger, sweating and shakiness, with the risk of seizure if the blood sugar drops too low. Because of this risk, alternate medications are generally used in children. Once blood is drawn, the low blood sugar is treated with food and drink.

 

Arginine is an amino acid, and a 10% IV solution is rapidly infused over 30 minutes. Side effects are related to low blood sugar that can occur, allergic reaction, and infusion in a vein that has a leak from when the IV was placed, causing pain and potential harm to the skin and underlying tissues in the area. Its effects typically wear off by the end of the test.

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Clonidine is a medicine that reduces the action of adrenaline. It is given as an oral tablet that can be chewed or swallowed whole. The main side effects are low blood pressure and sleepiness. Low blood pressure is treated by giving hydration during the test, in the form of IV saline, or salt water, to keep blood volume a little bit greater than usual. The medication effects typically wear off by dinnertime.

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Glucagon is a medicine that is given to sharply increase blood sugar - which then causes a rapid decline in the blood sugar level. This is used similarly as an insulin test, but has a more predictable decline of blood sugar, so is considered safer to use. Since blood sugar levels drop quickly, the uncomfortable signs and symptoms of low blood sugar occur, but resolve quickly with treatment of the low blood sugar.

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L-dopa is an oral medication, transformed into dopamine in the brain, where its action on the hypothalamus leads to GH secretion. Side effects are nausea and frequently vomiting, generally limited to 1-2 hours.

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What is IGF-1? Somatomedin-C, aka Insulin-like Growth Factor-1, is made in the liver in response to GH. Its synthesis is also dependent on adequate nutrition. As a result, IGF-1 is low when there is low GH, in conditions in which there is a low response to GH, or if there is undernutrition. If there is undernutrition, it is important that increased calories or treatment of any underlying condition is addressed so that growth and IGF-1 can be evaluated with normalized weight and/or absorption of nutrients.  Celiac disease, Crohn's and colitis, ARFID and constipation are important to address for a child's emotional and physical health - and growth - as well as normal IGF-1. If nutrition is normal, and a child is thought to be otherwise healthy, but has a low IGF-1, this is consistent with GHD.

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What is a bone age? The skeleton changes dramatically over time, forming bone where there was once cartilage. Since cartilage is not visible on an x-ray, but the minerals in bone are, the maturation of the bones of the left hand are evaluated according to films standardized in the last century. A child's hand x-ray - their "bone age" - is compared to these standards, which are then compared to their chronological age. Typically, a child with GHD has bones that are less mature than 97.5% of other children their age - a "young" bone age. Formulas for how much more growth bones are going to grow were developed and refined over the last 70 years, originally by Bailey and Pinneau.  They are variable in their accuracy for an individual child, but give a general sense of the maturity of the skeleton. A "height prediction" is made based on height and concurrent bone age, with that prediction compared to the parents' heights and of the general population. If the bone age is "young", and the prediction is at least 4 inches shorter than would be expected for the family, or short for the general population, this is consistent with GHD.

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How is growth hormone taken? GH is a protein, or peptide, hormone. Like any protein, if it were taken orally, it would be digested in the stomach and intestines. To avoid digestion - to remain useful in its function, as a whole protein - it must be injected, usually 6-7 evenings per week. The needles used are very small, with GH injected into the fat layer just under the skin. 

 

The dose of GH varies from person to person, and changes over time as a child grows and enters puberty. Different brands contain different ingredients, some of which are more acidic - so sting - more than others, and others contain preservatives that cause allergic reactions in some children. Some formulations come as a pen that is ready to use, others as a vial or pen cartridge that needs to be mixed with a diluent, or solution, and mixed. All brands are considered effective to promote growth by the FDA, with the brand used usually dictated by a child's insurance or pharmacy plan.

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If my child takes growth hormone, how much will they grow? This is impossible to predict, as each child's response is different. The amount of growth depends on the dose being just enough to promote normal growth, but not so much that skeletal maturation is overly rapid and results in a shorter duration of therapy to permit catch-up growth. That sweet spot changes over time, with dose adjustments needed for weight, puberty, health and individual factors.

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Typically, there is considerable catch-up growth in the first 12-18 months of therapy, usually until the age when bone age catches up to a child's chronological age. Thereafter, growth velocity is more normal or only mildly rapid until the final 6-12 months of therapy. At that time, growth slows considerably, and then stops with near-maturation of the skeleton.​ After growth is complete, growth hormone replacement therapy is discontinued in the vast majority of teens.

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What side effects are associated with GH treatment? If given in an appropriate dose, there should be minimal side effects. A small percentage of children develop increased pressure in their brain from increased CSF production. An equally small percentage of children develop instability of the hip, termed SCFE. For these children, GH is halted, with the concern addressed, and restarted - with a lower dose - only following treatment and reevaluation. With small doses that are increased appropriately, these side effects are rare. More typically, there is increased growth of the hands, feet, nose and ears during treatment. Fertility appears to be unaffected. ​There are no clear concerns for long-term risks unless treatment is with inappropriately high doses of GH. These include risk of diabetes and certain cancers, but only at high doses, which most pediatric endocrinologists are careful to avoid prescribing.

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If it's not GHD, why is a child short? There are dozens of reasons why a child might be growing slowly, or is short compared to their peers. Typically, pediatric endocrinologists check for low thyroid hormone levels, celiac disease, and measures of health in blood tests and by history to determine if there are other conditions that may be affecting growth. If there is another diagnosis that may be contributing to slow growth or short stature, it is strongly recommended that it is treated first to see if correcting that concern can normalize growth.

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What is Idiopathic Short Stature? ISS is "Idiopathic" Short Stature, a term used when there isn't a clear medical cause for a condition. ISS includes the short stature, slow growth, and short predicted height of GHD, and lack of other explanation for them, but their measured levels of GH on a GH stimulation test are normal. In my own practice, children with true ISS are few, with undiagnosed or as yet undiscovered genetic causes likely for most of them. That said, for those with true ISS, GH treatment can be used under certain guidelines, but doses required for growth are generally high, and results at maturity - their final height - vary widely.​ 

 

For most short and/or slowly growing children, it is likely multiple factors - heredity in height and puberty, as well as nutritional, medical, and functional challenges - that are additive and contributing to a child's growth pattern. Each of these must be evaluated for a comprehensive understanding of a child's slow growth. Addressing the unique set of underlying causes for a particular child can avoid treatments - like GH - that may superficially promote growth in the short term, but fail to maximize growth or health for a child's lifetime. 

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To schedule a two-hour appointment with Dr. Lerner to learn more, to discuss a

child's evaluation and diagnosis with slow growth, short stature, or growth hormone deficiency,

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Resources:

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1. Hormone Health Network: https://www.hormone.org/diseases-and-conditions/growth-hormone-deficiency

2. WebMD: https://www.webmd.com/fitness-exercise/human-growth-hormone-hgh#1

3. EMedicine Pediatric Growth Hormone Deficiency: https://emedicine.medscape.com/article/923688-overview