Introduction to Growth Hormome & Down Syndrome

Petronio Filho
Brasilia, Brasil

Hormone Functions
     Growth Hormone (GH), also called somatotropin, is a peptide hormone secreted by the anterior lobe of the pituitary gland. This hormone has several important functions. It stimulates skeletal growth as well as the growth and constant repair of many organs. It also has a powerful effect on metabolism and in the immune system. And recent studies have proven that it enhances cognitive functions in older subjects.
     Growth hormone is not the only hormone related with growth. Thyroid hormone, the sex hormones testosterone and estrogen, and the pituitary gonadotropic hormones are all known to influence growth.

Treatment History
     GH was isolated in animals in 1945 and in humans in 1956. The first GH treatment took place in 1957, when Maurice Raben of Tufts University Medical School used GH to make a short boy grow six times as fast as before the treatment.
     During the initial decades, natural GH was extracted from donated cadavers' tissues. There was a major scarcity of the product, and the treatment was extremely expensive. In 1971 GH was finally synthesized in laboratory. This discovery could have represented a major boom in the treatment, but the Food and Drug Administration (FDA) required more than a decade of studies and tests before authorizing the sale of synthetic GH.
     In October 1985, synthetic GH was finally approved by the FDA. Since then, several brands of synthetic GH were introduced in the market. Thanks to increased competition, GH prices diminished drastically during the last decade. Now the treatment can be afforded by average income families. And if the patient has proven GH deficiency, health insurance might sponsor the treatment.

Complications and Risks
     After over 40 years of treatment of children with GH deficiency, no significant metabolic, visceral or immunological side-effects have been found. But some rare side effects should be mentioned. A few patients develop hypothyroidism or insulin resistance. There is also a slight increase in slipped growth plates.
     The sole serious doubt concerns 18 cases of leukemia reported in GH-deficient (non-Down syndrome) patients 10 to 23 year of age who were treated with GH. This number is calculated to be 1.5 times the rate for healthy individuals, but the comparison is misleading. In order to attribute GH for the increased incidence of leukemia one would need to compare it with the incidence observed in GH-deficient untreated individuals. Unfortunately there is no such data. It is not know whether the increased incidence of leukemia is related to GH-deficiency itself, GH treatment, or neither. Regardless, it is important to notice that the incidence of leukemia is not high: it affects one patient in every 24.000 patient-years1.

The Controversy over Growth Hormone Deficiency Tests
     Unfortunately, growth hormone deficiency is far from being an easy diagnosis. The human body continually manufactures GH throughout the day, and the pituitary does it in surges. So there are dramatic ups and downs in our blood concentration of GH. The largest surge of GH occurs at night, one or two hours after sleep. During the day, our blood concentration of GH changes every three hours.
     Testing for growth hormone deficiency is indicated only when all other possibilities for slow growth have been ruled out. The available tests require several blood samples and are not very trustworthy. The patient takes an injection of a substance known to stimulate GH (such as clonidine, L.dopa, ornithine, glucagon, etc.) and blood samples are taken several times to measure the rise in GH concentration. The patient will be considered GH-deficient if s/he does not secrete GH at an appropriate level. Most laboratories will perform this test in 3 hours.
     In the U.S., most health care professionals would not recommend GH therapy unless the individual is growth hormone deficient. But several practicing doctors don't think too much of the GH deficiency tests. They consider them complicated, uncomfortable and unreliable. A patient might test positive with substance A and negative with substance B.
     According to Schulman and Sweitzer, "in the uncertainty over testing, some experts in Europe, especially, but also a minority in the U.S. finally said in so many words: So much for GH tests. Let's try short kids on GH and if they grow they must need it"2.

Growth Hormone Treatment in Down Syndrome (DS)
     It is known that children with Down syndrome have a reduced growth pattern. According to Dr. Siegfried Pueschel, the expected height of the adult male with Down syndrome varies from 4 feet, 8 inches (1.42 meter) to 5 feet, 5 inches (1.65 meter). The height of the adult female is approximately between 4 feet, 5 inches (1.34 meter) and 5 feet, 3 inches (1.60 meter)3.
     All children with DS would be potential patients for GH therapy if it was not for the fact that several of them test negative in some GH deficiency tests. This is strange because most people with DS have normal growth as a response to GH therapy. Experts like Dr. Castells believe that when children with DS have a good response to GH therapy it might indicate that they need it:

"...What does it matter what the testing shows? If growth velocity accelerates with recombinant GH treatment, they must have insufficient GH production. It has been suggested that a trial test of GH for a period of six months or one year may be important to determine if a deficiency of GH is present. Our data on recombinant GH treatment showed very clearly that GH is effective in treating short stature in Down's syndrome."4
     The first GH treatments for people with Down syndrome started in the late eighties. The results of these studies are very promising. Most of the treated children have the benefit of normalized head circumference and increased height.
     In a five-year study involving 12 children with DS with microcephaly (abnormally small head) and severe growth retardation, there was not only a dramatic increase in growth velocity, but also reversibility to normal head circumference in all children with DS. Bone age did not advance during the period of treatment as compared with chronological age. No side-effects were observed5.
     Another recent GH study consisting of 16 very young children with DS without proven GH deficiency had positive results. After three year of treatment, 15 children had normal growth and no significant side effects. 1 child was excluded after 12 months because of increased aminotransferases (which was probably not caused by GH). The treated children also had a significant improvement in fine motor skills compared to the control group. No acceleration of bone age was observed. This study was very significant because it involved very young children without proven GH deficiency6.
     Most parents of GH-treated children are enthusiastic about GH therapy, but the medical organizations warn that the number of children treated is small, and the long term effects are not known.

My Testimonial
     I am the father of Bibiana, a girl with DS. My daughter was 2 year and 10 months old when she was started on GH. At the beginning of the treatment she was 82 cm tall. Her height was normal for children with DS, but extremely short compared to normal children. In fact, she was 13 cm (5.1 inches) below the 50th percentile curve for normal girls.
     Bibiana grew up 32 cm during 3 year and 8 months of GH therapy. Now she is a girl of near-average height. She is only 4 cm (1.6 inch) below the 50th percentile curve for normal girls.
     I also noticed positive results in head growth, greater muscle strength and decreased fat percentage. There were also some subjective benefits which are difficult to report.
     I am not a doctor and this article should not be considered medical advice.

Recommended Reading
     Understanding Growth Hormone by Schulman and Sweitzer's is an excellent introduction for parents. This book is about GH treatment in general. It does not have information about DS.
     Doctors and health care professionals might be interested in reading Growth hormone treatment in Down syndrome, published by John Wiley & Sons, New York, 1993, edited by S. Castells and K. E. Wisniewski. This book reports the results of the International Conference on Growth Hormone Treatment in Down's Syndrome. This conference took place in New York on October 1992, and was attended by 125 people. The book includes several papers presented during the conference, a summary of the discussions and two parents testimonials.

References

  1. This incidence was obtained by the Lawson Wilkins Pediatric Endocrine Society (LWPES) and was presented at the International Workshop on Growth Hormone and Leukemia in May 1988.
  2. Neil Shulman and Letitia Sweitzer. Understanding Growth Hormone. New York: Hippocrene Books, 1993, p. 128.
  3. Siegfried M. Pueschel. Parents Guide to Downs Syndrome: Toward a Brighter Future, 4th edition. Baltimore: Paul H Brookes Pub, 1995, p. 96.
  4. Summary Discussion of Presentations of the First Day in S. Castells and K. E. Wisniewski (ed). Growth Hormone Treatment in Down's Syndrome. West Sussex: John Wiley & Sons Ltda., 1993, p. 223.
  5. Salvador Castells, Islande Beaulieu & Krystina E. Wisniewski. Long-term effects of Recombinant Human Growth Hormone (rhGH) on Children with Down's Syndrome with Short Stature in S. Castells and K. E. Wisniewski (ed). Growth Hormone Treatment in Down's Syndrome. NY: John Wiley & Sons Ltd., 1993. pp. 163-182.
  6. Annerén G, Tuvemo T, Sara VR, et al. Growth Hormone Treatment in Young Children with Down's Syndrome: Effects on Growth and Psychomotor Development. J Endocrinol Invest 80: 334-338 (1999).
 
  Revised: July 3, 2001.