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Growth Hormone Replacement Therapy

by Jenna Algozzine, Pharm.D. Candidate, University of Florida College of Pharmacy

Recombinant human growth hormone (rhGH) is often abused in combination with anabolic steroids to increase muscle strength and athletic performance. The illicit use of androgens is seen not only in athletes, but is now being used by a significant number of adults between the ages of 35 and 60 to get rid of love handles and build muscle as they try to stay young, as prescriptions for human growth hormone have become more frequent from “anti-aging” clinics. Adolescent boys feeling pressure from society to increase muscle mass and do better at sports are also increasing their use, and competitive athletes who might be tested for steroid use often turn to rhGH to improve performance.

Introduction

RhGH products are FDA approved for treatment of multiple conditions associated with short stature in children and adults. These include genetic disorders, growth hormone deficiency (GHD) in children and adults, HIV associated wasting, and short bowel syndrome. Since the development of the first recombinant human growth hormone (rhGH) product in 1981, Protropin, multiple rhGH products have become available for use in children and adults. All rhGH products available today are composed of the identical 191 amino acid sequence found in pituitary-derived human growth hormone (hGH). The available brands include Accretropin, Biotropin, Genotropin, Humatrope, Norditropin, Nutropin, Omnitrope, Saizen, Serostim, Tev-Tropin, and Zorbtive. The products vary in reconstitution requirements, delivery devices, storage, preservatives, and time to expiration along with specific indications for each product.1

Growth hormone therapy in children

Pediatric GHD is either congenital or acquired. Congenital etiologies result from genetic abnormalities to the GH releasing hormone receptor, GH gene, pituitary transcription factors, or anatomic malformations. Acquired GHD is due to neoplasms, cysts, inflammatory or infiltrative processes, head trauma, surgery, radiation, chemotherapy, or psychosocial deprivation. Children present with short stature, slow growth, and delayed skeletal maturation along with low stimulated GH secretion. Rare adverse events with GH therapy include Type 2 DM, benign intracranial hypertension, and slipped capital femoral epiphysis. Peripheral edema, anthralgias, myalgias, and mild gynecomastia are more common adverse effects.1 rhGH should not be used in children with active malignancies or previous malignancies due to an increased risk of secondary malignancy with GH therapy.2

A second indication for rhGH therapy in children is chronic kidney disease (CKD). Thirty-five percent of these children are prone to severe growth failure due to energy malnutrition, water and electrolyte disturbances, metabolic acidosis, anemia, and hormone disturbances. Children should be treated with rhGH if growth remains suboptimal despite correction of modifiable abnormalities.3 Upon kidney transplant, GH therapy should be discontinued since growth at this stage is affected by immunosuppressive therapy and graft failure. Treatments that start earlier, and in younger patients with less severe renal dysfunction, are more likely to be successful. CKD patients should be closely monitored due to adverse effects of benign intracranial hypertension and Type 2 DM.1

Children born small for gestational age (SGA) have a birth weight or height at least 2 standard deviations below the mean for their respective gestational age. Eight percent of these children do not adequately catch up to normal growth by 2 years of age and remain short throughout childhood. GH deficiency should be confirmed in these patients and replaced when appropriate. There is concern with using rhGH in these patients due to SGA increasing their risk for insulin resistance, hypertension, dyslipidemia, Type 2 DM, and cardiovascular disease. GH therapy may further increase risk for Type 2 DM but studies have not shown changes to fasting glucose, post-glucose load, or lipids; an increase in insulin levels has been observed during GH therapy.1

Genetic disorders with indications for rhGH therapy include Turner syndrome (TS), short stature homeobox (SHOX)-containing gene deficiency, Prader-Willi syndrome (PWS), and Noonan syndrome (NS). A universal feature of TS is short stature. The average height of untreated women is eight inches below the average of adult women in the US. The SHOX gene was discovered during the search for genes related to short stature of TS. Deficiency of one or both SHOX genes causes short stature or extreme dwarfism, respectively, in TS and other genetic disorders. Children with PWS usually have normal growth during the first year but subsequently short stature develops in 50% of this population. NS is characterized by proportionate postnatal short stature along with dysmorphic facial features, chest deformities, and congenital heart disease. rhGH therapy has shown to be beneficial in each of these populations associated with short stature. Doses of rhGH are specific to each syndrome and depend on which rhGH is used.1

Growth hormone therapy in adults

The syndrome of adult growth hormone deficiency (AGHD) is characterized by abnormal fat and muscle mass composition, dyslipidemia, decreased bone mineral density, exercise capacity, and quality of life. AGHD can be a continuation of childhood GHD or result from hypothalamic or pituitary damage. An increase in mortality is seen in these patients attributed to cardiovascular risk factors. It is unclear if these risk factors are exclusively due to GHD or a result of reduced quality of life and sedentary lifestyle. Daily rhGH injections to treat AGHD are associated with improvements in body composition, muscle strength, bone density, cardiovascular markers, and quality of life.Fluid retention is an adverse effect of GH therapy in adults and may cause symptoms of edema, carpal tunnel syndrome, arthralgias, and myalgias. Glucose intolerance and possibly Type 2 DM may also develop during treatment.1

HIV-associated wasting is linked to alterations in the GH-IGF-1 axis and can be improved with GH treatment. HIV wasting is defined as unintentional loss of body weight and lean body mass in patients infected with HIV. Other treatments for HIV-associated wasting include testosterone and anabolic steroids which increase fat mass but not lean body mass. Increases in lean body mass correlate with improved survival. Clinical trials have shown improvements in weight, lean body mass, and decreases in fat mass when patients are treated for 12 weeks with rhGH.1

Short bowel syndrome (SBS) is the loss of two-thirds of the small intestine and can be caused by impaired blood flow to the GI tract, inflammatory bowel disease, radiation enteritis, trauma, or cancer. In animals, GH increased mucosal mass and villi proliferation, improved transport of water, electrolytes, and nutrients across the gut and stimulated IGF-1 the intestinal mucosa. In humans, the goal of GH therapy is to promote intestinal adaptation and decrease parenteral nutrition (PN) requirements in PN dependent patients. A prospective clinical trial in SBS patients receiving 4 weeks of rhGH therapy showed a significantly greater reduction in PN volume than those receiving glutamine-supplemented diet alone. Response was maintained for 12 weeks after discontinuation of rhGH therapy and no significant adverse effects were documented. Multiple other open-label studies have shown improvements in PN reliance with rhGH treatment.

Off-label indications for rhGH include cystic fibrosis, inflammatory bowel disease, juvenile rheumatoid arthritis, osteoporosis, HIV-associated adipose redistribution syndrome, and chronic glucocorticoid administration. There are currently multiple clinical trials being conducted in each of these populations.

rhGH is often abused in combination with anabolic steroids to increase muscle strength and athletic performance. The illicit use of androgens is seen not only in athletes, but is now being used by a significant number of adults between the ages of 35 and 60 to get rid of love handles and build muscle as they try to stay young, as prescriptions for human growth hormone have become more frequent from “anti-aging” clinics. Adolescent boys feeling pressure from society to increase muscle mass and do better at sports are also increasing their use, and competitive athletes who might be tested for steroid use often turn to rhGH to improve performance.

In the UK, rhGH use increased by 18% from 2001 to 2006. GH can induce proliferation and differentiation of sebaceous glands worsening bodybuilding acne associated with androgen abuse.4 An additional concern with illicit rhGH use is cancer development. The amount of GH administered, in addition to the length of use, is unknown and likely produces supraphysiologic levels when used illicitly. These supraphysiologic levels of GH along with abuse of other androgenic agents can lead to unknown adverse effects including cancer.5 Many websites advertise the bodybuilding effects of GH including weight loss, improved metabolism, and increased energy levels. Adults and adolescents should be educated about the risks of using prescription drugs without medical supervision if they are at risk of abusing androgens and GH products.

Insulin resistance and GH therapy

GH is associated with insulin resistance and may cause Type 2 DM in patients receiving rhGH therapy. A long-term, prospective trial of rhGH showed that GHD patients with normal BMI did not experience an increase in Type 2 DM. Subjects showed a transient increase in fasting glucose but hemoglobin A1c levels were not increased during the study. The association of Type 2 DM with rhGH therapy may be confounded by high BMI and low physical activity in patients requiring rhGH. Other hormones which may be affected by rhGH include thyroid and glucocorticoids. These hormones, along with blood glucose levels, should be monitored during titration.6

The National Cooperative Growth Study (NCGS) evaluated the safety of rhGH in children for over 20 years. The incidence of developing Type 1 DM was not higher than controls. The incidence rate for Type 2 DM was approximately 14 per 100,000 GH treatment-years from the NCGS database and 34.4 per 100,000 in a second database. The incidence of Type 2 DM in the general US population is 0.7-7 per 100,000. Insulin resistance associated with GH therapy is usually transient and compensated for by increased insulin levels therefore rarely leads to over diabetes. Over the past 15 years, an increase in the Type 2 DM in adolescents in the US has been observed which could explain the higher rates in the NCGS population.2

Conclusion

The uses for rhGH are widespread and continue to grow. Many concerns exist with regard to the serious adverse effects associated with rhGH. Randomized control trials have yet to confirm an increase in Type 2 DM with rhGH compared to the general population. The increase in secondary malignancies in children is a valid concern and should be considered before recommending rhGH. rhGH is safe and effective for the labeled indications when dose and administered appropriately. Further evaluation of adverse events with additional prospective trials is warranted to confirm the potential associations.

References

1.    Franklin SL, Geffner ME. Growth hormone: the expansion of available products and indications. Endocrinol Metab Clin North Am. 2009 Sep;38(3):587-611.

2.    Bell J, Parker KL, Swinford RD, et al. Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab. 2010 Jan;95(1):167-77.

3.    Mahan JD, Warady BA, Frane J, et al. First-year response to rhGH therapy in children with CKD: a National Cooperative Growth Study Report. Pediatr Nephrol. 2010 Jun;25(6):1125-30.

4.    Melnik BC. Androgen abuse in the community. Curr Opin Endocrinol Diabetes Obes. 2009 Jun;16(3):218-23.

5.    Tentori L, Graziani G. Doping with growth hormone/IGF-1, anabolic steroids or erythropoietin: is there a cancer risk? Pharmacol Res. 2007 May;55(5):359-69.

6.    Mathioudakis N, Salvatori R. Adult-onset growth hormone deficiency: causes, complications and treatment options. Curr Opin Endocrinol Diabetes Obes. 2008 Aug;15(4):352-8.

 

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