Safety Guidelines for Growth Hormone Treatment
in Prader-Willi Syndrome

(Last updated November, 2006)

Note: This article is a work-in-progress and still somewhat incomplete. Feedback about this article would be very welcome, please consider writing me or posting your thoughts in the guestbook.

Introduction

The purpose of this page is not to discuss the merits of growth hormone (GH) treatment in those with Prader-Willi Syndrome (PWS) but to help ensure that it is administered in the safest way possible. In those for which it is medically indicated, growth hormone treatment is probably one of the safer medical interventions offered by modern medicine, but like everything else in life, it is not entirely risk-free.

In their analysis of growth hormone treatment and adverse events in PWS using data from the Pfizer International Growth Database, Craig 2006 found five sudden deaths out of the 675 children with PWS in the database. The fact that the children died during the course of growth hormone treatment does not, of course, constitute proof that growth hormone treatment had anything to do with their deaths; indeed, it is entirely possible that growth hormone treatment had nothing to do with the deaths. It is also possible that the effects of growth hormone treatment helped to prevent some deaths that might have otherwise occurred. However, the appropriately cautious approach is to assume that the deaths were related to growth hormone treatment and to formulate appropriate precautionary measures to reduce the possibility of serious adverse events. That is what this page is about - providing information about the precautionary steps recommended by PWS researchers and clinicians and the manufacturers of growth hormone products in order to minimize any risks that growth hormone treatment might pose.

Medline has excellent generic information about growth hormone treatment and should be bookmarked or printed out for reference. In additon, a list of the medical journal abstracts about growth hormone in the Research Database can be found here.

Patient Information Sheets (PIS)

In general, patient information sheets are your friends - memorize the ones for any prescribed medications (or at least keep them someplace handy and review them periodically :-). Here are links to the PIS for some of the more commonly used growth hormone products in the U.S.:

• Pfizer - Genotropin
• Eli Lilly - Humatrope - (PIS not available, link is to "Important Safety Information")
• Serono - Saizen
• Genentech - Nutropin

Brands

As far as I can tell, the growth hormone in all injectable brands is chemically identical and the differences between brands have to do with the process by which the growth hormone is synthesized; the other constituents (e.g., adjuncts and preservatives) in the preparations; reconstitution and administration procedures; and dosage recommendations.

Currently, Pfizer is the only company in the U.S. that (1) specifically lists PWS as an indication for treatment with its growth hormone product (Genotropin) in its PIS, and (2) references clinical trials of its product in PWS patients. That's because Pfizer (actually Pharmacia, which Pfizer bought in 2003) submitted trials of Genotropin in PWS patients to the U.S. Food and Drug Administration (FDA) and secured FDA approval (in 2000) of Genotropin under the Orphan Drug Act for the "long-term treatment of pediatric patients who have growth failure due to Prader-Willi syndrome." Genotropin's Orphan Drug status gives Pfizer the exclusive right to market it for use in those with PWS until 2007.

PWS and growth hormone deficiency

Although the literature suggests that growth hormone deficiency is common in PWS, it is not universal. For example, two of the five subjects with PWS studied by Grosso 1998 were found to have normal growth hormone and insulin-like growth factor-1 (IGF-1) serum levels. However, it could be that some or most of those who don't test as growth hormone-deficient are still functionally deficient due to other metabolic or hormonal conditions.

Growth hormone therapy and respiratory problems in PWS

Most of the reported deaths in those with PWS who have been undergoing growth hormone treatment have been due to respiratory problems such as sleep apnea in school-age children who were significantly overweight. (see, e.g., Nagai 2005) Children with PWS already often have some level of respiratory compromise due to weak respiratory muscles, pharyngeal narrowing, and/or central hypoventilation, a situation that is exacerbated by obesity. (For more about respiratory function in PWS, please see the article, Hypoventilation and Apnea in Prader-Willi Syndrome.) Several studies have shown an increase in respiratory functioning and a reduction in adverse respiratory events in children with PWS undergoing growth hormone treatment (see, e.g., Lindgren 1999, Haqq 2003 and Myers 2000), but a recent study (Miller 2006) reported that sleep apnea worsened in 32% of the study subjects and specifically noted an increase in obstructive apnea events in two children with high serum IGF-I (insulin-like growth factor). Growth hormone increases IGF-1 levels (which typically are low in PWS) and the high IGF-1 levels suggests the children might have been receiving too much growth hormone. Excessive growth hormone secretion is associated with thickening of the pharyngeal wall in adults and is suspected to be the cause of the increase in sleep apnea, both obstructive and central, that occurs in such adults. There is therefore a possibility that growth hormone treatment in children might cause an increase in the size of the adenoids, tonsils, and other airway tissues, thereby increasing the risk of sleep apnea, but so far no studies have specifically addressed that issue.

Studies of the effects of growth hormone treatment on respiratory function in PWS have concluded that monitoring for respiratory infections and aggressive treatment of such infections is indicated for those being treated with growth hormone. See, e.g., Eiholzer 2005 (one of the world's leading researchers in growth hormone treatment for PWS) and Festen 2006. Festen states, "We recommend monitoring of SRBD [sleep-related breathing disorders] by PSG [polysomnography] and regular ENT-evaluation in all PWS children, both before and during GH-treatment. If adenoid hypertrophy or tonsillar hypertrophy occurs, adenotonsillectomy should be considered."

Similarly, in their analysis of growth hormone treatment and adverse events in PWS using data from the Pfizer International Growth Database, Craig 2006 concluded that, "Prior to commencement of GH, examination of the upper airways and sleep studies should be performed in PWS patients."

The Patient Information Sheet (PIS) for Pfizer's Genotropin includes the following statement:

Polysomnography exams performed during the Festen study of the effect of growth hormone treatment on sleep-related breathing disorders in children with PWS found "a marked increase in sleep-related breathing disorders, and particularly obstructive sleep apnea" in those with mild upper respiratory tract infections (URTIs) or enlarged adenoids and/or tonsils. One three-year-old boy with a mild URTI died during the study despite a previous "near-normal" polysomnography, leading the study authors to state, "It is important to mention that a relatively normal PSG does not exclude the possibility of unexpected death during mild URTI. Based on our results, cardiorespiratory monitoring during URTI in children with PWS before and during GH-treatment should be considered."

Based on the foregoing, the following is indicated:

• A polysomnography (performed overnight in a hospital with continuous monitoring of blood oxygen and carbon dioxide levels, chest wall movements and nasal air flow) and an otorhinolaryngologic (ENT) examination for enlarged adenoids and tonsils should be done both before and periodically after initiating growth hormone therapy.
• Ongoing monitoring for symptoms of obstructive sleep apnea (OSA) - snoring, restless/disturbed sleep, frequent partial or total awakening, and day-time mouth breathing - is required, particularly in the first few months after beginning growth hormone treatment. (Other possible signs of OSA are odd sleep positions, often with the neck bent backwards, and profuse sweating during sleep.)
• IGF-1 levels should be regularly tested during growth hormone treatment and not allowed to go above physiological (normal) levels. For example, Miller 2006 suggests that IGF-1 levels should be used to determine growth hormone doses, rather than just following the usual dosage per body weight recommendations, and Park 2004 makes the same suggestion. You may want to discuss that suggestion with your endocrinologist.
• Monitoring for respiratory infections (fever, runny or stuffy nose, etc.) needs to be ongoing. Since those with PWS often have a lower basal temperature, it might also be a good idea to track their temperature periodically throughout the day for a week or so to determine what a normal temperature is for them.
• Per Festen 2006, cardiorespiratory monitoring during upper respiratory tract infections in children with PWS before and during GH-treatment should be considered.
• An effective weight control program should be established for children with hyperphagia prior to beginning growth hormone therapy.

Growth hormone therapy and insulin resistance and diabetes

Those with PWS are at increased risk of developing insulin resistance and diabetes and growth hormone is a known diabetogenic agent (i.e., it can increase insulin resistance). (See, e.g., Zipf 1999, as well as Bramnert 2003, who concluded that, "It is thus important to monitor glucose tolerance during long-term treatment with even moderate doses of GH.") One five-year study of 18 children with PWS aged 3-11 receiving growth hormone noted that two developed diabetes following a period of rapid weight gain; the diabetes disappeared when growth hormone treatment was terminated. (Lindgren 1999a) Another study by the same author found that "children with PWS showed a slow glucose disappearance rate which deteriorated during GH treatment" and concluded that "the observed dose-dependent increase in insulin levels during GH treatment, that reached supranormal concentrations in 6/19 patients, and the occurrence of NIDDM [non-insulin dependent diabetes mellitus] in 1 patient during follow-up suggest that close surveillance and low doses of GH should be applied, especially if the PWS patient is very obese." (Lindgren 1999b) There is also a case report of a 13-year-old boy with PWS who developed steatohepatitis with diabetic ketoacidosis four weeks after the initiation of growth hormone treatment. (Yigit 2004)

The foregoing indicates that glucose metabolism and insulin levels need to be closely monitored during GH therapy.

Growth hormone therapy and scoliosis

Infantile scoliosis can occur due to hypotonia and scoliosis is common in those with PWS. One study found that growth hormone treatment did not appear to necessarily increase the incidence of scoliosis or worsen it. (Nagai 2006) However, many of the studies of growth hormone treatment in children with PWS chose not to enroll children with scoliosis greater than 20 degrees out of concern that the increased growth rate caused by growth hormone could worsen the condition and Craig 2006 found that scoliosis was the most commonly reported adverse event (n = 24) among the 675 children with PWS in the Pfizer growth hormone database.

The foregoing suggests that children with PWS should be evaluated for scoliosis prior to beginning growth hormone treatment and monitored for scoliosis during growth hormone treatment.

Growth hormone therapy and water retention/edema

Growth hormone elevates sodium levels and water retention is therefore a somewhat common side effect of growth hormone treatment. By increasing the cardiovascular, respiratory and renal load, edema can have adverse respiratory, cardiovascular and renal consequences. Some of the studies of growth hormone treatment in those with PWS noted the development of edema in some subjects, e.g., 3 out of 17 adults in Hoybye 2004. Another report noted possible water retention in a 4-year-old girl with PWS who died of cardiorespiratory failure seven weeks after beginning growth hormone therapy. (Riedl 2005)

During the Festen 2006 study, the children were treated with growth hormone at a dose of 1mg/m²/day. However, during the first month of growth hormone treatment, they received only half of the usual dose - 0.5 mg/m²/day - specifically to avoid the possible development of fluid retention.

Based on the foregoing, the following is indicated:

• Discuss with your endocrinologist the possibility of starting off with one-half of the usual growth hormone dose during the first month of GH treatment.
• Monitoring for signs of water retention and edema (decrease in urinary output, "pitting" facial puffiness (usually most noticeable at first around the eyes) as well as hands, feet and ankles, etc.) should be ongoing during growth hormone treatment. If edema is suspected, press hard with your thumb or finger for a few moments on the area of suspect puffiness (e.g, ankles) and then release. Normal tissue will quickly rebound in one or two seconds to its normal contour, but the depression ("pit") will only slowly fill in if edema is present.

Growth hormone therapy and intracranial hypertension (IH)

Patient Information Sheets for growth hormone typically state the following:

Papilledema is the swelling of the optic nerve where it enters the back (fundus) of the eyeball due to increased intracranial pressure and can only be detected by a ophthalmological exam. The recommendation for ophthalmological monitoring should be followed, especially in infants and toddlers, given that they will not be able to tell you about any changes in vision or headaches.

Growth hormone therapy and hypothyroidism

Patient Information Sheets for growth hormone products also typically note that hypothyroidism has developed in a small percentage of children undergoing growth hormone treatment and that ongoing monitoring for the symptoms of hypothyroidism (fatigue; weakness; weight gain or increased difficulty losing weight; coarse, dry hair; dry, rough pale skin; hair loss; cold intolerance; muscle cramps and frequent muscle aches; constipation; irritability; memory) is therefore indicated, along with regular thyroid hormone testing.

Preservatives used in growth hormone products

Most growth hormone products contain preservatives, most commonly m-cresol (a coal-tar derivative chemically related to creosote). For example, according to the patient information sheet, the 5.8-mg and 13.8-mg presentations of Genotropin contain m-cresol as a preservative. Studies have found that users of insulin that contain m-cresol had significantly more inflamed injection sites than those using insulin containing methyl p-hydroxybenzoate as its preservative. (van Faassen 1990) Glycerol and m-cresol used as a preservative in growth hormone diluent were also associated with myalgia and elevated creatine kinase activity in a case report. (Bach 1992) Other growth hormone preparations, such as Eli Lilly's Humatrope, include instructions for reconstitution with Bacteriostatic Water for Injection, USP, which uses benzyl alcohol as a preservative and has been associated with toxicity in newborns.

In general, if possible, I would suggest using a growth hormone product that is preservative-free.

Summary checklist for growth hormone treatment

• Polysomnography both before and periodically after initiating growth hormone therapy.
• Otorhinolaryngologic examination both before and after initiating growth hormone therapy.
• Funduscopic examination both before and periodically after initiating growth hormone therapy.
• Evaluation for scoliosis both prior to and periodically during growth hormone treatment.
• Consider starting out at one-half of the expected dose during the first month of growth hormone treatment.
• Use of a preservative-free growth hormone preparation, if possible.
• Ongoing monitoring for symptoms of obstructive sleep apnea (OSA).
• Ongoing monitoring of IGF-1 levels.
• Ongoing monitoring for respiratory infections.
• If an upper respiratory tract infection occurs, cardiorespiratory monitoring should be considered.
• Ongoing monitoring for signs of water retention and edema.
• Ongoing monitoring of glucose metabolism and insulin levels.
• Ongoing monitoring for signs of hypothyroidism and regular thyroid hormone testing.

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Potential growth hormone side effects (from Medline)

• Growth hormone side effects that should be checked by a doctor as soon as possible:
  • More common
    • abnormal or decreased touch sensation
    • blurred vision
    • burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
    • dizziness
    • ear infection or other ear problems (in patients with Turner's syndrome)
    • nervousness
    • pounding in the ears
    • severe headache
    • slow or fast heartbeat
  • Less common
    • chest pain
  • Rare
    • abdominal pain or bloating
    • changes in vision
    • depression of skin at place of injection
    • headache
    • limp
    • nausea and vomiting
    • pain and swelling at place of injection
    • pain in hip or knee
    • skin rash or itching
• Growth hormone side effects that usually do not need medical attention and may go away during treatment, but discuss with your health care provider if they continue or are bothersome:
  • More common
    • back pain
    • chills
    • cough or cough producing mucus
    • constipation
    • depressed mood
    • diarrhea
    • difficulty in breathing
    • difficulty in moving
    • dizziness
    • dry skin and hair
    • ear congestion
    • feeling cold
    • fever
    • general feeling of discomfort or illness
    • hair loss
    • hoarseness or husky voice
    • loss of appetite
    • loss of voice
    • runny nose
    • shivering
    • shortness of breath
    • sore throat
    • slowed heartbeat
    • sneezing
    • stuffy nose
    • sweating
    • swollen joints
    • tightness in chest
    • trouble sleeping
    • weight gain
    • wheezing
  • Less common or rare
    • carpal tunnel syndrome
    • discouragement
    • breast enlargement
    • feeling sad or empty
    • increased growth of birthmarks
    • irritability
    • joint pain
    • loss of interest or pleasure
    • muscle pain, cramps, or stiffness
    • skeletal pain
    • sleepiness
    • swelling of hands, feet, or lower legs
    • trouble concentrating
    • unable to sleep
    • unusual tiredness or weakness
• Additional growth hormone-related issues
  • Leukemia has been reported in a few patients after treatment with growth hormone but it is not definitely known whether the leukemia was caused by the growth hormone treatment.
  • If growth hormone is given to children or adults with normal growth, who do not need growth hormone, serious unwanted effects may occur because growth hormone levels in the body become too high. These effects include:
    • the development of diabetes
    • abnormal growth of bones and internal organs such as the heart, kidneys, and liver
    • atherosclerosis (hardening of the arteries)
    • hypertension (high blood pressure)