| Main Menu   | Home  |  About Us  |  What's New | FAQSite Search   | Contact Us   |  Books  | Privacy Policy | 

Legal Status of Growth Hormone (HGH) Replacement Therapy

HGH replacement for adult growth hormone deficiency is an FDA approved use, as well documented below. If adult HGH deficiency is suspected, from clinical or laboratory evaluation, patients are free to request a trial of replacement therapy.

Release of HGH by the pituitary gland declines progressively with age in virtually all adults. Clinical studies show an average cumulative growth hormone decline of 15 percent per decade from the age of 20 through senescence. By the age of seventy it is common for growth hormone levels to have fallen by 75% or more, compared with healthy young adults. This age-related decline is ubiquitous and is caused by progressive loss of hypothalamic releasing factors, growth hormone releasing hormone (GHRH), and other hypothalamic peptides.  HGH release is progressively opposed by increasing hypothalamic somatostatin. This common form of deficiency rarely involves a primary disease of the pituitary gland. A provocative test for pituitary disease is not useful in such cases, and will indicate a false negative or normal result, despite hypothalamic induced deficiency.

Published literature (1-11) documents many benefits including the following medical and quality-of-life benefits from HGH replacement therapy for age-associated deficiency:

Improved healing and protein synthesis
Improved cognitive function, mental alertness and memory
Improved immune function and resistance to infection
Improved quality of sleep
Reduced risk of falls and injury
Reduced osteoporosis and improved bone density
Reduced cardiovascular risk factors (including hypertension, inflammation,          dyslipidemia, atherosclerosis, and insulin resistance)
Improved cardiac contractility, with less risk of congestive heart failure
Improved sexual function
Improvement of mood disorders with less depression and anxiety
Improved quality of life

Link to list of many more published references

It is illegal to prescribed HGH only to increase muscle mass, to enhance athletic ability or for any use that is not FDA approved. HGH is abused by competitive athletes and body builders with excessive doping doses. Because of such unethical doping, Congress passed a federal law prohibiting the use of HGH for uses not approved by the FDA. If the term "anti-aging" is used at times associated with legal and FDA approved uses of HGH, it should be interpreted in the generic sense of treating age-related symptoms, such as those listed above, not treating old age per se, in the same way that prescriptions for statin drugs could be considered "anti-aging" therapy for age-related elevations in cholesterol.

Clinical research in the use of HGH for common age-related symptoms has been published predominantly in Europe, Asia, and Australia. Editorial comments in mainstream U.S. medical journals tend to ignore that large body of scientific evidence for both safety and benefit as published in other countries.

The label “growth hormone” is unfortunate because it has many other functions than"growth. Many other hormones also have an effect on growth. Thyroid hormone is also essential for growth and thyroid deficiency can also cause dwarfism. Anabolic hormones  play a role in growth. Growth hormone would best be called a "metabolic support hormone," essential for many aspects of health and metabolism throughout life.

The FDA specifically approves the use of HGH to treat HGH adult deficiency of hypothalamic origin. The following is taken from the FDA approved package insert for HGH (Lily Humatrope).(9)

“Adult Patients

"Humatrope is indicated for the replacement of endogenous GH in adults with GH deficiency who meet either of the following two criteria [see Clinical Studies (14.1)]:

“Adult-Onset (AO): Patients who have GH deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; . . .”

In healthy young adults the pituitary gland releases on average 1.5 to 2 units of HGH daily (1 unit = 0.333 mg). This is the amount needed by the body for optimal health and vitality. Symptoms that commonly occur with advancing age have been well documented to result from progressive decline of HGH throughout adult life. Benefit from replacement is well proven. Improvement occurs using low, safe, and physiologic replacement doses of HGH—using doses of 1.0 to 1.5 units daily of HGH. HGH may be administeredwhen laboratory and/or clinical assessment indicate deficiency. Occasionally doses may be increased to 2 units daily, but only with periodic IGF-1 laboratory measurements to insure that levels do not exceed a normal, physiologic, safe adult level of 300 ng/ml. More than 2 units daily has been reported in studies to cause undesirable side effects.

Excessively high doses were used in most of the early clinical studies of adult HGH therapy and side effects were predictable—although those side effects were usually reversible with a reduction in dose or by temporarily discontinuing or titrating to lower doses. Many published articles in U.S. medical journals are critical of HGH replacement. However, they focused in a misleading way on the side effects caused by excessive dosing. All hormones are potentially harmful when overdosed, while at the same time they are all necessary in physiologic amounts for optimal health and quality of life. Doses of HGH used in many published clinical studies were excessive, and, not surprisingly, caused significant and undesirable side effects. Studies cited by critics who claim that HGH replacement is unsafe rely on studies where doses used were as much as 10 times their normal physiological amounts. A tenfold overdose of any hormone can be disastrous.

The FDA is on record as ruling that the doses recommended here are safe. Doses higher than 2 units daily are approved and ruled safe by the FDA for purely cosmetic purposes in normal, healthy children of short stature. These children are not pituitary dwarfs, they are merely shorter than average. FDA approval for use of HGH in otherwise healthy children with a familial trait for short stature is for a purely cosmetic purpose—to increase their eventual adult height (see Humatrope® package insert)(9) . This provides evidence that the FDA does not consider safety to be an issue at these doses. Treated patients  are normal and healthy and the FDA approved doses exceed the 1.0 to 2.0 units daily recommended here for adult physiologic replacement. If HGH treatment at higher doses has been ruled safe for normal children, and for a purely cosmetic use, then the smaller doses recommended for adults with the expected amount of age-associated growth hormone loss should be considered even safer.

If replacement doses of HGH do not exceed amounts that are released daily by the pituitary during the earlier decades of adulthood (1.5 to 2 units daily), there is no potential for either overdose or abuse. Normal hormone feedback will prevent excessive circulating levels. Since the amount administered will create what was necessary for optimal health in early adulthood, those same levels should be safe in later lifethroughout life. There are no studies to indicate otherwise and there are many studies that show clinical benefit in later life, when endogenous levels fall markedly in most adults. A large number of clinical studies support both safety and benefit from low-dose, physiologic replacement therapy with advancing age.

Using physiologic doses, the body’s feedback control mechanisms will keep circulating levels within a normal physiologic range.(1) Feedback will lower endogenous production if levels are above normal in the circulation. There is general agreement in the peer-reviewed literature that low-dose replacement therapy (up to 2.0 units daily) can provide benefit without significant risk of harm.1,2,7,8,10)

The pituitary gland rarely stops producing HGH. Primary pituitary disease in adults is rare. What occurs in almost all adults is a progressive decline with age in release of HGH by the pituitary. The pituitary usually remains full of youthful amounts of HGH. it is release triggered by hypothalamic releasing factors that fails. There is decline of growth hormone releasing hormone (GHRH) and growth hormone releasing peptides (GHRP) from the hypothalamus, combined with increased activity of somatostatin, a hypothalamic growth hormone inhibitor. Treatment with HGH is FDA approved for this hypothalamic mediated  condition.

A requirement that the diagnosis of adult GH deficiency must be documented with a provocative, stimulation test using growth hormone releasing hormone (GHRH), arginine, or some other agent, makes no sense at all. Provocative testing replaces the missing hypothalamic stimulus and gives a false negative result. Those who insist that treatment of adult growth hormone deficiency is an “off-label” use, because stimulation testing is not abnormal, ignore the true pathophysiology of this condition. A stimulation test does just the opposite and masks a true diagnosis by providing the very hypothalamic stimulating factors that are lost with age. The pituitary gland normally remains loaded with HGH throughout life, primed for HGH release if releasing factors are administered exogenously during provocative testing, obscuring the diagnosis and causing false negative results.(1-6,8,10)

In one published study, Müller, et al, state, “Recent evidence has shown that growth hormone-releasing hormone (GHRH) enables investigation of the pathophysiology of GH secretion in a variety of different states, but it cannot be used as a test for probing pituitary somatotrophic function ". . . during aging the releasable pool of GH is preserved and that impaired GH secretion is due to defective hypothalamic GHRH function and a relative predominance of somatostatinergic function.”(3)

Corpas, et al, working at NIH, published a report stating that that the common form of HGH deficiency with aging is hypothalamic in origin and not a primary pituitary disease. They state that “. . .administration of GHRH to healthy old men reverses age-related decreases in GH.”(6) Thus provocative testing is of no use to diagnose of the most common age-related deficiency state, but instead masks the diagnosis.

The Endocrine Society Clinical Practice Guidelines, authored by a committee of university affiliated endocrinologists, states, “. . . because GHRH directly stimulates the pituitary, it can give a falsely normal GH response in patients with GHD of hypothalamic origin.”(7) They state that stimulation testing is only useful to diagnose primary pituitary disease or after surgical removal of the pituitary, and they indicate further that it is controversial even for that purpose. Ghigo. et al, confirm that fact.(5)

Unfortunately there exists no “gold standard” for laboratory testing in ambulatory patients for a diagnosis of this common type of adult growth hormone deficiency. An insulin tolerance test to produce profound hypoglycemia is considered a more reliable indicator of HGH deficiency, perhaps even of hypothalamic origin, but the risk of seizures, coma and brain damage makes that type of testing unjustified for routine practice. The total picture must be considered and clinical judgment is required.

Because insulin-like growth factor (IGF-1) is produced by the liver in direct response to average levels of circulating HGH, baseline IGF-1 measurement before HGH replacement seems the only practical laboratory test in an outpatient setting—although interpretation must be considered as part of the whole clinical picture. If there is a “gold standard,” it might best be response to a trial of HGH replacement therapy.

Serum IGF-1 levels reflect the overall pituitary release of HGH in frequent small pulses throughout a 24-hour period. Because of the short half-life in circulation and widely variable levels throughout the day, direct testing for blood levels of growth hormone is not practical for routine use. (4) An IGF-1 level of 350 ng/ml or higher is commonly measured in young adults. Levels fall progressively with advancing age. LabCorp clinical laboratory (and its affiliate Endocrine Sciences) publishes an average measurement of IGF-1 at age 20 of 371 ng/ml, falling progressively throughout life to a mean level of 131 ng/ml at age 80, with wide individual variations.

Clinical laboratories are regulated by the Clinical Laboratory Improvement Act (42 CFR 493.2), which defines the "Reference Range" printed on report forms as ". . . the range of test values expected for a designated population of individuals, e.g., 95 percent of individuals that are presumed to be healthy (or normal)." The key word here is "presumed." Reference ranges on report forms are computed separately for each decile of age. Data from all patients tested by that laboratory is separated into 10-year age-groups, after eliminating outliers. Each 10-year span of life (decile of age) is entered into a statistical computer program to produce bell curve representing results for patients within the 95th percentile for that decile. The mean for each successive 10-years of age has been measured separately and found to decline by approximately 15% for each 10 years. The reference ranges listed on laboratory report forms are derived in this manner, and cannot be defined as "normal" in the sense of "healthy" or "optimal." They are computed for each decile of age from all patients tested by that laboratory. Reference ranges thus reflect the inevitable and  progressive decline with age and are not either optimal or healthy, but merely represent levels "normally measured" (as opposed to "normal") in the population at large. Clinical interpretation of "Reference Ranges" on laboratory report forms  requires the use of clinical judgment. Laboratories rarely state on report forms that “reference” ranges are “normal.”

It cannot be presumed that 95% of individuals tested in the 60 to 70 age group have optimal levels of IGF-1, if measurements reflect an HGH decline of 75% over the prior 4 to 5 decades. Declines of IGF-1 of that magnitude are well documented in the published literature, and such deficiencies result in age-related health and quality-of-life problems.

HGH is expensive and requires frequent self-injections. It seems unlikely that patients would continue this therapy for long if they did not experience benefit. Placebo effects do not persist. If in doubt about benefit, patients are advised to inject one unit of HGH daily for several months, then stop treatment for a for several months, repeating this process as necessary, with no other changes, to determine whether HGH replacement is worth the expense and effort. Benefit often comes on slowly over several months, and benefit fades slowly if treatment is stopped.

Fifty percent loss of thyroid hormone, adrenocortical hormones, estrogen or testosterone are routinely diagnosed as treatable deficiency states, while an even greater across the board loss of HGH is largely ignored in United States population. Endocrinologists seem to ignore the impressive amount of published clinical research elsewhere, which proves safety and benefit from physiologic replacement of HGH in the routine practice of geriatric medicine. To do otherwise in the U.S.A. would cause clinical endocrinologists large amounts of time-consuming paperwork answering the expected payment refusals from Medicare and other insurance companies. Medicare regulations impose strict paperwork requirements for uncovered services and denied claims, even for denial of services that are beneficial and technically not "off-label."

The medical profession justifiably opposes the huge black market in HGH by sports trainers, competitive athletes, body builders and Hollywood Rambo types, often using huge doses, and from suspect sources sold illegally over the Internet, with no assurance of purity or quality control.

Before prescribing HGH a thorough history and physical examination should be performed. Patients are warned against Internet sales and other questionable sources. To insure purity and quality control, patients are advised to use only FDA approved HGH, manufactured by a licensed pharmaceutical company, with a FDA assigned NDC code on the label. So-called HGH stimulators or releasers seem to lose effectiveness over time (tachyphylaxis) and have not yet proven useful for long term replacement.

Safe and effective doses of HGH replacement are given in a range of from from 4 to 14 units weekly. The most common replacement dose for clinical benefit is 1 unit daily for at least 4 days, and preferably for 7 days per week. The maximum safe daily dose has been shown to be 2 units daily, although minor and reversible side effects are sometimes seen at that level. For that reason the initial dose might be limited to 1 unit daily.


Initial Examination

The initial evaluation prior to beginning HGH replacement should include a thorough medical history, physical examination, and laboratory testing to detect contraindications and precautions, including baseline IGF-1 and an “executive panel” of blood and urine testing.

Contraindications

Acute critical illness requiring other treatment (inappropriate otherwise)
Active malignancy (this is on the FDA package insert but there is no scientific evidence for harm)
Active proliferative or severe non-proliferative diabetic retinopathy (one report of possible augmentation)
Carpal tunnel syndrome (normal rehydration of tissues by HGH can cause aggravation)

Precautions in adults

Neoplasm: It is common sense to monitor patients with preexisting tumors for progression or recurrence. Although this is a reasonable precaution, published studies indicate that HGH replacement does not increase the risk of malignancy or neoplasm when administered as low-dose replacement therapy.
Impaired Glucose Tolerance or Diabetes Mellitus: Advise patients to carefully monitor glucose levels. Doses of concurrent anti-hypoglycemic drugs in patients with diabetes may require adjustment with higher doses of HGH. At the low recommended doses, this should not be a serious problem.
Intracranial Hypertension: Exclude preexisting papilledema. This has been reported with excessive doses of HGH, and was reversible after discontinuation or reduction in dose.
Fluid Retention (e.g., edema, arthralgia,): Reduce or temporarily stop treatment if such signs develop. These patients can usually be managed safely by dose reduction or temporarily stopping, followed by slow titration to the desired dose. As patients age and as HGH declines, tissues become progressively dehydrated. Replacement therapy restores normal hydration and may take time for adjustment.
Carpal tunnel syndrome occasionally occurs at higher doses, seemingly related to edema and fluid retention, presumably as a trigger for a pre-existing and latent problem, and can often be managed by reduction or temporary cessation of HGH.
Hypothyroidism: latent hypothyroidism has been reported to worsen after initiation of HGH replacement. Hypothyroidism should be tested for, and first corrected—which is very easy to do with replacement therapy.

Prior to initiating therapy, patients should be thoroughly instructed in correct procedures for adding diluent, preparation, sterility, and injection technique. These procedures can be taught and demonstrated by trained medical personnel until patients feel confident and until patients demonstrate that they can safely perform self-administration.

REFERENCES:

1. Jull, Anders; Jorgensen, Jens O L (eds): (2000). Growth Hormone in Adults, Physiological and Clinical Aspects (2nd ed). Cambridge, UK, and New York: Cambridge University Press.

2. Jull, Anders; Jorgensen, Jens O L (eds): (2000). Growth Hormone in Adults, Physiological and Clinical Aspects (2nd ed). Cambridge, UK, and New York: Cambridge University Press. Chapter 19: O’Connor K G, Blackman M R: Growth Hormone and Aging. 498pp

3. Müller EE, Cocchi D, Ghigo E, Arvat E, Locatelli V, Camanni F: Growth hormone response to GHRH during lifespan. J Pediatr Endocrinol. 1993 Jan-Mar;6(1):5-13.[PubMed ID: 8374689]

4. Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab. 1991 Nov;73(5):1081-8.[PubMed ID: 1939523]

5. Ghigo E, Goffi S, Nicolosi M, Arvat E, Valente F, Mazza E, Ghigo MC, Camanni F. Growth hormone (GH) responsiveness to combined administration of arginine and GH-releasing hormone does not vary with age in man. J Clin Endocrinol Metab. 1990 Dec;71(6):1481-5
[PubMed ID: 2229304 ]

6. Corpas E, Harman SM, Piñeyro MA, Roberson R, Blackman MR: Growth hormone (GH)-releasing hormone-(1-29) twice daily reverses the decreased GH and insulin-like growth factor-I levels in old men. J Clin Endocrinol Metab. 1992 Aug;75(2):530-5.[PubMed ID: 1379256]

7. Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on adult growth hormone deficiency. The Journal of Clinical Endocrinology and Metabolism, 2005 83(2), 379-381.

8. Mark E. Molitch, David R. Clemmons, Saul Malozowski, George R. Merriam, Stephen M. Shalet, Mary Lee Vance for The Endocrine Society’s Clinical Guidelines Subcommittee. Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2227. The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 5 1621-1634. Copyright © 2006 by The Endocrine Society

9. Humatrope® Lily. FDA Approved Prescribing Information (full text online link)

10 Medscape Clinical Presentation: Growth Hormone replacement in Older Men

11 References by symptom and disease category

Copyright © 2012 Elmer M. Cranton, M.D., all rights reserved

Last modified: