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Growth
Hormone Use and Abuse
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E-Newsletter No.
1
5
Over the last decade,
GH has become one of the most commonly abused drugs in sports. It is being sold
widely by "fitness trainers" to their clients in gyms throughout the
country. Its popularity lies in the belief that it not only possesses marked
ergogenic properties, but also that its administration is currently
undetectable. Current scientific evidence of its performance enhancing effect is
limited. However, these limitations could be due to the study designs employed.
Athletes are almost unanimous in the opinion that the illicit taking of GH is
worthwhile. It is therefore likely that the scale of this abuse will increase.
Of course, federal law prohibits dispensing or using any drug without a
prescription, so it is illegal for anyone to receive or distribute drugs
"on the street." To do so is to face the risk of severe criminal
penalties, including fines and imprisonment.
Although abuse has been
reported in competitive athletes, by far the largest group that abuse GH are
competitive and recreational body builders. In both groups, GH is
self-administered without any medical supervision. The enormous doses injected,
and the often simultaneous abuse of other substances such as the black market
use of anabolic steroids lead to frequent side-effects which may be severe, if
not fatal. Finally, there is a growing segment in the healthy aging "baby
boomer" population that believe GH use is not only safe, but also that it
is the "miracle drug that stops aging, and everyone who can afford it
should be using it."
In order to understand
and responsibly administer GH replacement therapy to adults, it is necessary to
first consider the differential diagnosis of adult onset GH deficiency. In
addition, the study of the side-effects of recombinant human GH (rhGH)
administration to GH-deficient adult patients will elucidate a scientific basis
for the establishment of a standard of care protocol in the treatment of
idiopathic adult-onset of GH deficiency disorder (Somatopause).
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Safety
Aspects of Growth Hormone Replacement in Adults
- A GH pulse is released roughly every
second hour with a mean daily secretion of 0.5mg. GH secretion is amplified
during fasting and stress, whereas meals suppress GH release.
- Blood sugar rises drastically
following a single supraphysiologic 10 mg dose of human growth hormone (GH)
to totally GH deficient adults. And, high dose of GH administration in
normal adults markedly reduced forearm muscle uptake of glucose, which
reduces energy production in the muscle cell.
- The metabolic effect of a
physiologic dose of GH in the postabsorptive (digestive) state is
stimulation of fatty deposit breakdown following a lag time of 2-3 hours as
the most consistent effect. Plasma glucose, on the other hand exhibited only
minor fluctuations, and serum insulin and C-peptide levels remained
completely stable. However, there are subtle reductions in muscle glucose
uptake and oxidation. By contrast, the effect of high doses of GH causes
liver and muscle resistance to insulin, increased lipid oxidation to fatty
acids, and reduced muscle glycogen synthesis (hastening muscle
fatigability). The fatty acid build-up ultimately leads to beta cell
"exhaustion" and overt to diabetes mellitus.
- GH deficient adults have a higher
prevalence of impaired glucose tolerance as compared to healthy, age and
sex-matched controls. Determinants of abnormal glucose tolerance include old
age, female sex, and obesity. Paradoxically, fatty plasma levels of glucose
and insulin were normal.
- A predominant site of insulin
resistance appears to be the skeletal muscle synthase activity. The
mechanism for this is unknown, but it may be due to increased free fatty
acid (FFA) flux from visceral fat since visceral (abdominal) adiposity is a
hallmark of adult GH deficiency. In this regard, it is noteworthy that a
normal body mass index does not exclude visceral obesity.
- GH replacement in GH deficient
adults causes fasting plasma levels of glucose and insulin to increase after
6 weeks, but returns to baseline somewhere between 3 and 18 months. GH
replacement in GH deficient adults (GHDA) may cause insulin resistance and
glucose intolerance, and the risk is determined by the following factors: GH
dosage, body composition, cause of GH deficiency, chronological age, and
duration of therapy.
- Fluid retention and arthralgia
(joint pain) as side-effects of GH administration were first reported in
1959. These symptoms were associated with retention of sodium and increased
extracellular volume. Fluid retention is also seen with IGF-I
administration, and it is thought that secondary insulin resistance may be
contributing to the fluid retaining effects.
- GH interacts with other hormones. It
increases the extrathyroid conversion of T4 to T3,
which may unmask incipient hypothyroidism. The effect on the gonadal axis is
complex and not fully clarified. It has been shown to stimulate
steroidogenesis, fertilization, enhancement of peripheral (muscle) androgen
actions, increase estradiol concentrations, and reduce circulatory levels of
prostatic specific antigen (PSA).
- GH impact on glucocorticoids is very
complex. Unchanged, increased, and reduced levels of basal and
ACTH-stimulated cortisol levels have been reported. GH administration in
hypo- pituitary GHDA adults may reduce the bioavailability of administered
glucocortisol to cortisone, and one study suggests that GH reduces the level
of cortisol binding globulins.
- Short-term treatment with GH has
overall beneficial effects on cardiovascular and cerebrovascular death rates
in GHDA, but information about long-term effects is lacking. Of concern in
this context are the long-term effects of heart structure and function, and
on lipoprotein (a) {Lp (a)}. Lipoprotein (a) is a risk factor for ischemic
heart disease, and demonstrates in some studies a marked increase in
response to GH administration.
- Short-term placebo-controlled
treatment trials with GH in GHDA have demonstrate an anabolic effect on
cardiac structure and increased systolic function (blood being pumped out of
the heart during the contractile phase). These effects may explain the
improved exercise capacity and cardiac work obtained in response to
short-term GH treatment as compared with placebo controls.
Monitoring the
long-term effects of GH are of major importance, mainly because of the
well-known cardiovascular consequences of acromegaly. Short-term uncomplicated
acromegaly results in a high cardiac output state with a reduction in
peripheral resistance and increase left ventricular mass. Acromegalic patients
having diabetes mellitus and hypertension also have the highest risk of
developing left ventricular hypertrophy, systolic, and diastolic dysfunction.
- The most common reasons for growth
hormone insufficiency in adults are tumors occurring in the pituitary gland
or in the hypothalamic area of the brain. Chemical treatment, radiation, or
surgical removal of these tumors usually results in hypopituitarism. When GH
replacement was introduced to the hormone replacement protocol for treatment
of hypopituitarism, one concern was the increased risk of recurrence and
regrowth of these tumors. In addition, GH and IGF-I receptors are present on
many cancer cells and the risk that GH replacement would increase the
incidence of other tumors should be acknowledged.
- The few data of GH treatment on
tumor recurrence and growth obtained from the pediatric literature suggest
the risk was not increased by GH treatment. Published data from KIMS, the
Pharmacia-UpJohn Corporation International Metabolic DATABASE, treated 1034
hypopituitary adults compared with 43 clinical trials initiated by Pharmacia
Corp., involving 1145 hypopituitary patients showed no statistically
significant differences between GH treated patients and controls for tumor
recurrence. However, these data are considered too few to rule out concern.
- The reports on the occurrence of
other neoplasia (cancers) during GH replacement in adults is also lacking.
The risk may, however, be discussed in the context of risk of cancer in
patients with acromegaly and recent data showing an association between high
serum levels of IGF-I and risk of cancer. Patients with acromegaly and thus
long-standing high levels of serum GH and IGF-I in retrospective trials
(looking back at events that have occurred) have increased frequency of
malignant disease. The most frequently found are mammary and colorectal
cancers. The overall observed: expected ratio for cancer in these studies is
between 1.27 and 2.5. In prospective trials (looking forward to monitor
events as they occur), the rate of tubular adenomas and hyperplastic colon
polyps is increased with some studies also showing more than the expected
numbers of colon cancer.
- A meta-analysis (comparison of
results from a number of separate studies), including the Physician’s
Health Study, of hormonal predictors of prostate cancer found that men with
either testosterone or IGF-I levels in the upper quartile of the population
had an approximately two-fold higher risk of developing prostate cancer. The
analysis included 28 studies of the role of sex steroids, and three studies
on the role of serum IGF-I in prospective, nested case-control studies. In
the Nurse’s Health Study, there was a 4.5 fold relative risk of breast
cancer in the highest quartile of serum IGF-I as compared with the lowest
quartile.
Similar results were
also found for colorectal cancer in men in the Physician’s Health Study.
That study together with the above mentioned studies of prostate and breast
cancer demonstrated an inverse relationship between risk of cancer and serum
IGFBP-3 concentration.
- The Nurse’s Health Study also
demonstrated that higher plasma levels of sex steroids and prolactin in
postmenopausal women are positively correlated with increased risk of breast
cancer. This raises the question of the primary importance of serum IGF-I as
a causative agent. Activation of the prolactin receptor in mice has been
shown to be required before high levels of GH or IGF-I could be associated
with the development of mammary cancer. Moreover, with increasing age the
association between the GH status and serum IGF-I levels is reduced
indicating that other factors including environmental or nutritional factors
may be of more importance with increasing age.
This was supported by
a study in a random population of 197 men and 195 women aged 25-64 years which
found that serum IGF-I was, positively and independently from age, associated
with plasma fibrinogen and smoking habits in men and negatively with coffee
consumption in women. It should also be kept in mind that tumor cells can
remain robust even though they are in a GH/IGF-I deficient setting.
We should also
consider the possibility of an association between hypothalamic-pituitary
tumors and other malignancy when considering the risk of GH replacement. Some
studies indicate that other forms of cancer may be associated with pituitary
tumors and/or their treatment.
Go to Top
Establishing
a Standard of Care Protocol
The author recommends a
standard of care protocol be established for evaluation of suspected cases of GH
deficiency. This would include a preliminary work-up of a complete colonoscopy
and a comprehensive cardiovascular evaluation comprising of an analysis for risk
factors (genetics, lifestyle, cholesterol subtypes and particle distribution,
Lp(a), fibrinogen, C-reactive protein, homocysteine, fasting insulin) and the
presence of existing atherosclerotic plaque utilizing the electron beam CAT scan
(EBCT), as well as all appropriate endocrine studies.
A detailed evaluation
by a neuroendocrinologist of other pituitary hormones is, of course, also
required in adult patients with suspected GH deficiency. Radiologic
investigation of the pituitary gland should be performed using either CT or MRI,
and assessment of the visual fields is obligatory, as in all patients with
suspected pituitary disorders. It is recommended that all adult patients
receiving GH therapy be closely supervised by a neuroendocrinologist on an
ongoing basis.
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