From Lewis Blevins, MD
Growth Hormone is a peptide hormone produced by the anterior pituitary gland. Growth hormone-releasing hormone from the hypothalamus stimulates it’s release while somatostatin from the hypothalamus inhibits GH. Somatostatin is the principal hypothalamic regulator.
Most GH is made at night during sleep. In normal adults, GH is undetectable 50% of the time during the daytime. GH is secreted in pulses. Thus, levels are quite variable. Isolated unstimulated values are not useful in making a diagnosis of GH deficiency. IGF-I, because of its half life and protein binding, is a good marker of re sufficiency of GH.
GH binds to its receptors in various tissues to cause different effects. In the liver, it causes the generation of a protein called IGF-I. IGF-I from the liver accounts for about 90% of circulating IGF-I. Other tissues, and in particular bone, also make IGF-I in response to GH. GH and IGF-I result in long bone growth, in conjunction with other hormones, and cause an increase in stature. GH, and probably IGF-I, cause salt and water retention at the level of the kidney. GH does a number of things to build muscle. It also burns fat, especially the visceral fat located in the stomach, and is responsible for body composition.
Much of what we know about the effects of GH come from studies in patients with GH deficiency. We will cover these later. Suffice it to say that GH is an important regulator of metabolism and body composition. It is definitely important at all ages and stages of life.
Epidemiology and General Clinical Presentation
Growth hormone deficiency is relatively uncommon. I once heard that they were about 6000 new diagnoses of GH deficiency annually in the United States. Truthfully, this probably represents only a fraction of those patients who have GH deficiency. Many people are never diagnosed and thus considered for treatment.
Most patients with GH deficiency have pituitary disorders. It is estimated that about 40% of patients with pituitary disease and otherwise normal pituitary function will have GH deficiency. Those patients with panhypopituitarism have about a 99% likelihood of having GH deficiency. Some children and adults have idiopathic GH deficiency that is probably related to some form of a neurosecretory defect in growth hormone release. Their pituitary functions are otherwise normal.
In my opinion, there is a syndrome of GH deficiency. Of course, the symptoms and signs relate to both the severity and duration of deficiency. Generally, patients complain of fatigue, decreased energy, weakness, poor exercise capacity, loss of muscle mass, gain of fat mass, weight gain, and “brain fog.” Patients with hypopituitarism, not taking growth hormone, often notice that something just isn’t right despite the fact that all other hormone replacements are adequate. Those with newly acquired GH deficiency often feel fine initially only to present six months to a year later with classic symptoms and signs. Some patients feel fine but have other clinical manifestations of GH deficiency detected by screening tests to be discussed later.
Growth hormone deficiency is associated with disturbances in sleep. Most patients fall asleep easily but have difficulty staying asleep. They tend to awaken more regularly as a consequence of dreams during REM sleep. As a result, they awaken and do not feel rested. Some find it difficult to find the energy to go to work. I have seen data indicating the average person with GH deficiency misses about 15 to 18 days of work in a six-month period. After initiation of GH replacement, the number of missed days averages two days out per six month period.
Growth hormone deficiency is associated with several abnormalities of the skin. Chronic hypopituitary patients used to be said to have fine wrinkling of the skin about the face. It makes some patients look older than their stated age. In my opinion, this is a manifestation that is directly attributed to GH deficiency. GH deficiency also leads to dryness of the skin, with decreased ability to sweat and produce oils. The skin is also thinner and more friable. Some patients describe their skin as being more lax. Hair and nails are often described as being dry and brittle.
Growth hormone deficiency is associated with changes in body composition. As mentioned earlier, GH burns fat. Thus, patients with GH deficiency gain fat mass. Much of this is in the abdomen and in the flanks but it can be generalized as well. Patients often describe the fat as “blubber.” Losing weight is difficult. Muscle mass is significantly decreased and this is associated with recognizable decreases in strength. GH deficiency is also associated with poor exercise capacity and poor exercise tolerance. These abnormalities compound the problem of gaining fat and losing muscle. To further complicate matters, the oxygen carrying capacity of the blood is diminished in patients with GH deficiency. Further evidence in support of these observations relating to body composition come from studies of children with GH deficiency who take GH to increase their height. Within two years of discontinuing growth hormone once a final height has been achieved, these older children, or young adults, typically lose muscle mass and gain remarkable amounts of body fat.
Growth hormone deficiency is associated with important changes in the skeletal system. Adults with hypopituitarism have a higher incidence of osteoporotic fractures. In one study, osteoporotic fractures had occurred in about 25% of patients with hypopituitarism but in only 7 to 8% of age- and sex-matched control subjects. While these might be attributed to overzealous administration of thyroid hormone or steroids, or deficiencies of sex steroids, they appear to also be related to GH deficiency. Overall, bone mineral density is lower in patients with GH deficiency than in normal people. Children with GH deficiency also have low bone mineral density.
Cardiovascular Risk and Mortality
Growth hormone deficiency may contribute to adverse cardiovascular risk and increased mortality. It is clear that patients with hypopituitarism have higher than expected mortality rates. Most of the excess mortality is attributed to cardiovascular disease. Cardiovascular mortality in patients with GH deficiency may be increased as a result of several abnormalities. The increased intra-abdominal fat seen in growth hormone deficiency may be an independent predictor of cardiovascular risk. Further, patients with GH deficiency have elevated cholesterol levels with a profile that favors the development of atherosclerotic vascular disease.
There are also abnormalities in several “inflammatory markers” that favor development of cardiovascular disease in patients with GH deficiency. Some believe that GH deficiency is associated with important alterations in cardiac structure and function that lead to poor cardiovascular performance. The internal lining of blood vessels is thicker in patients who have GH deficiency. This has been associated with an increased cardiovascular risk. In one study, evaluating an isolated community where there are families with isolated GH deficiency, affected family members had a life expectancy of 48 to 50 years whereas their unaffected siblings and other members of the community lived to be about 70 years of age. The principal causes of mortality were cardiovascular in nature.
Growth hormone deficiency affects the brain and psychology in ways that we do not fully understand. Patients with GH deficiency often complain of impaired concentration, “brain fog,”poor short-term memory, forgetfulness, emotional lability, depression, apathy, social isolation, and impaired sexuality. They perform poorly on standardized tests designed to gauge the overall sense of well-being.
GH Replacement Therapy
Once a diagnosis of GH deficiency is confirmed, GH replacement should be considered in light of current symptoms and signs, goals, and desired outcomes, risks, etc.
The goals of replacement therapy and children are not only to treat growth hormone deficiency but also to promote growth and to increase height. In the adults, the principal goals of therapy are to improve the overall sense of well-being, reverse the symptoms and signs of growth hormone deficiency in regards to body composition, bone density, etc.
I usually recommend that younger and middle-aged adults start on a GH dose of approximately 0.3-0.4 mg daily. The average final dose for most of these patients is 0.4-0.6 mg daily. Older adults usually start on a dose of 0.1-0.2 mg daily. The average dose for the elderly patient ranges from 0.2-0.4 mg daily.
The goal of treatment is to normalize the IGF-I level. My own personal preference is to treat so that the IGF-I is in the upper part of the normal range, preferably, somewhere between the middle of the normal range and the 75th percentile. I attempt to do this while resolving the symptoms of growth hormone deficiency without causing symptoms of growth hormone excess. The IGF-I level should be checked 6-8 weeks after starting treatment and in 6-8 weeks after any subsequent dose changes. I check the IGF-I levels every 6 months once a stable dose has been achieved. Based on many years of experience, I will tell you that it is preferable to start with a low dose and to increase the dose in a stepwise fashion to find the least amount of growth hormone necessary to achieve the desired effect rather than to use a weight-based calculation to select a starting dose or to start patients on a dose that might be expected to be their final dose.
Women taking oral estrogens require a higher dose of growth hormone than women not taking oral estrogens because estrogens inhibit generation of IGF-I. Conversely, women who take growth hormone and oral estrogens will likely need to decrease their doses of growth hormone if they discontinue estrogens.
GH replacement accelerates the metabolism of cortisol. Thus, patients with untreated mild or undiagnosed central adrenal insufficiency may develop fatigue and decreased energy in response to taking growth hormone. These symptoms should prompt investigation of the adequacy of the hypothalamic-pituitary-adrenal
Patients who have had long-term and severe GH deficiency may develop symptoms of growth hormone excess just after starting GH replacement therapy even though the IGF-I levels are normal. The symptoms might include swelling in the hands and feet, pain in the large joints, and carpal tunnel syndrome. My usual approach is to lower the dose slightly and to reassess the IGF-I level in 6 weeks. The doses can then be increased gingerly if necessary. Sometimes, glucose intolerance or mild diabetes mellitus might be worsened by starting GH replacement. In these patients, attention to the diabetes mellitus is of paramount importance. Usually, the diabetes mellitus improves with time as beneficial changes in body composition take place in response to GH replacement.
GH replacement is not indicated in the presence of an active malignancy and in those for whom their antitumor therapy has not been completed. In my patients who have a history of an active malignancy, I wait until they have been proclaimed disease-free by their oncologist before I either start or reinitiate treatment with GH. In some patients, this can mean several years of interrupted therapy. In patients with craniopharyngioma or some other aggressive neoplastic process involving the hypothalamus or pituitary, I usually wait 6-12 months after completion of therapy before starting GH. With this said, simply replacing GH and bringing the IGF-I levels to normal should not exacerbate any underlying malignancy nor should it cause the malignancy to develop in a patient who has hypopituitarism and is treated with GH. Curiously, however, an epidemiological study published many years ago indicating that women with breast cancer and men with prostate cancer had a high normal IGF-I levels. Also, in a practice that was abandoned at least 25-30 years ago, patients with bone metastases from breast and prostate cancer used to undergo resection of the pituitary gland to take out GH and LH and FSH to minimize all potential growth factors for their tumors.
I would estimate that, for various reasons, approximately 70-80% of my patients with GH deficiency are treated with GH. The remainders are not candidates for one reason or another, such as an active malignancy, or patient preference, or even insurance denial (which is rare) and are followed with an eye towards growth hormone replacement if deemed clinically important at a later date. Most patients report significant benefit from treatment and the discontinuation rate is extremely low. I saw data at a meeting many years ago indicating that only 3% of patients with GH deficiency discontinued GH replacement over a 10 year period. My clinical experience is in keeping with this reported observation. An occasional patient does not notice any changes whatsoever in sense of well-being following initiation of treatment, discontinues therapy, and then restarts in 6-12 months later after they realized that the GH was providing some benefit.
Unfortunately, many physicians tell their patient’s that GH replacement therapy is “experimental.” Patients have also been told by their physicians that they “did not believe in it” and that the patients “did not need it.” GH was approved to treat GH deficiency by the US Food and Drug Administration in the mid late 1990s. It is not experimental. Patients do need GH if they are deficient! Educate yourself. Know the data. Be prepared to have intelligent, informed, and respectful conversations with your treating physicians if they seem to want to deny you treatment. Also, be prepared to take on your insurance company if they deny treatment. Most will reverse their denials if your treating endocrinologist supports the need for therapy at the time of an appeal.
Responses to Treatment
Some of the most remarkable benefits of GH replacement are related to improvements in the overall sense of well-being reported by treated patients. Pituitary World News recently asked FaceBook users to report their personal experiences with GH replacement. Here is what some had to say:
“I have been on GH for 4 months. ….. I saw an automatic improvement in energy.”
“I was finally tested for GH deficiency and started treatment. It turned my life around or gave me back my life. I felt “normal” for the first time in 16 years. The wonderful benefits lasted for years.”
“I’ve been on GH for 3 months. …. saw a huge decrease in my appetite…. have lost 17 pounds, can now exercise without becoming exhausted and feel so much more positive about life.”
“I just started GH again after being off for 2 years……memory has improved, energy levels are so much better, and I’ve already lost about 10 lbs after only being back on it for 3 months.”
“My depression lifted; my memory challenges improved; my isolation went away; my strength has improved; I’ve regained muscle; and most of all….I want to live. I’ve been injecting for about 6 years now and I don’t ever want to stop!”
“My life went from night to day went I went onto GH 20+years ago. I have lost 9 stone in weight and have a life which I didn’t before mentally or physically.”
“I’ve been on GH for 2 years..It was not a game changer for me but I have been able to lose 40 lbs, and I am a little less exhausted.”
Research has demonstrated improvements in energy, less social isolation, improved sex life, less emotional lability, improved work performance. Patient’s often report improved concentration, improved short-term memory, more energy, and better sleep.
GH replacement decreases intra-abdominal fat by as much as 45% within a year. Some of this gain is lost over time but, 5 years out patients still have a decrease in intra-abdominal fat by about 25% compared to baseline. Subcutaneous fat deposits are also diminished. Patient’s report decreases in belt size, dress size, and a need to change wardrobe, etc. Some patients lose marked amount of weight while others report no change in weight at all because they build lean body mass and thus substitute fat mass for lean mass. In fact, and it is no surprise given the growth hormone builds muscle, research has showed as much as an approximate 28% increase in the leg muscle area as measured by CT scan. This is accompanied by corresponding increases in muscle strength. Both exercise capacity and oxygen carrying capacity and improve markedly when compared to baseline. These changes result in improved exercise capacity which permits further weight loss through exercise, improves activity, decreases social isolation, and leads to better quality of life.
GH replacement increases the bone mineral density by as much as 12% in some sites as measured by DEXA over a five-year period of treatment. Studies have showed that the lower the bone density at the outset then the better the gains in bone density after the initiation of treatment with GH. These changes in bone density should be associated with a decreased osteoporotic fracture risk based on a multitude of studies that show the potential benefit of osteoporosis drugs. Of note, anti-resorptive osteoporosis drugs are not believed to work in patients with osteopenia or osteoporosis due to growth hormone deficiency because these drugs work for high bone turnover states and the low bone mineral density of growth hormone deficiency is a low bone turnover state.
GH replacement results in a more favorable cardiovascular risk profile by lowering the bad cholesterol and total cholesterol levels. GH replacement also moves the inflammatory markers of cardiovascular disease in a positive direction that is more preventive of the development of atherosclerosis. It will take many more years to determine whether GH replacement alters the mortality in hypopituitary patients.
In my experience, those with more severe and profound GH deficiency benefit the most from GH replacement. I do think of GH replacement as preventative health in patients who have not yet developed the clinical syndrome that I have come to recognize as that related to GH deficiency. It is imperative to treat to avoid side effects. The IGF-I level should be “just right” and this varies from one individual to the next.
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