Human Growth Hormone

Hormone Replacement & Balancing Therapies

Aspects of Growth Hormone Replacement in Adults

Establishing a Standard of Care Protocol

Growth Hormone & IGF Research 2002

Growth Hormone & IGF 2003 Updates

Human Growth Hormone

Somatotrophin is the proper name for Growth Hormone (GH), a natural hormone of the body that was originally named because of its ability to stimulate growth in children. However, subsequent research has shown that GH is necessary for proper maintenance and function of practically all systems in the body. Disease or trauma that destroys tissue responsible for production of GH by the body rapidly results in many negative changes including loss of muscle and strength, gain of abdominal fat, loss of bone, heart and circulatory disorders, reduced metabolism, loss of insulin sensitivity with an inability to regulate blood sugars and many other subtle effects that reduce quality of life. That is why the hormone's proper name is Somato (relating to the body)-trophin (relating to nutrition or support). During aging, one of the first hormone systems to progressively lose activity is that which produces GH. This negative change can be detected in most people during the mid to late 30’s and probably accounts in part for the undesirable changes in body form and function that we associate with aging. Accordingly, GH replacement has become popular as a method intended to delay the progression of age-related, physical and mental decline.

However, this indication for GH has not been approved by the US Food and Drug Administration (FDA) and therefore, many people are taking the hormone without benefit of a program to monitor the safety and effectiveness of GH replacement during normal aging. As a physician trained in Anti-Aging Medicine, Dr. Ghaly recognizes the potential value of GH replacement after age 40, but he is first and foremost concerned with his patient’s health and well-being. Balancing these issues, he has initiated an FDA-reviewed study in his clinic that is intended to provide a carefully monitored program of hormone replacement using either GH itself, or a hormone that stimulates the body to produce more of its own GH. In addition to the FDA, this program has been

Hormone Replacement & Balancing Therapies

Hormone Balancing

In order to understand why hormone balancing is important, you have to understand that your body ages from the brain down; from the pineal gland, the control center, a pea-sized computer in the center of the brain which releases melantonin, down to the hypothalamus lying just behind the eyes at the base of the brain, which sends signals down to the pituitary gland, a walnut sized outcroping extending below the hypothalamus which releases growth hormone, thyroid stimulating hormone, follicle stimulating hormone and luteinizing hormone (both necessary for female and male reproduction), prolactin (the milk producing hormone and immune and testosterone suppressant), and adrenocorticotrophic hormone (ACTH), which travels down from your pituitary to your adrenal glands to initiate the conversion of cholesterol into all of your steroid hormones, including the intermediate adrenal hormone DHEA.

Therefore, the cascade down from the brain affects the end organs: the thyroid and adrenal glands mentioned above, the ovaries and uterus producing estrogen and progesterone, and the testes producing testosterone. In return, the end organ hormones affect the brain through feedback mechanisms, and also each other through biochemical conversion pathways. This can result in an imbalance from inhibition of production, or an excessive production of one hormone overriding the beneficial effects of one or more of the other hormones.

To offset aging and degeneration of your hormonal system by replacement therapy, you need to replace hormones from the brain down by balancing them in combination to ensure they all remain within youthful normal ranges. Points of intervention, their hormones, and other chemicals that we know most about are summarized in the table below.

The  Beverly Hills Institute of Wellness Program’s Balanced Hormone Replacement 
for the Clinical Age Management Program

And finally, hormones, drugs, nutrients and foods are all parts of the same single system of chemistry. Once you realize this, the arguments about "natural" versus "unnatural" evaporate as anti-science hype from unregulated "health food" pitchmen. The real question is: "How much of a particular chemical, and when should I put it into my body for successful Clinical Age Management?"

People considering hormone replacement therapy need the guidance of a highly experienced neuro-endocrinologist to consider the following issues:

1. What bodily hormones and other chemicals can benefit human health when they are restored to youthful levels?
2. If the form of the chemical is a man-made derivative of a chemical that occurs in nature, does it match the natural form sufficiently to be beneficial?
3. What are the beneficial doses? Remember that any substance you put into your body can have side effects. The dose of a substance frequently determines whether it is beneficial or toxic to your system.
4. What are the best ways to deliver these chemical substances to the sites of action within the body, in the right dose, at the right time, and in a way that does not interfere with normal homeostatic mechanisms of synchronized daily and monthly rhythms of the myriad of body functions that are vital to your health?

Warning:
There are profound biochemical differences between individuals that can negate any conclusion drawn from the averages that result from scientific studies of groups. Only your physician can obtain the correct testing and other information required to estimate the unique needs of your individual physiology.

Aspects of Growth Hormone Replacement in Adults

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.

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.

Human Growth Hormone Scientists represent molecules in different ways depending on the information they need to review.            These pictures represent different ways of viewing the Human Growth Hormone molecule,a complex structure consisting of a chain of 191 amino acids.

People considering hormone replacement therapy need the guidance of a highly experienced neuro-endocrinologist to consider the following issues:

Warning:
There are profound biochemical differences between individuals that can negate any conclusion drawn from the averages that result from scientific studies of groups. Only your physician can obtain the correct testing and other information required to estimate the unique needs of your individual physiology.

Click here for scientific information on human growth hormone from the Protein Data Bank

Click here for structural information.  Scroll down to the ATOM records (left hand column is "ATOM").  Columns 6-8 are the 3 dimensional coordinates of each atom in the hGH molecule.

Click here for the main page of the Protein Data Bank

Features of Adult GH Deficiency

Features of GH Replacement Therapy in Adults

Somatropin [rDNA origin] for Injections
Somatropin is a generic name for human growth hormone replacement therapy for individuals who do not produce enough growth hormone of their own. 

The human body produces many different kinds of hormones-one of which is growth hormone. Hormones are made by glands and are secreted into the bloodstream to stimulate other parts of the body to perform specific activities. For example, the pancreas produces the hormone insulin, and the ovaries produce the hormone estrogen.

Somatropin is exactly like the natural growth hormone produced by the body’s pituitary gland. The only difference is that Somatropin is produced in a laboratory, using technology that copies the natural growth hormone molecule.

Product Administration
Somatropin is given by subcutaneous injection-that is, with a tiny, insulin needle injected just below the skin. This "injection" method is necessary because growth hormone is made of the same type of protein found in foods. If Somatropin were taken by mouth, it would be digested in the stomach and become inactivated. An "injection" of Somatropin allows it to get directly into the blood stream, avoiding digestion in the stomach. In this way, the growth hormone remains active to contribute its normal metabolic effects.

Injections of Somatropin are relatively easy to give. Follow the steps in the handout provided to you at the end of your office consultation on self-administration for taking Somatropin.

Your dose will be individualized for you. If you took growth hormone as a child, you will be reevaluated for your need to take it as an adult. If continued treatment is appropriate, your adult dose will be smaller than the one you used as a child.

Side Effects
Serious side effects do not usually occur. In studies of adults with growth hormone deficiency, the most common side effects were mild to moderate symptoms of fluid retention, swelling of extremities, painful joints, pain, and stiffness of the extremities, muscle pain, an abnormal sensation (such as burning or prickling), or an abnormal decreased sensitivity to stimulation. By dividing your daily dosage in half, and taking one half in the morning and one half just before bedtime, you will reduce the possibility of developing any of the above side effects. The best time to administer really depends on your schedule. Try to give it at the same time each day, at a time when you are not rushed.

Somatropin should be stored under refrigeration. (Do not freeze.)

If for some reason your vial of Somatropin is left outside a refrigerator for an extended length of time, contact my office for instructions before using.

The Benefits of hGH Treatment
Low dose (rDNA) hGH normalizes bone metabolism and improves bone density in adults without causing adverse effects.  

Growth Hormone & IGF Research 2002
Cortisol in the presence of insulin, activates Lipoprotein Lipase (LPL), which is a main regulator of triglyceride assimilation in adipose tissue. (Metabolism 1990; 30:1021-1025). In support of this, the specific glucocorticoid and progesterone receptor antagonist, RU-486, inhibits cortosol-induced LPL expression in human adipose tissue. (Obes. Res. 1995; 3:233-240). LPL activity is higher in visceral than in subcutaneous adipose tissue (J Clin Endocrinol Metab 1995; 80:936-941.)
According to a recent study, an increase in evening cortisol levels is present after midlife in men, whereas the morning values show no age-dependent change (JAMA 2000: 284: 861-868.) In addition, it is thought that there is a subtle change in the sensitivity of the HPA axis with aging (Aging Milano 1997; 9: 19-20.) Studies in humans suggest that there is an age-related decline in the resilience of the HPA axis, leading to progressively greater exposure to glucocorticoids (J Clin Endocrinol Metab 2001; 86:545-550).
Two factors might facilitate this process:
1. The age-related decrease in brain corticosteroid receptors leads to a decrease in the hypothalamic-pituitary sensitivity to negative feedback from glucocorticoids; 
2. Repeated cortisol-generating stress challenges.
Dexamethasone (DEX) inhibition on peripheral cortisol concentration has a reduced response of the HPA axis to DEX with aging; higher mean cortisol levels of post-DEX were observed in the elderly. Recently published data noted that a dose of 1mg DEX is too high to detect individual differences in feedback sensitivity within a normal population, since near total suppression occurred in most individuals (J CLin Endocrinol Metab 1998;83:47-54).

Low Dose Dexamethasone Suppression Test
A control 8am plasma and a 24 hour urine-cortisol with creatinine are obtained, followed by low-dose DEX 10µg/kg/max 0.5mg) every 6 hours for 2 days. Plasma cortisol and creatinine are obtained on the second day of DEX. On day 3, collect 8am blood sample for cortisol level. Normal responses are suppression of plasma cortisol <5µg/dl and suppression of urine free cortisol to <20µg/24h.

Combined role of cortisol, insulin and GH at the adipose tissue site.
Cortisol and insulin facilitate lipid accumulation, particularly in the visceral adipose tissue, whereas GH causes lipolysis. GH inhibits LPL expression induced by cortisol and insulin; and lipolysis is increased. This makes teleological sense, since the main metabolic effect of GH is the protection of LBM (protein) during times of energy deficit (fasting). To prevent protein utilization GH increases lipolysis, fatty acid utilization and non-oxidative glucose disposal. Dexamethasone down regulates expression of a factor: Pref-I (preadipocyte factor1) which blocks differentiation of adipocytes, while GH prevents its down regulation in preadipocytes. The net effect is glucocorticoids facilitate and GH inhibits differentiation of adipocytes.

Increased glycocorticoid levels lead to inhibition of protein synthesis, as well as inhibition of amino acid transport into muscle. DEX blunts BCAA--stimulated phosphorylation of key proteins (IF4-BP1and p70S6K) involved in activating the mRNA translation apparatus. This may explain the catabolic effect of glucocorticoids on protein metabolism in skeletal muscle. Glucocorticoids also cause resistance to the antiproteolytic effects of insulin in muscle. Short-term high dose Predisone also leads to a negative leucine balance in both the fasted and fed state(GH and IGF-I Res 2002; 12: 147-161).

Several studies suggest that these cortisol-related effects on body proteolysis may be prevented by GH. Fry, et al, showed that GH increases protein synthesis in forearm tissue within 6-8 hrs of intra-arterial infusion and GH compensates for the nitrogen losses induced by glycocorticoids by increasing protein synthesis (GH and IGF-I Res 2002; 12:152).

Since both cortisol and GH increase peripheral tissue resistance to insulin, this may be a relative obstacle to the use of GH to prevent cortisol induced catabolism. However, this likely is dose related and it is unclear what dose of GH is necessary to minimize the catabolism of physiological concentrations of cortisol.

Growth Hormone & IGF 2003 Updates

Effects of GH on  Body Fluid Balance
Approximately 60% of body weight is water. Total Body Water (TBW) is subdivided into intracellular volume (ICV), 40% predominated by the cation and anion potassium and phosphate, respectively, and extracellular volume (ECV) 20% dominated by sodium and chloride, which is further subdivided into interstitial volume (IV) 15% and plasma volume (PV) 5%.

Measurement of body fluids suffers from a lack of a “gold standard” method. As a consequence, many different methods have been developed, which are difficult to compare. Despite differences in estimating these body fluid compartments, most authors seem to agree that body fluid volume is decreased in GH-deficient adults, and that GH treatment normalizes body fluid volume in these patients. There is also agreement that GH causes volume expansion, when administered in pharmacological doses to normal subjects and when secreted in excess in active acromegaly (Giantism).

Evaluation of fluid status in GH-deficient patients is complicated by the fact that some patients suffer from additional pituitary deficits such as ACTH, gonadotropins, and TSH potentially influencing body fluid compartmental balances. In addition, secretion of another hormone from the pituitary gland, Vasopressin, may be impaired. Although the problem may be reduced by optimal substitution of all pituitary hormones, the potential differences of this group of patients should be kept in mind when assessing the effect of GH on body fluid balances (Homeostasis).

A common side effect to GH administration are symptoms and signs of fluid retention, which seem to occur mainly during the initial phase of treatment [Jorgensen, et al, Lancet I (1989) 1221-1225 and Cuneo et al. Clin. Endocrinol. (Oxf) 37 (1992) 387-397]. In a more recent study full normalization of ECV compared to a normal control group was obtained only after 3 weeks of administration [Moller, Growth Hormone & IGH Research 13(2003) 55-74]. These data indicate that the symptoms of fluid retention often encountered by GH-deficient patients during the first days of treatment probably is related to the changes in fluid distribution rather than absolute overhydration.

Conclusion
GH causes volume expansion and transient sodium retention without affecting PV in normal man when administered in pharmacologic doses. Volume expansion following GH administration has been demonstrated in catabolic (wasting-syndrome) patients. Some data suggest this to be a beneficial effect, since intracellular dehydration has been demonstrated to correlate well with the degree of protein loss during critical illness. In addition, vascular volume optimization improves outcome after various surgical procedures.

GH deficiency is associated with decreased TBW, ECV, ICV and PV. Extracellular volume and in particular PV are important for measurement of cardiovascular function such as mean arterial pressure and left ventricular filling volume [Miller et al. The Kidney. WB Saunders. Phil 1996, pp. 817-872].

Intracellular dehydration has been suggested to trigger protein breakdown, and cell swelling stimulates protein formation [Hausinger et al. Lancet 341 (1993) 1330-1332]. Thus, a normalization of the internal environment (ECV and PV) and ICV should in theory be beneficial to GH-deficient patients, and, in fact, this does occur following GH replacement. It could be speculated that the improvements in cardiac and renal function, and in protein and lipid metabolism seen during GH replacement could be at least partly due to normalization of body fluid balance (homeostasis).

Consequently, the fluid and sodium-retaining effect of GH should be regarded to represent a physiological normalization rather than an unpleasant side effect. The extracellular and plasma volume expanding effect of GH excess is clearly seen in acromegalic patients. It seems reasonable to speculate that a number of distinct symptoms such as carpal tunnel syndrome, headache and parasthesias are related to volume expansion due to excessive GH secretion in acromegalic patients.

Effects of GH replacement therapy on metabolic and cardiac parameters in adult patients with childhood-onset GH-deficiency. (16 patients age between 18 and 35 years) [Jallad et al. Growth Hormone & IGF Res. 13 (2003) 81-88].

Results
1. Hormone and Metabolic Values
After 6 months of GH replacement, IGF-I was normal for age and sex in 15 patients and remained reduced in only one patient, whereas IGFBP-3 was normal in 6 and remained reduced in ten patients. After 12 months of GH-therapy, IGF-I was normalized in all patients, whereas IGFBP-3 was normal in 10 and still reduced in six patients. The serum concentration of IGF-I before and after replacement therapy did not differ between male and female patients. A decrease in total cholesterol and LDL/HDL-cholesterol ratio was detected during the GH-therapy period in comparison with that at basal levels. Despite the tendency toward increased insulin values during GH-replacement, no statistical differences between before and during the GH therapy period were noted, parallel to no variation in fasting serum glucose and glycated hemoglobin levels.

2. Body Composition
A significant increase in lean body mass and concomitant and similar decreases in fat body mass were observed after 12 months of GH-therapy, without a significant change in body weight. No differences regarding body composition could be observed between male and female patients.

3. Cardiac Parameters
Echocardiographic results: before treatment, patients had significant decreased left ventricular (LV) mass, such as interventricular septal thickness, LV posterior wall thickness and LV mass index, compared with those in healthy control subjects. After 12 months of therapy, all these indexes had significant increases, and had no more significant differences compared with those in normal control subjects.

Treadmill exercise test results: All exercise tests were negative for myocardial ischemia. At baseline, 5 patients had submaximal tests (because of leg weakness or exhaustion). After 6 months of GH replacement, only one patient had a submaximal test, and after 12 months all had maximal tests (95% of age-predicted maximum heart rate). Between pre- and post- treatment, the patients had notable improvement in exercise performance, such as increased exercise duration, double product, and estimated peak oxygen uptake consumption.

4. Correlation
Only a discreet correlation was found between LV mass index and exercise duration after 12 months with GH replacement treatment.

5. Clinical Tolerance
When comparing pre-treatment with 12 months of GH-replacement, resting arterial systolic blood pressure (106.3 plus or minus 11.5 mmHg x 111.3 plus or minus 10.8 mmHg) and diastolic pressure (68.1 plus or minus  7.5 mmHg x 70.6 plus or minus 6.8 mmHg) had no significant changes. Some previous studies observed that by using doses of GH based on body weight or body surface, side effects are more prone to occur, associated mainly with fluid retention [Johannsson, et al. Clin. Endocrinol (Oxf) 47 (1997) 571-581]. In the present study, two women and four men reported mild arthralgia, particularly in the hands, knees, and feet, and peripheral mild edema, in the beginning of treatment and that disappeared with continual therapy. When the patients visited the clinic for physical examination and assessment after 3 months of therapy, no side effects were seen. No patient withdrew from treatment because of side effects. All patients had good adherence to GH replacement therapy.

Discussion
A current consensus indicates that diagnosis of GH deficiency (GHD) in the presence of pituitary deficiencies requires a single dynamic test to confirm it in adult life [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. J Clin. Endocrinol. Metab. 83 (1998) 379-381]. Increasing degrees of anterior pituitary failure predict a high probability of GHD, and when two or more hormone deficiencies are present, the possibility of GHD is very high [Toogood, et al. Clin. Endocrinol. (Oxf) 41(1994) 511-516].

IGF-I levels are not consistently low in patients with GHD of adult-onset. In fact, normal IGF-I levels were reported in 73.3% of patients with partial GHD, and in 29.2% of patients with very severe GHD [Colao, et al. J. Clin. Endocrinol. Metab. 84 (1999) 1277-1282]. Thus IGF-I may be a more useful guide to GH status only in younger adults (ages 18-35) who have childhood-onset severe GH deficiency.

A dose titration regimen of GH replacement based upon achieving and then maintaining IGF-I levels above the median level, but below the upper limit of the age-related reference, rapidly obtaining effective but lower maintenance doses of GH, minimizing the potential adverse effects of GH treatment have been suggested [Johannsson, et al. J Clin. Endocrinol. Metab. 81 (1996) 1575-1581; Johannsson, et al. Clin. Endocrinol (Oxf) 47 (1997) 571-581; Drake, et al. J. Clin. Endocrinol. Metab. 83 (1998) 3912-3919].

GHD is associated with cardiac risk factor indices such as abnormal circulating lipid profile, body composition with increases in total body fat, central obesity, and decreases in lean body mass, and cardiovascular abnormalities. There is growing evidence that treatment with GH can ameliorate lipids and body composition, as well as reverse most of the cardiovascular abnormalities associated with childhood and adult onset GHD. [Ter Maaten, et al. J. Clin. Endocrinol. Metab. 84 (1999) 2373-2380; Gibney, et al. J. Clin. Endocrinol. Metab. 84 (1999) 2596-2602; Colao et al. J. Clin. Endocrinol. Metab. 87 (3) (2002) 1088-1093]. The reduced cardiac death after GH replacement therapy could be due mainly to reducing cardiovascular risk factors more than improving the cardiac structure and performance.

The minimum period of treatment for ideal correction of heart indexes seems to be 12 months. However the changes, especially in performance and strength are very subtle and occur over long periods of time. Data from Jorgenson indicates that about 36 months is required before they begin to respond as measured by exercise capacity [Jorgenson, et al. Eur. J. Endocrinol.130 (1994); 224 fig 1]. Because cardiac indices appear to return to pretreatment values after some months of GH replacement’s interruption [Amato, et al. J. Clin. Endocrinol. Metab. 77 (1993) 1671-1676; Valcalvi, et al. J.Clin. Endocrinol.Metab. 80 (1995) 659-666; Colao, et al. J. Clin. Endocrinol. Metab. 87 (2002) 1088-1093], it is widely believed that a permanent dosage of GH replacement seems to be imperative. More long-term trials are needed to confirm these benefits and to determine the ideal dosages to be used in long-term GH replacement therapy of GHD.

Growth Hormone & IGF Update 2004-2006:
Click Here to View: GrowthHormone -- Adult Deficiency
Click Here to View: Effects of Growth Hormone on Visceral Fat and Obesity
Click Here to View: Current Concepts of Estrogen Regulated Secretion
on Menopausal Women