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YOUNG AGAIN: HISTORY OF hGH, PAST TO PRESENT

"I am not young enough to know everything."
 -Oscar Wilde          

CHAPTER 1

In May of 1989, Daniel Rudman held the first of 12 syringes up to the light. Seated before him was a 73 year-old man. "Are you ready?" he asked his elderly patient. "Ready as I'll ever be," came the reply. The syringe contained a small amount of recombinant growth hormone dissolved in clear liquid. Rudman swiftly injected him.

Dr. Daniel Rudman was doing something never done before within the confines of medical research: he was giving perfectly healthy men a cloned version of what has come to be known as GH. Growth hormone is a hormone secreted in the brain by the pituitary. Everyone who ever attained normal height has it. Or - had it. GH levels drop off with age, and not so coincidentally, all the things that go with it become history as well: strength, muscles, energy, strong bones and teeth, thick skin, sex drive - that indefinable optimism of youth - gone. But what would happen if older people were given back their GH?

Four years before Rudman began his experiment, a very strange thing occurred at movie theaters across America. Next to the Rambo crowd were lines of white-haired moviegoers-some in wheelchairs, others leaning on canes. People who hadn't seen a movie in 20 years were waiting patiently to see a movie, which, by all accounts, starred bunch of old fogies. The movie was Cocoon, and it was Hollywood's incarnation of one of mankind's most persistent reveries: what if an older person could become young again?

Four years later, Daniel Rudman was making the first steps towards answering that question by injecting 12 people with growth hormone (GH). Fortunately for them, he was relying on Eli Lilly rather than alien pods to supply the solution.
The preliminary data was in as quickly as it appeared in Cocoon; energy, vitality, endurance, sex drive, optimism and happiness all rebounded with GH.

Within 6 months, Rudman had the final data. In a strict scientific sense, his patients had become younger. Ten to twenty years of aging were peeled from their laboratory profiles. Their skin was thicker, muscles were bigger, age related stomach fat was disappearing, and lost bone from the spine was restored. Their levels of insulin-like growth factor (IGF- 1 *) had become equivalent to that of a20-year old.

The first indication that earthlings might be able to reverse the aging process was published in the New England Journal of Medicine in July 1980, starring Dr. Rudman and his group of 12. Just as Hollywood producers scramble to imitate a box office hit, scientists all over the world began to assemble clinical studies that would eventually confirm Rudman's results and reveal new applications for growth hormone.


   Effect of Human Growth Hormone on Lean
   Body Mass, Adipose (fat) - Tissue Mass, Skin
   Thickness and Bone Density in Healthy Men
   Ages 61-73

   Lean Body Mass.................................. +8.8%
   Bone Density (Lumbar vertebrae)........ +1.6%
   Adipose-Tissue Mass........................... -14.4%
   Skin Thickness from 4 sites.................. +7.1%
 

* Instead of measuring GH, scientists rely on IGF-1, which is provoked by GH and elicits most of the benefits associated with growth hormone. IGF-1 measurements are easier and much more accurate than GH measurement.

 

What Is Growth Hormone ?

The discovery and designation of the term growth hormone was derived from its visible manifestations. Physicians had long known that there was a substance from the brain that made people grow. But it wasn't until 1912, that the eminent researcher and surgeon, Harvey Cushing, identified this elusive substance and termed it "the hormone of growth".

In 1956, endocrinologist Maurice Raben finally isolated "the hormone of growth" from human and monkey cadavers.
In 1958, he advanced growth hormone research to the next level by injecting it into a dwarf child.
As the child began to grow, the hormone finally lived up to its name.

The pituitary gland, which manufactures growth hormone, is located at the base of the brain, and GH is only one of many hormones it releases. GH production is controlled by its manufacturing cells called "somatotrophs", while its release is controlled by chemical messages from the hypothalamus. These important distinctions between GH and other hormones present options in treatment methods, which we will clarify in future chapters. Studies have clarified human GH releasing patterns, by measuring GH every 5 minutes for an entire day. It is released in four main bursts, or "pulses", in young men, while young women exhibit more frequent bursts that collectively represent 50% more daily secretion of GH.
Most of the day's GH release occurs at night during slow wave sleep, and the remainder is released in smaller bursts during the day, which are often determined by exercise and dietary patterns. GH may be released about 12 times during a 24-hour period, but after the age of 50, the number and intensity of pulses is decreased. GH decreases about 14% every decade into old age to the point that some elderly people don't release any detectable GH at all.

GH has many effects in the body, and what it does maybe best illustrated by what happens when it's not there.

 

Growth Hormone Deficiency

Children

In children, the effects of GH deficiency are easily discernible. Children lacking GH have short stature, small hands, feet and skull. Teeth are late in coming in, and skin is so pale that the veins show through. Nails don't grow, and the voice is high-pitched. Even little kids get the fat-around-the-middle that is so characteristic of GH deficiency in adults. In addition, their bones are porous and their lean tissue mass is reduced.

Skin

In adults with GH deficiency, the skin is thin and collagen deficient. Wrinkles known as "crow's feet" may be caused,
in part, by GH deficiency. People who have had their pituitaries removed have pronounced "crow's feet". While the connection hasn't been absolutely proven, research has shown that GH treatment increases serum Type III procollagen-an important building block for skin and connective tissue. Decreased skin thickness and resultant wrinkles are signs of old age; increased skin thickness and smoother skin are evidence of GH treatment.

Dehydration

GH deficiency also causes dehydration and decreased sweating. People with GH deficiency can't tolerate cold and have difficulty cooling off during exercise. In short, these people cannot thermoregulate. Lack of hydration often becomes evident when blood is drawn; people with GH deficiency are often told by the phlebotomist that he or she "can't find a vein". Not surprisingly, GH related dehydration is associated with kidney problems. Adults with GH deficiency have reduced filtration and reduced renal plasma flow. Age-related dehydration, or "shriveling up" of bones and skin, is largely caused by GH deficiency.

Heart and Exercise

Decreased blood volume due to dehydration may contribute to the heart problems experienced by adults who are GH deficient, but there seem to be other ways in which GH deficiency inhibits proper cardiac function. Atrophy of the heart muscle is an important factor. Studies suggest that GH elicits an anabolic effect on cardiac muscle. This is not surprising, given its effect on lean muscle mass. People with GH deficiency also have extremely reduced exercise performance. Maximal oxygen uptake (V02 max) is only 70-80% of normal. It has been reported that this will reverse within three years of GH injection therapy.

Metabolism

Metabolism of glucose, protein, and fats is abnormal in GH deficient adults. Sugar metabolism and accompanying insulin resistance is a problem particularly in obese adults with GH deficiency. GH therapy has a known insulin regulating effect and often results in normalization of blood glucose.

Proper protein metabolism requires insulin regulation and other mechanisms, which are greatly improved with GH therapy. The benefits of GH in this area are evident in the increase of lean muscle mass due to improved muscular protein uptake.

Fats

Lipids are a real problem for GH-deficient adults. Total cholesterol, LDL cholesterol and apolipoprotein-B are elevated. HDL ("good") cholesterol has been reported in some studies to be subnormal. GH deficiency causes increased thickening and hardening of arteries, and increased plaque formation. These physical changes, along with the changes in blood lipid profile contribute to the increased risk of heart disease for GH deficient adults. Increased body fat, particularly in the abdominal area, is common in those who are GH deficient.

Psychological

Long term studies show GH deficiency to be consistently associated with extreme impairment of psychological well being. Patients in these studies typically exhibit similar symptoms, including lack of energy, optimism, and "zest for life". They are frequently "loners" who lack friendship, intimacy and career satisfaction. They report difficulty with memory, concentration, and motivation. They are frequently "in a bad mood", and. depressed. Unfortunately, many of these people, including the elderly, are frequently mistreated with antidepressant drugs.

All of the symptoms of GH deficiency that we have described thus far were at first founded in their consistent association with low GH levels. These correlations were then substantiated by the reversal of these symptoms with the use of GH therapy. In chapter two, we will detail some of the studies that support these and other areas of therapeutic potential that growth hormone therapy has to offer.

 

CHARACTERISTICS OF GROWTH HORMONE DEFICIENCY

Anabolic Tone
Reduced lean body mass and/or skeletal muscle mass
Reduced skeletal muscle strength
Reduced exercise performance
Increased total body fat
Increased abdominal and visceral fat

Lipid Effects
Elevated LDL cholesterol
Decreased HDL cholesterol
Elevated apolipoprotein-B

Bone Effects
Osteopenia (lack of bone)

Metabolic Effects
Insulin resistance (in obese people)
Hypoglycemia
Possible abnormal resting metabolic rate
Reduced T4 to T3 conversion

Protein Synthesis
Thin skin Lack of collagen
Decreased size of organs
Decreased nail and hair growth

Dehydration
Reduced glomerular filtration and renal plasma flow
Reduced sweating - inability to thermoregulate
Reduced cardiac output (potentially)
Increased vascular resistance

Mental Health
Reduced energy
Emotional instability
Poor memory and concentration
Depression ILL
Lack of social interaction
Lack of purpose
Reduced Sex Drive

 

________________________________________________________________________________________________________________
Adapted from Cuneo RC, Salomon F and PH Sönksen. The syndrome of growth hormone deficiency in adults. In Anders Juul and Jens O.L. Jorgensen, eds. Growth Hormone in Adults: Physiological and clinical aspects. New York: Cambridge University Press, 1996; 145-167.
________________________________________________________________________________________________________________

 

Factors that Influence GH

Obesity diminishes pulsatile secretion of GH. It also causes accelerated breakdown of GH by the body. On the other hand, sustained high-intensity exercise increases the quantity and number of pulses of GH release. Intense is the key word here; garden-variety jogging won't do it.

Fasting increases both the pulsatile frequency and the amount of GH secreted. Eating shuts it down by stimulating insulin, which opposes GH. Over the long term, a poor diet can tremendously interfere with proper GH release and IGF-1 formation. The correct diet will assist in overcoming excess insulin in order to promote growth hormone. In chapter six we will detail diet and exercise routines that will help to optimize your GH release and response.

Testosterone, estrogen, and other hormones enhance GH secretion. The synergistic effect of replacing a variety of deficient hormones cannot be overstated. Results in this area are enhanced with the use of the proper forms of these hormones that are recognized by the body. In chapter seven we offer some guidelines for understanding the role that various hormones play in GH management.

The amino acids L-arginine and ornithine can cause GH release if taken in high enough amounts. Certain drugs also cause GH release, including L-dopa and clonidine. In chapters three and four, you will gain some insight to the complexity and function of GH secretagogues.

The liver synthesizes insulin-like growth factors (IGF-1 and 2) as part of a feedback loop that regulates GH.
The relationship between GH and IGF-1 is extremely complex. Binding proteins and GH receptors are involved in how GH affects the body. African pygmies are a living example of the importance of GH receptors. One would think that giving pygmies GH would make them grow, but it doesn't. Pygmies have plenty of GH, but they are lacking receptor sites on their cells. Later, you will learn how to optimize IGF formation and sensitize GH and IGF-1 receptor sites in order to optimize response to GH therapy.

 

Treatment in the Early Days

From 1958 until the time it was finally synthesized, GH was painstakingly extracted from human cadavers and injected into GH-deficient children and adults. Heat was known to destroy this precious substance, so in the early days of GH treatment the extract could not be heated to the point of killing all contaminants. Consequently, some of the early GH batches, which came from people who harbored the catalyst for the human version of "mad cow" disease, were contaminated. Creutzfeldt-Jakob disease (CJD), as it is known, is a horribly debilitating brain disorder for which there is no known cure. CJD belongs to a family of diseases that afflict sheep, cows and humans. The prion that causes it is neither viral nor bacterial, but is thought to be a normal protein. that has become distorted. Prion contamination ceased
to be a problem when the FDA banned the natural version of GH and approved the synthesized version in 1985.

 

Synthetic GH Arrives

During the early 1980s, two phenomena occurred that would eventually lead to synthetic human GH; no longer would it have to be taken from cadavers. Yuppie fever hit, and DNA cloning was invented. Cloning allowed researchers, for the first time, to ferret out the individual sequences of DNA that code for proteins. The discovery of cloning techniques has fueled a scientific revolution that is still in its infancy. "Recombinant DNA" technology allows DNA to be snipped into little pieces with "molecular scissors" and placed into bacteria. The bacteria then chum out little Xerox copies of the snippet. By amplifying DNA in this fashion, it becomes possible to really study and understand individual sequences. This is how the DNA sequence that codes for GH was found. The first product of this method offered on a commercial scale was insulin. The second was GH. The same company, Genentech, synthesized both of them.

The large scale cloning of human GH had come about in large part because of the actions of congress, which, in 1983, wrote The Orphan Drug Act into law. The law was designed to provide incentive for drug companies to develop and market drugs that would help people with rare diseases. Many of these people were falling through the cracks because drug companies could not justify spending money to develop drugs for which there wasn't a large market. The law provided that the federal government would heavily subsidize the development of drugs that affected 200,000 or fewer people, and any drug company that took on the task would have a 7-year monopoly on the market.

Genentech wasted no time in applying for "Orphan" status for the development of GH. The "orphan" market for GH was 7,000 GH-deficient kids. These children have severely inhibited growth, a condition that doctors refer to as "hypopituitary dwarfism". By 1985, Protropin was FDA approved for hypopituitary dwarfism. Initial sales were estimated to be $4M.
One might wonder.. Why would the biotech darling of Wall Street go after a market comprised of only 7,000 children? GH, like insulin, has to be taken every day for life. With the monopoly provided by the Orphan Drug Act, there would be no competitive pricing. The company holding the monopoly on GH could name their price.

At $15,000 per child per year-the price Genentech decided on-the $4M market for GH quickly turned into an $150M market. By the third quarter of the first year Protropin was on the market, it raked in $23M. In 1987, Adelle Haley, financial Sialyst at Smith Barney, declared that "short stature is a small market". According to her, Protropin sales wouldn't go above $23.8M. Her financial soothsaying proved to be wrong. Protropin ended the year with $43.6M in sales. The following year, sales were at $86M, and by 1989 sales were $122M. In 1995 Genentech was predicting sales of $lB worldwide.

 

YUPPIES, Lawsuits, and the Government

Genentech got a big boost in sales by a social phenomenon. About the same time that Genentech hit the market with growth hormone, YUPPIE fever gripped America. The credo of YUPPIE Dom was all the perfection money can buy.
People with short kids soon found out that perfection could be bought for about $15,000 a year. The number of children diagnosed with hypo pituitary dwarfism (the only condition for which GH was approved) rose to 15,000 in 1989, from the original 7,000 in 1985. By 1995, 30,000 children per year were diagnosed with it. Company spokesmen attributed the increase to enhanced diagnostic abilities on the part of pediatricians. The whole thing was out of control during the '80s. Jeremy Rifkin's anti-biotech group sued the National Institute of Health (NIH) to stop trials of GH on short kids, and the FDA and Congress launched an investigation of Genentech's promotion of the drug.

The pharmaceutical giant, Eli Lilly, wanted GH too. It successfully cloned GH a few months after Genentech, and called its version Humatrope. As far as Genentech was concerned, it was fine to clone Humatrope. It was not fine to put it on the market.

Despite Genentech's "orphan" protection, the FDA approved Humatrope in 1987. Genentech promptly sued the FDA.
In September of 1987, the first of its claims were shot down in a federal court. This was not the end of the litigation, however. In all, five companies went after GH and each other. Both Hoffmann-LaRoche and Lilly ended up suing Genentech, and Genentech sued them back over patent rights. Lilly and Genentech wrangled in court for 8 years,
with Lilly finally throwing in the towel, agreeing to pay Genentech at least $145M over several years.

 

Enormous Potential

Even as Genentech went to market with Protropin, the company knew it could be used for a lot more than just dwarfism. Before Genentech made the synthetic version, athletes-notably Olympic athletes-were injecting GH from cadavers.
It was widely believed in the athletic community that GH could increase endurance and strength. This "underground" use of GH by athletes was problematic in two significant ways. First, pharmacological (as opposed to physiological) doses of GH were being used, secondly, the long term effects were unknown. A pharmacological dose is one that far exceeds levels that would occur naturally in the body. A pharmacological dose is designed to act like a drug on the body's systems. This is far different from the physiological doses being injected into kids to make them grow. A physiological dose merely brings levels up to normal. No one -including the athletes themselves- knew what the side effects of huge doses of GH would be. Because the natural hormone was undetectable, policing it was impossible.

Publicly, Genentech admitted that GH might be used for enhanced wound healing. Osteoporosis was a maybe. But the scientific literature contained tantalizing hints that the market for GH would be huge. Growth hormone affects many systems of the body; in fact, it targets nearly all tissues. The insulin like effect of GH that results in lowering of blood glucose made it a very attractive target for diabetes research. In addition, GH was known to be "lipolytic" (fat burning). From the drug company's perspective, the fat-lowering, sugar-lowering capability of GH gave it an exciting and potentially huge market.

Hundreds of studies later, GH has become one of the most exciting hormones ever studied. The anti-aging potential is so great that the National Institute on Aging is conducting long-term, large-scale studies. There is nothing to suggest that GH won't live up to its reputation. Unlike other hormones with anti-aging potential, GH has been extensively studied in humans. The scientific literature is replete with new studies. GH has been associated with improvement in some of the most prevalent and intractable diseases of aging: Parkinson's disease, osteoporosis, heart disease and diabetes.
And the good news is that people don't have to travel to Anterea to get it. It's available here -on earth.

_______________________________

I'm so excited about Symbiotropin. I have lost 30 inches in three months, it has burned the cellulite very fast off my legs and hips. The next best thing is my skin. My skin was so thin it was tearing almost daily... it is now thick again, it looks and feels like when I was much younger!! My age spots have disappeared from my hands... my eyes have improved so much I seldom wear my glasses anymore... I have increased my muscle mass and strength tremendously. My memory has really improved also. My hair is thicker and grows really, really fast...

-H.G. (Female, Age 57)

_______________________________

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