"'Getting Real' about hGH and Aging:
An Update on Growth Hormone and IGF Research and the Growth-Hormone Industry,"
A Report on the Third International Growth Hormone Research Society Meeting
held in San Francisco, California on September 3-6, 1998.
by
Karlis Ullis, M.D
Assistant Clinical Professor
UCLA School of Medicine and
Medical Director
Sports Medicine and Anti-aging Medical Group
1807 Wilshire Boulevard, Suite 205
Santa Monica, CA 90403
Voice: 310-829-1990
FAX: 310-829-5134
E- mail: kullis@ucla.edu or kullis@saonet.ucla.edu
Also, please check the website of the American Association of Clinical Endocrinologists and
the American College of Endocrinology for their 12-page report of the 24-member Growth
Hormone Task Force at
[Editor's Note: Click here here to see a copy of Dr. Ullis'
letter to the Health Editor of the Los Angeles Times regarding some of the fraudulent
products now on the market.
ABSTRACT
This paper reviews the significant changes that have occurred in the growth hormone pharmaceutical industry between 1996-98, and their implications for the clinical practice of anti-aging medicine. Much of the information comes from the Third International Growth Hormone Research Society Meeting in San Francisco on September 3-6, 1998. The author interprets an abstract that may elucidate why women on Growth Hormone (GH) therapy do not experience as much of an effect as men do. Recommendations are made regarding how to make GH more effective in the female GH-deficient patient. New tests are developed for GH doping control in sports. The Growth Hormone Research Society's debate on the significance of elevated plasma Insulin-like Growth Factor-1 (IGF-1) and prostate cancer and other cancers is presented.
I began my observation of the evolution of the GH pharmaceutical industry in 1970-71 while I was in postgraduate training under the tutorship of Barbara Lippe, M.D., at the UCLA Pediatric Endocrinology Department. Dr. Lippe now serves as the director of GH and peptide research at Pharmacia Upjohn. In the 1990's, my focus has been on the research and treatment of adult onset GH deficiency diseases and aging of the GH/IGF-1 axis. Back in the 1970's, we had only limited amounts of cadaver-derived GH. In the early 1990's there was an abundance of engineered recombinant hGH available, and a variety of GH secretagogues and GH-related compounds in the pharmaceutical research pipelines.
After attending the Second International Growth Hormone Research Society Meeting in London in 1996, I came home optimistic about GH research and the multitude of promising GH and IGF-1 products which could potentially be used clinically for the diseases associated with aging as well as aging itself. The industry's "cupboards appeared full." The adult GH-deficiency indication would soon be FDA-approved in the US, as well as GH for AIDS wasting. I was enthusiastic about the favorable oral secretagogue human clinical trials with a Merck compound called "MK0677" as well as the use of recombinant IGF-1 as an adjunct to GH therapy or for those who are GH resistant or insensitive.
Today, September 6, 1998, upon returning to Santa Monica, California, I am now a "disappointed realist." The research cupboards are three-fourths empty compared to 1996. Many in the anti-aging clinical field were anticipating, in 1999, the release of numerous significant GH-related compounds. Instead, a "major industry shakeout" has occurred. Two major "bombshells" have hit with significant implications for those of us who are in the clinical specialty called "Anti-Aging Medicine."
Bombshell Number 1
Merck has terminated all research studies on the orally active potent GH releaser, the non-peptidal secretagogue called "MK 0677" and will not pursue FDA approval after all. The principal researcher at Merck and an international pioneer secretagogue investigator, Roy G. Smith, M.D., has left Merck to go work at Baylor University's Aging Research Center. Drs. A. D. Howard, M.D. and Roy G. Smith, M. D. and colleagues at Merck Research Laboratories in 1995 [1] were the first to isolate and report on the cloning of the Growth Hormone Secretagogue Receptor (GHS-R). Since then, Merck has continued to more finely define the active sites of the GHS-R. The ligand active binding sites (structural pockets) are spatially similarly disposed to the well-defined catechol-binding-site in the beta-2 adrenergic receptor. The GHS-R now has been isolated in rodents, humans, dogs, pigs, and even fish and has a strong cross-species structural concordance. Merck appears to have the lead in identifying the natively occurring ligand for the GHS-R. Whoever identifies and isolates this ligand may be deserving of a Nobel Prize, since this novel ligand will provide new tools and therapies involving GH physiology. [2]
Dr. M. A. Bach, M.D. (GHS Clinical Research Director, Merck Research Laboratories) stated that it was a high-level corporate business decision to drop MK0677. The rumors were that it was just not effective enough in the "frail elderly" market that it was intended to reach. Studies on healthy aging population were favorable and safe, but helping "healthy aging people" is not an indication the FDA would buy. Merck needed a specific disease that MK 0677 could effectively treat, and -- strictly speaking -- "aging" is not a disease. The paper that Bach presented in San Francisco suggested that MK0677 is beneficial for earlier and better functional improvement in elderly patients hospitalized for hip fractures. [3]
Bombshell Number 2
Genentech and Pharmacia Upjohn have terminated their research and attempts to get FDA approval for their recombinant IGF-1 product. The combination of GH and IGF-1 has very potent synergistic clinical effects in the elderly and has a good safety profile. Furthermore, IGF-1 by itself has worthy anti-aging uses.
The anti-aging medical community sadly has just been deprived of two very promising tools in its battle on aging.
Orally-active GHS research is not entirely dead. Nova Nordisc is in early animal and in vitro trials with a compound called "NNC26-0703." Human research is continuing with a variety of injectable growth hormone secretagogues.
The Good News
Dr. Ho from Sydney, Australia also presented an Abstract. [4] After I discussed his research findings with him, I was finally able to appreciate why some of my older female GH-deficient patients did not respond as well as age-matched men to their GH-therapy protocol. The answer is now obvious. Dr. Ho elucidated that oral estrogen (Premarin 1.25 mg) blocks liver production of IGF-1 resulting in decreased IGF-1 levels while simultaneously increasing the levels of Sex Hormone Binding Globulin (SHBG) and Growth Hormone Binding Protein (GHBP). When Estrogen (E) was given transdermally (100 mcg of Estraderm) these effects in the liver were not observed. When different oral Progesterone (Pg) preparations were given with oral E the Pgs modulated E's effect on liver production of IGF-1. Indeed, the degree of Pg androgenicity determined the degree of modulation. The most androgenic progesterones (noerethisterone at 2.5 mg) produced the greatest IGF-1 increase and the lowest SHBG and GHBP concentrations while 10 mg of Medroxyprogesterone (Provera), being second in androgenic potency, had a proportional effect on the levels of these proteins. These effects of the androgenic Pg's are understandable, since all compounds with androgenicity have some anti-estrogen effects and thereby modulate E effects on liver protein synthesis of IGF-1, SHBG, and GHBP. [5]
Special Message to Clinicians Using GH Therapies
If you are treating GH-deficient women with GH and they are on oral estrogens switch them to a transdermal estrogen preparation (patch, gels, or creams, etc.) to get the greatest IGF-1 response from GH administration. Add an androgenic Pg or use a natural (neutral androgenic Pg) plus testosterone (T) (T-transdermal from a good compounding pharmacy) if the women are androgen deficient. The downside of using androgenic Pg's and T is that they can be "unfriendly" to the cardiovascular system. If your GH and sex hormone replacement is done correctly with appropriate doses, it should give women the same GH effect as the male GH response. The IGF-1 levels should rise without having to increase the GH dose. The GHBP and SHBG levels should decrease. The overall result should be increased fat loss, an increased lean mass, increased energy, a greater sense of well being, and all of the other positive parameters seen with correct therapy of adult- onset GH-deficiency diseases or occurring with the aging of the GH/IGF-1 axis, also called the "somatopause."
Bad News for GH-Abusing Athletes Participating in the Sydney, Australia's 2000 Summer Olympic Games
The International Olympic Committee and the European Union and GH Research Society's liaison called GH 2000 is on target in developing new methods to detect hGH abuse in sports. The detection technology focuses on IGF-1, the acid-labile subunit of IGF-1 called ALS, insulin binding protein-3 (IGFBP-3) and a bone turn-over marker called carboxyterminal cross-linked telopeptide of type 1 collagen (ICTP). These four are considered to be good markers for GH doping and more are being tested. The Sydney 2000 Summer Olympic Games may produce some interesting doping results with these new tests being employed. [6]
The Growth Hormone Society's debate on Plasma Insulin-like Growth Factor and Prostate Cancer Risk
The epidemiological prospective prostate cancer study by June M. Chan, et al, presented in Science on January 23, 1998 [7] sent a chill through the quarters of responsible clinicians treating GH-deficient patients. Chan's study noted that there was a strong positive correlation between IGF-1 levels and prostate cancer risk. The higher the IGF-1 level, the greater the risk. An IGF-1 level between 99-185 (ng/ml) had a relative risk of 1.0. At 186-237 the risk was 1.9. At 238-294 it was 2.8, and at 295-500 the risk was 4.3.
In the book Grow Young With HGH by Ron Klatz, D.O. (Harper Collins, New York; 1997) [8] it is suggested that IGF-1 levels of 350 ng/ml or more is the ideal youthful IGF-1 level that "youth docs" should have their patients attain to make them younger.
Michael Pollak and colleagues from McGill University (co-collaborator with June M. Chan in the Science paper of 1998) have found a similar strong association between IGF-1 levels and breast cancer. This data should be published shortly. Mantrzoros, C.S., and colleagues in 1997 [9] examined blood samples from 52 patients with prostate cancer, 52 patients with Benign Prostatic Hyperplasia (BPH), and an equal number of controls. They found no correlation between BPH and IGF-1. Increased IGF-1 levels were associated with increased risk of prostate cancer. An increase of 60 ng/ml increased the odds ratio by 1.91. There was also some relationship between high levels of testosterone and IGF-1 and prostate cancer. Some scientists are suggesting that by increasing the binding protein of IGF-1 called IGFBP-1 that the undesired effects of IGF-1 could be controlled.
The Debate Regarding Acromegaly
The senior clinicians in the Growth Hormone Research Society with 10-20 years of experience in treating adults and children with well-defined GH deficiency (failure of GH production from pituitary disease, ablation, and failure to produce GH with two or more standard GH stimulation tests) took the position of "let's wait and see." Their argument was that persons who are acromegalic have been exposed to supraphysiologic levels of GH and IGF-1 for many years. Yet the incidence of bowel and other malignancies is only marginally increased, and there seems to be no increase in mortality from them. Peter H. Sonksen, M.D., President of the GH Research Society and Joint Editor of the Journal Growth Hormone and IGF Research stated: "Worry about developing malignancies is inevitable, but may not be real." [10]
The Counter-Argument
The consensus among non-clinician IGF-l molecular biologists was that the acromegalics have built adaptations with a different GH and IGF binding protein balance that make them more resistant to the mitogenic-carcinogenic effects of IGF-1.
This Reviewer's Recommendations and Suggestions for Future Research
An interesting study would be to find out what was unique about the males that were prone to prostate cancer in the Chang study and compare their blood samples with acromegalics who appear "cancer resistant" with very high GH and IGF-1 levels for many years.
Until we have defined which subset of patients is protected by the anticancer expression or "acromegalic factor," clinicians should aim to keep their older patients (over 50-55) at the low-risk levels of IGF-1 (under 200 ng/ml). For long term commitment to GH therapy and at higher IGF-1 levels, male patients need to be screened with transrectal sonography and prostate biopsies, as indicated. Do not rely on PSA levels alone. Women need mamographies and biopsies for abnormalities; while both genders need to have colonoscopies performed. The possible use of new blood and other tissue markers for early cancer detection needs to be explored, if someone is medically committed to a life-time of GH replacement.
Dr. Karlis Ullis, M.D.
1807 Wilshire Blvd., Suite 205
Santa Monica, CA 90403
1. Howard, A.D., M.D., Roy G. Smith, M.D. et al, A Receptor in the Pitutary and Hypothalamus that Functions in Growth Hormone Release. Science 1996 273:974-977.
2. Howard, A.D. et al., (Merck Research Laboratories), Structural Requirements for the Activation of the Human Growth Hormone Secretagogue Receptor by Peptide and Non-Peptide Secretagogues. (abstract) Growth Hormone and IGF Research August 1998 Vol 8, No 4, 313.
3. Bach, M.A., M.D., Science 1997 278:419.
4. Ho, K.K.Y., M.D., Progesterone Modulates the Effects of Estrogen on IGF-1 in Post Menopausal Women., Growth Hormone and IGF Research ,(abstract), August 1998 Vol 8, No 4, 316.
5. Ho, K.K.Y., M.D., Crampton. L., et al., Progesterone Modulates the Effects of Estrogen on IGF-1 in Post Menopausal Women. Journal of Clinical Investigation September 1998.
6. Wallace, J. D., M. D., et al, Detection of Growth Hormone Abuse in Athletes ,Growth Hormone and IGF Research ,(abstract), August 1998 Vol 8, No 4, 329, 348.
7. Chan, June M., Stampfer, Meir J., et.al., Plasma Insulin Growth Factor-1 and Prostate Cancer Risk: A Prospective Study. Science 279: 563-566.
8. Klatz, Ron, M.D. with Carol Kahn, Grow Young with HGH, Harper Collins, New York, 1997.
9. Mantzoros, C.S., Tzonou,A., et al., Insulin Growth Factor 1 in Relation to Prostate Cancer and Benign Prostatic Hyperplasia. Br.J.Cancer. 1997 76(9): 1115-1118.