The marketing of human growth hormone (HGH) has only increased since this commentary was published in JAMA (the Journal of the American Medical Association) several years ago:

“The distribution and marketing of human growth hormone (HGH or GH) via Web sites and antiaging clinics has grown into a multimillion-dollar antiaging industry. Despite congressional hearings warning of deceptive marketing claims and the potential health and economic dangers associated with the antiaging industry, and statements issued by the National Institute on Aging and the Federal Trade Commission, the distribution and use of GH for antiaging is now common. For example, entering the terms “HGH” and “anti-aging” into the Google search engine generated 3 410 000 hits as of September 26, 2005, many representing Web sites and clinics marketing and selling GH.”

Is the marketing of GH to people without an objective test demonstrating growth hormone deficiency a safe and effective practice? A number of studies indicate that using supraphysiological (abnormally high) levels of growth hormone as a ‘shortcut’ to improve body composition (lose fat) is neither necessary nor safe. A perspective published in The New England Journal of Medicine recalls the single study that launched the GH anti-aging industry:

“An article by Rudman et al. that appeared in the Journal in 1990 reported the effect on body composition of administering human growth hormone for six months to 12 older men. This article incited a proliferation of “antiaging” clinics and lay publications, such as “Grow Young with HGH,” extolling the benefits of growth hormone in reversing or preventing aging…First, it is necessary to recall exactly what the study…demonstrated. Twelve healthy men…received growth hormone for six months…The weekly dose of growth hormone was approximately twice as high as the dose used in adult men with a growth hormone deficiency…The administration of growth hormone in older men resulted in a 4.7-kg increase in lean body mass, a 3.5-kg decrease in adipose mass, and an increase of 0.02 g per square centimeter in lumbar-spine density; systolic blood pressure and the fasting glucose concentration increased significantly. The study was not double-blind (there was a control group consisting of nine men who received no treatment); there were no assessments of muscle strength, exercise endurance, or quality of life. This study is the basis for claims that growth hormone reverses aging…A recent…study…confirmed the effects of growth hormone on body composition; there was no change in muscle strength or maximal oxygen uptake during exercise in either group…”

Is this improvement in body composition, without any increase in strength or oxygen efficiency, anything that can’t be accomplished with simple lifestyle measures?

“Not mentioned on the “antiaging” Web sites is a study of 18 healthy men, 65 to 82 years of age, who underwent progressive strength training for 14 weeks, followed by an additional 10 weeks of strength training plus either growth hormone or placebo. In that study, resistance exercise training increased muscle strength significantly; the addition of growth hormone did not result in any further improvement. Going to the gym is beneficial and certainly cheaper than growth hormone.”

But what about safety, especially the increased risk of developing cancer?

“In 152 healthy men, the relative risk of the subsequent development of prostate cancer was increased by a factor of 4.3 among men who had serum concentrations of insulin-like growth factor I in the highest quartile, as compared with those whose concentrations were in the lowest quartile (Insulin-like growth factor I mediates the action of growth hormone, and its concentration reflects the circulating concentration of growth hormone).”

The author concludes by stating:

“Studies that have followed the 1990 report by Rudman et al. confirm the effects of growth hormone on body composition but do not show improvement in function. In contrast, resistance training improves muscle strength and function, indicating that real effort is beneficial. There is no current “magic-bullet” medication that retards or reverses aging.”

Several years later a review of the matter was published in the Annals of Internal Medicine. The authors first note:

“Human growth hormone (GH) is widely used as an antiaging therapy, although its use for this purpose has not been approved by the U.S. Food and Drug Administration and its distribution as an antiaging agent is illegal in the United States.”

Their data synthesis encompassed 31 papers and 18 study populations with an average treatment duration of 27 weeks. The picture that emerged from their data was very interesting:

“In participants treated with GH compared with those not treated with GH, overall fat mass decreased and overall lean body mass increased, and their weight did not change significantly. Total cholesterol levels decreased although not significantly after adjustment for body composition changes. Other outcomes, including bone density and other serum lipid levels, did not change. Persons treated with GH were significantly more likely to experience soft tissue edema, arthralgias, carpal tunnel syndrome, and gynecomastia [breast enlargement] and were somewhat more likely to experience the onset of diabetes mellitus and impaired fasting glucose.“

The authors conclude:

“The literature published on randomized, controlled trials evaluating GH therapy in the healthy elderly is limited but suggests that it is associated with small changes in body composition and increased rates of adverse events. On the basis of this evidence, GH cannot be recommended as an antiaging therapy.”

The authors of the first paper cited above published in JAMA state in a subsequent reply that while there are legitimate therapeutic uses of GH:

“We are concerned that patients are led to believe that they have adult growth hormone deficiency (AGHD) and then are provided with GH inappropriately, when the clinical requirements for this diagnosis have not been met. The package inserts for GH state unambiguously that to make a diagnosis of AGHD that satisfies FDA criteria, both a specific pathology involving the anterior pituitary gland and a defined lack of a response to a stimulation test are required.”

We can also appreciate the paper published a year and a half ago in Clinical Interventions in Aging that undertakes an extensive and detailed review of the scientific evidence:

“Although advanced age or symptoms of aging are not among approved indications for growth hormone (GH) therapy, recombinant human GH (rhGH) and various GH-related products are aggressively promoted as anti-aging therapies. Well-controlled studies of the effects of rhGH treatment in endocrinologically normal elderly subjects report some improvements in body composition and a number of undesirable side effects in sharp contrast to major benefits of GH therapy in patients with [actual, as determined by tests] GH deficiency. Controversies surrounding the potential utility of GH in treatment of a geriatric patient are fueled by increasing evidence linking GH and cancer and by remarkably increased lifespan of GH-resistant and GH-deficient mice [lower GH = longer lifespan].”

Their massive accumulation of data led to this conclusion:

“We suggest that the normal, physiological functions of GH in promoting growth, sexual maturation and fecundity involve significant costs in terms of aging and life expectancy. Natural decline in GH levels during aging likely contributes to concomitant alterations in body composition and vigor but also may be offering important protection from cancer and other age-associated diseases.”

What data is there for the dangers of a supraphysiological increase in GH (as measured through IGF-I levels because direct GH measurement is not practical)? A study published 10 years ago in the Journal of the National Cancer Institute considers this in relation to colorectal cancers in women:

“Leading a Western lifestyle, being overweight, and being sedentary are associated with an increased risk of colorectal cancer. Recent theories propose that the effects of these risk factors may be mediated by increases in circulating insulin levels and in the bioactivity of insulin-like growth factor (IGF)-I.”

The authors investigated this association in a cohort of 14,275 women over a period of six years. What did the data show? Remember that GH works partly by increasing IGF-I.

“Chronically high levels of circulating insulin and IGFs associated with a Western lifestyle may increase colorectal cancer risk, possibly by decreasing IGFBP-1 and increasing the bioactivity of IGF-I.”

Further evidence was reported in a paper published in the journal Cancer Research:

“It has been shown previously that slight elevations in serum levels of insulin-like growth factor-I (IGF-I) are correlated with an increased risk for developing prostate, breast, colon, and lung cancer. The aim of this study was to determine the role of serum IGF-I levels in the process of stimulating tumor growth and metastasis…”

When they compared injections of GH in ‘normal’ and GH-deficient mice to saline injections a disturbing picture emerged:

“Both control and LID mice treated with recombinant human IGF-I displayed significantly increased rates of tumor development on the cecum and metastasis to the liver, as compared with saline-injected mice. The number of metastatic nodules in the liver was significantly higher…vessel abundance in the cecum tumors was dependent on the levels of serum IGF-I. This study supports the hypothesis that circulating IGF-I levels play an important role in tumor development and metastasis.”

Another study published around the same time in The Lancet discusses similar concerns even for patients with documented GH deficiency:

“Despite these limitations, the high incidence of cancer, and in particular of colon cancer, is worrying. That growth hormone might increase the risk of colorectal cancer is plausible for several reasons. Growth hormone causes raised serum IGF-I and to a lesser extent IGF binding protein-3 (IGFBP-3), and consequently causes a raised ratio of IGF-I to IGFBP-3, with this ratio being greater as growth hormone concentrations increase. IGF-I receptors have been identified on human colorectal cells, mRNAs for IGF-I have been detected in colorectal tumours, IGF-I is a potent stimulator of colorectal-cancer-cell proliferation in vitro, and blockade of IGF-I receptors inhibits growth of human colorectal cancer cells.”

Note that their study cohort was young people (39% under 10 and 60% under 19 years of age) with proven GH deficiency. The risk of death from cancer overall was increased approximately 3-fold, from colorectal cancer and Hodgkin’s disease approximately 11-fold and incidence of colorectal cancer was increased approximately 8-fold.

“In conclusion, we found a significantly raised frequency of colon cancer mortality after growth hormone treatment which, although based on small numbers, is of concern because it concurs with raised risks found in patients with acromegaly and in individuals with previously increased concentrations of IGF-I…Our data…suggest the need for increased awareness of the possibility of cancer risks, and for surveillance of growth hormone-treated patients.”

A different group of researchers reported high levels of IGF-I receptors in human colon cancers in a study published in the journal Cancer:

“High concentrations of insulin-like growth factor (IGF)-I and IGF-II have been demonstrated in human colonic adenocarcinomas and exert mitogenic effects through paracrine/autocrine interactions with the IGF-I receptor (IGF-IR).”

Their findings confirm the role of IGF-I (which mediates the effects of increases in GH) in human colon cancers:

“Our results demonstrate that, in addition to IGF-II, a strong overexpression of IGF-IR is found in the majority of colorectal carcinomas, supporting the hypothesis of an important role of the IGF system in the pathogenesis of colorectal carcinoma.”

More evidence of the link between ‘anti-aging therapy’ with GH and cancer appeared in a paper published in Clinical Gastroenterology and Hepatology:

“Our findings of increased tumor tissue IGF1R expression as compared with normal colon lends support to an etiologic role for the GH/IGF1 axis in the development and progression of colon cancer, as has been previously described…”

They present a case report of colorectal cancer after administration of GH for ‘anti-aging’ purposes:

“That it occurred in an individual already at increased risk for colon cancer underscores the need for further investigation of the pro-neoplastic [pro-cancer] potential of growth hormone supplementation for anti-aging.”

There is an important principle of functional endocrinology implicit here: it is mandatory that hormone replacement be used only to treat true deficiencies, administration must not exceed physiological levels, and it must be cautiously managed with pre and post testing to affirm safety and efficacy.

-

It has long been known that tumor cells defy destruction by immune cells by producing cytokine ‘decoys’ called soluble TNF-α (tumor necrosis factor-alpha) receptors. TNF-α is a ‘guidance system’ for the immune attack that seeks its receptors on malignant cell membranes. The soluble receptors (TNF-R) shed by tumor cells into their local environment divert the TNF-α by binding them. A paper published sixteen years ago in the British Journal of Cancer documents their presence in breast cancer:

“The expression of tumour necrosis factor alpha (TNF-alpha) and its two distinct receptors, TNF-R p55 and TNF-R p75 [soluble receptors], was…was not detectable in normal breast tissue or in non-malignant breast tissue adjacent to the tumours.”

It was a different story for the tumors examined:

“TNF-R p55 was expressed by a population of stromal cells in all the tumours examined, and a varying proportion of neoplastic cells in 75% of these tissues. TNF-R p75 was detected in about 70% of the tumours…”

It has been known for just as long that the presence of soluble tumour necrosis factor receptors can predict the outcome for a cancer patient. A paper published in The Lancet around the same time references a number of earlier studies on the topic.

A couple years later a similar observation was reported in a paper published in the European Journal of Cancer for melanoma. The authors note:

“It has been recently suggested that soluble tumour necrosis factor receptors (sTNF-Rs) may represent prognostic factors in cancer.”

They proceed to describe increased concentrations of soluble TNF receptors in association with adhesion molecules that also participate in tumor development:

“We report in this study the serum concentrations of sTNF-R1 and sTNF-R2 in 32 patients with primary melanoma and in 21 patients with metastatic melanoma, in correlation with those of soluble ICAM-1 (sICAM-1). Significantly raised sTNF-Rl levels were detected only in patients with metastatic melanoma compared with normal controls, whereas sTNF-R2 levels were increased both in primary and metastatic melanoma…A correlation between sTNF-Rs and sICAM-1 concentrations in patients’ sera was observed in metastatic melanoma. The combined adverse effects of these soluble proteins on normal immune effector functions may contribute to tumour progression.”

These observations were soon followed by research that further confirmed the blockade of anti-tumor immune mechanisms by soluble TNF receptors. A paper published in the journal Immunology also mentions early trials of ultrapheresis (another term for immunepheresis = filtering from the blood of soluble TNF receptor ‘decoys’):

“Soluble tumour necrosis factor receptor type I (sTNFRI) is a potent inhibitor of TNF with the potential to suppress a variety of effector mechanisms important in tumour immunity. That sTNFRI influences tumour survival in vivo is suggested by results from human clinical trials of Ultrapheresis, an experimental extracorporeal treatment for cancer.”

The authors designed their study to resolve definitive proof that sTNFRI specifically blocks immune efforts at tumor removal (full text available here):

“While the considerable clinical benefit provided by Ultrapheresis is correlated with the removal of plasma sTNFRI, there is no direct evidence that sTNFRI inhibits immune mechanisms which mediate tumour cell elimination.”

Their findings proved that soluble TNF receptor (sTNFRI)-secreting tumor cells resisted destruction by TNF:

“These findings confirm the suggestion that sTNFRI inhibits immunological mechanisms important in tumour cell eradication, and further support a role for sTNFRI in tumour survival in vivo. In addition, these observations suggest the development of methods for more specific removal and/or inactivation of sTNFRI as promising new avenues for cancer immunotherapy.”

We have another interesting study published just weeks ago in the journal Clinical Chemistry and Laboratory Medicine that adds more evidence that soluble tumour necrosis factor receptor type I concentrations are a powerful predictor of outcome in breast cancer.

“The aim of this study was to exploit the potential clinical use of circulating cytokine assessment in patients with breast cancer.”

The authors surveyed cytokines in breast cancer patients including interleukin 6 (IL-6), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII, interleukin 1 receptor antagonist (IL-1ra), interleukin 10 (IL-10), macrophage colony-stimulating factor, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)and followed them for ten years. Their data led them to this conclusion:

“…a significant value of pretreatment serum sTNF RI concentrations, next to stage and oestrogen receptors status, was its utility as an independent prognostic factor of the overall survival in patients with breast cancer… Serum sTNF RI may be considered an additional, independent and clinically useful factor of poor prognosis in patients with breast cancer.”

In other words, the soluble TNF receptors, the worse the breast cancer patient will do. But what about other types of cancer? A research article published in the Journal of Surgical Oncology shows the link between serum cytokine receptor levels and bone sarcoma:

“We analyzed the correlations between pretreatment serum levels of 11 cytokines and soluble cytokine receptors (interleukin 6 (IL-6); interleukin 8 (IL-8); interleukin 10 (IL-10); vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF); macrophage colony-stimulating factor (M-CSF); granulocyte colony-stimulating factor (G-CSF); interleukin 1 receptor antagonist (IL-1ra); sIL-2R; tumor necrosis factor receptor I (TNF RI), and TNF RII) with clinico-pathological features and survival of patients with bone sarcomas.”

They used multiple metrics to show the association between cytokines and soluble receptors and tumor characteristics along with overall outcome. Their data led to this conclusion:

“These findings indicate that cytokines and soluble cytokine receptors, both physiologically involved in bone destruction and bone formation, have an essential role in the progression of malignant bone tumors.”

A research article published in the journal Tumor Biology finds the same kind of evidence for colorectal cancer. While they found a correlation with a number of circulating cytokines, their summary observations are the most striking:

“sTNF RI (soluble TNF receptor 1), IL-8, IL-6 and vascular endothelial growth factor measurements demonstrated the highest diagnostic sensitivity. sTNF RI was found elevated in the greatest percentage of all CRC [colorectal cancer] patients, in the greatest proportion of stage I patients and presented the best diagnostic sensitivity. In addition, the sTNF RI level strongly correlated with tumor grade and invasion and proved to be an independent prognostic factor.”

And another paper published in the same journal concludes with concordant evidence for solid carcinomas in general:

“…for the soluble tumor necrosis factor (TNF) receptors type I (p55) and type II (p75) and IL·2 receptor we determined their levels in the plasma of 378 patients with various solid carcinomas, 56 patients with benign tumors, and 241 healthy controls. The plasma concentrations of both TNF receptors as well as the IL-2 receptor were significantly higher in the cancer patients than in the healthy controls, independent of the origin or histology of the tumor. The incidence and the extent of the receptor increase correlated with the extent of the disease. In the patients with benign tumors plasma levels of TNF receptor p75 and IL·2 receptor were not significantly different from the controls.”

A study published around the same time in the journal Oncology makes the same case for non-small cell lung cancer (NSCLC) as well, with an interesting comparison to the standard markers:

“…increases in IL-6, IL-8 and sTNF RI were noted in the greatest proportion of stage I patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers…A significant prognostic value of pretreatment serum M-CSF and CEA levels in NSCLC patients has been shown, but only M-CSF proved to be an independent prognostic factor.”

We also have the evidence from a study published in the journal Cellular Immunology in which the authors blocked the decoy effect of soluble tumor necrosis factor receptor type I (sTNFRI)receptors with neutralizing antibodies and observed the effect. Their data led to this conclusion:

“These data demonstrate that sTNFRI directly influences tumor formation and persistence in vivo and suggest the selective removal and/or inactivation of sTNFRI as a promising new avenue for cancer immunotherapy.”

Obviously an intervention that gets rid of the ‘decoy’ receptors so the immune system can effectively attack the tumor makes excellent sense. In a paper published in the Proceedings of the National Academy of Sciences (USA) we have early evidence that the soluble tumor necrosis factor receptors can be filtered out of the blood of human cancer patients:

“Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor alpha (TNF-alpha) in vitro.”

The investigators proceeded to show that the blocking factor is derived from malignant cell membrane TNF receptors. They further observed that:

“Purified BF blocks the lytic [malignant cell destroying] activity of recombinant human and mouse TNF-alpha…The BF also inhibits the necrotizing activity of recombinant human TNF-alpha… The BF may have an important role in…interaction between the tumor and the host antitumor mechanisms…”

A paper published in 2002 by a leader in the field of immunepheresis in the journal Therapeutic Apheresis and Dialysis documents the emerging insights and outstanding outcomes with cancer patients that were already being accomplished:

“Immunosuppression is a hallmark of advanced malignancies in man. Over the past 40 years, many investigators have identified soluble immunosuppressive factors in blood, serum, ascitic fluid, and pleural fluid from cancers in man and other species. Suppressive factors have also been identified that are produced by tumors.”

The author also draws attention to the similarity of immunologic tolerance in cancer and pregnancy (which has also been referred to as the ‘trophoblastic theory‘):

“The description of immunosuppressive factors in the blood of vertebrates who either have cancer or who are pregnant is significant, for only in pregnancy and cancer does a seemingly normal immune system tolerate immunogenic neoantigen. Tumor necrosis factors (TNFs) are …thought to be suppressed in patients who have cancer or who are pregnant. Recently, elevated blood levels of soluble tumor necrosis factor receptors (sTNFRs) have been reported in the blood in a variety of cancers and pregnancy.”

He notes that much evidence has accumulated validating the connection between elevations of sTNFRs and a poor prognosis:

“In 1990, after our initial publication of the discovery of sTNFRs in the serum and low molecular weight ultrafiltrates of serum from a variety of cancer patients, others confirmed significant elevations of sTNFRs in cancer patients. This elevation was found to correlate with a poor prognosis.”

The author then reviews the suppressive role of soluble receptors shed from tumor cells and the positive effects of ultrapheresis—filtering the blood to remove reduce these suppressive molecules. A few years a ago a paper published in the same journal reported advances in the filtering technology:

“Using these methods, an improvement in performance status and clinical symptoms and reduction of tumor size have been observed.”

Two years ago further advances and positive clinical outcomes were reported in Therapeutic Apheresis and Dialysis in a paper presented by the same pioneer mentioned above:

“Mean reductions in sTNF-R1 (48%), sTNF-R2 (55%), and sIL2-R levels (72%) were observed … Clinical findings indicated tumor inflammation and necrosis in most patients. Side-effects were low-grade fever, flu-like symptoms; tumor pain and redness, warmth, tenderness, and edema. The column demonstrated safety and efficacy in lowering plasma sTNF-R1, sTNF-R2, and sIL2-R levels.”

Personally I know of patients who have undergone this procedure who have had outstanding outcomes characterized by dramatic reductions in tumor mass.

Is this a safe treatment? A paper published in the Journal of Clinical Apheresis reports that, in contrast with chemotherapy, short term side-effects of immune activation were only mild-moderate, and there were no long-term side-effects at all:

“The most common side effects observed among 1,306 treatments were chills (28% of treatments), low grade fever (28%), and musculoskeletal pain (16%). Side effects were mild to moderate and required no treatment or only symptomatic treatment…Of 64 patients available for long-term follow-up evaluation (mean of 11 months), none exhibited evidence of long-term treatment-related side effects.”

Immunepheresis (therapeutic apheresis, ultrapheresis) is worthy of far more research resources and clinical utilization. For more information see the International Immunology Foundation. Treatment is available for suitable candidates from M. Rigdon Lentz, M.D. (an American oncologist and immunepheresis pioneer) and Kiran Lentz, M.D. at their clinic in Prien am Chiemsee, Bavaria, Germany. As usual, the papers presented above are a small selection from a much larger body of literature. A 170 page report by Dr. Ralph Moss of Cancer Decisions on the work of Dr. Lentz is available here.

Note: Removal of soluble receptor blockade to permit immune destruction of malignant cells is an elegant physiological intervention to reduce tumor burden. Practitioners and patients alike must also bear in mind the need to investigate and treat from a functional medicine perspective the underlying causal factors that develop malignancies in the first place and promote their recurrence.

-

As the authors of this paper published last month in Molecular Cancer Research state:

“Agents that are safe, affordable, and efficacious are urgently needed for the prevention of chronic diseases such as cancer.”

They establish their rationale for investigating the sesame seed lignan called sesamin as a cancer chemopreventative:

“Sesamin…has been linked with prevention of hyperlipidemia, hypertension, and carcinogenesis through an unknown mechanism. Because the transcription factor NF-κB has been associated with inflammation, carcinogenesis, tumor cell survival, proliferation, invasion, and angiogenesis of cancer, we postulated that sesamin might mediate its effect through the modulation of the NF-κB pathway.”

They found in fact that sesamin packs quite a punch:

“…sesamin inhibited the proliferation of a wide variety of tumor cells including leukemia, multiple myeloma, and cancers of the colon, prostate, breast, pancreas, and lung. Sesamin also potentiated tumor necrosis factor-α–induced apoptosis and this correlated with the suppression of gene products linked to cell survival, proliferation, inflammation (e.g., cyclooxygenase-2), invasion (e.g., matrix metalloproteinase-9, intercellular adhesion molecule 1), and angiogenesis (e.g., vascular endothelial growth factor). Sesamin downregulated constitutive and inducible NF-κB activation induced by various inflammatory stimuli and carcinogens…”

Those of you who may be pursuing immunopheresis for cancer (filtering TNF-α soluble receptors that barricade tumors from the immune system’s attack) may very well wish to include sesamin in your protocol since it enhances cytotoxic TNF-α activity. Interestingly, sesamin is included in some of our omega-3 fatty acid formulae for brain support as an evidence-based agent for reducing brain inflammation. So the authors’ conclusion is a welcome one:

“Overall, our results showed that sesamin may have potential against cancer and other chronic diseases through the suppression of a pathway linked to the NF-κB signaling.”

-