Pro-aging signaling, cancer and diabetes are reduced with LESS growth hormone effect

Posted on February 20, 2011 by Dr. Jonathan

Research just published in the journal Science Translational Medicine is a further reminder of the critical need for caution and sound physiological thinking when considering the use of growth hormone. The authors note in their introduction:

“Reduced activity of growth hormone (GH) and insulin-like growth factor–1 (IGF-1) signaling proteins or of their orthologs in nonhuman organisms…contribute to extended life span and protection against age-dependent damage or diseases…”

Pursuant to these earlier observations they formulated an important investigative objective:

“Mutations in growth signaling pathways [that diminish the GH effect] extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies.”

Combining this information with surveys that identified the cause and age of death for their subjects who died before this period, the data paint a compelling picture:

“The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects.“

They describe earlier studies that help explain the very low incidence of cancer. In one, serum from subjects with GHR deficiency had reduced DNA breakage yet increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. In others, serum from GHR-deficient subjects caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells. These changes in signaling promote cellular protection and life-span extension in model organisms.

Importantly, in their present study the authors also observed:

“……reduced insulin concentrations and a very low HOMA-IR (homeostatic model assessment–insulin resistance) index in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects.”

These comments, along with an earlier post on growth hormone research, are a plea for caution along with sound thinking. There seem to be good reasons why we have evolved to reduce growth hormone activity with age. The authors advance the idea that blocking growth hormone receptor function may…

“…prevent or reduce the incidence of cancer, diabetes, and other age-related diseases, including inflammatory disorders, stroke, and neurodegenerative diseases.”

Clinicians and individuals tempted to experiment with growth hormone therapy should consider the authors’ conclusion:

“Our finding that human GHRD [growth hormone receptor deficient] subjects are protected against age-related pathologies is consistent with the elevated cellular protection in both yeast and human cells with reduced expression of specific pro-growth genes and with the effect of serum from GHRD subjects in lowering their expression. The results from the human cohort also show similarities with those from GHRD- and GH-deficient mice, which display lower incidence (49%) or delayed occurrence of fatal neoplasms and increased insulin sensitivity… These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.”

Body fat distribution, insulin and breast cancer

Posted on December 29, 2010 by Dr. Jonathan

A report just published in the Journal of the National Cancer Institute adds more evidence to the importance of insulin regulation in ER (estrogen receptor) negative breast cancer. The authors first note a conundrum in breast cancer epidemiology:

“Body mass index is inversely associated with risk of premenopausal breast cancer, but the underlying mechanisms for this association are poorly understood. Abdominal adiposity is associated with metabolic and hormonal changes, many of which have been associated with the risk of premenopausal breast cancer.”

They investigated the association between body fat distribution, hip circumference, and waist to hip ratio, and the incidence of premenopausal breast cancer in the Nurses’ Health Study II:

“During 426 164 person-years of follow-up from 1993 to 2005, 620 cases of breast cancer were diagnosed among 45 799 women. Hormone receptor status information was available for 84% of the breast cancers.”

When they looked at the group as a whole, no statistically significant associations were found. However…

“…each of the three body fat distribution measures was statistically significantly associated with greater incidence of estrogen receptor (ER)–negative breast cancer.”

The risk for ER-negative breast cancer was increased by 275% for waist circumference, 240% for hip circumference, and 195% for waist to hip ratio (comparing the highest to the lowest quintile). The authors state:

“These findings may suggest that an insulin-related pathway of abdominal adiposity is involved in the etiology of premenopausal breast cancer.“

The implication is that factors associated with increased abdominal adiposity influence the development of breast cancer through estrogen independent pathways, specifically the influence of excess levels of insulin on tumor growth that also promote the accumulation of fat around the waist. As experienced clinicians know, tumors often have mixed cell types. The role of insulin as a tumor promoter should never overlooked in case management, with careful attention to the regulation of blood sugar and insulin.

Bioelectrical phase angle predicts quality of life and mortality with cancer

Posted on December 18, 2010 by Dr. Jonathan

Bioelectrical phase angle, which we easily and non-invasively measure in the clinic by bioelectrical impedance analysis, has been validated by numerous studies as a prognostic indicator for a variety of medical conditions. A study recently published in The American Journal of Clinical Nutrition offers evidence for its accuracy in predicting life quality, nutritional status and mortality for patients with cancer. The authors state:

“The bioelectrical phase angle has shown predictive potential in various diseases…This study evaluated the prognostic value of the fifth percentile of sex-, age-, and body mass index–stratified phase angle reference values in patients with cancer with respect to nutritional and functional status, quality of life, and 6-mo mortality.“

They then examined how the standardized phase angle and its deviation from population averages (‘z score’) on these life and mortality variables. They tested phase angle with bioelectical impedance analysis, muscle strength by handgrip and peak expiratory flow, employed assessments for quality of life and nutritional status, and documented survival after 6 months for 399 patients. What did the data show?

“Patients with a phase angle of less than the fifth reference percentile had significantly lower nutritional and functional status, impaired quality of life, and increased mortality. The standardized phase angle emerged as a significant predictor for malnutrition and impaired functional status in generalized linear model regression analyses. It was also a stronger indicator of 6-mo survival than were malnutrition and disease severity in the Cox regression model…”

Having an accurate, easy and inexpensive instrument to objectively evaluate the effectiveness of therapeutic case management in cancer in respect to mortality, function, quality of life and nutritional status is a resource that should not be overlooked by clinicians. The authors conclude:

“The standardized phase angle is an independent predictor for impaired nutritional and functional status and survival. The fifth phase angle reference percentile is a simple and prognostically relevant cutoff for detection of patients with cancer at risk for these factors.”

Note: This refers to bioelectrical impedance analysis measured by a professional clinical-grade instrument.

Cannabis suppresses the immune system

Posted on December 5, 2010 by Dr. Jonathan

A study just published in the European Journal of Immunology resolves how Cannabis sativa (marijuana) suppresses the immune system. The authors state:

“Cannabinoid receptor activation by agents such as Δ9-tetrahydrocannabinol (THC) is known to trigger immune suppression. Here, we show that administration of THC in mice leads to rapid and massive expansion of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) expressing functional arginase and exhibiting potent immunosuppressive properties both in vitro and in vivo.”

Myeloid-derived suppressor cells (MDSC) are a class of white blood cells that act to regulate the immune system by suppressing immune activity. While their expansion can help to reduce the inflammation and pain of autoimmunity, in cancer they suppress immune system activity in the environment of a tumor. The authors further state:

“Use of selective antagonists SR141716A and SR144528 against cannabinoid receptors 1 and 2, respectively, as well as receptor-deficient mice showed that induction of MDSC was mediated through activation of both cannabinoid receptors 1 and 2. These studies demonstrate that cannabinoid receptor signaling may play a crucial role in immune regulation via the induction of MDSC.”

In other words, THC stimulates cannabinoid receptors 1 and 2 which triggered the proliferation of the immune suppressing MDSC. This is also likely to be at least part of the mechanism by which THC can cause an increase in susceptibility to opportunistic infections. Although this may be a rational therapy for organ transplantation where immune suppression is called for, it makes the use of marijuana worrisome for conditions where a deficient immune response needs support such as most cancers.

Even with a family history of breast cancer breast healthy behavior pays off

Posted on November 1, 2010 by Dr. Jonathan

Whatever the genetic disposition for breast cancer, epigenetic influences—conduct and environmental factors that modify gene expression—are often decisive. A study just published in the journal Breast Cancer Research offers further evidence that those with a family history of breast cancer can act effectively to reduce the risk:

“A family history of later-onset breast cancer (FHLBC) may suggest multi-factorial inheritance of breast cancer risk, including unhealthy lifestyle behaviors that may be shared within families. We assessed whether adherence to lifestyle behaviors recommended for breast cancer prevention–including maintaining a healthful body weight, being physically active and limiting alcohol intake–modifies breast cancer risk attributed to FHLBC in postmenopausal women.”

The authors analyzed breast cancer outcomes in relationship to lifestyle and risk factors collected by questionnaire of 85,644 postmenopausal women into the Women’s Health Initiative Observational Study.

“The rate of invasive breast cancer among women with an FHLBC who participated in all three behaviors was 5.94 per 1,000 woman-years, compared with 6.97 per 1,000 woman-years among women who participated in none of the behaviors. The rate among women with no FHLBC who participated in all three behavioral conditions was 3.51 per 1,000 woman-years compared to 4.67 per 1,000 woman-years for those who participated in none.”

The data showed benefit for women both with and without a family history of breast cancer as they state in their conclusion:

“Participating in breast healthy behaviors was beneficial to postmenopausal women and the degree of this benefit was the same for women with and without an FHLBC.“

And we have evidence to suggest that if breast healthy behaviors were to include such important factors and blood sugar and insulin management, healthy hormone regulation, metabolic and other components of the functional medicine approach the outcomes would further improve.

Hormone blockade therapy for prostate cancer entails risks of diabetes and cardiovascular disease

Posted on October 31, 2010 by Dr. Jonathan

A recent FDA MedWatch announcement alerts doctors to the increased risk of diabetes, heart attacks and strokes for patients with prostate cancer undergoing hormone blockade therapy, specifically treatment with Gonadotropin-Releasing Hormone (GnRH) agonists such as Lupron.

“Gonadotropin-Releasing Hormone (GnRH) agonists will have new safety information added to the Warnings and Precautions section of the drug labels. This new information warns about increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.”

The normal action of gonadotropin-releasing hormone is to stimulate the secretion of the gonadotropins LH (luteinizing hormone) and FSH (follicle stimulating hormone) from the pituitary. These hormones in turn stimulate the production of testosterone and sperm by the testes. The GnRH agonists flood the pituitary receptors causing an inhibition of gonadotropin secretion in the same way that over-stimulation of any hormone receptor suppresses the system (as occurs with topical hormone replacement, insulin resistance, etc.)

Incidentally the FDA also notes:

“The benefits of GnRH agonist use for earlier stages of prostate cancer that have not spread (non-metastatic prostate cancer) have not been established.“

I have personally seen how GnRH agonists exacerbate tendencies for metabolic syndrome and cardiovascular disease and appreciate the seriousness of their advice to practitioners:

“Healthcare professionals should evaluate patients for risk factors for these diseases and carefully weigh the benefits and risks of using GnRH agonists before determining appropriate treatment for prostate cancer. Patients who are receiving treatment with GnRH agonists should undergo periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c). Healthcare professionals should also monitor patients for signs and symptoms suggestive of development of cardiovascular disease and manage according to current clinical practice.”

Most US doctors are still not paying proper attention to blood sugar

Posted on October 30, 2010 by Dr. Jonathan

It’s disturbing and worrisome to see how few doctors seem to be alert to the blood sugar dysregulation that precedes type 2 diabetes and many other chronic diseases in their patients as evidenced by a study just published in the journal Diabetes Care. The authors conducted their investigation to…

“…estimate the rates of prevalence, diagnosis, and treatment of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).”

They examined a representative sample of the U.S. population that included 1,547 nondiabetic adults without a history of heart attack to determine the proportion who met the criteria for IFG/IGT, and the proportion of them who: 1) received a diagnosis from their physicians; 2) were prescribed lifestyle modification or medication for blood sugar; or 3) were currently on therapy. Their data painted a dismal picture:

“Of the 1,547 subjects, 34.6% had pre-diabetes; 19.4% had IFG only; 5.4% had IGT only, and 9.8% had both IFG and IGT. Only 4.8% of those with pre-diabetes reported having received a formal diagnosis from their physicians. No subjects with pre-diabetes received oral antihyperglycemics, and the rates of recommendation for exercise or diet were 31.7% and 33.5%, respectively.”

Yikes. It’s really up to the patient to be informed (one of the purposes of this blog) and seek proper care. Blood sugar dysregulation wrecks almost everything that clinicians practicing according to the functional model try to do to correct brain, hormone and immune dysregulation. It’s importance as a clinical focus is hard to over-emphasize. The authors’ disappointment is almost palpable in their conclusion:

“Three years after a major clinical trial demonstrated that interventions could greatly reduce progression from IFG/IGT to type 2 diabetes, the majority of the U.S. population with IFG/IGT was undiagnosed and untreated with interventions. Whether this is due to physicians being unaware of the evidence, unconvinced by the evidence, or clinical inertia is unclear.”

Perhaps this says something about why the scientists who authored another paper in the same issue of Diabetes Care saw fit to ask whether sugar-sweetened beverages would contribute to the risk of metabolic syndrome and type 2 diabetes (!):

“Consumption of sugar-sweetened beverages (SSBs), which include soft drinks, fruit drinks, iced tea, and energy and vitamin water drinks has risen across the globe. Regular consumption of SSBs has been associated with weight gain and risk of overweight and obesity, but the role of SSBs in the development of related chronic metabolic diseases, such as metabolic syndrome and type 2 diabetes, has not been quantitatively reviewed.”

Their meta-analysis included 310,819 participants from 11 acceptable studies. It’s troubling to allow that there may be physicians who might not anticipate the conclusion that their data defined:

“In addition to weight gain, higher consumption of SSBs is associated with development of metabolic syndrome and type 2 diabetes. These data provide empirical evidence that intake of SSBs should be limited to reduce obesity-related risk of chronic metabolic diseases.”

It seems that even fewer physicians and their patients are aware of the role of glucose in ‘feeding’ cancer and the research being done to block the metabolism of sugar by tumor cells as described in a paper just published in the journal Oncogene. The authors state:

“Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials.”

While research investigates possible interventions to aggressively interrupt the glycolytic metabolism of tumor cells, doctors should assist their patients in controlling blood sugar and insulin (another tumor promoter) with the appropriate tools:

“Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels…Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death…”

Blood sugar dysregulation contributes to most chronic diseases including cardiovascular, autoimmune, neurodegenerative and malignant conditions. Supporting healthy blood sugar and insulin regulation is one of the most important things that practitioners and their patients can do together.

Breast cancer surgery margins are essential

Posted on October 25, 2010 by Dr. Jonathan

A paper just published in the International Journal of Clinical Practice clarifies the importance and parameters of operating to excise a margin of healthy tissue around a breast tumor. The authors state:

“In breast-conserving surgery, the width of free margin around a tumour to ensure adequate excision is controversial. The aim of this study was first to evaluate the frequency of residual disease in wider excision specimens in patients who undergo further surgery because of close margins of < 5 mm.”

The assessed 303 patients undergoing wider excision for the presence of residual disease, and this was tested for association with the width of the initial free margin. What did they find?

“”With a free margin of 2 mm or more from invasive tumour, the probability of finding residual disease was 2.4% [versus 35.3%]. The probability of residual disease was higher for ductal carcinoma in situ (DCIS) and did not decline with increasing the free margin width…Our results clearly show a relationship between the width of the free margin and the likelihood of finding residual disease at further surgery.”

Patients who choose breast conserving surgery for an invasive tumor should ascertain that their surgeons excise with a free margin of at least 2 mm. The authors state in conclusion:

“This study has demonstrated that in patients undergoing BCT, a free margin of 2 mm from invasive tumour is associated with a low risk of residual disease. A free margin of up to 5 mm from DCIS is associated with residual disease in one-third of patients. Large tumour size, as determined preoperatively by ultrasound, and lobular cancer type are associated with close margins and these patients should be counseled at the time of first surgery concerning the higher risk of further excision and mastectomy.”

Metabolic syndrome accelerates prostate cancer

Posted on October 10, 2010 by Dr. Jonathan

An important study just published in the Annals of Oncology adds more evidence of the exceptional importance of metabolic syndrome for prostate cancer. The authors state:

“Metabolic syndrome (MS) is a set of risk factors that includes obesity and insulin resistance and has been implicated in the development of prostate cancer.”

They proceeded to examine the impact of metabolic syndrome on prostate cancer patients treated with androgen deprivation therapy (ADT, blocking the production or signaling of male hormones). Comparing the data between patients with and without metabolic syndrome for the average time to PSA progression and overall survival (OS) yielded a stark contrast:

“Median time to PSA progression for patients with MS was 16 versus 36 months without MS. The median OS for patients with MS was 36.5 months after commencing ADT compared with 46.7 months for those patients without MS.”

The authors sum up their evidence in the usual understated fashion:

“This preliminary data suggest that MS is a risk factor for earlier development of castration-resistant prostate cancer and support the need for a prospective evaluation of this finding.”

It’s troubling to see how often clinicians fail to emphasize the great importance of blood sugar and insulin control when managing prostate cancer. Patients need to be aware that the lifestyle factors that address this are among the most important things they can do.

Breast cancer risk decreased with higher vitamin D

Posted on September 21, 2010 by Dr. Jonathan

A study just published in the journal Cancer Epidemiology, Biomarkers & Prevention increases the weight of evidence for the importance of vitamin D in breast cancer prevention. The authors state:

“High 25-hydroxyvitamin D [25(OH)D] serum concentrations have been found to be associated with reduced breast cancer risk. However, few studies have further investigated this relationship according to menopausal status, nor have they taken into account factors known to influence vitamin D status, such as dietary and serum calcium, parathyroid hormone, and estradiol serum levels.”

The authors investigated the connection in 636 French women diagnosed with breast cancer compared with 1,272 controls with considerations for age, menopausal status, and other variables. What did the data show?

“We found a decreased risk of breast cancer with increasing 25(OH) vitamin D3 serum concentrations among women in the highest tertile. We also observed a significant inverse association restricted to women under 53 years of age at blood sampling.”

They concluded from their evidence:

“Our findings support a decreased risk of breast cancer associated with high 25(OH) vitamin D3 serum concentrations, especially in younger women, although we were unable to confirm a direct influence of age or menopausal status… the maintenance of adequate vitamin D levels should be encouraged by public health policy.”

In other words, vitamin D concentrations were found to be a significant influence regardless of age or menopausal status. How do you find out how you’re doing with vitamin D? Ask your doctor for a 25-hydroxyvitamin D [25(OH)D] blood test.