We last reviewed metformin reduction of breast cancer in April;
- In our last review of metformin and prostate cancer 6 months ago, there was only one definitive study on prostate cancer, showing that human prostate cancer cells grown in mice are 50% reduced by oral metformin; this was not due to metformin’s inhibition of the AMPK pathway, but associated with metformin causing a strong reduction of cyclin D1 protein level in tumors.
Now McGill University confirms that metformin activated AMPK and has growth inhibitory actions on prostate and colon cancer cells via reducing adiponectin activation; suggesting that metformin may be of particular value in attenuating the adverse effects of obesity on neoplasia.
University Washington at Seattle has now published a population case-controlled study : “epidemiologic studies suggest a decreased relative risk of cancer with metformin use, and preclinical studies of prostate cancer (PCa) show antitumor activity with metformin. In this study in 1001 men aged 35-74 years diagnosed with PCa between 2002 and 2005 in King County, in Caucasian men (but not Blacks), metformin use was more common in controls than in cases (4.7 vs. 2.8%, p = 0.04), resulting in a 44% risk reduction for PCa (adjusted OR = 0.56; 95% CI 0.32-1.00).
But in a Cardiff University UK general practice study published next month in 62,809 diabetics treated after 2000, metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer.
So the evidence for metformin effect against human prostate cancer seems likely (p=0.04) at least in vitro and in Washington state whites if not blacks, or in Cardiff men..
But a small new study from Tehran Iran confirms that diabetes mellitus (DM) is associated with decreased risk of prostate cancer (PC) in several reports. In 194 newly diagnosed prostate cancer patients, those with DM were significantly less likely to have PC (OR: 0.44, P = 0.003). Time since DM diagnosis was also inversely correlated with the risk of cancer (P trend < 0.0001). Control patients had significantly higher testosterone, estradiol, and testosterone/SHBG ratio (P < 0.05). As time since DM diagnosis increased by quartiles, testosterone significantly increased (P trend < 0.05). The risk of PC also significantly declined (P trend < 0.0001) following an initial remarkable increase early after DM diagnosis. After including the hormones in the logistic regression model, there was a weak, yet significant inverse association of testosterone/SHBG and DM duration with the risk of PC. CONCLUSIONS: Based on our results DM duration is inversely correlated with the risk of prostate cancer. Our results do not support the hypothesis that sex hormones, including testosterone, play a major role in the protective effect of DM against PC.
We recently reviewed that both appropriate HRT, and metformin, halve the risk of premature death from both breast cancer and all causes.
A small new international trial (APHRODITE) of lowdose transdermal testosterone for low sexual desire in 277 overweight postmenopausal women around 54 years of age produced 4 cases of breast cancer in the next 2 years ie a rate of 0.72% a year. Testosterone patches increased the free testosterone levels 4 fold after 6 months, and doubled free estradiol levels without change in SHBG or estrone levels. Hence the testosterone: estradiol ratio was only about doubled by the low dose of testosterone used. There was no significant increase in virilization on either the 150 or 300 mcg/day testosterone dose.
But transdermal testosterone is the most likely route for aromatization to estrogen; and no data has yet been published on morbidity or mortality in the APHRODITE women so treated. No other studies have shown that testosterone replacement increases breast cancer- quite the contrary. Hence from Aphrodite one can postulate that the unmasking of a few dormant breast cancers in the first two years was due to the high-aromatization route ( ie transdermal) chosen, with lowdose testosterone not increasing the testosterone: estradiol ratio protectively enough to compensate for the cancer-activating increase in estradiol level. This differs greatly from the standard 20:1 ratio of testosterone:estradiol dose eg 1mg testosterone: 0.05mg estradiol used the past 60 years in standard subcutaneous Mixogen-like combinations established as the gold standard for postmenopausal women by Masters and Grody 1953 in the first, 13month RCT, and used for the next 50 years by eg Gelfand ea in Quebec, and our group in Cape Town.
This column has previously reviewed strong data showing that testosterone replacement – mostly by implant or depot injection, usually by combined testosterone and estradiol- in both rodent, monkey and human females , reduces breast cancer mortality and incidence.
A 2002 study in Toronto showed that in early-stage female breast cancer, fasting insulin was associated with distant recurrence and death; the hazard ratios and 95% confidence intervals (CI) for those in the highest versus the lowest ( insulin quartile were 2.0 (95% CI, 1.2 to 3.3) and 3.1 (95% CI, 1.7 to 5.7), respectively. There was some evidence to suggest that the association of insulin with breast cancer outcomes may be nonlinear. Insulin was correlated with body mass index (Spearman r = 0.59, P <.001), which, in turn, was associated with distant recurrence and death (P <.001). In multivariate analyses that included fasting insulin and available tumor- and treatment-related variables, adjusted hazard ratios for the upper versus lower insulin quartile were 2.1 (95% CI, 1.2 to 3.6) and 3.3 (95% CI, 1.5 to 7.0) for distant recurrence and death, respectively. CONCLUSION: Fasting insulin level is associated with outcome in women with early breast cancer. High levels of fasting insulin identify women with poor outcomes in whom more effective treatment strategies should be explored.
- increased testosterone production is a physiological defence mechanism against increasing adiposity and insulin ;
- metformin lowers free testosterone levels modestly;
- low testosterone is associated with lower prostate and breast cancer incidence, but higher incidence of high-grade prostate/ breast cancer and thus prostate/breast cancer mortality.;
- both insulin resistance and type 2 diabetes and low testosterone levels increase all-cause morbidity and all-cause and cancer mortality..
- The fatter the woman, the more estrone is produced from fat (while testosterone production from the ovary rises)- hence the virilizing polycystic ovary syndrome; which is reversed by metformin; in those not treated with metformin, the increased estrone effect on breast is balanced by the increased testosterone as shown by the neutral effect on breast cancer incidence in 8year and 31year followup of PCOS cases;
- The Women’s Health Initiative showed that in women under 60yrs treated appropriately with oral sexhormone therapy, all-cause morbidity and mortality and breast cancer incidence and mortality were all reduced by about a third;
hence it is plausible that while metformin may increase the incidence of prostate cancer in diabetics through lowering testosterone levels, it remains to be seen whether there is any exception to the rule that appropriate hormone modulation with insulin sensitizers (appropriate balanced human sexhormone -testosterone-estrogen replacement and metformin reversal of insulin resistance, overweight and diabetes) lowers the all-cause and cancer mortality in both men and women.
This increases the rationale for early appropriate balanced hormone replacement in both men and women, and preventative metformin in increasing overweight before development of full-blown metabolic syndrome, obesity, diabetes and cancer. The cost of delay of such appropriate permanent proven physiological therapy is horrendous- high-risk bariatric surgery for obesity, or sudden death heartattack, stroke, blindness or kidney failure; if not radio-chemotherapy and organ removal for cancer.