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Hormones, Body Composition, and Sexual Function in Men
A team of Massachusetts researchers, led by Joel S. Finkelstein, MD, found that estrogen as well as testosterone affects men's body composition and sexual function. The researchers gave 400 healthy men, ages 20 to 50 years old, goserelin acetate to suppress their production of testosterone. When testosterone production decreases, estradiol levels also decline; over 80% of estradiol in men is derived from testosterone. In order to track testosterone's effects, the researchers randomly assigned 198 of the 400 men a placebo gel or one of four concentrations of testosterone gel (1.25 grams, 2.5 grams, 5 grams, or 10 grams) to apply daily for 16 weeks. The remaining 202 men received anastrozole in addition to a placebo or testosterone gel. Anastrozole inhibits the conversion of testosterone to estradiol. Every four weeks, the participants gave blood samples to assess hormone levels and completed questionnaires regarding physical function, health status, vitality, and sexual function. At baseline and 16 weeks, researchers used dual-energy X-ray absorptiometry to assess body fat and lean muscle, computed tomography to a assess subcutaneous- and intra-abdominal-fat areas and thigh muscle, and leg press to assess lower-extremity strength.
Changes in body fat and lean muscle were the primary outcomes. The results indicate that testosterone promotes lean muscle mass and estradiol prevents body fat. Men receiving placebo gel in both cohorts showed a significant decrease in lean muscle mass. The men in cohort 1 who were getting 1.25 g/day of testosterone also showed a decline in lean muscle, whereas the men in the estradiol-inhibited group taking 1.25 g did not. The percentage of body fat increased significantly in all estradiol-inhibited participants. Only men receiving 10 g/day of testosterone gel without the estradiol inhibitor showed a decrease in the percentage of body fat. Men in the first cohort who received less than 10 grams of testosterone per day (and, therefore, produced less estradiol than the 10 g receivers) showed an increase in body fat percentage that mirrored the estradiol-inhibited group: "Subcutaneous-fat area increased by a factor of 2 to 3 in men receiving 1 g, 1.25 g, or 2.5 g of testosterone daily, as compared with men receiving 5 g or 10 g daily, though only the comparisons with the 10-g dose group were significant."
The authors state: "In the groups that received testosterone, inhibition of estrogen synthesis (cohort 2), as compared with intact estrogen synthesis (cohort 1), was associated with significant increases in the percentage of body fat (P<0.001), subcutaneous-fat area (P<0.001), and intraabdominal-fat area (P=0.002) and with significant decreases in sexual desire (P<0.001) and erectile function (P=0.022); these findings provide additional evidence of an independent effect of estradiol on these measures."
In addition to showing that estradiol affects male body composition and sexual desire and function, this study also questions the current definition of low testosterone, currently stated as "at least 2 SD below the mean value for healthy young adults." "Although convenient, this classification fails to consider the physiological consequences of specific testosterone levels," say the authors. They suggest using a mean serum level of about 200 ng/dl as the point at which to provide testosterone supplementation. Lean mass, muscle strength, and erectile function remained stable as long as testosterone levels were ≥200 ng per deciliter in most, but not all, participants. Practitioners need to adjust serum target levels according to an individual's functional outcome. Given estradiol's role in male body composition and sexual function, the researchers suggest using aromatizable androgens, which can convert to estradiol, when supplementing instead of nonaromatizable androgens.
Finkelstein et al.state: "Our finding that estrogens have a fundamental role in the regulation of body fat and sexual function, coupled with evidence from prior studies of the crucial role of estrogen in bone metabolism, indicates that estrogen deficiency is largely responsible for some of the key consequences of male hypogonadism and suggests that measuring estradiol might be helpful in assessing the risk of sexual dysfunction, bone loss, or fat accumulation in men with hypogonadism."
Finkelstein JS, Lee H, Burnett-Bowie S-AM, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. September 12, 2013;369(11):1011–1022.
Inner Conflict of War Veterans
About one-third of war veterans who seek counseling for posttraumatic stress disorder (PTSD) suffer from moral injury. These vets do not have terrifying flashbacks of life-threatening events, nor are they stricken with grief over the loss of a buddy, which accounts for another one-third of PTSD. Moral injury, also called "inner conflict" by the Marine Corps, arises when a soldier performs an action or witnesses or fails to prevent an event that violates his/her moral code. "A moral injury tortures the conscience; symptoms include deep shame, guilt and rage," according to Associated Press journalist Pauline Jelinek. "'You may not have actually done something wrong by the law of war, but by your own humanity you feel that it's wrong,'" retired Col. Elspeth Ritchie, chief clinical officer at the District of Columbia's Department of Mental Health, told Jelinek.
People with moral injury exhibit some typical PTSD symptoms, such as avoidance and numbing; but, according to a framework proposed by Brett Litz, PhD, and colleagues, moral injury is primarily characterized by shame, guilt, demoralization, self-sabotage, and self-harm. These patients do not have the anxiety and hyperarousal seen in those with typical PTSD. Forgiveness, specifically self-forgiveness, helps dissipate the inner conflicts and guilt. An intervention called Adaptive Disclosure uses exercises such as having an imagined conversation with the deceased or with "a compassionate and forgiving moral authority" to resolve inner conflict.
"'Human beings aren't just turn-on, turn-off switches,' Veterans of Foreign Wars spokesman Joe Davis [told Jelinek], noting that moral injury is just a different name for a familiar military problem. 'You're raised on "Thou shalt not kill," but you do it for self-preservation or for your buddies.'"
Jelinek P. Veterans suffer "moral injury" from war. Spartanburg Herald-Journal. February 23, 2013. Available at http://bigstory.ap.org/article/im-monster-veterans-alone-their-guilt. Accessed September 13, 2013.
Maguen S, Litz B. Moral injury in veterans of war. PTSD Res Q. 2012;23(1):1–6. Available at www.ptsd.va.gov. Accessed September 13, 2013.
Overdiagnosis
"Medicine's much hailed ability to help the sick is fast becoming challenged by its propensity to harm the healthy," say Roy Moynihan, Jenny Doust, and David Henry in a British Medical Journal article. " … Narrowly defined, overdiagnosis occurs when people without symptoms are diagnosed with a disease that ultimately will not cause them to experience symptoms or early death." Overdiagnosis causes unnecessary anxiety and stress to basically healthy people and their loved ones as well as burdening them with the costs of further tests and treatments – interventions that may jeopardize their health. The problem of overdiagnosis has gained international attention.
Several factors are fueling the overdiagnosis epidemic. Screening technology improvements are making it possible to find increasingly small "abnormalities," many of which never cause symptoms or contribute to death. "It is becoming clearer that a substantial proportion of these earlier 'abnormalities' will never progress, raising awkward questions about exactly when to use diagnostic labels and therapeutic approaches traditionally deployed against much more serious forms of disease," say Moynihan and colleagues. Companies that make and sell these tests and treatments have tremendous influence on medical care. To promote their products, companies fund disease awareness campaigns, medical education, and research foundations, and advertise directly to consumers. More sales mean more profit. Hospitals, clinics, and practitioners also financially benefit from widespread screening programs. Doctors and patients have long followed the belief that it's better to treat than to wait and see, but treatment often has its own risks. At this point, tests cannot always tell whether an abnormality is life threatening and should be treated or not.
In addition to technology, parameters that define a disease are expanded to include more people. "As definitions broaden and thresholds fall, people with smaller risks or milder problems are labeled," say the authors, "which means the potential benefits of treatment decline, raising the possibility that harms will outweigh benefits." Being "at risk" is too often treated as if the disease is actually present. Once again, financial gain has had a role: " … the members of panels that write disease definitions or treatment thresholds often have financial ties to companies that stand to gain from expanded markets." Moynihan and colleagues call for a policy change that would bar people with conflicts of interest from being on such panels.
"An intuitive belief in early detection, fed by deep faith in medical technology is arguably at the heart of the problem of overdiagnosis," the authors write. While appropriate medical care can be lifesaving, patients and practitioners need to be educated about the harms that come with believing "more is better." BMJ plans to publish an article series that focuses on overdiagnosis of specific conditions such as ADHD, asthma, bipolar disease, cholesterol, chronic kidney disease, depression, high blood pressure, melanoma, osteoporosis, prostate cancer, and type 2 diabetes. Consumer Reports is working on lay-friendly summary versions. BMJ and Consumer Reports joined Dartmouth Institute for Health Policy and Clinical Practice (Hanover, New Hampshire) and Bond University (Robina, Queensland, Australia) to host the first international scientific conference called "Preventing Overdiagnosis" on September 10–12, 2013. The 2014 conference takes place at Oxford University in the UK on September 15–17. More information about overdiagnosis is available at http://www.preventingoverdiagnosis.net and http://consumerhealthchoices.org.
Moynihan R, Doust J, Henry D. Preventing overdiagnosis: how to stop harming the healthy. BMJ. May 29,2012; 344:e3502. Available at www.ncbi.nlm.nih.gov/pubmed/22645185. Accessed September 24, 2013.
Winding back the harms of too much medicine [Web page]. Consumer Health Choices. http://consumerhealthchoices.org/campaigns/preventing-overdiagnosis. Accessed September 13, 2013.
Answers to Critics of the 2012 Séralini GM Study
The 2012 publication of "Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize" received an onslaught of criticism and accusations of "pseudoscience" from those affiliated with GM crop productions. The rat study, led by French biochemist and molecular biologist Gilles-Eric Séralini, investigated the effects of lifelong consumption (2 years) of genetically modified NK603 maize (corn) and the Roundup pesticide formula used on it. Herbicide safety studies have focused solely on glyphosate, the active ingredient in Roundup. In actual practice, glyphosate-based pesticides such as Roundup include adjuvants that enhance glyphosate's effect. The Séralini study is the first long-term study on this crop. The Monsanto safety assurance study, conducted by B. Hammond (2004), lasted 13 weeks.
The 2012 Séralini study randomly assigned by weight 100 male rats and 100 female rats into groups of 10. The control group ate standard feed made from non-GM maize with the closest possible DNA to NK603 and plain water. Three groups ate Roundup-tolerant NK603 that was treated with Roundup; the GM maize made up 11%, 22%, or 33% of the rats' diet. Another three groups also ate NK603 as 11%, 22%, or 33% of their diet, but this maize was not treated with Roundup. Rats in the last three groups ate the control standard non-GM diet and Roundup (R) was added to their drinking water in one of three concentrations: "1.1 X 10-8% of R (0.1 ppb of R or 50 ng/L of glyphosate, the contaminating level of some regular tap waters), 0.09% of R (400 mg/kg, US [maximal residual level] of glyphosate in some GM feed) and 0.5% of R (2.25 g/L, half of the minimal agricultural working dilution)." The GM maize and the pesticide were associated with kidney deficiency in both male and female rats. Both treatments also affected sex hormonal balance. Treated males exhibited liver congestions and necrosis 2.5 to 5.5 times higher than controls. Males also had four times more large tumors than controls. Treated females developed more and larger mammary tumors than controls: "In females, all treated groups died 2-3 times more than controls, and more rapidly."
In their 2012 response to criticism about the study's design, Séralini et al.emphasized that they followed the Organization for Economic Co-operation and Development (OECD) guideline for testing and the 2004 Hammond safety study (which also used OECD guidelines) as the basis for their design. In addition to lasting longer than the Hammond study, the Séralini study looked at three dietary levels of GM food, while the Hammond study used only two. OECD recommends using three. It is impossible to track unusual dose-response patterns, such as caused by endocrine disruptors, using only two. Also, Séralini et al. used the same breed of rat (Sprague Dawley) and biochemically measured the same number of rats per sex as Hammond's Monsanto study in accordance with OECD guidelines for chronic toxicity testing. Critics attributed the high number of large tumors to the rats' breed; Sprague Dawley rats are known to be susceptible to cancer. Séralini and colleagues point out that Sprague Dawley rats are "preferentially used by some agencies such as for the National Toxicology Program … for 2-year carcinogenicity and other long-term studies." Moreover, the breed's propensity to develop cancer does not explain the severity and number of tumors found in treated animals compared with controls.
Critics also disputed the nonlinear dose-response effect caused by the different Roundup concentrations: the highest dose did not produce the greatest toxicity or mortality. Séralini et al. point out that U-, inverted U-, or J-shaped response curves are often produced by environmental toxins that have endocrine-disrupting effects. In response to critics' claim that glyphosate has shown no endocrine-disrupting effects in safety studies, Séralini et al. state, "The results of the study presented here clearly demonstrate that lower levels of complete agricultural glyphosate herbicide formulations, at concentrations well below officially set safety limits, induce severe hormone-dependent mammary, hepatic and kidney disturbances." (my emphasis) Farmers use glyphosate-based formulas, not glyphosate alone, on crops.
The reported safety of pesticide-resistant GM crops is based on short-term, manufacturer-funded, safety trials, such as the one conducted by Hammond and colleagues, and on the assumption that GM crops do not significantly differ from non-GM crops. The biotech industry is not monitoring farm animals or humans for adverse effects. Séralini and colleagues say, "[The NK603 maize and Roundup study] is the most detailed test conducted to date that is also independent from biotechnology and pesticide companies. We encourage others to replicate such chronic experiments, with greater statistical power. What is now urgently required is for the burden of proof to be obtained experimentally by studies conducted independent from industry. … "
Séralini GE, Clair E, Mesnage R, et al.Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize. Food Chem Toxicol. 2012;50:4221–4231. Available at http://dx.doi.org/10.1016/j.fct.2012.08.005. Accessed September 13, 2013.
Séralini GE, Mesnage R, Defarge N, et al. Answers to critics: Why there is a long term toxicity due to a Roundup-tolerant genetically modified maize and to a Roundup herbicide. Food Chem Toxicol. 2012 (in press). Available at http://dx.doi.org/10.1016/j.fct.2012.10.57. Accessed September 13, 2013.
Jule Klotter
jule@townsendletter.com
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