Should I Add Sugar or Splenda to My Coffee?

June 6, 2013

By Reda Issa

Faculty Peer Reviewed

As a medical student, I adjusted to waking up at 6 AM every day – with the help of coffee, of course. Living in New York City and its fast-paced routine requires that extra kick those beans provide. So, should I add sugar or Splenda to my coffee? Half a century ago this question did not exist, but obesity was not a word in the Merriam-Webster then. Today, we have to think more carefully.

Non-sucrose based sweeteners can be either natural or artificial. The best known natural sweetener is Stevia, an extract of leaves from Stevia rebaudiana Bertoni that has been used for many years in the traditional treatment of diabetes in South America [1]. Artificial sweeteners have existed since 1879 when saccharin was incidentally discovered by Constantine Fahlberg, who licked his finger after accidentally splashing himself with a substance during an experiment at Johns Hopkins – and found that it was sweet [2]. Currently, the U.S. Food and Drug Administration has five approved artificial sweeteners, including the famous three: saccharin (Sweet’N Low), aspartame (Equal), and sucralose (Splenda). Most of these sweeteners are non-caloric (i.e. it takes 0 kcal/g to metabolize them) [2].

High-sugar foods and beverages are a major cause of weight gain. Substituting sugar with artificial sweeteners that provide very few or no calories seems, logically, to be helpful in the prevention of weight gain. Indeed, a trial in 2002 provided overweight subjects with food containing either sucrose or artificial sweeteners as supplements to their diets. The artificial sweetener–supplemented group took in 105kcal less of daily energy, an amount that prevented the 1.3 kg weight gained by the sucrose group over a 10 week period [3]. The reason for this difference is that subjects consuming the sucrose-containing supplements did not decrease their carbohydrate intakes to compensate for the added calories provided by the supplements, resulting in significant increases in carbohydrate consumption, while the artificial sweetener-supplemented group did not modify their carbohydrate consumption, nor did they need to. Additionally, there was no difference between the two groups in hunger, fullness, and well-being [4]. These results, in addition to those of other similar trials, support the idea that artificial sweeteners significantly reduce body weight [5].

Both the American Heart Association (AHA) and the American Diabetes Association (ADA) recommend limiting added sugars as an important strategy for supporting optimal nutrition and healthy weight, and they state that although evidence is limited, nonnutritive sweeteners may be used in a structured diet to replace sources of added sugars, and that this substitution may result in modest energy intake reductions and weight loss [6]. Physiologically, sucralose does not stimulate insulin, glucagon-like peptide 1 (GLP-1), or glucose-dependent insulinotropic polypeptide (GIP) release, nor does it slow gastric emptying in healthy humans [7]. These artificial sweeteners therefore do not interfere with glucose metabolism and are passed through the gastrointestinal tract with no effect; thus artificial sweeteners may have no therapeutic benefit in the dietary management of diabetes other than as a substitute for carbohydrate.

Aside from weight loss, artificial sweeteners have many other beneficial effects. For example, the use of sucrose substitutes in sweets is believed to have contributed in part to the decline in the prevalence of dental caries in industrialized countries [8]. Stevia specifically was shown to be effective in lowering blood pressure in hypertensive patients, and small studies also report positive results with respect to improved glucose tolerance [1] in addition to some anti-fungal and anti-bacterial properties [9].

All these positive aspects seem to favor the use of non-sugar based sweeteners, so why have they not completely replaced sugar? Some rumors disseminated by the press reported serious adverse effects associated with the use of these substances, many of which have no scientific background Even some of the scientific publications in reliable medical journals, which caught media attention, were not well researched and ignored common statistical knowledge. For example a large study in 1996 titled ‘Increasing brain tumor rates: Is there a link to aspartame?’ linked the increase of brain tumors to the introduction of aspartame, two events that incidentally occurred around the same period. In epidemiology, this correlation is called ‘ecological fallacy’ and is not admissible, since there was no information available regarding whether the individuals who developed brain tumors consumed aspartame [10] The scare was mainly regarding bladder cancer, and it was based on rat studies that showed increased risk; in fact, this study resulted in a ban on saccharin in Canada and a black label in the USA in 1981. However, the National Institute for Environmental Health Sciences removed saccharin as a potential cancer-causing agent in 2000 because it was shown that the cancer-inducing mechanisms in rats do not apply to humans [10]. Many more human studies found no evidence that artificial sweeteners bear a carcinogenic risk, unless very high doses are consumed (greater than 4000 mg/kg body weight per day which is about 560 teaspoons for the average 70-kg person, much higher than the normally consumed quantities) [11]; even then, the relative risk for bladder cancer is merely 1.3 (95% CI 0.9–2.1) [10]. After all, these sweeteners had to be approved as safe by the U.S. FDA before they were marketed [6]. The American Dietetic Association states that artificial sweeteners are safe to use overall. The AHA’s position favors their use for diabetics and people on a weight loss diet.

Of note, the benefits of artificial sweeteners in adults have not been reproduced in pediatric populations [12], other than for diabetics; in fact, the American Academy of Pediatrics recommends that such products should not form a significant part of a child’s diet [13].

In summary, research has failed to prove any detrimental effects of artificial sweeteners; on the contrary, many benefits have been ascertained, the most important of which is weight loss. Obesity, on the other hand, continues on its exponential hike toward the disastrous level, with all associated adverse health consequences. So – if you are deciding between a diet and a regular soda, go with the diet. Add Splenda to your coffee. Or even drink it black! As with everything in life, moderation is key.

Reda Issa is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons


1. Ulbricht C, Isaac R, Milkin T, et al. An evidence-based systematic review of stevia by the Natural Standard Research Collaboration. Cardiovasc Hematol Agents Med Chem. Apr 2010;8(2):113-127.  http://www.ncbi.nlm.nih.gov/pubmed/20370653

2. Whitehouse CR, Boullata J, McCauley LA. The potential toxicity of artificial sweeteners. AAOHN J. Jun 2008;56(6):251-259; quiz 260-251.  http://www.ncbi.nlm.nih.gov/pubmed/18604921

3. Raben A, Vasilaras TH, Moller AC, Astrup A. Sucrose compared with artificial sweeteners: different effects on ad libitum food intake and body weight after 10 wk of supplementation in overweight subjects. Am J Clin Nutr. Oct 2002;76(4):721-729.  http://www.ncbi.nlm.nih.gov/pubmed/12324283

4. Anton SD, Martin CK, Han H, et al. Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite. Aug 2010;55(1):37-43.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900484/

5. St-Onge MP, Heymsfield SB. Usefulness of artificial sweeteners for body weight control. Nutr Rev. Jun 2003;61(6 Pt 1):219-221.

6. Gardner C, Wylie-Rosett J, Gidding SS, et al. Nonnutritive sweeteners: current use and health perspectives: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. Aug 2012;35(8):1798-1808.

7. Ma J, Bellon M, Wishart JM, et al. Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects. Am J Physiol Gastrointest Liver Physiol. Apr 2009;296(4):G735-739.

8. Matsukubo T, Takazoe I. Sucrose substitutes and their role in caries prevention. Int Dent J. Jun 2006;56(3):119-130.

9. Goyal SK, Samsher, Goyal RK. Stevia (Stevia rebaudiana) a bio-sweetener: a review. Int J Food Sci Nutr. Feb 2010;61(1):1-10.

10. Weihrauch MR, Diehl V. Artificial sweeteners–do they bear a carcinogenic risk? Ann Oncol. Oct 2004;15(10):1460-1465.

11. Magnuson BA, Burdock GA, Doull J, et al. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev Toxicol. 2007;37(8):629-727.  http://www.ncbi.nlm.nih.gov/pubmed/17828671

12. Brown RJ, de Banate MA, Rother KI. Artificial sweeteners: a systematic review of metabolic effects in youth. Int J Pediatr Obes. Aug 2010;5(4):305-312.

13. Sylvetsky A, Rother KI, Brown R. Artificial sweetener use among children: epidemiology, recommendations, metabolic outcomes, and future directions. Pediatr Clin North Am. Dec 2011;58(6):1467-1480, xi.

Too Much of a Good Thing: The Evidence Behind the Need for a Bisphosphonate Holiday

May 9, 2013

By Jenna Piccininni

Faculty Peer Reviewed

Bisphosphonates are a relatively new medication having only been approved to treat osteoporosis in the US since 1995 [1]. In addition, large placebo controlled trials have, at most, 10 years of follow-up data. Thus, there are still questions regarding the long-term use of these agents. There are a few well-established side effects of bisphosphonates including rare osteonecrosis of the jaw and more common esophageal irritation. However, several more recent case reports suggest a correlation between prolonged bisphosphonate use and atypical femoral fracture [2]. This brings into question whether too much antiresorptive activity can lead to increased fracture risk and if a medication holiday is therefore appropriate.

The pharmacology and mechanism of bisphosphonates is integral in understanding the biological underpinnings of this potential association and the implications of discontinuing the medication. Once absorbed into the blood stream there is no systemic metabolism and the molecules directly bind to active bone [1]. These binding sites on bone are so numerous that saturation is physiologically unrealistic. In the setting of osteoclast activity an acidic microenvironment is created which causes the bisphosphonates to be released and taken up by these cells, leading to loss of osteoclast function and ultimately apoptosis. This decrease in bone resorption leads to increased bone density but also suppress the repair of microdamage that occurs with normal daily activities. One study in Beagle dogs examined how the use of bisphosphonates, at six times the clinical dose, affected bone structure [3]. In control dogs resorption spaces were more numerous but more likely to be associated with areas of microdamage cracks whereas treated dogs had a higher proportion of cracks that were not associated with resorption spaces. These findings suggest that bisphosphonates impair targeted repair of microdamage, which is the proposed mechanism by which long-term use is thought to lead to increased fracture risk.

Based on these case reports, controlled studies have looked for a significant association between prolonged bisphosphonate use and risk of atypical fracture. In 2010 a NEJM study used data from the FIT, FLEX, and HORIZON PFT large randomized controlled trials to assess this association and found no increased risk [4]. However in 51,287 patient years only 12 atypical fractures were identified resulting in wide confidence intervals and low power. Despite the lack of evidence for definitive causation, in 2010 the FDA issued a label change for all bisphosphonates requiring the risk of atypical subtrochanteric femur fractures to be included [5]. Then in 2011 a paper in JAMA reported the results of an epidemiological population based case-control study showing that women using bisphosphonates for more than five years have 2.74 times the odds of being hospitalized for a subtrochanteric or femoral neck fracture than women with only sporadic use (<100 days) [6]. Following 5 years of use the risk of fracture was .13% in the first year and .22% in two years. 64% of the fractures in long-term users were attributable to bisphosphonate use, but because the total incidence of these fractures is so low eliminating exposure would lead to only an 11% decrease in the total rate of fracture. While this study shows a significant association between prolonged bisphosphonate use and atypical fracture, the evidence should be interpreted keeping in mind that confounders may be present in this observational study. Larger controlled studies must be done confirm these findings. If this association is present, the effects of limiting bisphosphonate exposure though medication holidays could be beneficial.

The idea of a bisphosphonate holiday is particularly appealing due to the unsaturable accumulation of the molecules in bone allowing for continued effectiveness even after discontinuation of the medication. The Fracture Intervention Trial Long-term Extension (FLEX) study randomized women who previously had three to five years of alendronate in the FIT trial to receive either 5 more years of 10 mg alendronate/day, 5mg alendronate/day, or placebo [7]. Their results showed that while bone mineral density (BMD) at the hip decreased 2-3% in the placebo group this was less BMD loss than expected in women never treated with bisphosphonates and that their BMD remained above baseline levels at the start of the FIT trial. In addition, there was no difference in the rate of non-vertebral fractures between any of the groups, showing that loss of hip BMD in the placebo group was not clinically relevant. However, the women in the alendronate arms had a 2.9% absolute risk reduction and 55% relative risk reduction for clinical vertebral fractures compared to placebo, but the rate of morphometric fracture was equal. This benefit was most appreciable in women with past vertebral fractures and very low BMD. Another study in NEJM similarly followed women for 10 years assigned to either 10mg/day alendronate, 5mg/day alendronate, or 5mg/day alendronate for 5 years followed by 5 years of placebo [8]. They similarly found that changes in BMD in the placebo group varied depending on the site, but that the risk of morphometric vertebral fractures did not differ between the three groups. This data shows that after treatment for five years with a bisphosphonates a five-year holiday is only detrimental to women at high risk for fracture with very low BMD and previous fractures.

Although no official recommendations have been made regarding bisphosphonate holidays, some authors have proposed personal guidelines based upon the patient’s risk of fracture. Watts and Diab suggest an indefinite holiday for patients at mild risk after 5 years of treatment, a two to three year holiday for moderate risk patients after 5-10 years of treatment, and a 1-2 year “holiday” for high-risk patients after 10 years of treatment during which they receive an alternative medication such as a SERM [1]. During these holidays bisphosphonates should be restarted if BMD decreases significantly or if fracture occurs. I believe that the aforementioned studies support this type of algorithm. Discontinuing bisphosphonates after several years of treatment does not appear to have clinical implications in most low risk patients most likely due to their storage in bone and residual effects. Data regarding risk of atypical fracture with long-term treatment is not as clear but in the setting of this potential debilitating side effect physicians that are risk-averse are justified in giving their patients a medication holiday based on their clinical scenario. More controlled studies must be done examining the clinical outcomes of specific holiday durations, the optimal time to begin a holiday and indications for ending one. With that information more solid evidence based guidelines can be constructed, patient safety can be improved, and the use of these relatively new medications can be optimized.

Jenna Piccininni is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Michael Tanner, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


1. Watts N, Diab D. Long-term use of bisphosphonates in osteoporosis. Journal of Clinical Endocrinology and Metabolism. 2010;95(4):1555-1565.  http://jcem.endojournals.org/content/95/4/1555.full

2. Lenart B, Lorich D, and Lane J. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. New England Journal of Medicine. 2008;358:1304-1306.

3. Li J, Mashiba T, Burr D. Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Calcification Tissue International. 2001;69:281-286.  http://www.ncbi.nlm.nih.gov/pubmed/11768198

4. Black D, Kelly M, Genant H, et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. The New England Journal of Medicine. 2010;362(19):1761-1771.

5. Bisphosphonates 9osteoporosis drugs): Label change-Atypical fractures update. Food and Drug Administration Website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm229244.htm.  Accessed July 25, 2012.

6. Park-Wyllie L, Mamdani M, Juurlink D, et al. Bisphosphonate use and the risk of subtrochanteric for femoral shaft fractures in older women. Journal of the American Medical Association. 2011;305(8): 783-789.

7. Black D, Schwartz A, Ensrud K, et al. Effects of continuing or stopping alendronate after 5 years of treatment The fracture intervention trial long-term extension (FLEX): A randomized trial. Journal of the American Medical Association. 2006;296(24):2927-2938.  http://www.ncbi.nlm.nih.gov/pubmed/17190893

8. Bone H, Hosking D, Devogelaer J, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. The New England Journal of Medicine. 2004;350:1189-1199.  http://www.fosalan.co.il/secure/resources/publications/10years-English.pdf

In Search of a Competitive Advantage: A Primer for the Clinician Treating the Anabolic Steroid User

April 17, 2013

By David G. Rosenthal and Robert Gianotti, MD

Faculty Peer Reviewed

Case: A 33-year-old man comes to your clinic complaining of worsening acne over the last 6 months. You note a significant increase in both BMI and bicep circumference. After several minutes of denial, he reveals that he has been using both injectable and oral anabolic steroids. He receives these drugs from a local supplier and via the Internet. He confides that his libido has dramatically increased and he feels increasingly pressured at work, describing several recent altercations. He admits that these symptoms are a small price to pay for the amazing performance gains he has seen at the gym. He plans to compete in a local deadlifting tournament at the end of the month. He asks you if he is at increased risk for any health problems and whether short-term use is associated with any long-term consequences. You quickly realize that you have no idea what literature exists on the health consequences of anabolic steroids. Fortunately, you have set the homepage on your web browser to Clinical Correlations. Together, you read…

The recreational use of anabolic steroids has drawn increasing international attention over the last decade due to their use and abuse by athletes and bodybuilders. Athletes including Arnold Schwarzenegger, cyclist Lance Armstrong, baseball slugger Mark McGuire, and Olympic gold medal sprinter Marion Jones have all come under scrutiny for using steroids to gain a competitive advantage and shatter records. In fact, the 1990’s are notoriously known in Major League Baseball as the “Steroids Era.” Critics argue that the use of these substances contradicts the nature of competition and are dangerous given the abundance of reported side effects. Accordingly, the vast majority of sporting associations have banned the use of anabolic steroids, and their possession without a prescription is illegal in the United States, punishable by up to one year in prison. Nevertheless, the performance-enhancing, aesthetic, and financial benefits of anabolic steroids has led to rampant abuse by both professional and high school athletes with an astonishing 3.9% of students having tried anabolic steroids at least once during high school 1, 2.

Anabolic steroids are synthetic derivatives of testosterone, the primary male sex hormone. Androgenic effects of testosterone include maturation of secondary sex characteristics in both males and females, development of typical hair patterns, and prostate enlargement, while its anabolic effects include strength gains and bone maturation via regulation of protein metabolism 3. Administration of exogenous testosterone causes upregulation of the androgen receptor in skeletal muscle, resulting in increased muscle fiber size and number 4. Anabolic steroids can be absorbed directly into skin, injected, or taken orally. Synthetic oral steroids, including methyltestosterone and fluoxymesterone, are 17-alpha alkylated which prevents first-pass metabolism by the liver and may contribute to increased hepatotoxicity 5.

Much of the public opinion about anabolic steroids has been obtained from individual testimonies and well-publicized user narratives. While thousands of articles have been published in scientific journals describing both the desired and adverse effects of anabolic steroid abuse, a number of these studies have drawn questionable conclusions due to flawed methodologies, inadequate sample sizes, study biases, and most importantly the inability to replicate the actual drug dosages used by many athletes. The regimens of many steroid users often consist of twenty-fold higher concentrations than have been previously examined in the literature 6. Hence, the precise effects of the supraphysiologic doses of steroids that are commonly abused may never be known.

Strength, endurance and reduced recovery time are all attributes that the competitive athlete strives to obtain. Historically, institutions and even governments have dabbled in performance enhancement for competitive athletes. It has been well documented that Communist-era East Germany sought to build superior athletes to compete in the Olympic Games and flex their muscles on the world stage. Documents studying the effects of anabolic steroids, including oral Turinabol on Olympic athletes in East Germany from 1968-1972 showed remarkable improvements in strength sports: Discus throws increased by 11-20 meters; shot put distance improved by 4.5-5 meters; hammer throw increased by 6-10 meters; and javelin throw increased 8-15 meters 7. The strength gains among East German female athletes were most notable, as were the side effects including hirsutism, amenorrhea, severe acne, and voice deepening. In fact, when a rival coach commented on the voice changes of the competitors, the East German coach responded “We came here to swim, not sing”8. Following the implementation of “off-season” steroid screening by the International Olympic Committee and other competitive organizations in 1989, track and field sports saw a dramatic reduction in performance. Notably, the longest javelin throw by a female in the 1996 Olympics was 35 feet shorter than the world record of 1988.

The gains seen with anabolic steroid use extend beyond the Olympic athlete to recreational body-builders and gym-rats. In a small placebo controlled study from the Netherlands, a ten-week course of injectable nadrolone in a cohort of recreational body builders increased lean body mass by an average of 2-5 kg, with no accompanying increase in fat mass or fluid retention 9. These effects persisted for more than 6 weeks after the cessation of nandrolone. Surprisingly, performance enhancement can be seen with anabolic steroids even in the absence of exercise. In fact, one study including healthy, young men between the ages of 18 and 35 who had endogenous androgen production suppressed with GnRH showed that supraphysiologic doses of testosterone enanthate administered for 20 weeks caused a 15% dose dependent increase in muscle size and a 20% increase in muscle strength without any exercise 10. This study came as a logical follow up to a smaller study published in the New England Journal of Medicine in 1996 that showed impressive performance gains compared to placebo among both exercising and sedentary subgroups. At 10 weeks, the testosterone + exercise group was able to bench press a mean of 10kg more than both the testosterone alone and exercise alone subgroups11.

The performance gains from steroids have also been shown to extend into the eighth and ninth decades of life. A 2003 study in men aged 65-80 showed significant gains compared to placebo in both lean body mass and single repetition chest press after receiving either 50mg or 100mg of the orally bioavailable steroid, oxymethalone. The men in the 100mg group were able to chest press 13.9% +/- 8.1% (p<0.03) compared to placebo and had a 4.2 +/- 2.4 kg (p<0.001) increase in lean body mass 12. Many athletes also report that anabolic steroids increase endurance and decrease recovery time after workouts. This has been supported in the literature where indirect measures of fatigue, such as increased serum lactate and elevated heart rate were delayed after the injection of nandrolone decanoate with a notable improvement in recovery time4.

We now know from a small, but significant pool of data that the performance gains from anabolic steroids are real and can be seen not only in elite athletes but casual users as well. The existing data regarding the side effects of anabolic steroid is varied and relies heavily on self-reported outcomes and dosing regimens that are often variable and combine multiple unique drugs.

One method of obtaining data regarding the adverse effects of anabolic steroid abuse is by employing questionnaires. While this method is inherently biased, it may the only way to obtain data from subjects using very high doses that are considered unsafe or unethical for higher quality studies. Regardless of the method of data collection, it has been well established that up to 40% of male and 90% of female steroid users self-report adverse side effects including aggression, depression, increased sexual drive, fluid retention, hypertension, hair loss, and gynecomastia4. Other reported side effects include: increased levels of the hormone erythropoietin leading to an increased red blood cell count; vocal cord enlargement, leading to voice deepening; and increased risk of sleep apnea.

Exogenous administration of steroids can have immediate and profound effects on the reproductive system, largely mediated through disruption of the hypothalamic-pituitary-adrenal-gonadal axis. Within 24 hours of use, steroids cause a dramatic decrease in follicle stimulating hormone and luteinizing hormone, which can result in azospermia in males and menstrual irregularities in females within weeks, and infertility within months 13, 14. Supraphysiologic testosterone concentrations result in virilization of females, which is characterized by hirsutism, clitoromegaly, amenorrhea, and voice deepening 15. When steroids are abused for longer periods of time, men can suffer from hypogonadotropic hypogonadism, manifested by testicular atrophy, as well as gynecomastia due to peripheral conversion of the exogenous testosterone to estrogen 15. Some athletes try to increase their sperm count by using human chorionic gonadotropin or clomiphene, both commonly used female fertility drugs, but the efficacy of these hormones are debated; moreover, they do not reduce gynecomastia4. Commonly, drugs such as Propecia, routinely used to treat male-pattern baldness and benign prostatic hypertrophy, are used to increase testosterone levels. Although there have been reports of prostatic hypertrophy in steroid users, there is no known associated risk with the development of prostate adenocarcinoma 16, 17.

Adverse cardiovascular outcomes in steroid abusers have been published, including cardiomyopathy, arrhythmia, stroke, and sudden cardiac death18. However, causation has often been inappropriately attributed solely to anabolic steroid use and the data can be misleading due to confounding variables and study biases 4. The structural, functional, and chemical changes associated with steroid abuse are crucial to consider because many of the reported effects are independent risk factors for cardiovascular disease.

A study published in Circulation in 2010 evaluated left ventricular function in a cohort of weightlifters (n=12) with self-reported anabolic steroid use compared to age-matched weightlifting controls (n=7). After adjusting for body surface area and exercise, the investigators found a significant reduction in left ventricular systolic function (EF= 50.6% vs. 59.1%, p=0.003) 19, and the association remained statistically significant even after controlling for prior drug use including alcohol and cocaine. Interestingly, there appeared to be no relationship between cumulative anabolic steroid use and ventricular dysfunction, although the authors note limitations due to small sample size and the bias of self reported data.

Other studies investigating cardiovascular outcomes of anabolic steroid suggest a transient increase in both systolic and diastolic blood pressure in steroid users, although these values return to baseline within weeks of cessation 20. In addition, long term use of anabolic steroids can lead to increased platelet aggregation, possibly contributing to increased risk for myocardial infarction and cerebrovascular events 18.

Anabolic steroids cause a variable increase in LDL and up to a 40-70% decrease in HDL, often resulting in the misleading finding that steroids do not affect total plasma cholesterol 21. Fortunately, these effects are reversible within 3 months of cessation of the agent 22. The use of the 17-alpha-alkylated steroids can cause a 40% reduction in apolipoprotein A-1, a major component of HDL, while an injectable testosterone has been shown to have a tempered 8% reduction 23. Although these effects are reversible with cessation, they underscore the importance of screening anabolic steroid users for lipid abnormalities.

Steroid use has been linked with a number of hepatic diseases. The use of oral steroids is associated with a transient increase in transaminase levels, although some data suggest that this may be due to muscle damage from bodybuilding rather than from liver damage 24. The link between 17-alpha-alkylated steroids and hepatomas, peliosis hepatis (a rare vascular phenomenon resulting in multiple blood filled cavities within the liver), and hepatocellular carcinoma has been suggested in case studies, but no causal relationship has been established 25.

Possibly the most publicized adverse effect of steroid use is psychological, publicly coined “roid rage.” In one study using self-reported data, 23% of steroid users acknowledged major mood symptoms, including depression, mania, and psychosis 26. However, most studies report only subtle psychiatric alterations in the majority of patients, with few patients experiencing significant mood disorders 27. However, a 2006 cohort study from Greece found a dose dependent association between steroid use and psychopathology that was driven by significant increases in hostility, aggression and paranoia (P<0.001) 28. While this topic needs further research, it does lend credence to the theory that “’roid rage” exists, and its effects are exacerbated by higher doses of steroids.


The former baseball all-star Jose Canseco once claimed that “steroids, used correctly, will not only make you stronger and sexier, they will also make you healthier 29.” Although current research reveals that steroid abuse is not independently associated with increased mortality 16, and many of the adverse effects are rare and reversible with cessation of use, there is a dearth of knowledge about the effects of the actual regimens used, and the long-term side effects of these drugs are largely unknown.

Based on the paucity of quality data and frightening implications of metabolic derangements, heart failure, and infertility, your patient leaves convinced that he has made a poor decision in choosing to use anabolic steroids. He pledges to quit immediately and defer competing in the deadlifting tournament until next year after a “washout” period. He is eager to disseminate his new found knowledge at the local gym, but not before he makes a stop at GNC to load up on creatinine supplements and whey protein.

David G. Rosenthal is a 4th year medical student at NYU Langone Medical Center and Robert Gianotti, MD is Associate Editor, Clinical Correlations

Peer reviewed by Loren Greene , MD, Clinical Associate Professor, Department of Medicine (endocrine division) and Obstetrics and Gynecology

Image Courtesy of Wikimedia Commons


1. Eaton D, Kann L, Kinchen S, et al. Youth risk behavior surveillance – United States, 2009. MMWR. Surveillance summaries. 2010;59(5):1-142.  http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5905a1.htm

2. Handelsman DJ GL. Prevalence and risk factors for anabolic-androgenic steroid abuse in Australian secondary school students. Int J Androl. 1997;20:159-164.

3. Kochakian CD. History, chemistry and pharmacodynamics of anabolic-androgenic steroids. Wiener medizinische Wochenschrift. 1993;143(14-15):359-363.

4. Hartgens F, Kuipers H. Effects of androgenic-anabolic steroids in athletes. Sports medicine. 2004;34(8):513-554.  http://www.ncbi.nlm.nih.gov/pubmed/15248788

5. Stimac D, Mili? S, Dintinjana R, Kovac D, Risti? S. Androgenic/Anabolic steroid-induced toxic hepatitis. Journal of clinical gastroenterology. 2002;35(4):350-352.

6. Wilson JD. Androgen abuse by athletes. Endocrine reviews. 1988;9(2):181-199.  http://edrv.endojournals.org/content/9/2/181.abstract

7. Franke WW, Berendonk B. Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government. Clinical Chemistry. 1997;43(7):1262-1279.  http://www.ncbi.nlm.nih.gov/pubmed/9216474

8. Janofsky M. Coaches Concede That Steroids Fueled East Germany’s Success in Swimming. New York Times. 12.03.91, 1991.

9. Hartgens F, Van Marken Lichtenbelt WD, Ebbing S, Vollaard N, Rietjens G, Kuipers H. Body composition and anthropometry in bodybuilders: regional changes due to nandrolone decanoate administration. International journal of sports medicine. 2001;22(3):235-241.

10. Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. American journal of physiology: endocrinology and metabolism. 2001;281(6):E1172-E1181.

11. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. The New England journal of medicine. 1996;335(1):1-7.

12. Schroeder ET, Terk M, Sattler F. Androgen therapy improves muscle mass and strength but not muscle quality: results from two studies. American journal of physiology: endocrinology and metabolism. 2003;285(1):E16-E24.  http://ajpendo.physiology.org/content/285/1/E16.long

13. Bijlsma JW, Duursma SA, Thijssen JH, Huber O. Influence of nandrolondecanoate on the pituitary-gonadal axis in males. Acta endocrinologica. 1982;101(1):108-112.

14. Torres Calleja J, Gonzlez-Unzaga M, DeCelis Carrillo R, Calzada-Snchez L, Pedrn N. Effect of androgenic anabolic steroids on sperm quality and serum hormone levels in adult male bodybuilders. Life sciences. 2001;68(15):1769-1774.

15. Martikainen H, Aln M, Rahkila P, Vihko R. Testicular responsiveness to human chorionic gonadotrophin during transient hypogonadotrophic hypogonadism induced by androgenic/anabolic steroids in power athletes. The Journal of steroid biochemistry. 1986;25(1):109-112.

16. Fernndez-Balsells MM, Murad M, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. The Journal of clinical endocrinology and metabolism. 2010;95(6):2560-2575.

17. Bain J. The Many Faces of Testosteron. Clin Intern Aging. 2007;2(4):567-576.

18. Vanberg P, Atar D. Androgenic anabolic steroid abuse and the cardiovascular system. Handbook of experimental pharmacology. 2010 2010(195):411-457.

19. Baggish A, Weiner R, Kanayama G, et al. Long-term anabolic-androgenic steroid use is associated with left ventricular dysfunction. Circulation. Heart failure. 2010;3(4):472-476.

20. Kuipers H, Wijnen JA, Hartgens F, Willems SM. Influence of anabolic steroids on body composition, blood pressure, lipid profile and liver functions in body builders. International journal of sports medicine. 1991;12(4):413-418.

21. Glazer G. Atherogenic effects of anabolic steroids on serum lipid levels. A literature review. Archives of internal medicine. 1991;151(10):1925-1933.

22. Hartgens F, Rietjens G, Keizer HA, Kuipers H, Wolffenbuttel BHR. Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a). British journal of sports medicine. 2004;38(3):253-259.

23. Thompson PD, Cullinane EM, Sady SP, et al. Contrasting effects of testosterone and stanozolol on serum lipoprotein levels. JAMA (Chicago, Ill.). 1989;261(8):1165-1168.

24. Dickerman RD, Pertusi RM, Zachariah NY, Dufour DR, McConathy WJ. Anabolic steroid-induced hepatotoxicity: is it overstated? Clinical journal of sport medicine. 1999;9(1):34-39.

25. Overly WL, Dankoff JA, Wang BK, Singh UD. Androgens and hepatocellular carcinoma in an athlete. Annals of Internal Medicine. 1984;100(1):158-159.

26. Pope HG, Katz DL. Psychiatric and medical effects of anabolic-androgenic steroid use. A controlled study of 160 athletes. Archives of general psychiatry. 1994;51(5):375-382.

27. Pope HG, Kouri EM, Hudson JI. Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial. Archives of general psychiatry. 2000;57(2):133-140.

28. Pagonis T, Angelopoulos N, Koukoulis G, Hadjichristodoulou C. Psychiatric side effects induced by supraphysiological doses of combinations of anabolic steroids correlate to the severity of abuse. European psychiatry. 2006;21(8):551-562.

29. Canseco J. Juiced: Wild Times, Rampant ‘Roids, Smash Hits, and How Baseball Got Big. Philadelphia, PA: Reed Elsevier Inc.; 2005.

30. Young NR BH, Liu G, Seeman E. . Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J Clin Endrocrinol Metab. 1993;77:1028-1032.

The Effect of Bariatric Surgery on Incretin Hormones and Glucose Homeostasis

April 4, 2013

By Michael Crist

Faculty Peer Reviewed

Until recently, little thought was given to the important role played by the duodenum, jejunum, and ileum in glucose homeostasis. The involvement of the gut in glucose regulation is mediated by the enteroinsular axis, which refers to the neural and hormonal signaling pathways that connect the gastrointestinal (GI) tract with pancreatic beta cells. These pathways are largely responsible for the increase in insulin that occurs during the postprandial period. In 1964 McIntyre and colleagues first reported the phenomenon of oral glucose administration eliciting a greater insulin response than a similar amount of glucose infused intravenously [1]. This observation, later named the incretin effect, accounts for the role of certain gut hormones within the enteroinsular axis that promote insulin secretion [2]. Although many hormones are believed to contribute, the two that play the most significant role in nutrient-stimulated insulin secretion are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) [3,4]. GLP-1 is synthesized by L-cells found predominantly in the ileum and colon [5], and GIP is secreted from K-cells found predominantly in the duodenum [6]. Both GLP-1 and GIP are secreted in response to nutrients within the gut and are powerful insulin secretagogues, accounting for roughly 50% of postprandial insulin secretion [7]. They have both been shown to promote pancreatic beta cell proliferation and survival [7]. GLP-1 has also been shown to inhibit glucagon secretion and gastric emptying while promoting satiety and weight loss [7].

The incretin effect progressively diminishes with the onset of type 2 diabetes in a process that contributes to disordered glucose metabolism. GLP-1 secretion is significantly lower in type 2 diabetics than in non-diabetic individuals, and GIP loses its insulinotropic properties [8]. Malabsorptive bariatric surgery operations, which alter GI tract anatomy, have been shown to affect incretin hormone profiles and glucose homeostasis [9,10]. Many patients show a postoperative return to normal plasma glucose, plasma insulin, and glycosylated hemoglobin levels and discontinue the use of diabetes-related medication [10,11]. The dramatic resolution of diabetes and the return to euglycemia often occur within one week of surgery, before a significant amount of weight loss occurs [12,13]. In 2001 Pories and Albrecht reported long-term glycemic control in 91% of patients 14 years after they underwent malabsorptive bariatric surgery [12]. Furthermore, the improvement in insulin sensitivity postoperatively has been shown to prevent the progression from impaired glucose tolerance to diabetes [12].

The exact mechanism through which malabsorptive bariatric surgery improves glucose homeostasis is unclear. Much of the evidence in support of bariatric surgery as treatment for diabetes comes from studies that have focused on roux-en-Y gastric bypass and biliopancreatic diversion (which results in enteral nutrition passing directly from the stomach to the ileum) [9,10]. Both of these procedures surgically alter the GI tract such that nutrient chyme bypasses the duodenum and the proximal jejunum. Many initially hypothesized that enhanced nutrient delivery to the distal intestine promotes a physiological signal that ameliorates glucose metabolism. Enhanced GLP-1 secretion as a result of expedited nutrient delivery to the L-cell-rich ileum has been proposed as a mechanism that contributes to this process (14,15). Alternatively, the exclusion of nutrient flow through the duodenum and proximal jejunum may interrupt a signaling pathway that confers insulin resistance [11,12].

Rubino and colleagues tested both theories in a non-obese model of type 2 diabetic rats by comparing glucose tolerance among 3 surgery groups and one non-operated control. Of the 3 surgery groups, one underwent duodenal jejunal bypass (DJB), which excluded nutrient passage from the proximal foregut, resulting in early nutrient delivery to the distal gut. Another group underwent gastrojejunostomy (in which a surgical anastomosis was created between the stomach and jejunum while preserving the normal connection between the stomach and duodenum). This allowed both the normal passage of nutrients through the foregut and enhanced nutrient delivery to the hindgut. In effect, both the DJB and gastrojejunostomy promoted nutrient delivery to the ileum, whereas only the DJB procedure excluded the duodenum from nutrient passage. The third group was a sham-operated control. The DJB group showed better glucose tolerance than all other study groups even though there were no differences in food intake, body weight, or nutrient absorption [16]. Furthermore, when the DJB group underwent a second operation to allow nutrient passage through the foregut, glucose tolerance deteriorated. When the gastrojejunostomy group underwent a second operation to prevent nutrient passage through the foregut, glucose tolerance improved [16]. These findings suggest that exclusion of the duodenum and proximal jejunum is a necessary component of surgical interventions aimed at improving glucose tolerance.

Bariatric surgery holds great potential in the treatment of T2DM and will likely play an increasingly important role in diabetes management. Improved glucose regulation following malabsorptive bariatric surgery procedures is likely multifactorial, with alterations in gut microflora and the beneficial effects of weight loss contributing with time. Changes in gut hormone secretion profiles, however, appear to play an important role in the initial improvements reported in glucose homeostasis.

FIGURE 1. Interventions. A, Duodenal-jejunal bypass (DJB). This operation does not impose any restriction to the flow of food through the gastrointestinal tract. The proximal small intestine is excluded from the transit of nutrients, which are rapidly delivered more distally in the small bowel. Food exits the stomach and enters the small bowel at 10 cm from the ligament of Treitz, and digestive continuity is reestablished approximately 25% of the way down the jejunum. B, Gastrojejunostomy (GJ). This operation consists of a simple anastomosis between the distal stomach and the first quarter of the jejunum. The site of the jejunum that is anastomosed to the stomach is chosen at the same distance as in DJB (10 cm from the ligament of Treitz). Hence, the DJB and GJ share the feature of enabling early delivery of nutrients to the same level of small bowel. In contrast to DJB, the GJ does not involve exclusion of duodenal passage, and nutrient stimulation of the duodenum is maintained. C, Ileal bypass (ILB). This operation reduces intestinal fat absorption by preventing nutrients from passing through the distal ileum, where most lipids are absorbed.

Michael Crist is a 4th year medical student at NYU School of Medicine

Peer reviewed by Natalie Levy, MD, Department of Medicine (GIM Div.) NYU Langone Medical Center


1. McIntyre N, Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet. 1964;2(7349):20-21.

2. Creutzfeldt W. The incretin concept today. Diabetologia. 1979;16(2):75-85.  http://www.ncbi.nlm.nih.gov/pubmed/32119

3. Fetner R, McGinty J, Russell C, Pi-Sunyer FX, Laferrère B. Incretins, diabetes, and bariatric surgery: a review. Surg Obes Relat Dis. 2005;1(6):589-597.

4. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26(10):2929-2940. http://care.diabetesjournals.org/content/26/10/2929

5. Drucker DJ. Incretin-based therapies: A clinical need filled by unique metabolic effects. Diabetes Educ. 2006;32 Suppl 2:65S-71S.

6. Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia. 2004;47(3):357-366.

7. Fetner R, McGinty J, Russell C, Pi-Sunyer FX, Laferrère B. Incretins, diabetes, and bariatric surgery: a review. Surg Obes Rel Dis. 2005;1(6):589-597.

8. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29(1):46-52. http://www.ncbi.nlm.nih.gov/pubmed/3514343

9. Rosa G, Mingrone G, Manco M, et al. Molecular mechanisms of diabetes reversibility after bariatric surgery. Int J Obes (Lond). 2007;31(9):1429-1436.  http://www.ncbi.nlm.nih.gov/pubmed/17515913

10. Schauer PR, Burguera B, Ikramuddin S, et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003;238(4):467-84.

11. Rubino F, Gagner M, Gentileschi P, et al. The early effect of the Roux-en Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg. 2004;240(2):236-242.

12. Pories WJ, Albrecht RJ. Etiology of type II diabetes mellitus: role of the foregut. World J Surg. 2001;25(4):527-531.  http://www.ncbi.nlm.nih.gov/pubmed/11344408

13. Guidone C, Manco M, Valera-Mora E, et al. Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Diabetes. 2006;55(7):2025-2031.

14. Patriti A, Aisa MC, Annetti C, et al. How the hindgut can cure type 2 diabetes. Ileal transposition improves glucose metabolism and beta-cell function in Goto-kakizaki rats through an enhanced Proglucagon gene expression and L-cell number. Surgery. 2007;142(1):74-85.  https://www.ncbi.nlm.nih.gov/m/pubmed/17630003/?i=2&from=/16259883/related

15. Patriti A, Facchiano E, Sanna A, Gulla N, Donini A. The enteroinsular axis and the recovery from type 2 diabetes after bariatric surgery. Obes Surg. 2004;14(6):840-848.

16. Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244(5):741-749.

White Coat Hypertension: Are Doctors Bad for Your Blood Pressure?

March 20, 2013

By Lauren Foster

Faculty Peer Reviewed

Hypertension is a pervasive chronic disease affecting approximately 65 million adults in the United States, and a significant cause of morbidity and mortality [1]. Antihypertensives are widely prescribed due to their effectiveness in lowering blood pressure, thereby reducing the risk of cardiovascular events. However, the phenomenon of the “white coat effect” may be a complicating factor in the diagnosis and management of hypertensive patients. It is well established that a considerable number of people experience an elevation of their blood pressure in the office setting, and particularly when measured by a physician. The cause of this white coat hypertension, as well as its implications in the prognosis and treatment of hypertension, is still controversial.

The concept of white coat hypertension has existed for many years, with some of the first reports of blood pressure varying between a resting value and one taken by the physician written by Alam and Smirk in the 1930s [2]. Studies since then have continued to demonstrate the elevating effect of a physician’s office on blood pressure, with an estimated 20% prevalence of white coat hypertension in the general population [3]. The definition of white coat hypertension used in research continues to vary, however, producing a range of incidences from 14.7% to 59.6% [3]. Most studies characterize white coat hypertension as an office blood pressure of greater than 140/90 mmHg, with ambulatory blood pressures less than 135/85 [3]. The regular use of home blood pressure monitors and 24-hour ambulatory blood pressure monitoring (ABPM) has further demonstrated this discrepancy in clinical practice as well as in research.

White coat hypertension is hypothesized to be a result of anxiety and subsequent sympathic nervous system activation. Studies examining the presence of white coat hypertension among individuals with anxious traits have not found evidence of this association; rather it appears to be associated with a state of anxiety unique to the presence of a physician [5]. In a study by Gerin, Ogedegbe, and colleagues, ABPM measurements of patients’ blood pressure in a separate laboratory facility were compared to ABPM measurements in the waiting room of a physician’s office and a manual blood pressure performed by a physician in the examining room. Their results demonstrated a significant elevation of blood pressure on the day of the physician’s office visit, with a larger increase in previously diagnosed hypertensive patients, and no difference in blood pressure between the waiting room and the examining room [2]. This provides evidence for the notion that white coat hypertension is the result of a classically conditioned response to a physician’s office. That this occurred more often in patients with previously established hypertension may be due to an initial anxiety reaction as patients learn they have hypertension, which is further conditioned by the following office visits to check their blood pressure control [2].

The effect of isolated white coat hypertension on cardiovascular risk has been controversial. One study examining the target organ damage of hypertension in terms of left ventricular mass and carotid-femoral pulse wave velocity found a positive correlation with daytime blood pressure values, but not with those who had elevated office blood pressures alone [6]. A recent meta-analysis likewise showed that cardiovascular risk is not significantly different between white coat hypertension and normotension [7]. However, another study by Gustavsen and colleagues evaluating the rate of cardiovascular deaths and nonfatal events over a 10-year follow-up period found that patients with white coat hypertension and essential hypertension had similar event rates, but normotensive patients had significantly lower rates [8]. In contrast, a different study determined that the unadjusted rate of all-cause mortality in patients with white coat hypertension (4.4 deaths per 1,000 years of follow-up) was less than patients with sustained hypertension (10.2 deaths per 1,000 years of follow-up), and that this was clinically significant after adjusting for age, sex, smoking, and use of antihypertensive medication [9]. The effect of isolated white coat hypertension on cardiovascular risk still needs further investigation to determine the necessity of treating it with antihypertensives.

As hypertension is routinely diagnosed by the blood pressure measurements obtained by a physician in an office setting, it is likely that a significant portion of white coat hypertension is treated with antihypertensives. In the study by Gustavsen and colleagues, they noted that 60.3% of patients with white coat hypertension were treated with antihypertensives at some point during the 10-year follow-up [8]. In the Treatment of Hypertension Based on Home or Office Blood Pressure (THOP) trial, antihypertensive treatment was adjusted based on either self-measured home blood pressure values or conventional office measurements. At the end of the 6-month period, less intensive drug treatment was used for the home blood pressure group as opposed to those measured in an office, and more home blood pressure patients could permanently stop antihypertensive drug treatment (25.6% vs. 11.3%). However, those treated based on home blood pressure measurements had slightly higher blood pressures at the end of the trial than those treated in the office, which could potentially increase cardiovascular risk [10]. Evaluating whether a patient has sustained hypertension or white coat hypertension with normotensive ambulatory blood pressure using home devices or ABPM may help to identify those who do in fact require antihypertensive medications.

White coat hypertension may also play a role in cases of resistant hypertension. ABPM may be necessary to differentiate cases of true drug-resistant hypertension and those that are well controlled outside of the physician’s office in order to prevent overtreatment. One study found that when patients who were documented to have uncontrolled hypertension had their blood pressure monitored for 24 hours, only 69% were actually uncontrolled [11]. Studies have also looked for other ways to differentiate true resistant hypertension and white-coat resistant hypertension, and have determined that true resistant hypertension patients have excessive intake of salt and alcohol as well as higher renin values [12].

In clinical practice, white coat hypertension is likely a common confounding factor in the diagnosis and treatment of hypertension. Patients often insist that their blood pressure is much lower at home than at their office visit, and the anxiety of an appointment solely for a blood pressure check is likely a contributing factor. Shifts away from physician measurement of blood pressure or substitution with automatic blood pressure devices may help to counteract this phenomenon. Home blood pressure monitoring devices can be a useful tool in discerning whether a patient’s blood pressure is properly controlled on a current treatment regimen or if additional therapy is needed. Avoiding overtreatment of hypertension may also lower health care costs, although the cardiovascular risks of white coat hypertension must be further elucidated so that the importance of treating white coat hypertension can be determined. White coat hypertension is a real and ubiquitous phenomenon, and must be considered by physicians for all patients with elevated blood pressures.

Commentary by Dr. Stephen Kayode Williams

Attending Physician, Bellevue Primary Care Hypertension Clinic

Are doctors bad for your blood pressure? Yes! This is a timely discussion as we eagerly await updated national guidelines for the management of hypertension. How will JNC 8 address this issue that comes up at every visit to our primary care clinics? The latest US hypertension guidelines were published in 2003 [13]. The more recent 2011 UK guidelines are remarkable in stating that in order to confirm a new diagnosis of hypertension, ambulatory blood pressure monitoring (or alternatively home blood pressure monitoring) should demonstrate daytime blood pressures greater than or equal to 135/85 mmHg [14] . An exhaustive cost-effectiveness analysis performed for these guidelines came to the conclusion that, despite the expenses incurred with ambulatory blood pressure monitoring, there are vast cost savings that come with the prevention of an erroneous diagnosis of hypertension using office blood pressure readings alone. In this country, ambulatory blood pressure monitoring is not widely available in primary care. Stayed tuned to see how the upcoming hypertension guidelines address these clinical correlations.

Lauren Foster is a 4th year medical student at NYU School of Medicine

Peer reviewed by Stephen Kayode Williams, MD, MS, Bellevue Primary Care Hypersion Clinic

Image courtesy of Wikimedia Commons


1. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension. 2004;44(4):398-404.  http://www.ncbi.nlm.nih.gov/pubmed/15326093

2. Gerin W, Ogedegbe G, Schwartz JE, et al. Assessment of the white-coat effect. J Hypertens. 2006;24(1):67-74.

3. Pickering TG. White coat hypertension. Curr Opin Nephrol Hypertens. 1996;5(2):192-198.  http://circ.ahajournals.org/content/98/18/1834.full

4. Verdecchia P, Schillaci G, Boldrini F, Zampi I, Porcellati C. Variability between current definitions of ‘normal’ ambulatory blood pressure. Implications in the assessment of white coat hypertension. Hypertension. 1992;20(4):555-562.

5. Ogedegbe G, Pickering TG, Clemow L, et al. The misdiagnosis of hypertension: the role of patient anxiety. Arch Intern Med. 2008;168(22):2459-2465. http://archinte.jamanetwork.com/article.aspx?articleid=773457

6. Silveira A, Mesquita A, Maldonado J, Silva JA, Polonia J. White coat effect in treated and untreated patients with high office blood pressure. Relationship with pulse wave velocity and left ventricular mass index. Rev Port Cardiol. 2002;21(5):517-530.

7. Pierdomenico SD, Cuccurullo F. Prognostic value of white-coat and masked hypertension diagnosed by ambulatory monitoring in initially untreated subjects: an updated meta analysis. Am J Hypertens. 2011;24(1):52-58.  http://ajh.oxfordjournals.org/content/24/1/52.abstract

8. Gustavsen PH, Høegholm A, Bang LE, Kristensen KS. White coat hypertension is a cardiovascular risk factor: a 10-year follow-up study. J Hum Hypertens. 2003;17(12):811-817.

9. Dawes MG, Bartlett G, Coats AJ, Juszczak E. Comparing the effects of white coat hypertension and sustained hypertension on mortality in a UK primary care setting. Ann Fam Med. 2008;6(5):390-396.  http://www.annfammed.org/content/6/5/390.full.pdf

10. Den Hond E, Staessen JA, Celis H, et al. Treatment of Hypertension Based on Home or Office Blood Pressure (THOP) Trial Investigators. Antihypertensive treatment based on home or office blood pressure–the THOP trial. Blood Press Monit. 2004;9(6):311-314.

11. Godwin M, Delva D, Seguin R, et al. Relationship between blood pressure measurements recorded on patients’ charts in family physicians’ offices and subsequent 24 hour ambulatory blood pressure monitoring. BMC Cardiovasc Disord. 2004;4:2.  http://www.biomedcentral.com/1471-2261/4/2/

12. Veglio F, Rabbia F, Riva P, et al. Ambulatory blood pressure monitoring and clinical characteristics of the true and white-coat resistant hypertension. Clin Exp Hypertens. 2001;23(3):203-211.

13. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.  http://www.ncbi.nlm.nih.gov/pubmed/12748199

14. Krause T, Lovibond K, Caulfield M, McCormack T, Williams B. Management of hypertension: summary of NICE guidance. BMJ. 2011;343:d4891.  http://www.bmj.com/content/343/bmj.d4891?tab=responses

What Is Andropause? Is Testosterone Supplementation the Answer in Older Men?

September 20, 2012

By Kylie Birnbaum

Faculty Peer Reviewed

Women have long bemoaned menopause and its physiological, psychological, and sexual effects. Fortunately, hormone replacement therapy has provided relief for symptomatic women. Less attention is paid to men, who also experience declines in their sex hormones. Decreased testosterone may explain many symptoms experienced by elderly men, such as poor sexual function and libido, decreased bone mineral density, fatigue, and decreased muscle mass and strength. Should physicians treat elderly men with testosterone replacement therapy?

Late-onset hypogonadism, or “andropause,” is the gradual decline in testosterone levels in aging men. It differs from menopause in that it is a gradual process with a constant rate of androgen decline over decades, rather than years. Hypogonadism is defined as serum levels less than 280-300 ng/dL for total testosterone and 5-9 ng/dL for free testosterone, the lower limits of normal in healthy young men.[1] Total testosterone (T) declines gradually with age at a relatively constant rate of 1-2% (3.2 ng/dL) per year, beginning in men’s 20s.[2] Free T declines more rapidly than total T owing to an increase in sex hormone binding globulin (SHBG) with age. Declining levels of T with age are independent of other variables that are associated with low T, such as obesity, chronic illness, and chronic alcohol use.[2] Of men older than 80 years old, 90% have free testosterone levels in the hypogondal range (less than 5 ng/dL) and 50% have total testosterone in the hypogonadal range (less than 320 ng/dL).[2]

Primary hypogonadism is a result of testicular insufficiency, while secondary hypogonadism is a central problem arising from the hypothalamus or pituitary gland. Primary pathology presents with low testosterone and high levels of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Central hypogonadism is characterized by both low gonadotropins and testosterone.

Men with late-onset hypogonadism have increased FSH and LH; however these values are not high enough to indicate a primary (testicular) etiology alone.[3] Instead, late-onset hypogonadism is attributed to both testicular and hypothalamic-pituitary dysfunction. Although we know that testosterone declines with age, much is still unconfirmed as to its nature—is this decline physiologic or pathologic?

Testosterone is known to have widespread effects on tissues throughout the body, including bone, muscle, bone marrow, brain, skin, hair, prostate, and external genitalia. Frank hypogonadism due to known testicular or pituitary disease causes decreases in libido, bone density, muscle mass and strength, and energy. Yet it remains unclear whether low T in elderly men has a physiologic benefit, and if replacement may exacerbate testosterone-dependent diseases such as prostate cancer, benign prostatic hyperplasia, erythrocytosis, and sleep apnea.

Testosterone deficiency has been associated with many symptoms in sexual, physical, and psychological domains, but most data on associated symptoms in elderly men are varied. A recent cross-sectional study examined 32 of these broad domains and concluded that only sexual symptoms have a strong association with decreasing T levels.[4] These authors propose that at least 3 sexual symptoms–decreased frequency of morning erection, erectile dysfunction, and decreased frequency of sexual thoughts–are a necessary component for diagnosis.[4]

To diagnose androgen deficiency, patients must have symptoms and low serum testosterone. Testosterone levels vary throughout the day and are most reliably measured in the morning when they are highest. Levels should be confirmed with a repeat measurement. Total and free T levels should be obtained in older men, since there is often SHBG alteration with age and comorbid conditions (diabetes, obesity, cirrhosis, and HIV).[1] LH should be measured when low T is confirmed to assess for secondary hypogonadism, which, if indicated by a low LH value, should be worked up separately. Only after confirming hypogonadism due to age with clinically significant symptoms should patients begin to consider treatment.

The lack of high-quality, longitudinal, randomized trials assessing long-term effects of testosterone replacement therapy has led to disagreement among experts over treatment guidelines. The 2010 clinical practice guideline by the Endocrine Society recommends against general T replacement in older men with low T levels. Treatment should be discussed on an individual basis, and patients should have both clinically significant symptoms and confirmed low T levels. Some experts advise therapy when the total T level in symptomatic men is less than 280 ng/dL whereas others advise a more conservative approach, treating at a level of less than 200 ng/dL.[1]

Current data from both longitudinal and cross-sectional studies reveal inconsistent and imprecise results for benefits in bone mineral density, physical function, sexual function, depression, cognition, and quality of life. Replacement in older men is associated with an increase in lean body mass and reduction in fat mass, as well as a modest trend toward increased bone density, but there is no clear evidence for improved libido, cognition, depression, or energy.[5]

Patients and providers must be aware of the risks of T therapy. A 2010 randomized placebo-controlled trial of the effect of testosterone gel on muscle mass and strength in 209 elderly men (half of whom had pre-existing cardiac disease) was terminated early due to increased cardiovascular events in the treatment group.[7] Studies have brought to light additional adverse effects associated with testosterone replacement, such as increased hemoglobin and hematocrit, decreased HDL cholesterol, and a higher rate of prostatic events in treated groups versus placebo groups.[6,7]

Patients must be made aware of the risks and benefits of testosterone therapy, as elderly men with low testosterone may have higher risks for cardiac and prostatic disease while on T therapy.[6,7] Additionally, before initiation of therapy patients should be screened for testosterone-dependent disease with a digital rectal exam, PSA, and hematocrit measurements. If treatment is initiated, serum T levels should be monitored with a target T level of the lower limit of normal for young men (400-500 ng/dL) to decrease the risk of testosterone-associated adverse effects. These patients should continue to be monitored for prostate disease throughout treatment.[1]

Kylie Birnbaum is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Robert Lind, MD, Medicine (Endocrinology), NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Bhasin S, Cunningham GR, Hayes FJ, et al; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559. http://www.ncbi.nlm.nih.gov/pubmed/16720669

2. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR; Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab. 2001;86(2):724-731. http://www.ncbi.nlm.nih.gov/pubmed/11158037

3. Morley JE, Kaiser FE, Perry HM 3rd, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-simulating hormone in healthy older men. Metabolism. 1997;46(4):410-413.  http://www.ncbi.nlm.nih.gov/pubmed/9109845

4. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123-135.

5. Snyder PJ. Hypogonadism in elderly men–what to do until the evidence comes. N Engl J Med. 2004;350(5):440-442.  http://www.ncbi.nlm.nih.gov/pubmed/14749451

6. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005;60(11):1451-1457.  http://jcem.endojournals.org/content/95/6/2560.long

7. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122.  http://www.ncbi.nlm.nih.gov/pubmed/20592293

A Study of Cultural Complications in the Management of Diabetes

April 18, 2012

By Kimberly Jean Atiyeh

Faculty Peer Reviewed

Ms. KS is a 49- year-old Bangladeshi woman with a history of diabetes mellitus and non-adherence to medical treatment or follow up, who was reluctantly brought to the Bellevue ER by her family for nausea, vomiting, and fevers for one day. Her most recent hospitalization was 9 months prior for epigastric discomfort in the setting of uncontrolled diabetes with a hemoglobin A1C of 12.4%. On arrival, her physical exam was significant for tachypnea, tachycardia, and dry mucus membranes. Her labs revealed hyponatremia, severe hyperglycemia, metabolic acidosis, and prerenal azotemia. She was diagnosed with hyperosmolar hyperglycemic nonketotic syndrome and treated with fluid replacement and IV insulin.

Diabetes is a rapidly growing, deadly, and costly epidemic. One in every 12 New Yorkers has diabetes now and the number will double by 2050. It is the sixth most common cause of death, and one of every five U.S. federal health care dollars is spent on treating people with diabetes [1]. Most health care workers know about the medical challenges associated with diabetic patients, but the social and cultural dilemmas are not as well characterized. Ms. KS’s case was a paragon of anthropologic complexity. She spoke Bengali, but refused to use the translator phone, insisting on only using her son as a translator. She avoided contact with the medical team—her son confirmed that she was extremely anxious in a hospital setting and generally avoided doctors. Furthermore, she adamantly protested any blood draws or IVs, as she believed that taking her blood was equivalent to “taking her energy”. While well-known complications of diabetes may include neuropathy, renal disease, and retinopathy, Ms. KS’s case was complicated by generalized distrust of Western medicine and non-adherence to medical advice. While it is entirely possible that her distrust, anxiety, and beliefs are purely personal, her case is a valuable opportunity to learn more about Bangladeshi-American culture and to explore how cultural background can influence healthcare, both at home and in the hospital.

Records of small numbers of Bangladeshi immigrants to the US trace back to the 1880s, but the 2000 US Census estimates a Bangladeshi-American population of over 140,000 [2]. This increase in Bangladeshi population was primarily a result of a major influx of immigrants during the 1990s, which is not surprisingly when Ms. KS’s family immigrated to America. During this decade, the Bangladeshi population grew by over 450% [2]. There are dense communities of Bangladeshi people in New York City, Los Angeles, Miami, Washington D.C., Atlanta, and Dallas. Limited English proficiency is quite common among this population. 65% of working-age Bangladeshi New Yorkers and 83% of Bangladeshi senior citizens speak limited English [3]. These numbers are markedly elevated compared to the city-wide averages of 25% and 27% adults and senior citizens respectively. Although English is a common second language in Bangladesh, some anthropological readings suggest that many immigrants may speak primarily Bengali as a means of maintaining cultural identity [4]. Ms. KS refused to use a medical translator, but these services are fortunately becoming increasingly available. However, financial strains remain a common obstacle to healthcare, especially in Bangladeshi patients. Census data indicates that Bangladeshi populations in New York City on average have incomes of less than half of the city-wide averages and are 50% more likely to live in poverty [3]. Based on this data, Ms. KS’s limited English proficiency is not surprising even though she has lived here for many years. She is also more likely to have financial hardships than the average New Yorker, possibly requiring the help of a social worker.

An interesting article published in the British Medical Journal in 1998 provides insight into Bangladeshi beliefs in the context of Western medicine. This qualitative study used narratives, semi-structured interviews, focus groups, and pile sorting exercises to explore the influence of cultural background on 40 British Bangladeshi diabetic patients as compared with 10 non-Bangladeshi controls. The study explores important aspects of diabetes education and management and reveals that there are some interesting similarities and differences between the Bangladeshi population as compared to non-Bangladeshis:

Body Concept/Exercise. When asked to pick out images of “healthy-appearing” individuals, Bangladeshi subjects were more likely to select those of a larger body habitus, correlating size with strength. This correlation only held to a certain extent though, with morbidly obese patients being identified as less healthy [5]. Although most subjects acknowledged that they had been given advice to exercise, this advice appeared to have little cultural meaning. Some viewed exercise as a cause for illness exacerbation. Notably, some dialects of Bengali do not even have a word for “exercise” [5]. Sports and games are infrequent among adults in Bangladesh [6]. This information suggests that physicians should steer clear of advising Bangladeshi patients to “lose weight” and “exercise”. Rather, the emphasis should be placed on an active lifestyle, the significance of visceral fat, and replacing fat with muscle.

Diet/nutrition. When asked to sort foods as health or unhealthy, Bangladeshi subjects most commonly picked foods perceived to provide the most energy and strength as “healthy”, including white sugar, lamb, beef, solid fat, and spices. Interestingly, raw, baked, and grilled foods were largely considered “indigestible” and “unsuitable” for elderly, debilitated, or young people [5]. A common nutritional recommendation to bake or grill foods rather than fry them may therefore be seen as discordant with cultural dietary perceptions. Although time-saving, broad generalizations in dietary advice may be less successful and should be replaced by customized meal plans in accordance with both the diabetic diet and cultural beliefs. Furthermore, the impact of snacks on glycemic control should be directly addressed with Bangladeshi patients. 18 out of 18 study participants were in favor of eating snacks between meals to “sustain strength”. Only 5 of these 18 subjects thought snacks could cause any harm [5]. Ms. KS commonly snacked throughout the day, and although a diabetic diet was delivered to her for each meal, she never ate the prescribed diet and instead chose to eat food that her family brought, which commonly featured beef and white rice. Ms. KS is a perfect example of how cultural preferences and perceptions of food may make diabetes difficult to control.

Diabetic monitoring. Most patients in this study reported that they monitored glucose levels as instructed by their doctors; however understanding of the importance of surveillance was limited. Most Bangladeshi patients believed that a lack of symptoms implied health and well-controlled diabetes. They did not see a need to visit a doctor if they were feeling well [5]. This appeared to be the case for Ms. KS—she had a glucometer at home but reported rarely using it and her only visits to a medical professional were in an emergency setting. For patients like her, repeated education about routine glucose testing and preventative care visits to primary care, podiatry, and ophthalmology clinics cannot be stressed enough.

While these study results provide interesting insights, it should be acknowledged that no scientific or anthropological studies of Bangladeshi culture can be uniformly applied to all Bangladeshis, nor should cultural beliefs be considered static. However, they can be invaluable as a basis for culturally sensitive diabetes education. A thorough interview of future diabetic Bangladeshi patients includes questions about the patient’s beliefs regarding the cause and treatment of diabetes, the role of exercise, and attempts at reconciliation of the patient’s traditional diet with the diabetic diet. While the statistics and beliefs identified in this discussion are targeted toward the Bangladeshi population, the information can be conceptually extended to patients of other cultural backgrounds. Ms. KS’s past history of medical non-adherence and poor glycemic control may indicate that her future care could be difficult, but given her unique background, her case was also an opportunity for cultural sensitivity to prevail over differences in beliefs.

Kimberly Jean Atiyeh is a student at NYU School of Medicine

Peer reviewed by Val Perel, MD, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. New York State Department of Health. Information for a Healthy New York: Diabetes. www.health.state.ny.us.   2010.

2. U.S Census Bureau. American Community Survey. American FactFinder. 2007. Factfinder.census.gov.  http://factfinder2.census.gov/legacy/aff_sunset.html

3. Asian American Federation of New York. Census Profile: New York City’s Bangladeshi American Population. Asian American Federation of New York Census Information Center. 2005. www.aafny.org

4. Jones J. Bangladeshi Americans. Countries and Their Cultures. Everyculture.com.  Accessed September 26, 2010.

5. Greenhalgh T, Helman C, Chowdhury A. Health beliefs and folk models of diabetes in British Bangladeshis: a qualitative study. Brit Med J. 1998. 316:978. http://www.bmj.com/content/316/7136/978.abstract

6. Chowdhury A. Household kin and community in a Bangladesh village. Exeter: University of Exeter. 1986.

Obesity 2.0: More Than Just the Extra Weight

February 9, 2012

By Aviva Regev

Faculty Peer Reviewed


Few people these days are unaware of the “obesity epidemic,” with its inception here in the United States and its steady, insidious spread around the globe. The numbers are truly staggering: in 2008, the World Health Organization estimated that 1.5 billion adults–over 20% of the earth’s population–were overweight, and 500 million of those were classified as obese, with a body mass index greater than 30.[1] In the United States, over a third of the population is overweight, and another third is obese.[2] Perhaps most concerning is that children are affected as well: 18% of adolescents ages 12-19, 20% of children ages 6-11, and 10% of children ages 2-5 were considered obese.[2] The numbers are trending steadily up (for a visual representation of obesity in the US from 1985-2010, see the Centers for Disease Control and Prevention website).[3]

Of course, there is more to the problem than just expanding waistlines. Most people are also familiar with some of the major health problems associated with obesity: diabetes, cardiovascular disease, and cancer.[4] Add to those heavy hitters the sleep apnea, liver and gallbladder disease, osteoarthritis, stroke, and gynecological dysfunction, and we have a disease that affects every organ, spreading across the globe.

That obesity contributes to this plethora of disease is well known, but how? What is the common pathway linking excess weight to this wide range of ailments? The answer, it seems, is inflammation.

Excess adipose tissue and inflammation

Adipose tissue, it seems, is not just inert fat. In the setting of obesity, adipose tissue produces numerous inflammatory cytokines and hormones that it does not produce in “healthy weight” individuals. Why does this occur? One theory proposes that the excess nutrients lead to a state of endoplasmic reticulum (ER) stress, which activates an inflammatory cascade.[5] In other words, the processing machinery is so overwhelmed by the amount of raw materials pouring in that it sounds an alarm signal. As the fat mass increases, adipose cells become relatively hypoxic. The presence of hypoxia activates inflammatory pathways and also contributes to the ER inflammatory response.[6] Finally, the excess nutrients themselves can stimulate other immune players such as toll-like receptors, which are usually triggered by microbial pathogens and activate cellular immune responses. It is likely that all three of these pathways play a role in the chronic inflammatory state seen in obesity, and may even act synergistically.

Once these cascades get going, an impressive variety of cytokines and immune cells appear to play a role. Obese adipose tissue has been shown to produce tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6), macrophage chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and leptin [6], all of which contribute to inflammation. The activation of the c-jun terminal kinase (JNK) stress pathway and the transcription factor NF-B stimulates further production of these molecules.[7] The immune function of obese adipose tissue is also different from that of lean adipose tissue, in that obese tissue has a higher proportion of pro-inflammatory T cells which secrete interferon-gamma (IFN-), best known for its role in activating the immune system against viral or bacterial invaders.[8] Adipocytes themselves can function as phagocytic cells, and their immune function is so robust that “it is challenging to find exceptions to [the] functional and molecular overlap between fat cells and macrophages.”[9]

Why is the inflammatory cascade in obese adipose tissue allowed to continue uninhibited? There are fewer anti-inflammatory T-regulatory cells in obese tissue, which may help explain why the immune response in adipose tissue is not controlled the way an inappropriate inflammatory response normally would be.[10] Another factor contributing to this unchecked response is a relative deficiency in adiponectin, a cytokine secreted by adipose tissue. Adiponectin has anti-inflammatory and antiatherogenic properties and is found in lower levels in obese individuals.[6] Many of the cytokines activated in individual over-expanded adipocytes also act in a paracrine fashion, activating the inflammatory response in other nearby cells, and may find their way into the bloodstream, where they can have an effect on a systemic level.

Insulin Resistance

The development of insulin resistance as a result of chronic inflammation is due to a complex interplay of the pathways discussed above. TNF- was one of the first culprits identified [11], but it is not a solitary player.[12] While the exact mechanism of insulin resistance in obesity is yet to be elucidated, recent trials have evaluated whether anti-inflammatory drugs may decrease insulin resistance in type 2 diabetics. Data on whether TNF- blockade with infliximab or etanercept increases insulin sensitivity and reduces fasting blood sugar are equivocal, with some studies reporting a beneficial effect [13,14] and others reporting none.[15]

Interestingly, reduction in glycosuria with high doses of salicylates was reported over a century ago [12], though not pursued further. A study published in 2008 evaluated high-dose salsalate, a salicylate that does not have gastric toxicity, in patients with type 2 diabetes. A dose-dependent reduction in fasting blood sugars, increase in insulin levels, and decrease in C-peptide levels were observed. The higher insulin levels coupled with lower C-peptide levels suggest reduced insulin clearance as well as decreased insulin secretion, indicating an improvement in insulin sensitivity.[7] Free fatty acid levels and C-reactive protein (CRP), were also decreased at higher doses, though tinnitus was sometimes a limiting factor in the dosing. These small studies show promise, and warrant further evaluation into anti-inflammatory therapy for insulin resistance and type 2 diabetes.

Cardiovascular Disease

As with insulin resistance, no discrete molecule or pathway is responsible for cardiovascular disease in obesity. Insulin resistance, dyslipidemia, and hypertension are all more common in obese individuals and appear to be independent risk factors for cardiovascular morbidity.[6] On top of this, the activation of IL-6 and TNF- as well as high levels of leptin and low levels of adiponectin may contribute to oxidative stress and endothelial dysfunction, the inciting step in atherogenesis.[6] A meta-analysis of over 160,000 patients demonstrated a linear association between CRP and vascular and non-vascular mortality in people without a history of vascular disease [16], and numerous studies have found elevated CRP to be an independent risk factor for cardiovascular mortality even in apparently healthy adults.[17] Statins, well known for lowering LDL and reducing mortality risk from myocardial infarction and stroke, also exhibit anti-inflammatory properties. In the JUPITER trial, rosuvastatin was found to reduce the risk of cardiovascular mortality in healthy adults with elevated CRP and without hyperlipidemia [18], demonstrating that part of the mortality benefit associated with statin use is related to anti-inflammatory properties and not solely lipid-lowering effects. Increased CRP is likely a marker of inflammatory activation and not a causal factor in excess risk [19], but may be useful in risk stratifying obese individuals and adjusting therapeutic goals.


Excess weight is a known risk factor for cancer mortality, especially from non-Hodgkin’s lymphoma; multiple myeloma; and gastrointestinal, renal, prostate, breast, and gynecological cancers. In a prospective study of 900,000 US adults, obesity was found to be responsible for up to 14% of cancer deaths in men and 20% in women.[20] Based on these results, the authors determined that over 90,000 annual cancer deaths could be prevented “if men and women could maintain normal weight.”

How does inflammation factor in to the cancer risk? The inflammatory mediators TNF- and IL-6 are well-known culprits in cancer. TNF- is thought to play a role in tumor initiation, angiogenesis, and metastasis, and is associated with multiple myeloma, bladder, liver, gastric, colon, and breast cancers.[21] IL-6, which may contribute more to tumor progression than initiation, is known for its role in Kaposi’s sarcoma, multiple myeloma, Hodgkin’s lymphoma, and colon cancer.[21]

Some of the hormones that are overproduced in obesity have been implicated in carcinogenesis as well. Leptin, for example, has a proliferative effect on esophageal, breast, and prostate cancers.[22] Insulin excess has a proliferative effect through stimulation of insulin-like growth factor-1 (IGF-1), and contributes to increased risk for colorectal, kidney, breast, endometrial, and prostate cancers.[22] Leptin and IGF-1 have a synergistic effect on growth, migration, and invasion of breast cancer cells [23], and IGF-1 independently contributes to colon and pancreatic cancer growth.[22]


As the concept of obesity as an inflammatory disease continues to be explored, new treatments for its myriad health consequences may become available, including immunomodulatory or anti-inflammatory regimens. Weight loss leads to a reduction in a multitude of inflammatory markers elevated in obesity, including IL-6, CRP, TNF-, and many others.[24] This effect may be responsible for the reduction in morbidity seen following weight loss either through lifestyle changes or bariatric surgery. Even with these advances, the medical community and the public should not forget that obesity is largely preventable, if individuals, policy makers, the food industry, and society as a whole work together to fight it. With 2.8 million deaths a year as well as 44% of diabetes, 23% of ischemic heart disease, and up to 40% of certain cancers due to overweight or obesity [1] and annual health care costs estimated at $147 billion for 2008 [25], it is worth the effort. If this were a virus, so deadly, so widespread, so costly, and so preventable, would we be doing more to stop it?

Aviva Regev is a 4th year medical student at NYU Langone Medical Center

Peer reviewed by Michelle McMacken, MD, Medicine (GIM), NYU Langone Medical Center

Images courtesy of Wikimedia Commons


1. World Health Organization. Obesity and overweight. http://www.who.int/mediacentre/factsheets/fs311/en/ .  Updated March 2011. Accessed September 15, 2011.

2. Centers for Disease Control and Prevention. Faststats: obesity and overweight. http://www.cdc.gov/nchs/fastats/overwt.htm.  Updated June 18, 2010. Accessed September 15, 2011.

3. Centers for Disease Control and Prevention. Overweight and obesity: U.S. Obesity Trends. http://www.cdc.gov/obesity/data/trends.html.  Updated July 21, 2011. Accessed September 15, 2011.

4. Haslam DW, James WP. Obesity. Lancet. 2005;366(9492):1197-1209.

5. Hummasti S, Hotamisligil GS. Endoplasmic reticulum stress and inflammation in obesity and diabetes. Circ Res. 2010;107(5):579-591.

6. Rocha VZ, Folco EJ. Inflammatory concepts of obesity. Int J Inflam. 2011;2011:529061. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151511/?tool=pubmed.  Epub 2011 Aug 3.

7. Goldfine AB, Silver R, Aldhahi W, et al. Use of salsalate to target inflammation in the treatment of insulin resistance in type 2 diabetes. Clin Transl Sci. 2008;1(1):36-43.

8. Kintscher U, Hartge M, Hess K, et al. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler Thromb Vasc Biol. 2008;28(7):1304-1310.

9. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112(12):1785-1788.

10. Feuerer M, Herrero L, Cipolletta D, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009;15(8):930–939.

11. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87-91.

12. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116(7):1793-1801.

13. Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, et al. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006;24(1):83-86.

14. Stanley TL, Zanni MV, Johnsen S, et al. TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab. 2011;96(1):E146-E150. Epub 2010 Nov 3.

15. Wascher TC, Lindeman JH, Sourij H, Kooistra T, Pacini G, Roden M. Chronic TNF-α neutralization does not improve insulin resistance or endothelial function in “healthy” men with metabolic syndrome. Mol Med. 2011;17(3-4):189-93.

16. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132-140.

17. Mora S, Ridker PM. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)–can C-reactive protein be used to target statin therapy in primary prevention? Am J Cardiol. 2006;97(2A):33A-41A.

18. Ridker P, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.

19. Keavney B. C reactive protein and the risk of cardiovascular disease. BMJ. 2011;342:d144.

20. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625-1638.

21. Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117(5):1175–1183.

22. Harvey AE, Lashinger LM, Hursting SD. The growing challenge of obesity and cancer: an inflammatory issue. Ann N Y Acad Sci. 2011;1229:45-52.

23. Saxena NK, Taliaferro-Smith L, Knight BB, et al. Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor. Cancer Res. 2008;68(23):9712–9722.

24. Cottam DR, Mattar SG, Barinas-Mitchell E, et al. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Obes Surg. 2004;14(5):589-600.

25. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health

When Is Hemoglobin A1c Inaccurate In Assessing Glycemic Control?

February 1, 2012

By Joseph Larese

Faculty Peer Reviewed

Hemoglobin A1C (HbA1c) is an invaluable tool for monitoring long-term glycemic control in diabetic patients. However, many clinicians managing diabetics have encountered the problem of HbA1c values that do not agree with fingerstick glucose logs. Before suspecting an improperly calibrated glucometer or poor patient record keeping, it is useful to consider the situations in which HbA1c may be spuriously elevated or depressed. These issues are best understood after reviewing how HbA1c is defined and measured–topics fraught with considerable confusion.

Glycosylation is a non-enzymatic, time-dependent chemical reaction in which glucose binds to the amino groups of proteins.[1] Historically, and long before its precise chemistry was discovered, glycosylated Hb was defined as an area of an elution chromatogram containing hemoglobin glycosylation products. This elution peak was labeled as HbA1, in keeping with the existing nomenclature (HbA, HbA2, HbF, etc. had been identified previously). Later it was recognized that the chromatographic HbA1 region is not homogeneous and consists of several component peaks, designated A1a, A1b and A1c, with HbA1c being the dominant one.[1] The HbA1c fraction also turned out to correlate best with mean serum glucose concentrations, ie, to be a better index of long-term glycemia.

Relatively recently HbA1c was redefined chemically: now glycohemoglobin refers to hemoglobin glycosylated at any of its amino groups, while HbA1c is defined as glycohemoglobin with glucose bound specifically to the terminal valine of the beta-globin chain. Consequently, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) has developed a standard reference method for HbA1c in which hemoglobin is cleaved with a specific peptidase into multiple oligopeptides, including a terminal hexapeptide containing the site of glycosylation in HbA1c. Glycosylated and non-glycosylated hexapeptides are separated by high-performance liquid chromatography (HPLC) and quantified. The ratio of concentrations of HbA1c to total Hb A is then reported.[2,3] All methods currently in use at NYU-affiliated hospitals are calibrated against that new IFCC standard.

Multiple epidemiologic studies and, most critically, the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) showed that HbA1c was a strong predictor of at least some forms of diabetes morbidity.[4,5] Based on that, HbA1c has been universally accepted not just as a measure of long-term glycemia, but as a clinically relevant surrogate measure of glycemic control. Consequently, an enormous (and impressively successful) international effort was undertaken to standardize all existing A1c assays so that their results can be referenced to the DCCT and UKPDS. However, both these trials measured HbA1c chromatographically. Compared to the modern reference standard these techniques overestimate HbA1c, as they detect various hemoglobin variants and non-HbA1c glycohemoglobins. Nonetheless, these two trials have formed the basis of HbA1c-based diabetes management, and in order to ensure historic continuity and interpretability, most of the HbA1c methods in current use (and all in use at NYU-affiliated hospitals) are back-referenced to DCCT “units.” For the most part, HbA1c of 7% in the UKPDS trial has the same meaning as HbA1c of 7% obtained on a patient in 2012.

A multitude of HbA1c assays employing a variety of methods are available commercially. All of them essentially are two tests packaged in one: serum HbA1c and HbA, with the ratio of the two being reported as A1c%. There are multiple conditions that interfere with one or both measurements: some are purely physiologic and are assay-independent, others depend on a particular test being used.

Physiologic “errors” occur when the average age of red blood cells is significantly altered and therefore the time that each molecule of HbA is exposed to blood glucose deviates from usual. Conditions that decrease mean erythrocyte age, such as recent transfusions or increased erythropoiesis secondary to hemolysis or blood loss, lower hemoglobin A1c[1,6,7], while those increasing mean erythrocyte age, such as asplenia, tend to increase HbA1c levels.[7] In all these instances, even if HbA1c itself is measured correctly, a given value of A1c% will correspond to a different average serum glucose concentration. Such “physiologic” errors do not depend on the particular assay used.

Because HbA1c is reported as a ratio of HbA1c to HbA, errors in either HbA1c or HbA measurement will cause spurious A1c% results. Most problems in HbA measurements occur when, instead of measuring HbA concentration directly, it is calculated from total hemoglobin. These calculations assume normal hemoglobin fractionation, and any condition in which HbA constitutes a smaller than normal fraction will affect the results. For example, in hereditary persistence of hemoglobin F, a calculation of HbA would overestimate HbA concentration. If absolute HbA1c concentration is measured accurately, the reported HbA1c% will be spuriously decreased.[1,8]

A particular HbA1c assay may not be sufficiently specific for HbA1c itself and may cross-react with either genetically determined hemoglobin variants or a chemically modified Hb species. Patients heterozygous for a variant hemoglobin, including hemoglobin S, C, E, and rarer variants can thus have falsely elevated or lowered glycohemoglobin results.[1,9,10] This is especially important to remember in diabetic patients of African, Mediterranean, or Southeast Asian descent, as these patient populations have a high incidence of these hemoglobin variants and because heterozygotes can be undiagnosed and asymptomatic.[11] The National Glycohemoglobin Standardization Program maintains an online spreadsheet of commercially available HbA1c assays, reporting interferences from each of the major hemoglobin variants and modified hemoglobins.[12] Information on the assays currently used at NYU-affiliated hospitals is provided in the table below.

In real patients, HbA1c measurements are affected by a complex combination of the above factors. For example, in patients with sickle cell trait, care must be taken to select an assay that does not cross-react with HbS or hemoglobin F. The lab should also measure, not calculate, the concentration of HbA. As the lifespan of erythrocytes is normal in sickle-cell trait, selection of an appropriate assay should produce valid HbA1c results.[1,13] In patients homozygous for a variant hemoglobin, such as patients with sickle cell anemia or hemoglobin C disease, hemolysis significantly shortens erythrocyte lifespan. Consequently, the fraction of terminally glycosylated variant hemoglobin measured by HbA1c assays in these patients is not a useful measure of glycemia in such patients, regardless of the assay used. Glycemic control in these patients must be assessed through other means (for example, by measuring serum fructosamine).

In diabetic patients with end-stage renal disease, erythrocyte lifespan tends to be decreased. This may result in part from iron deficiency anemia, recent transfusions, or other effects of kidney disease on erythrocyte survival. Uremic patients with blood urea nitrogen levels greater than about 85 mg/dL also develop significantly high levels of carbamylated hemoglobin, which interferes with some HbA1c assays.[14] In spite of these complications, HbA1c (measured with an assay that does not cross-react with carbamylated hemoglobin) has been shown to correlate well with average blood glucose levels in diabetic patients on hemodialysis, with questionably significant overestimation of average blood glucose for values of HbA1c greater than 7.5%.[15]

Other factors, such as chronic alcohol, opioid, and salicylate abuse and ingestion of large amounts of vitamin C and E have been reported to skew A1c results.[10,13,16] Given the lack of large studies, the sometimes contradictory conclusions of these reports, and the unclear mechanisms of these effects, it is impractical to dismiss A1c as invalid in all of these cases. However, knowing that these effects may exist can help guide decision-making in situations in which the index of suspicion for an inaccurate A1c is already high.

Since HbA1c measurement is ubiquitous, it seems advisable for providers to become familiar with factors affecting the test in general and the limitations of the assays offered in their laboratory in particular.

Hospital Assay in use at time of writing Is HbA1c spuriously affected by variant hemoglobin?
HbS HbC HbE HbD HbF Carbamylated Hb
Tisch Tosoh G7 variant analysis mode No Yes Yes No No (for <30%) No
Manhattan VA
Bellevue Quest Diagnostics Teterboro, NJ-Roche Tina-quant Hemoglobin A1c Gen 2 No No No No No data, but probably yes for >10-15% No
HbA1c Assay Interferences. National Glycohemoglobin Standardization Program Web site. http://www.ngsp.org/interf.asp. and http://www.ngsp.org/factors.asp Updated July 2013.  Accessed 1/11/2014

Joseph Larese is a 4th year medical student at NYU Langone medical Center

Peer reviewed by Gregory Mints, MD, Medicine (GIM div.), NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Little RR, Roberts WL. A review of variant hemoglobins interfering with hemoglobin A1c measurement. J Diabetes Sci Technol. 2009;3(3):446-451.

2. Jeppsson JO, Kobold U, International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Approved IFCC reference method for the measurement of HbA1c in human blood. Clin Chem Lab Med. 2002;40:78–89.

3. Hanas R, John G; International HBA1c Consensus Committee. 2010 consensus statement on the worldwide standardization of the hemoglobin A1C measurement. Diabetes Care. 2010;33(8):1903-1904.

4. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.

5. UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.

6. Factors that interfere with HbA1c test results. National Glycohemoglobin Standardization Program Web site. http://www.ngsp.org/factors.asp.  Updated April, 2010. Accessed September 19, 2010.

7. Panzer S, Drorik G, Lechner K, Bettelheim P, Neumann E, Dudezak R. Glycosylated hemoglobins (GHb): an index of red cell survival. Blood. 1982;59(6):1348–1350.

8. Rohlfing CL, Connolly SM, England JD, et al. The effect of elevated fetal hemoglobin on hemoglobin A1c results: five common hemoglobin A1c methods compared with the IFCC reference method. Am J Clin Pathol. 2008;129(5):811-814.

9. Little RR, Rohlfing CL, Hanson S, et al. Effects of hemoglobin (Hb) E and HbD traits on measurements of glycated Hb (HbA1c) by 23 methods. Clin Chem. 2008;54(8):1277-1282.

10. Sacks DB, Bruns DE, Goldstein DE, Maclaren NK, McDonald JM, Parrott M. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clinical Chemistry. 2002;48(3):436-472.

11. Sickle cell trait and other hemoglobinopathies and diabetes: important information for physicians. National Diabetes Information Clearinghouse (NDIC) Web site. http://diabetes.niddk.nih.gov/dm/pubs/hemovari-A1C/index.htm.  Published November 2008. Accessed September 19, 2010.

12. HbA1c assay interferences. National Glycohemoglobin Standardization Program Web site. http://www.ngsp.org/interf.asp.  Updated April 1, 2010. Accessed September 19, 2010.

13. Bunn FH, Forget BG. Hemoglobin: molecular, genetic and clinical aspects. Philadelphia, PA: WB Saunders Co; 1986:425-427.

14. Ansari A, Thomas S, Goldsmith D. Assessing glycemic control in patients with diabetes and end-stage renal failure. Am J Kidney Dis. 2003;41(3):523-531.

15. Joy MS, Cefalu WT, Hogan SL, Nachman PH. Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis. 2002;39(2):297-307.

16. Davie SJ, Gould BJ, Yudkin JS. Effects of vitamin C on glycosylation of proteins. Diabetes. 1992;41:167-173.

Male Hormonal Contraception

January 20, 2012

By Kaley Myer, Class of 2012

Faculty Peer Reviewed

As a female, I like the idea of males taking hormonal contraceptives. In a semi-sadistic way, I relish the idea of a man taking a pill every day to prevent impregnation of my gender. Traditionally, contraception has been a female responsibility, from diaphragms to oral contraceptive pills to intrauterine devices. Male condoms, coitus interruptus, and the more permanent vasectomy require male participation, but these methods do not dominate the contraceptive market. Indeed, couples are encouraged to go beyond condom use (which is often inconsistent) with a form of female birth control. Vasectomy is not advisable unless a man is certain that he does not desire future fertility. And coitus interruptus is ineffective at preventing pregnancy.

In 2006-8, the National Survey of Public Growth studied 61.8 million women of childbearing age (15-44 years old).[1] Sixty-two percent were using some form of contraception. The most common methods were…

Oral contraceptives – 28%

Tubal ligation – 27%

Condom – 16%

Vasectomy – 10%

Intrauterine device – 6%

Withdrawal – 5%

That the burden of birth control falls upon females is related to the female hormonal cycle and its production of a single egg per month, which is easily manipulated. Also, placing this burden on females just makes sense. If birth control fails, it is the woman who becomes pregnant, who experiences physical and psychological changes, and who must take time away from her life and career. A woman thus has more of a stake in taking control of her reproductive status and only creating a life when desired.

This thinking can be a bit unfair, however. There are males who take great responsibility for their reproductive potential and who, upon creating a life, care for the child with equal or greater zeal than their female counterparts. Shouldn’t these men have the same opportunity to control their ability to reproduce?

The problem that remains for these men is that they constantly produce millions of spermatozoa without variations in hormonal cycles. However, research in hormonal suppression of the male hypothalamic-pituitary axis has revealed a safe, reliable mechanism for inhibiting spermatogenesis while maintaining normal levels of blood gonadotropins. Testosterone alone reduces sperm counts, but not to levels low enough to prevent pregnancy reliably. Near-azospermia can be accomplished by combining oral medroxyprogesterone acetate and percutaneous testosterone (OMP/PT).[2]

An open-label, non-placebo-controlled French clinical trial of OMP/PT treated 35 men with normal spermiograms with progesterone 20 mg daily and testosterone 50-125 mg daily for up to 18 months.[3] At 3 months, 80% of the men had sperm counts less than 1 million per milliliter. Sperm counts returned to normal within months of stopping the regimen. The subjects cited a number of reasons for electing to participate, including adverse events with use of contraception and a desire to share the responsibility of contraceptive management.

The adverse effects OMP/PT are not yet completely known, but men may be attracted by the anabolic effects of testosterone on building lean muscle mass. However, similar to the worry with anabolic steroids, testicular volume can decrease due to the lack of spermatogenesis. This decrease is usually minimal and not reported by patients,[4] but the prospect may be unappealing to potential users. Other known side effects from supplemental testosterone include acne, hair loss, and gynecomastia. The frequency of these side effects with the testosterone in male contraception is not yet established.

OMP/PT seems promising, but one wonders how trusting our patients will be of this novel approach. Male sperm counts are reduced to near-zero levels, but are not zero. These levels are low enough for contraceptive efficacy,[3] but will they be adequate to gain the trust of the general population? Will females trust their reproductive fitness to their mates? To females, it can be unnerving to rely upon someone else in a matter as serious as reproduction. Indeed, one of the women in the Soufir clinical trial became pregnant due to her partner’s nonadherence to progesterone-testosterone.[3]

Also, do male patients want to take on this responsibility? They have long entrusted this duty to their female partners, and taking a medication every day can be a burden that leads to nonadherence. Testosterone is delivered not by a pill like female contraception, but via patches, gels, or injections, which are unappealing to some patients.

Still, increasing contraceptive options is inherently beneficial. Some couples desire male-initiated birth control for a variety of reasons, and it will be freeing for some women to trust the responsibility to someone else for a change. Other reversible methods of male contraception should be explored so that men, like women, have options.

Kaley Myer is a 4th year medical student at NYU School of Medicine

Peer reviewed by Robert Lind, MD, Assistant Professor Dept of Medicine (endocrine) and Orthopedic Surgery, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Mosher WD, Jones J. Use of contraception in the United States: 1982-2008. Data from the National Survey of Family Growth. Vital and Health Statistics, 2010, Series 23, No. 29.  http://www.cdc.gov/nchs/data/series/sr_23/sr23_029.pdf

2. Nieschlag E. Male hormonal contraception. Handb Exp Pharmacol. 2010;(198):197-223.  http://www.ncbi.nlm.nih.gov/pubmed/20839093

3. Soufir J-C, Meduri G, Ziyyat A. Spermatogenetic inhibition in men taking a combination of oral medroxyprogesterone acetate and percutaneous testosterone as a male contraceptive method. Hum Reprod. 2011;26(7):1708-1714.  http://humrep.oxfordjournals.org/content/26/7/1708.full

4. Ilani N, Swerdloff RS, Wang C. Male hormonal contraception: potential risks and benefits. Rev Endocr Metab Disord. 2011;12(2):107-117.

Bariatric Surgery: A Cure for Diabetes?

October 20, 2011

By Amy Dinitz

Faculty Peer Reviewed

The lifetime risk of developing diabetes for persons born in 2000 is around 35%[1] and the NHANES database has suggested a greater than fourfold increase in prevalence over the last three generations.  While bariatric surgery has become the most effective treatment for obesity, it has also been found to be an extremely effective treatment for type 2 diabetes.  It was initially thought that the weight loss experienced by patients after bariatric surgery was responsible for improved glycemic control.  However, patients experience improvement after only a few days, suggesting that hormonal changes are partly responsible.[2] Discovering exactly which hormones are involved and how they “cure” diabetes has proven difficult.

The major players seem to be the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP); peptide YY (PYY); and ghrelin.  GLP-1 is secreted by the L cells of the distal ileum in response to ingested nutrients, and acts as a potent insulin secretagogue.[3] It has also been shown to slow gastric emptying and induce satiety in the central nervous system.[4] GLP-1 increases lipogenesis in adipocytes and glycogenesis in liver cells and skeletal muscle.[5]

GIP is secreted by the K cells of the duodenum and jejunum in response to carbohydrate and fat intake, and acts on pancreatic beta cells as an insulin secretagogue.[6] However, it has no effect on gastric emptying or satiety.[7] Like GLP-1, PYY is secreted by the L cells of the ileum, increases satiety, and slows gastric emptying through binding of receptors in the central and peripheral nervous systems.[8]

Ghrelin is a hormone secreted by cells in the gastric fundus and proximal gut that acts on the hypothalamus to stimulate appetite and food intake, as well as decrease energy expenditure and fat catabolism. Serum ghrelin levels are high before a meal to stimulate appetite and decrease afterward.[9] Ghrelin also acts in a paracrine manner in the pancreas to inhibit insulin secretion.[10] Serum ghrelin levels are inversely proportional to body weight, while weight loss causes increased ghrelin levels [11], both of which suggest that ghrelin is important in maintaining body weight at a “set point.”

The hypothesis that the caloric restriction induced by bariatric surgery is responsible for improved blood glucose levels does not explain why bypass procedures have better diabetes remission rates than restrictive procedures.  Moreover, bypass procedures cause remission in a few days[12], but remission doesn’t occur until months after laparoscopic gastric banding (LAGB).[13]

There are two theories, both supported by studies of surgical procedures conducted on mice, to explain the rapid improvement in glucose metabolism following bypass procedures.  In the hindgut hypothesis, rapid delivery of nutrients to the distal bowel increases secretion of GLP-1 and PYY, thus increasing glucose-dependent insulin secretion.[14] The foregut theory, in contrast, suggests that causing food to bypass the duodenum and the jejunum prevents secretion of an unidentified “putative signal” that contributes to insulin resistance and type 2 diabetes.[15]

Consistent with the hindgut theory, GLP-1 levels increase as much as threefold soon after bypass, but not after gastric banding[16], and PYY has been shown to increase as soon as two days after bypass.[17] The effect of LAGB and bypass on GIP secretion is not as well understood, though studies have shown decreased levels two weeks after bypass.[18] This makes sense physiologically, as GIP is secreted by cells in the proximal gut that would be bypassed by the procedure.  Ghrelin levels after gastric bypass are more variable, and seem to be based on surgical technique.  The amount of residual ghrelin-producing tissue and vagal innervation seem to determine the post-operative levels.[19]

As more about the hormonal changes seen after bypass and gastric banding is learned, it becomes clear that it is not simply weight loss that causes improvements in glucose tolerance.  Gastric banding is an effective treatment for diabetes; thus, more research should be done to assess its safety in patients with diabetes who are not obese.  Further studies of patients after bariatric surgery will continue to elucidate the pathophysiologic mechanisms involved in diabetes.  Based on these studies, medications can be created that mimic the effects of bypass in the body to treat diabetes effectively without an invasive surgical procedure.

Amy Dinitz is a 4th year medical student at NYU School of Medicine

Reviewed by  Manish Parikh, MD, Assistant Professor, Bariatric Surgery, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Narayan KM, Boyle JP, Thompson TJ, Sorenson SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003;290(14):1884-1890.  http://www.cdc.gov/diabetes/news/docs/lifetime.htm

2. Rubino F. Bariatric surgery: effects on glucose homeostasis. Curr Opin Clin Nutr Metab Care. 2006;9(4):497-507.  http://www.ncbi.nlm.nih.gov/pubmed/16778583

3. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409-1439.  http://physrev.physiology.org/content/87/4/1409.full.pdf

4. Flint A, Raben A, Ersbøll AK, Holst JJ, Astrup A. The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat Metab Disord. 2001;25(6):781-792.  http://www.nature.com/ijo/journal/v25/n6/full/0801627a.html

5. Luque MA, González N, Márquez L, et al. Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes. J Endocrinol. 2002;173(3):465-473.  http://www.ncbi.nlm.nih.gov/pubmed/12065236

6. Hansotia T, Drucker DJ. GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice. Regul Pept. 2005;128(2):125-134.

7. Meier JJ, Nauck MA, Schmidt WE, Gallwitz B. Gastric inhibitory polypeptide: the neglected incretin revisited. Regul Pept. 2002;107(1-3):1-13.  http://www.ncbi.nlm.nih.gov/pubmed/12137960

8. Ballantyne GH. Peptide YY(1-36) and peptide YY(3-36): Part I. Distribution, release and actions. Obes Surg. 2006;16(5):651-658.  http://www.springerlink.com/content/73p70u3312n10675/

9. Cummings DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest. 2007;117(1):13-23.

10. Kageyama H, Funahashi H, Hirayama M, et al. Morphological analysis of ghrelin and its receptor distribution in the rat pancreas. Regul Pept. 2005;126(1-2):67-71.

11. Cummings DE, Shannon MH. Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss? J Clin Endocrinol Metab. 2003;88(7):2999-3002.  http://www.ncbi.nlm.nih.gov/pubmed/12843132

12. Pories WJ, Swanson MS, MacDonald KG, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3):339-350; discussion 350-352.

13. Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316-323.  http://jama.ama-assn.org/content/299/3/316.full

14. Cummings DE, Overduin J, Foster-Schubert KE, Carlson MJ. Role of the bypassed proximal intestine in the anti-diabetic effects of bariatric surgery. Surg Obes Relat Dis. 2007;3(2):109-115.

15. Rubino F. Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable hypothesis. Diabetes Care. 2008;31 Suppl 2:S290-296.  http://care.diabetesjournals.org/content/31/Supplement_2/S290.short

16. Korner J, Bessler M, Inabnet W, Taveras C, Holst JJ. Exaggerated glucagon-like peptide-1 and blunted glucose-dependent insulinotropic peptide secretion are associated with Roux-en-Y gastric bypass but not adjustable gastric banding. Surg Obes Relat Dis. 2007;3(6):597-601.  http://www.covidien.com/BariatricsProPhysician/pages.aspx?page=PosOutcome:About/181893&topicID=181893

17. Moriñigo R, Moizé V, Musri M, et al. Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab. 2006;91(5):1735-1740.  http://jcem.endojournals.org/content/91/5/1735.full

18. Clements RH, Gonzalez QH, Long CI, Wittert G, Laws HL. Hormonal changes after Roux-en Y gastric bypass for morbid obesity and the control of type-II diabetes mellitus. Am Surg. 2004;70(1):1-4; discussion 4-5.  http://www.ncbi.nlm.nih.gov/pubmed/14964537

19. Cummings DE, Shannon MH. Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss? J Clin Endocrinol Metab. 2003;88(7):2999-3002. http://www.ncbi.nlm.nih.gov/pubmed/12843132

Metabolic Syndrome: Fact or Myth?

September 30, 2011

By Vicky Jones, MD

A 40-year-old female presented to her primary care provider with a chief complaint of weight gain over the past year.  She wants to be fully evaluated for any kind of medical disorder that could have caused it.  She has been seen by multiple specialists but no one can give her a “straight diagnosis”.  Their advice is for her to lose weight.  She insists she never had problems with her weight in the past and has no known medical disorders. Her physical exam is significant for a blood pressure of 130/80 and excess fat around her waistline.  Her labs show an elevated serum glucose, an increased total cholesterol and LDL, and a decreased HDL.  Otherwise, she has normal endocrine markers.  Her primary care provider discussed the findings of her workup with her and tells her that she has metabolic syndrome. The patient is grateful for finally finding out what is wrong with her.

Many Americans suffer from the same disorder.  According to the CDC, 34% of American adults have metabolic syndrome.(18)  With such a high prevalence, clinicians have to understand what it is and what it means for their patient.  Researchers and clinicians have been trying to clearly define Metabolic Syndrome since its original inception in the 1980’s.  Thirty years later, it seems the medical community has finally come to a consensus.

During the beginning, Metabolic Syndrome was an explanation for epidemiological trends of patients with concurrent hypertension and hyperglycemia.  A Stanford physician postulated that these conditions were inter-related having one causal pathway related to hyperglycemia, leading to hyperinsulinemia, leading to excess free fatty acids.  This original idea was termed, Syndrome X.[1]  The pathophysiology of Syndrome X was that high levels of free fatty acids induce a state of insulin resistance both in the muscle (glucose uptake) and in the liver (glucose release).  The effect of hyperinsulinemia to increase renal sodium absorption was thought to contribute to hypertension through increased circulating blood volume.

Three years later, the same Stanford physician expanded his definition by discussing how insulin resistance leads to an increase in plasma triglycerides and a decrease in high density lipoprotein-cholesterol concentration, and high blood pressure.  For this reason, he extrapolated that Syndrome X plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high blood pressure, and coronary heart disease. [2]  The cause- effect relationship interested physicians across disciplines leading to a boom of research related to the etiology, pathophysiology, effects and prognosis of the syndrome.

After further examination, some physicians felt that the syndrome’s original definition was not adequate.  The same population of patients with syndrome X were noted to have a disproportionate prevalence of obesity.  They felt that obesity was likely to play the central role in the syndrome in causing insulin resistance. Research suggested that excess adipose tissue releases free fatty acids and glycerol into the circulation by lipolysis, therefore contributing if not initiating insulin resistance.[4]  Obesity linked with insulin resistance, hypertension and hyperlipidemia became known as the “deadly quartet”.[3]  This addition did not end debate, however.  If anything, it opened more controversy.  Scientists debated whether obesity causes insulin resistance or  vice versa?  Others debated whether obesity or diabetes played any role in the syndrome at all.

The World Health Organization saw the activity and controversy spurred by these theories and in 1998, compiled definitions and described what became recognized as the “metabolic syndrome”: obesity, insulin resistance, dyslipidemia, and hypertension—focusing on insulin resistance as a central tenet.[5]  This was a huge step in validating the syndrome.  However, even after the WHO made the definition official and gave it an ICD code, clinicians continued to question the clinical utility of the definition.

Interdisciplinary meetings further examined research and decided that the clinical utility of describing these patients was to identify a high risk group for cardiovascular disease.[6] Atherosclerosis was shown to be associated with all the parameters of metabolic syndrome. [7] In addition, by this time, scientists had discovered other diseases to be associated with the syndrome as well, such as fatty liver, polycystic ovary syndrome, cholesterol gallstones, sleep apnea, lipodystrophies, and protease-inhibitor therapy for HIV.  Prevention and intervention of the syndrome was viewed as a necessity.

Fast forward to 2005 when the research and discussion up to this point convinced almost all of the major medical associations to agree on the existence and importance of metabolic syndrome.  The American Heart Association in conjunction with the National Heart, Lung, and Blood Institute came up with the most current and widely accepted definition of  metabolic syndrome.[7]  In order to be diagnosed with Metabolic Syndrome, a patient needs 3 of 5 of the following:

– Elevated waist circumference: 102 cm (40 inches) in men, 88 cm (35 inches) in women

– Elevated triglycerides 150 mg/dL (1.7 mmol/L) or on drug treatment for elevated triglycerides

– Reduced HDL-C, < 40 mg/dL (1.03 mmol/L) in men, <50 mg/dL (1.3 mmol/L) in women or on drug treatment for reduced HDL

– Elevated blood pressure 130 mm Hg systolic blood pressure or 85 mm Hg diastolic blood pressure or on antihypertensive drug treatment in a patient with a history of hypertension

– Elevated fasting glucose 100 mg/dL or on drug treatment for elevated fasting glucose

The five criteria listed represent abnormal physical and lab findings that suggest but do not necessarily meet the requirements for a diagnosis of obesity, hyperlipidemia, hypertension, and diabetes, respectively.  The creators seemed to want to catch patients with pre-morbid conditions that increase their risk for morbid conditions. Being able to have a combination of any three allowed for more sensitivity in diagnosis.

Even with the verified definition. there still remained inconsistencies in the pathophysiology behind the disease. Either there is an inherit metabolic disorder (with or without obesity) causing insulin resistance with subsequent release of free fatty acids and pro-inflammatory factors, or it is the adipose tissue in obese people that is insulin resistant, which in and of itself worsens metabolism by muscle and the liver,  also releasing adipokines, a pro-inflammatory byproduct. [8]

Without a set pathophysiology or single pathway of disease, the ability to establish evidence base treatment strategies was stalled.  There were no articles published that suggest any treatment strategies better than those that have already existed for each individual part of the syndrome alone.  For example, if the patient is overweight, he or she should still try behavioral modification to lose weight.  If he or she has hyperlipidemia, diet and pharmacologic therapy is still tried and true.  Glycemic control would not differ between some one with or without metabolic syndrome who has insulin resistance.  It depends on already established parameters such as fasting glucose or glycosylated hemoglobin.

Another flaw exposed after the formation of a widely accepted definition was the fact that there was no established prognostic evidence for the syndrome. Studies showed that there is a higher mortality and cardiovascular risk for patients with metabolic syndrome. [9-11] However, the degree of severity of morbid conditions affected mortality risk to a greater extent rather than whether or not patients met the criterion of metabolic syndrome.  Ten year risk for these patients seemed better predicted by degree of glycemic control or Framingham Risk analysis. [12]  Therefore, questions about clinical utility of the diagnosis lingered.

The World Health Organization met again in 2009 to re-evaluate a consensus statement regarding metabolic syndrome after a decade of shifting meanings and research.  The conclusion was that “While [metabolic syndrome] may be considered useful as an educational concept, it has limited practical utility as a diagnostic or management tool.” [15]  Furthermore the WHO deemed that clinicians should not use this term as a clinical diagnosis and that further research regarding the syndrome would be an inappropriate use of resources.  Even more recently, the proginitor of it all—the Stanford physician that originally created the idea of Syndrome X—published a review article in December of 2010.  In it, he states that “despite the many publications…it is not clear that it is a diagnostic category worth continuing”[16].

What all of this means is that our patient from the case at the beginning does have metabolic syndrome.  Having metabolic syndrome may place this patient at a higher risk for cardiovascular disease and/or death.  It may not change the advice that she receives from her doctors regarding lifestyle changes or medical treatment; however it may appropriately target her for aggressive intervention.

In conclusion, Metabolic Syndrome has not proven to be as solid of a “disease” as it was once theorized.  It describes a set of pre-morbid conditions without a unifying underlying disease, making it fall shy of the official definition of a “syndrome”.[17] And it is important to understand that the international community does not view it as a valid diagnosis.  Although, physicians may still use the terminology as a way to describe a patient or a way to closely watch patients at higher risk for developing co-morbidities.  In this way, it may still prove to have clinical utility as a descriptor.

Dr. Vicky Jones is a 3rd year resident at NYU Langone Medical Center

Image courtesy of Wikimedia Commons


  1. Reaven G.M.:  Banting lecture 1988. Role of insulin resistance in human disease.  Diabetes 37. (12): 1595-1607.1988.
  2. Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med. 1993;44:121-31.
  3. Kaplan NM. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med. 1989; 149:1514 –1520
  4. “Obesity” Goldman: Cecil Medicine, 23rd ed. 2007.
  5. Gallagher E G, LeRoith D, Karnieli E.  The Metabolic Syndrome – from insulin resistance to Obesity and Diabetes.   Endocrinol Metab Clin N Am 37 (2008) 559–579.
  6. Grundy S, Cleeman J, Daniels S, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112(17):2735–-52.  http://circ.ahajournals.org/content/112/17/2735.full
  7. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421. Circulation. 2002;106:3143–3421.
  8. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92:347–355.  http://journals.cambridge.org/download.php?file=%2FBJN%2FBJN92_03%2FS0007114504001795a.pdf&code=560b41b8c0825a15a8274c4fdfabca59
  9. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683– 689.
  10. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288: 2709–2716.
  11. Sattar N, Gaw A, Scherbakova O, Ford I, O’Reilly DS, Haffner SM, Isles C, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation. 2003 Jul 29;108(4):414-9. Epub 2003 Jul 14.
  12. McNeill AM, Rosamond WD, Girman CJ, Golden SH, Schmidt MI, East HE, Ballantyne CM, Heiss G. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care. 2005;28:385–390.
  13. Solymoss BC, Bourassa MG, Lesperance J, Levesque S, Marcil M, Varga S, Campeau L. Incidence and clinical characteristics of the metabolic syndrome in patients with coronary artery disease. Coron Artery Dis. 2003;14:207–212.
  14. Turhan H, Yasar AS, Basar N, Bicer A, Erbay AR, Yetkin E. High prevalence of metabolic syndrome among young women with premature coronary artery disease. Coron Artery Dis. 2005;16:37– 40.
  15. Simmons RK, Alberti KG, Gale EA, Colagiuri S, Tuomilehto J, Qiao Q, Ramachandran A, Tajima N, Brajkovich Mirchov I, Ben-Nakhi A, Reaven G, Hama Sambo B, Mendis S, Roglic G. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia. 2010 Apr;53(4):600-5. Epub 2009 Dec 11.
  16. Reaven GM. The metabolic syndrome: time to get off the merry-go-round? (Review) J Intern Med 2011; 269: 127–136.  http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02325.x/abstract
  17. “Syndrome.” Oxford English Dictionary. 2nd edition. 1989.
  18. Ervin RB. Prevalence of Metabolic Syndrome Among Adults 20 Years of Age and Over, by Sex, Age, Race and Ethnicity, and Body Mass Index: United States, 2003–2006. National Health Statistics Reports. Number 13.  May 5, 2009. http://www.ncbi.nlm.nih.gov/pubmed/19634296