The overweight/ obesity epidemic revisited

Low fat, low carb, or Mediterranean?

Abstract

The prevalence of obesity is of monumental concern and has been growing at an exponential rate over the last few decades. Abdominal adiposity is associated with cytokine perturbations leading to prothrombotic and proinflammatory states and these metabolic changes promote cardiometabolic complications. To date, body mass index (BMI) has been strongly and positively linked to an increase risk of type 2 diabetes, cardiovascular disease, sleep apnea, osteoarthritis, dyslipidemia, asthma and certain cancers. Aside from increased co-morbidities obese and overweight populations have a decreased life expectancy compared to their normal weight counterparts. Modest caloric restriction based on energy expenditure is favored long-term over very low calorie diets. Dietary interventions based on macronutrient proportions alone seem over simplistic and fail to demonstrate any clinically relevant difference in weight loss. Weight loss in general improves cardiometabolic parameters; however, no other diet supports the primary and secondary improvement of hard outcomes such as cardiovascular mortality and all-cause mortality as the MedDiet. Both the Mediterranean Diet (MedDiet) and a Low Glycemic Diet (LGD) show effective weight loss results as well as important improvements in common comorbidities. A modified low-glycemic MedDiet includes smaller more frequent meals, moderate consumption of healthy fat (olive oil), high intake of vegetables and fruit, low quantities of red meat using poultry and fish to replace beef and lamb, and the inclusion of high fiber, LG whole grains. Obesity must be viewed as a chronic condition since weight regain is common. A maintenance dietary program, continual support and behavioural strategies are critical for long-term success.

The prevalence of obesity is of monumental concern and has been growing at an exponential rate over the last few decades (WHO 2002). In 2004, according to the Canadian Community Health Survey, 23.1% of adult Canadians were obese (body mass index= 30kg/m2) and an additional 36.1% were overweight (body mass index= 25kg/m2). To give perspective on the magnitude of concern this represents six out of every 10 Canadians are overweight or obese (Tjepkema 2005). Abdominal adiposity is associated with cytokine perturbations leading to prothrombotic and proinflammatory states (Grundy2004, Grundy 2008) and these metabolic changes promote cardiometabolic complications (Grundy 2004). To date, body mass index(BMI) has been strongly and positively linked to an increase risk of type 2 diabetes, cardiovascular disease, sleep apnea, osteoarthritis, dyslipidemia, asthma and certain cancers (Fabricatore 2006, NHLBI 1998, Schelbert 2009, Tjepkema 2005).

Aside from increased co-morbidities obese and overweight populations have a decreased life expectancy compared to their normal weight counterparts (Peeters 2003). Despite the significance of this prevalence, an initial weight loss of 5-10% can confer positive improvements in cardiometabolic risk factors regardless of initial BMI (Fabricatore 2006, NHLBI 1998). Dietary intervention is an essential component of a comprehensive weight loss strategy and is considered first line therapy in numerous guidelines (NHLBI 1998). Furthermore, the ideal dietary intervention would not only be effective for weight loss but would also prevent, stabilize or reverse the most common associated comorbidities. A therapeutic lifestyle intervention can be an effective strategy in high risk individuals with coronary heart disease (Gordon 2004). Dietary interventions as they relate to weight loss and the most common comorbidities are the subject of this review.

Regulation of Body Weight and Energy Balance

Daily caloric expenditure depends on three basic elements: basal metabolic rate (BMR), post meal thermogenesis and non-exercise activity thermogenesis. Total caloric expenditure is the sum of an individual’s daily caloric expenditure and exercise induced caloric expenditure. It is well accepted that overall caloric deficiency must be induced for weight loss to occur (Schelbert 2009). Regulation of caloric intake is influenced by the central nervous system. Research is burgeoning in this field and the following neuropeptides have been shown to influence eating behavior by modulating hunger and satiety: vagal stimulation, cholecystokinin, Apolipoprotein A-IV, insulin, PYY, Glucagon-like peptide-1, other glucagonrelated peptides, leptin, gherlin, tumor necrosis factor- α and obestatin (Jensen 2011).

Physiologic Impact of Caloric Deficiency

Dietary caloric restriction antagonizes weight loss efforts by reducing BMR through reductions in thyroid hormones, triiodothyronine (T3) from thyroxine (T4) as well as preferential use of lean muscle mass over adipose tissue for energy. This phenomenon can be mitigated by the inclusion of exercise which favors the maintenance of lean muscle tissue and increases BMR (Jensen 2011).

Dietary Interventions for Weight Loss Caloric Restriction

Caloric restriction is a critical component of successful weight loss (Schelbert 2009). A very low calorie diet (VLCD) is defined as less than 800 kcal/day while a low calorie diet (LCD) is defined as 800-1350kcal/day. A meta-analysis of randomized trials evaluated the efficacy of caloric restriction on short and long term efficacy of weight loss. At the end of six months the average lost was 16.1% and 9.7% of body weight in the VLCD and LCD respectively (Tsai 2006). Despite this initial short statistical difference between the two diets, a greater regain of weight in the VLCD was seen which subsequently equalized the benefits of the diets by one year so that there was no difference in weight loss between the groups (Tsai 2005).

The literature is devoid of studies assessing the long-term metabolic impact of caloric restriction (Kim 2008). A study by Wadden (1990) assessed the influence of caloric restriction influence on thyroid hormones: T3, T4 and reverse T3. Reverse T3 (rT3) is the enzyme responsible for converting T3 (the more active thyroid hormone) to the less active T4. In the VLCD group serum T3 was reduced by 66% while rT3 increased by 27%. When the VLCD group returned to a LCD thyroid function increased but remained 22% lower than baseline at the end of study (Wadden 1990). Further research is needed to better understand if T3 depression and rT3 augmentation effect are temporary or longer term.

Moderate caloric restriction based on estimated total energy expenditure is preferred over VLCD long term. Mild caloric deficiency will result in less antagonizing reflective mechanisms, less thyroid suppression and less BMR suppression. Even with successful weight loss obesity should be viewed as a chronic condition as long-term weight gain is common and should be monitored regularly (Wadden 1993).

Macronutrient Quantity

Many commercial and popular diets tout that their clinical weight loss success is based on a particular combination of carbohydrate, protein and fat. This topic has indeed earned the interest of several investigators.

Low Carbohydrate, High Protein Diet vs. Low Fat, High Carbohydrate Diet

A systematic review analyzed 13 randomized controlled trials that compared low carbohydrate, high protein (LC/HP) ‘ketogenic’ diet to low fat, high carbohydrate (LF/HC) diets. By 12 months a statistically significant difference of 1.05 kg (P <0.05) favored the LC/HP diet (Hession 2009). Despite a statistical significance at 12 months it is questionable whether a modest 1.05 kg difference is of clinical significance at 12 months.

LC/HP Diet vs. LF/HC Diet vs. MedDiet

A two-year prospective trial evaluated three diets head to head. An LC/HP diet according to Atkin’s guidelines, LF/HC diet according to the American Heart Association guidelines and a Mediterranean Diet (MedDiet). The caloric restriction for LF/ HC and MedDiet was 1500 kcal per day for women and 1800 kcal a day for men. The LC/HP diet was restricted based on 20g of carbohydrates per day (Shai 2008).

The greatest amount of weight loss occurred in the first six months for all diet types. At six months, LC/HP showed the most significant weight loss. At the two-year mark, the MedDiet and the Atkin’s diet demonstrated a close to equal average weight loss of 4.4kg and 4.7kg respectively. The LF/HC diet demonstrated inferior weight loss throughout the two-year period with an average 2.9kg of weight loss (Shai 2008). Systematic reviews and prospective studies have consistently reproduced these findings. The statistical differences between the diets are inconsistent at the end of one year. After two years weight regain to some degree is common across all diet types. At two years the LF/HC appears to be inferior to the Mediterranean and LC/HP diet to questionable degree of clinical relevance.

Protein vs. Carbohydrate vs. Fat

A study by Sacks and colleagues (2009) investigated four diet groups based on intakes of carbohydrates, protein and fat. All four groups received the same guidelines for healthy choices of each macronutrient. At six months, 12 months and 24 months there were no significant differences between the four groups regarding weight loss, satiety, hunger and satisfaction with the diet. The greatest weight loss was seen at six months and regain began after 12 months. All diets improved fasting insulin levels and cholesterol panels equally, possibly reflecting a decrease in adiposity and cytokine perturbation rather then the diets (Sacks 2009).

Therefore, from a simple weight loss perspective the optimal diet may be patient dependent since compliance and adherence are the greatest predictors for weight loss (Fabricatore 2006).

“Reduced-calorie diets result in clinically meaningful weight loss regardless of which macronutrients they emphasize (Sacks 2009).”

Impact of Glycemic Index and Glycemic Load on Weight Loss

Glycemic index ranks foods based on the rate that they impact blood sugar levels. Glycemic load is a reflection of the glycemic index plus the total absolute amount of carbohydrates (Wolever 1991). Factors that decrease the glycemic index are the co-ingestion of carbohydrates with fat, protein and/or fiber.

The glycemic index (GI) and glycemic load (GL) of the average North American diet has increased as food-processing advancements and refined carbohydrate intake have risen (Ludwig 2002). High glycemic index/load diets among individuals without diabetes are associated with physiological 24-hour hyperglycemia, hyperinsuliemia, higher C-peptide excretion and higher glycosylated hemoglobin (Hb A1C) concentrations. Homeostatis of glucose are tightly regulated by the endrocrine pancreas via insulin and glucagon. A high glycemic-index meal results in rapid postprandial hyperglycemia leading to reactive hyperinsulinemia. Two to four hours postprandial following a high glycemic meal, mild hypoglycemia occurs inducing hunger and hyperphagia in order re-establish homeostasis. This cycle has metabolic consequences promoting weight gain. Furthermore, this chronic glucotoxicity can lead to β-cell failure and increase the risk of type II diabetes. A low glycemic index meal induces a milder, more prolonged and controlled release of insulin and return to euglycemic state resulting in better glycemic control and satiety (Ludwig 2002).

A randomized controlled trial assessed four diets: high carbohydrate or high protein with low or high GI respectively. Lowering the GI in the high carbohydrate diets resulted in the doubling of fat loss from 2.8kg to 4.5kg in 12 weeks. In the high-protein diets GI did not impact fat loss. In addition, women were more responsive to changes in glycemic index (McMillan- Price 2006). Two Cochrane reviews support low glycemic index/ load meals for both the treatment of obesity (Thomas 2007) and glycemic control of type II diabetes (Thomas 2009).

Critical review of the Cochrane database concluded that there was statistically and significantly greater weight loss in the low glycemic diet (LGD) group as compared to the LF diets. Parameters such as weight loss from fat mass improved as well as satiety. In addition, the resting energy expenditure was not antagonized to the same degree as in the low fat group (Pereira 2004). High GI and GL diets are associated with higher weight gain, fat mass and waist circumference (Hare-Bruun 2006). The limitations of the current research are inconsistent cut-offs between LGD and HGD. This may contribute to some inconsistencies in the literature (Esfahani 2011).

Weight loss can be realized by a degree of caloric deficiency, regardless of macronutrient proportions. Nonetheless, one of the greatest hurdles of weight loss is the very common subsequent weight regain. Typical Western diets induce high glycemic responses that promote postprandial carbohydrate oxidation rather then fat oxidation. This may be a plausible mechanism for the long-term promotion of weight gain. Low glycemic diets support weight control by promoting satiety, maintaining insulin sensitivity and blunting insulin secretion (Brand-Miller 2002).

Dietary Intervention Impact on Mortality and Common Comorbidities

From a simplistic weight loss perspective the review of the literature indicates a slight superiority of the MedDiet and LC/ HP diet over that of the LF/HC. The clinical relevance of these findings is disputable given the negligible magnitude of difference on weight loss. Individuals who are overweight and obese are at increased risk of various comorbidities. Choosing a dietary intervention for weight loss should place a special emphasis on the impact the dietary intervention could have not only on weight loss but also on mortality and common comorbidities.

LF/HC Diet and Cardiometabolic Risk Factors

As reviewed a LF/HC diet has the tendency to be a higher in carbohydrates notably higher simple carbohydrates resulting in an overall higher glycemic index diet. It positively impacts triglyceride to a much lesser degree than both the LC/HP and MedDiet. Furthermore, the LF/HC promotes less glucose control than the Mediterranean Diet (Shai 2008).

HP/LC Diet and Cardiometabolic Risk Factors

A HP/LC diet has been associated with higher mortality from all causes (Trichopoulou 2007), increased risk of renal stone formation, high renal acid load, negative calcium balance and theoretically increased risk for bone loss (Reddy 2002, Fung 2010). While offering benefit relative to a LF/HC diet for the endpoint of weight loss as reviewed above, such a list of complications is concerning. Recommendation of such a strategy for long- term weight maintenance should be done with caution.

MedDiet and Cardiometabolic Risk Factors

The MedDiet has shown positive impact on various health parameters including mood, cognition, erectile function and endothelial function (Féart 2009, Giugliano 2010, Rallidis 2009, Sánchez-Villegas 2009). The MedDiet impacts risk factors such as cholesterol panel improvements as well as reducing the risk of subsequent coronary events (de Lorgeril 2008, Shai 2008).

The MediDiet resulted in a 52% four-year relative risk reduction in the incidence of type II diabetes in high-risk individuals (Salas- Salvadó 2011). With regards to secondary prevention among individuals newly diagnosed with type II diabetes there were 26% fewer individuals started on antihyperglycemics at the end of four years in MedDiet group as compared to the American Diabetic Association diet. We could expect to see much greater impact if the MedDiet was compared to a typical western diet.

Weight loss in general improves cardiometabolic parameters; however, no other diet supports the primary and secondary improvement of hard outcomes such as cardiovascular mortality and all-cause mortality as the MedDiet.

A Low-Glycemic Modified MedDiet, The Future?

A Cochrane review confirmed that glycemic control is improved in a low-glycemic index diet without any increased risk of hypoglycemic events (Thomas 2009). A low glycemic index diet improves glycemic control among individuals with normal glucose control as well as individuals with type II diabetes (Thomas 2009), and improves body composition (Thomas 2007). Combining both the low glycemic diet with MedDiet food composition seems a promising future to synergize their independent benefits.

Adjunctive Consideration on Weight Loss

Several adjunctive treatments have appeared to enhance the results of diets. Adding structure to the diet with menus, recipes and grocery lists improved weight loss (Fabricatore 2009, Heymsfield 2003, Wing 1996) . The added structure of incorporating partial meal replacement has also been shown to produce greater weight loss than a conventional weight loss diet alone (Heymsfield 2003). Non-dietary interventions also play a major role in a comprehensive therapeutic lifestyle intervention. It is beyond the scope of this review to discuss these in any detail but their importance should be noted. Behavioural strategies including cognitive behavioural therapy, motivational interviewing, social support network and exercise regiment synergistically improve adherence, compliance, effectiveness and body composition.

Summary

Modest caloric restriction based on energy expenditure is favored long-term over very low calorie diets. Dietary interventions based on macronutrient proportions alone seem over simplistic and fail to demonstrate any clinically relevant difference in weight loss. Both the MedDiet and a LGD show effective weight loss results as well as important improvements in common comorbidities. A modified low-glycemic MedDiet including smaller more frequent meals, moderate consumption of healthy fat (olive oil), high intake of vegetables and fruit, low quantities of red meat, using poultry and fish to replace beef and lamb, the inclusion of high fiber, and LG whole grains appears to be a desirable intervention strategy given the current state of the literature. The plan must be individualized to the needs of each patient, however, and certain cultural/ religious/ personal preferences may force modification in order to maximize long term compliance. Obesity must be viewed as a chronic condition since weight gain is common. A maintenance dietary program, continual support and behavioural strategies are critical for long-term success.

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Endocrine Disruptors 

Abstract:

It can be hypothesized that the ingestion of endocrine disruptor (ED) metabolites (from the water supply and food chain) can result in detrimental outcomes for males and females, such as prostate and breast cancer, infertility and C-sections; either through mechanisms of hormonal imbalance or dysfunctional metabolism. Physiological and biological mechanisms of action thought to be involved include creation of a state of estrogen dominance, and that EDs can alter the morphology and function of sperm and the estrogen receptor. Although further evidence is needed to establish causation between an increased use of the BCP, a high level of metabolites in the water supply, and an increasing number of reproductive diseases, the alarming patterns between these variables warrant additional study.

CONCERNS ABOUT ENDOCRINE DISRUPTORS IN THE WATER SUPPLY AND BIOACCUMULATION

Endocrine disruptors, although detrimental on their own, are not the only concern; there is a) a lack of consistent measurement standards of ED metabolites in the water supply, b) variability in the efficiency of methods that extract EDs and c) a lack of published evidence to link bioaccumulation of reproductive specific metabolites to human disease. Primarily, there is little formal regulation involving monitoring of pharmaceutical metabolites in regional water supplies. Additionally, several countries do not have legislation in place for continuous follow up of these specific chemicals. This variability is also present in treatment facilities. Processes in treatment plants have demonstrated varying removal rates for pharmaceuticals, ranging from less than 20% to greater than 90% (WHO 2011). A report by the International Joint Commission in Windsor showed that pharmaceutical metabolites can exert detrimental effects, such as alterations in the reproductive system of aquatic organisms and humans. Bioaccumulation of EDs has been demonstrated in various environmental compartments, however, their pathological endpoints have not been fully investigated, nor their causative chemical metabolites fully regulated in the United States and Canada (Kemp 2011).

An endocrine disruptor is defined as any natural or synthetic metabolite or compound that alters hormones, enzymes or receptors within the body. Endocrine disruptors can be classified into several categories, two of which will be addressed in this review: a) chemical toxins, and b) pharmaceutical metabolites.

Endocrine Disruptors: Chemical Metabolites

There are several types of toxin related endocrine disruptors, such as polychlorinated biphenyls (PCB), polyvinyl chlorides (PVC), pthalates and parabens that have been correlated with hormonal dysfunction. Bisphenol A (BPA), furans, polybrominated diphenyl ethers (PDBE) and dioxins are well known carcinogens (Kaur 2005). Organochlorines resist biochemical breakdown, have a long half life and also accumulate as EDs in the environment (Fisher 1999).

Food sample analysis in Spain, the USA, and Japan have collectively shown ED levels from 340-3000 parts per trillion (ppt) and have confirmed that all foods containing animal fats had PBDE by-products (Schuhmacher 2007, Seely 2007). It has been estimated that the daily human intake of PBDEs is approximately 0.51 nanograms (Ramos 2006). Further evidence of bioaccumulation was shown in patient fat biopsies that were chemically analyzed following exposure to polychlorinated dioxins, furans and PCBs. Levels of hepta- and octachlorinated furans and dioxins of up to 8400 parts per trillion (ppt) were found in one repeatedly exposed person in comparison to the fat from control group members (from patients with no overtly known exposure to furans or dioxins) that were several 100 ppt (Schecter 1985).

Endocrine Disruptors: Pharmaceutical Metabolites

In addition to toxins, pharmaceutical metabolites accumulate in the water supply and contribute towards physiological dysfunction. These include but are not limited to ethinyl estradiol (EE2), levonorgestrel (LNG) and norethindrone (NET). EE2 is one of the main metabolites of oral contraception, and is also administered as patches, injections and rings. EE2 is more chemically active than other estrogenic metabolites. It is not the largest contributor to estrogen in the water supply, however it has joined other synthetic estrogens, such as those from dairy cows, fertilizers and industrial chemicals (Moore 2011).

There are numerous studies that identify how contraceptives are: a) found in the water supply, and b) pose health hazards to wildlife and other species in the food chain. The Songhua River and Harbin drinking water study charted the removal rates of estrogenic activity, which was 34.6% to 50.5% in Harbin, and revealed that estrogenic pollutants in source water were not efficiently removed in treatment plants (Shao 2009). The Endocrine Society released a statement that low level, chronic exposure to environmental endocrine disruptors has caused or contributed to adverse human health effects (Diamanti-Kandarakis 2009). A collective of in vitro, animal and a few human studies has provided compelling evidence that exposures to either birth control pill (BCP) or estrogen metabolites through the water supply had biological consequences. This has been corroborated by the discovery of inter sex fish near sewage plants in various parts of the world, such as the U.S.A, Europe and Japan (Iwanowicz 2009, Jobling 2004). Another interesting animal study showed that chronic exposure to levonorgestrel (LNG) caused oxidative stress to Dreissena polymorpha (Contardo- Jara 2011). A human study showed that an insecticide altered sperm function by altered membrane depolarization and membrane dipole potential; this lowered water molecular dynamics in the superior part of the external membrane (Silvestroni 1997). It should be noted, however, that unlike other chemical toxic metabolites, comprehensive evidence of quantified bioaccumulation of BCP metabolites in humans is lacking to date.

TRENDS IN ENDOCRINE DISRUPTOR LEVELS AND GENITOURINARY DISEASE Increased Use of the Birth Control Pill

There has been a rise in the utilization of contraception, more specifically an overall trending to an increased use of the birth control pill (BCP) through recent decades (Moore 2011). The BCP was released into the Canadian market 50 years ago. The Canadian Contraception Study determined that 84 % of Canadian women use or have used the BCP (Fisher 2002, O’Malley 2001). Eighty three percent of the “effluent” sewage samples had EE2 from the BCP (0.07 to 2.6 ng/L); and induced estrogenic responses in fish (Tyler 2009).

There is an average daily dose range of 30 to 35 μg to 1 mg of EE2/ pill. Human urine is the major source of natural and synthetic estrogens in the water supply (Wise 2010). Of the 38.2 million women in the USA using contraception in 2006–2008, the pill accounts for about 28% of contraceptive users, and the percent of women aged 15-44 currently using the pill is 17% (Martinez 2012).

The Use of the Birth Control Pill and Reproductive Cancers

There is direct evidence for an increased risk of breast and cervical cancers with the use of BCPs (Burkman 2004). Several studies including but not limited to a 2003 analysis by the International Agency for Research on Cancer (IARC) and a systematic review by Lancet found an increased risk of cervical cancer with longer use of BCPs (Moreno 2002, Smith 2003). The results from a breast cancer study showed that the highest risk was found in women aged 20-34, who used BCPs within 5 years prior to diagnosis of disease (Althuis 2003). Evidence for indirect risk (through ingestion of BCP related EDs through the water supply) of reproductive female cancers is lacking, although intriguing patterns have been published for male cancers.

Male reproductive diagnoses, such as prostate cancer have recently been etiologically investigated. It was theorized that BCPs were excreted in the urine and travelled into the water supply; concurrently, scientific findings have suggested that low levels may cause cancer, including prostate cancer (Ubelacker 2011). They further postulated that in countries where BCP use was higher, prostate cancer had a greater incidence. A more recent study showed that BCP use was significantly associated with prostate cancer incidence and mortality in the individual nations worldwide (r=0.53), respectively; p<0.05 for all) and with BCP use in Europe (r=0.545, p<0.05), whereas other contraceptives did not correlate with prostate cancer incidence nor mortality (Margel 2011). Although these findings do not necessarily infer causation, these aligning trends should not be ignored, and further studies are warranted.

The Impact of Endocrine Disruptors on Infertility and Caesarean Sections

Recent human studies have elucidated that decreasing fertility could be due to environmental toxic metabolites; biochemically (hormones) or molecularly (cell interactions). One study in males from an infertility clinic demonstrated that an elevation in urinary BPA concentration was associated with decreases in sperm concentration, motility, and morphology of 23% (95%CI -40%, -0.3%), 7.5% (-17%, +1.5%), and 13% (-26%, -0.1%), respectively; this was also associated with a 10% (0.03%, 19%) increase in sperm DNA damage (Meeker 2010). A study of female exposure to the chemical pentachlorophenol, utilized as a lumber preservative, showed altered hypothalamic activity, and was thought to cause low level impaired ovarian function and hormonal insufficiency (Gerhard 1999).

There has also been a notable increase in Caesarean sections (C-section) in recent decades. The Canadian Institute for Health Information stated that the C-section rate has risen; up to 26% of babies born in hospitals in 2005, compared to 23% five years earlier and 17% in 1993 (Hall 2009). Some of the causes can be attributed to technological intervention, position of labour and birth complications; however, chemical causes through bioaccumulation may have been overlooked. Estrogen induces labour by increasing the expression of pro-contraction genes in cells of the myometrium around the time of delivery. The induction of contraction-related gene expression is modulated by signalling outside the nucleus (ERK/MAP) through the estrogen receptor (ER)α (Welsh 2011). Therefore, it can be postulated that dysfunctional estrogen metabolism, signalling and concentration that are caused by synthetic estrogens from ED could result in changes in labour patterns. Several mechanisms can be hypothesized: a) synthetic estrogens may not stimulate the ER with affinity that is sufficient to upregulate signalling, b) high levels of EDs in humans over time may downregulate the estrogen receptor by number or potency, and c) reactive oxygen species from ED accumulation may result in altered gene expression/protein production. Although published evidence between ED bioaccumulation in humans and rates of C-sections is lacking, the putative link and associated mechanisms of action deserve consideration.

RELEVANT BIOCHEMICAL AND MOLECULAR MECHANISMS OF ACTION

Hormone Metabolism

The release of EDs into the water supply is thought to create a state of estrogen dominance (associated with cancer, fibroids and endometriosis). Estrogen (comprised of 17 carbons), is hydroxylated at either C2, C4 or C16 positions; C4 and C16 are thought to be activated by EDs and are associated with breast cancer (Kabat 1997). Hormonal dysfunction is also seen in male reproductive hormones; studies have confirmed inverse associations between ED concentrations and testosterone levels (Meeker 2010).

Infertility

The mechanisms of action by which ED may cause male infertility consist of altered sperm count, altered quality of semen, dysfunctional cell signalling and DNA damage. A reduction in the sperm count and quality can be attributed to PI3K/c-Src/FAK and MAPK signalling on a molecular level, and anatomically, a destruction of cellular junctions by reactive oxygen species (Wong 2011). Regarding mechanisms of female infertility, the binding of EDs to the ER and activation of secondary messenger kinases, as well as calcium influx are at play (Robins 2011). During pregnancy, ED’s may alter meiotic spindle formation (Fujimoto 2011).

CONCLUSION

Although there is an overall lack of causal evidence linking estrogenic metabolites from birth control pills to reproductive diagnoses, there are critical trends and disease patterns identified: increased use of the birth control pill in recent decades, a rise in male and female reproductive cancers, infertility and caesarean sections. More importantly, it may be too early to witness the full effects of increased EDs in the water supply at this point in time, as a critical threshold concentration for detrimental effects may not have been reached for some diseases. Bioaccumulation may dredge up these detrimental effects over time. This principle is evident from the rise in the incidence of various cancers across the globe today that are thought to originate from exposures to toxins in previous decades. Research must include a focus on the past and the future, rather than waiting for the tipping point at present; observation should include searching the past for patterns and trends that may allude to disease incidence, and looking to the future to anticipate prophylactic strategies of modulating chemical toxins and pharmaceutical metabolites in the environment.

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Chronic Venous Insuffi ciency (CVI)

Integrative management approaches

Abstract

Chronic venous insuffi ciency (CVI), also known as varicose vein disease, is seen with comorbid conditions of ischemic heart disease, type II diabetes, and obesity which are growing in the Western world and as such the management and support of CVI is a necessity. Hallmark infl ammation and edema in the extremities in CVI is moderately well-managed to date with compression stockings and diuretics in conventional therapy. Recent exploration of the role of reactive oxygen species at the cellular level elucidates more causal reasons for this infl ammation and edema. Antioxidant therapies, protective nitric oxide supplied through acupuncture, dietary modifi cation in addition to herbal supports such as diosmin, hespiridin, and horse chestnut provide exciting future avenues for research of the maintenance and slowing of tissue damage in individuals with CVI.

Varicose vein disease, or chronic venous insuffi ciency (CVI), is a common health condition, aff ecting up to 65% of women and 50% of men over the age of 45, and accompanied by comorbidities of cardiovascular disease, type II diabetes, and obesity (Bergan 2006, Burkett 1973, McLaff erty 2008, Robertson 2008). Collapsed venous valves lead to pooled venous fl uid in tissues, inducing infl ammation that progresses to signifi cant tissue damage. To date, the etiology of this process has not been well elucidated. In recent years, however, the endothelial dysfunction of CVI has been viewed as related not only to the eff ects of long-term infl ammation but also to oxidative stress and a decreased capacity for antioxidant defence (Carrasco 2009). More rigorous identifi cation of herbal anti-infl ammatory supports for vascular dysfunction as well as the use of antioxidant-enhancing mechanisms such as acupuncture and L-arginine has made the role of complementary supports for CVI a more mainstream option for treatment in coming years.

Attempts to properly organize CVI symptomatology lead to the development of the CEAP rubric in 1995. Since tested for its consistency, the CEAP acronym organizes CVI by clinical (C), etiological (E), anatomical (A) and physiological (P) condition states (Porter 1995) and has been proven to be the best objective manner of testing and classifying CVI between patients and clinicians (Kistner 1996). Table 1 outlines the classifi cations for CEAP.

Common conventional treatments include compression therapy and sclerotherapy, with compression therapy the current gold standard (Braunwald 2001). Compression therapy (including specialized stockings; “TEDS”) provides mechanical support to minimize fl uid pooling and maximize limb function in patients with progressed disease.

e progression of CVI is characterized by infl ammatory mediators that cause collagen & elastin remodelling in the endothelium, and this results in loss of vessel wall integrity. is remodelling, coupled with ongoing infl ammation and reactive oxygen species production leads to vein collapse (Raff etto 2008). Vasorelaxation responses that are controlled by norepinephrine, acetylcholine, and serotonin dynamics are all decreased in individuals with CVI (Belcaro 1989, Belcaro 1988, Georgescu 2009).

Reactive oxygen species (ROS) play a key role in mediating chronic infl ammation; ROS cause oxidation of lipid membranes (Guzik 2011), and DNA damage that further amplifi es the infl ammatory response (Halliwell 2000). ROS are reactive chemical forms of oxygen that include superoxide anions (O2-) and hydroxyl radicals that are capable of damaging cells. Antioxidant mechanisms like the enzyme superoxide dismutase can minimize this damage by producing hydrogen peroxide (H2O2) from the superoxide anion (O2-) which will then be converted by catalase to water. However, in enzymatic defi ciency and infl ammation, superoxide anions can go “unchecked” by normal antioxidant mechanisms. Additionally, the enzymes NAD(P)H oxidase, cyclooxygenase, nitric oxide synthase, and xanthine oxidase can all form superoxide radicals (O2-) from molecular oxygen (O2), enhancing the problem (Halliwell 2000, Klaubunde 2012, Krzysciak 2011).

Produced by L-arginine reacting with nitric oxide synthase, NO is protective to the endothelium (Meletis 2006). Increased NO and its metabolites cause an increase in guanylate cyclase (GC) and cGMP, which leads to relaxation of vascular smooth muscle and vasodilation (Ignarro 1990, Ignarro 1993, Klaubunde 2012, Meletis 2006). NO is also anti-infl ammatory and anti-thrombotic as it discourages platelet aggregation in the endothelium and pro-inflammatory mediators. The presence of superoxide anion scavenges NO, reducing its bioavailability leading to vasoconstriction, increased leukocyte-endothelial adhesion through intracellular adhesion molecules (ICAM), and structural blood vessel changes contributing to vein collapse. Indeed, decreased nitric oxide (NO) is seen in atherosclerosis, type II diabetes, hypertension, and smoking (Guzik 2002). Inflammation causes more fluid to be drawn into the collapsed venous systems, exacerbating the condition (Krzyściak 2011, Yasim 2008). Hence, antioxidant therapy to support NO production is beneficial for CVI, as is management of inflammation to decrease immunemediated DNA destruction.

Integrative Treatments for Oxidative Stress with CVI

Acupuncture is a therapy that offers a multitude of beneficial effects for CVI. Acupuncture has proven to have analgesic effects via stimulation of alpha, delta and C-fibres in the skin and muscles responsible for pain perception; these fibres initiate cascades inducing peripheral vasodilation and production of proinflammatory agents such as substance P, opioids, somatostatin, and vasoactive intestinal peptide. As a result, acupuncture has the ability to influence fluid movement and edema in tissues (Cassileth 2011, Lewith 1983, Ma 2003, Sprott 1998). It is believed that acupuncture meridians and points themselves are regions of low electrical resistance and high electrical conductivity in the nervous system, and as a result may be able to impact the sympathetic nervous system, the release of substance P, and decreased pain perception (Ahu 1981, Ma 1993, Zhu 1989). 

An increased presence of NO has been found in skin areas where acupuncture meridians are found, as well as generally increased NO levels in the skin following acupuncture in vitro and in vivo in both human and animal models (Li 2003, Ma 2003). Twenty subjects with hand and forearm pain were exposed to two minutes of either acupuncture at the points LI 4, P6, P8, L6, and H5 or non-invasive sham acupuncture for the same length of time. Non-sham acupuncture sessions were found to have significantly increased blood flow around the chosen points both five and 60 minutes following the session, as well as increasing blood NO concentration (Tchiyua 2007). In other studies, however, sham acupuncture has also been found to have blood flow increasing effects, and further studies will be needed to understand the NO-enhancing capacity of standard acupuncture to truly distinguish between placebo effects (Lewith 1983, Park 2011, Takakura 2011,). A case report exists of a 69-year old male with bilateral venous ulcers and rheumatoid arthritis who was treated with compression bandages and an anti-inflammatory regime (NSAIDS, sulfasalazine, methotrexate), but without adequate healing; when treated with three weekly sessions of acupuncture at points ST36, KI3 and LR3 bilaterally, full healing of the ulcer on the left leg was seen within three weeks (Mears 2003). Since compression therapy is the current most utilized treatment for CVI, a larger study is being conducted to compare acupuncture with compression bandages (Vas 2011).     

Botanical Agents

Horse chestnut seed extract (HCSE) has been used widely in Europe for many years for CVI, hemorrhoids, and post-operative edema, and is slowly being recognized for these purposes in North America (Tiffany 2002, Sirtori 2001). Aescins, a combination of triterpene saponins from horsechestnut, are believed to be responsible for reducing the small vessel permeability of the venous system (Ulbricht 2002). Horsechestnut also contains anti-inflammatory bioflavonoids (quercitin and kaempferol), proanthocyanidin A2, and venotonic coumarins (fraxin and aesculin) (Tiffany 2002, Lorenz 1960, Mrwa 1986). HCSE’s are typically standardized to contain 16-20 percent aescin, and the oral dosage is typically 100-150 mg aescin/day in divided doses as a dried seed or 2-3 mL daily as a tincture (Abascal 2007, Tiffany 2002). HSCE cannot be used in those with kidney disease or broken skin due to irritating effects (Abascal 2007).   

On a molecular level, HCSE is thought to act by increasing sensitization to calcium ions, thus decreasing permeability of small vessels and enhancing venous contractile activity which decreases edema (Tiffany 2002). Its immune-stabilizing properties include the ability to decrease leukocyte migration and adherence, and reduce local levels of inflammatory mediators (Pangieri 1992). Systematic reviews of RCTs investigating HCSE have been conducted, with the most recent in 2006 (Pittler 2004, Pittler 2006). Pittler concluded that HCSE treatment was associated with a significant improvement in CVI symptoms of leg pain, itching, and fatigue, as well as reduction in lower-leg volume as a short-term treatment (2006). RCTs have also compared HCSE with compression therapy. Ottillinger and Greeske found that both therapies were equally effective in earlier stages of CVI, when irreparable damage has not occurred in the venous system; however in later stages of CVI, only compression therapy was effective compared to placebo (p <0.001), whereas HCSE was not (p = 0.115) (Diehm 1996, Ottillinger 2001). Further research needs to be done to determine the clinical stages in which HSCE is best administered.    

Diosmin and hespiridin are bioflavonoids used for CVI, and have been patented as Daflon ® or a micronized purified flavonoid fraction (MPFF). Danielsson (2002) compared 101 patients randomised to either MPFF twice daily (Daflon ® 500 mg, standardized as 90% diosmin and 10% flavonoids expressed as hesperidin) or placebo for 60 days. Evaluation was with CEAP (subjective symptoms of pain, edema, fatigue rated from 1-3  by patients), plethysmography (foot-volumetry), and duplexultrasonography before and after the treatments. Night cramps were significantly improved (p=0.03) with MPFF compared with placebo; however there was no significant effect on tiredness, heaviness, pain, and swelling as well as duplex-ultrasonography compared to placebo (Danielsson 2002).   

Pycnogenol, a French maritime pine bark extract was associated with endothelial improvements in CVI (Fitzpatrick 1998) when 150 mg or 300 mg daily were compared with Daflon® at 1000 mg/day for eight weeks in a randomized trial (Cesarone 1996). Pycnogenol resulted in significant (p<0.05) improvements in rate of edema formation, resting ankle flux, and rate of ankle swelling, compared to Daflon treatment at both the lower dose and in the higher dose groups (Cesarone 2006). Limitations of these studies include lack of standardization of diagnostic criteria, and use of subjective scoring as opposed to standardized CEAP scoring (Martinez-Zapata 2008). The diagnostic methods for the comparison of blood flow in the extremities are also varied (Martinez-Zapata 2008). Comparatively, pycnogenol demonstrates higher improvements in endothelial CVI attributes (edema and its rate) compared with the more popular diosmin and hespiridin to date.

Obesity, Diet and Chronic Venous Insufficiency

A plenitude of research supports physical activity and weight management in the improvement of CVI (Brand 1988). Malonylodialdehyde (MDA), a by-product of lipid peroxidation created by oxidative stress was examined in a group diagnosed with 2nd or 3rd degree CVI (n=62) compared to controls. BMI was assessed as a covariable. Not surprisingly, MDA was higher in patients with cardiovascular disease compared with the control group (p < or = 0.0005), however, MDA concentration was also significantly higher in obese patients compared to those with a normal BMI (p < or = 0.001) (Kózka 2009). These findings bring further attention to the use of lifestyle and dietary modifications as a way to reduce markers of inflammation, impact NO concentration, and benefit CVI as well as CVD risk. Some nutritional agents that may also assist in this include: folic acid and its substrates, L-arginine, and non-genetically modified soy. L-arginine is an important substrate for NO production, while folic acid and its cofactors vitamin B6 and B12 reduce homocysteine levels that contribute to oxidative destruction of NO (Meletis 2006). Folate inhibits intracellular superoxide production, which increases the half-life of NO, allowing for greater vasodilation and further tissue protection (Meletis 2006). A diet emphasizing increased healthy fats, complex carbohydrates, and plant-based antioxidants as per the Mediterranean diet are beneficial in cardiovascular disease as well as CVI.      

Future Directions for CVI: Influence of Estrogen

Women have a twofold higher incidence of CVI compared with men (Brand 1988). Serum levels of estradiol have been significantly associated with varicose veins, especially in post-menopausal women (Ciardullo 2000). Estrogen has been shown to upregulate vascular relaxation in the endothelium via nitric oxide (NO) and prostacyclin (PGI2) (Orsall 2004). Animal studies comparing the endothelium of male and female rats (n=12) have revealed significant sex differences in vasoconstriction/ relaxation, such as enhanced endothelium-dependent vasodilation and increased estrogen receptor activity in female rats, even independent of a NO pathway, suggesting there is an additional influence of estrogen on vasodilation, capable of acting synergistically with vasodilation effects of NO (Raffetto 2010). The influences of sex-hormone binding globulin (SHBG) and testosterone were also tested in the study, but were not found to influence varicose vein activity. Whether these findings can be replicated in human studies remains to be seen.     

CVI is an early warning sign of cardiovascular disease. Reactive oxidative species are found in higher concentration in varicose tissues, and these respond well to interventions that reduce oxidative stress and enhance nitric oxide presence in kind, including acupuncture, horse chestnut seed extract, hespiridin and diosmin and an emphasis on healthy dietary habits. Comparing these interventions with compression therapy and better developing our understanding of the role of estrogen will lead to more effective treatment of CVI.     

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