Understanding the experience of women living with obesity and reproductive pathology.

Improvement in quality-of-life questionnaire measures in obese adolescent females with polycystic ovary syndrome treated with lifestyle changes and oral contraceptives, with or without metformin

IntroductionObesity represents a significant health burden, and WHO recognises the importance of preventing weight gain and subsequent development of obesity among adults who are within the healthy weight range. Women...

Polycystic ovary syndrome (PCOS) is a complex, multifactorial metabolic and endocrine disorder in reproductive-age women. This review discusses the interlinked roles of lifestyle, metabolic dysregulation, insulin resistance, neuroendocrine impairment, genetic predisposition, and post-translational modifications (PTMs) in PCOS pathogenesis. Lifestyle components, especially those leading to obesity and insulin resistance, worsen the hyperandrogenism, ovulatory dysfunction, and inflammation. Dietary treatments such as, DASH diet and caloric restriction, particularly along with metformin, have been proven to improve metabolic and reproductive parameters. Environmental toxins, such as endocrine-disrupting chemicals (EDCs) and advanced glycation end-products (AGEs), further compromise ovarian function and hormone regulation. Oxidative stress and insulin resistance, driven by mitochondrial malfunction and chronic inflammation, create a self-perpetuating vicious cycle that compromises oocyte quality and worsens metabolic imbalance. Neuroendocrine disruption, characterized by increased GnRH and LH pulsatility, is initiated by dysregulated kisspeptin, dynorphin, and neurokinin B signaling in KNDy neurons, modified GABAergic input, and increased AMH and androgens. PTMs such as phosphorylation, methylation, acetylation, and ubiquitination also play essential roles in granulosa cell function, AR signaling, insulin sensitivity, and oocyte maturation. Current and novel treatment options vary from lifestyle modifications and pharmacological interventions (e.g., metformin, GLP-1 receptor agonists, myoinositol, vitamin D, and statins) to regenerative measures like mesenchymal stem cells and fecal microbiota transplantation. Newer therapies focusing on PTMs and neuroendocrine regulators remain the future hope. Multidisciplinary individualized management is critical for successful PCOS therapy and averting long-term complications.

BackgroundEndometrial cancer is rare in reproductive aged women. Standard surgical treatment can impact fertility. Non-standard conservative management with progestins can be used in very specific populations to give women an...

Overweight is an increasingly prevalent condition throughout the world. Current estimates, which are probably conservative, indicate that at least 500 000 000 people worldwide are overweight as defined by a body mass index (BMI) of between 25.0 and 29.9 and an additional 250 000 000 are obese with a BMI of 30.0 or higher.1 In the United States, recent data indicate that as much as 66% of the adult population is overweight or obese.2 Overweight and obesity are established risk factors for cardiovascular disease (CVD), stroke, noninsulin dependent diabetes (NIDDM), certain cancers, and numerous other disorders.3,4,5,6,7 It is also a risk factor for hypertension.8 Hypertension, defined as a systolic blood pressure in excess of 140 mm Hg or a diastolic blood pressure higher than 90 mm Hg, is also a globally increasing public health concern. Roughly 1 billion individuals worldwide are estimated to exhibit clinically significant elevated blood pressure with about 50 million of those residing in the United States.8 Hypertension, in turn, is associated with increased risk for CVD, stroke, renal disease, and all-cause mortality.9,10,11,12 The JNC VII report defines Stage 1 hypertension as blood pressure levels between 140 and 159 mm Hg systolic and 90 and 99 diastolic. Additionally, the report establishes a category of Prehypertension (Systolic blood pressure between 120 and 140 mm Hg or diastolic between 80 and 89 mm Hg). These 2 blood pressure classifications are deemed to be appropriate primary targets for lifestyle modification interventions, including weight loss. Higher levels of blood pressure, or stage 1 hypertension that is maintained over a long period, should be addressed primarily with medications or other physician directed treatments. There is a positive relationship between overweight or obesity and blood pressure and risk for hypertension. As early as the 1920s, a significant …

Context:A lack of consensus in the literature examining reproductive health experiences of women with disability prevails, in part, due to various operational definitions of disability.Methods:Results from the 2015–2016 National Health and Nutrition Examination Survey (NHANES) were utilized to assess reproductive health, disability, and demographic variables among women aged 20–44. Disability was assessed using the six functional limitation subgroups. Analyses included modified Poisson regression and negative binomial regression.Results:One hundred eighty-two (14%) women reported having any functional limitation. Women with at least one functional limitation (WWFL) were significantly more likely than women without a functional limitation (WWOFL) to have had a hysterectomy and had more cesarean deliveries. WWFL did not differ significantly from WWOFL in key pregnancy outcomes (ever been pregnant, number of pregnancies, or number of unsuccessful pregnancies). A high degree of overlap between mobility and self-care (66.1%), cognitive and independent living (61%), and mobility and independent living (37.4%) limitations was found.Conclusions:This work summarizes key reproductive health variables among US women of reproductive age and contextualizes disability experiences through subgroup and overlap analysis. Subgroup analysis results demonstrate the need for detailed operational definitions of disability to accurately capture experiences of women with different limitations, and overlap analysis indicates the interconnectedness of limitations among this group. Findings call for future exploration of reproductive health-related similarities and differences between WWD and women without disability, and employment of detailed operational definitions of disability.

The prevalence of obesity has risen substantially during the past 25 years in the United States and most developed countries, with a related increase in type 2 diabetes mellitus.1,2 Almost one third of the adult US population is considered to be obese (body mass index [BMI] ≥30), and 1 in 20 is extremely obese (BMI ≥40).3 Nearly 17% of children and adolescents are overweight in the United States.3 Obesity is associated with increased risk for type 2 diabetes mellitus, coronary heart disease (CHD), hypertension, obstructive sleep apnea, and cancer, higher overall mortality rate,4–6 and decreased longevity.7,8 Extreme obesity can truncate life expectancy in young adults by 5 to 20 years.8 Accordingly, the expected benefits of weight reduction for obese individuals are profound. Weight loss of 5% to 10% generally lessens many health risks, including cardiovascular risks, although such improvements are most notably demonstrable in studies specifically conducted in high-risk populations, and the benefits are presumed to be greater when healthier weight is maintained for long periods.9,10 In overweight and obese individuals, weight loss achieved with most interventions over 1 to 2 years generally leads to improvements in blood pressure (BP), glycemic measures, and triglycerides (TGs). Improvements in total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) have been reported in studies using dietary interventions combined with exercise. When weight loss is achieved primarily via pharmacological interventions, these benefits have not occurred quite so consistently.11 Reduced caloric intake and increased physical activity are generally accepted as the foundations of any approach directed at weight reduction, but these lifestyle interventions do not appear to provide long-lasting success for obese individuals wishing to lose weight. About half of the weight lost with the help of lifestyle interventions is regained at 1 year; after …

Augmented levels of reactive oxygen species (ROS) that overpower the body’s antioxidant defenses result in oxidative stress (OS). Physiologically balanced levels of ROS and antioxidants maintain homeostasis in the body and allow for normal physiological processes to proceed. Physiological processes that involve oxygen consumption inevitably produce ROS. However, an overabundance of ROS leads to widespread injury to cells, and can damage DNA, lipid membranes, and proteins. An unfavorable reproductive environment hinders normal physiology secondary to this disruption of homeostasis. Infertility may be attributed to reproductive pathologies, leading to OS. Infertile couples often turn to assisted reproductive techniques (ART) to improve their chances for a successful pregnancy. In vitro techniques create an unfavorable environment for gametes and embryos by exposing them to a surplus of ROS in the absence of enzymatic antioxidant protection that normally exists in vivo. This article will review the currently available literature on the effects of ROS and OS on ART outcomes. The role of antioxidant supplementation of ART culture media continues to be a subject of interest to increase the likelihood for ART success. Keywords: Antioxidants, assisted reproduction, female infertility, oxidative stress, reactive oxygen species, Physiological processes, reproductive pathologies, gametes, embryos, Infertile couples

The destiny of myomas: should we treat small submucous myomas in women of reproductive age?

Background: Metabolic syndrome in obese individuals presents a significant global health challenge, with ongoing debate regarding the optimal treatment approach. This study aimed to compare the effectiveness of lifestyle modifications versus pharmacological interventions in managing metabolic syndrome among obese individuals over a 24-month period. Methods: This prospective cohort study enrolled 490 obese adults (BMI ≥30 kg/m²) with metabolic syndrome across three tertiary care centers. Participants were allocated to either lifestyle modification (n=245) or pharmacological intervention (n=245) groups. The lifestyle modification group received structured dietary counseling, supervised exercise programs, and behavioral support, while the pharmacological group received standardized medication regimens including metformin, antihypertensives, and statins. Primary outcomes included changes in body weight, waist circumference, blood pressure, and metabolic parameters. Secondary outcomes encompassed treatment adherence, quality of life, cost-effectiveness, and adverse events. Results: At 24 months, the lifestyle modification group demonstrated superior outcomes in weight reduction (-8.4 ± 4.2 kg vs. -6.1 ± 3.8 kg, p=0.008) and waist circumference reduction (-7.8 ± 3.9 cm vs. -5.4 ± 3.6 cm, p=0.006). The pharmacological intervention group showed greater improvements in blood pressure (systolic: -14.8 ± 8.9 vs. -12.3 ± 8.4 mmHg, p=0.042) and glycemic control (HbA1c: -0.7 ± 0.4% vs. -0.5 ± 0.3%, p=0.018). Treatment adherence was higher in the pharmacological group (83.2% vs. 68.9% at 24 months, p=0.002). The lifestyle modification group demonstrated better cost-effectiveness (ICER: $2,834 vs. $4,256 per QALY gained) but higher dropout rates. Adverse events were more frequent in the pharmacological group (32.4% vs. 18.7%, p<0.001) but were predominantly mild to moderate in severity. Conclusions: Both interventions demonstrated distinct advantages in managing different aspects of metabolic syndrome. Lifestyle modifications showed superior outcomes in anthropometric measures and cost-effectiveness, while pharmacological interventions achieved better results in blood pressure control, glycemic parameters, and treatment adherence. These findings suggest that personalized treatment approaches, potentially combining elements of both strategies, may be optimal for managing metabolic syndrome in obese individuals.

Inadequate hypertension control rates: A global concern for countries of all income levels.

BackgroundPolycystic Ovary Syndrome (PCOS) is known as the most common endocrine disorder of women in reproductive ages. With the increasing prevalence of PCOS in different countries, the use of herbal medicine as an alternative treatment is growing in these patients. This study aimed to evaluate the effects of flaxseed powder supplementation on metabolic biomarkers of patients with PCOS.MethodsThis randomized open-labeled controlled clinical trial was conducted on 41 patients with PCOS. The participants were randomized to take either flaxseed powder (30 g/day) plus lifestyle modification or only lifestyle modification for 12 weeks. Anthropometric and biochemical evaluations were performed for all patients at the beginning and end of the study.ResultsThe flaxseed group showed a significant reduction in body weight, insulin concentration, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Triglycerides (TG), high-sensitivity C-Reactive Protein (hs-CRP), and leptin and an increase in Quantitative Insulin-Sensitivity Check Index (QUICKI), High Density Lipoprotein (HDL), and adiponectin compared to the baseline (p < 0.05). Flaxseed supplementation also led to a significant reduction in insulin concentration, HOMA-IR, TG, hs-CRP, Interleukin 6 (IL- 6), and leptin and an increase in QUICKI, HDL, and adiponectin compared to the control group (p < 0.05). No significant changes were observed in other parameters.ConclusionsFlaxseed supplementation plus lifestyle modification was more effective compared to lifestyle modification alone in biochemical and anthropometric variables in patients with PCOS.Trial registrationThe trial protocol was approved by the Ethics Board at Ahvaz Jundishapur University of Medical Sciences and was registered at Iranian Registry of Clinical Trials (code: IRCT20120704010181N11).

Age of despair or age of hope? Elderly Palestinian women's perspectives on health in midlife

To explore Rwandan women's experiences, priorities, and preferences in accessing health care for non-pregnancy-related conditions and inform development of healthcare services related to these conditions among women of reproductive age at district hospitals and health centers in Rwanda. We used a mixed-methods, exploratory sequential design. Semi-structured qualitative interviews were conducted with Rwandan women and coded thematically. A cross-sectional quantitative survey based on the qualitative data was administered to women attending health centers. Seventeen interviews and 150 surveys were conducted. Women identified conditions including back pain, gynecologic cancers, and abnormal vaginal bleeding as concerns. They generally reported positive experiences while accessing health care and knowledge of accessing health care. Barriers to care were identified, including transportation costs and inability to miss work. Women expressed a desire for more control over their care and the importance of maintaining their dignity while accessing health care. These findings provide useful insights to inform development of non-pregnancy-related healthcare services for women in Rwanda according to their priorities and preferences. The reported end-user health concerns, barriers to care, and diminished control over their care point to a need to evolve health systems around user-tailored needs and design interventions optimizing access whilst promoting dignified care.

Human obesity is a complex, multifactorial disorder, with both genetic and environmental determinants, and affects approximately one-third of middle-aged Americans [1]. The incidence of obesity has increased dramatically in the past 10 years in the USA and other countries [2]. Even mild obesity appears to increase cardiovascular and total mortality, in part through accentuating cardiovascular risk factors [3,4]. Obesity is an important risk factor for the development of hypertension [5]. Weight gain promotes hypertension and weight loss decreases blood pressure [6–8]. There have been enormous strides in understanding the biology of obesity, propelled by the discovery of leptin, melanocortins, ghrelin and an avalanche of other compounds regulating appetite, metabolism and adiposity. These advances have emanated in large part from studies of murine models of obesity, but have also been extended to human forms of obesity. Nevertheless, except for rare Mendelian monogenetic forms, the molecular pathogenesis of human obesity is obscure. As a complex, polygenic, multifactorial disease, it is likely that the precise mechanisms of most cases of human obesity will remain obscure, but this should and may not forestall the development of effective therapy. The analogy with human hypertension is appropriate. We know many of the factors regulating arterial pressure. Nevertheless, except for rare Mendelian monogenetic forms, the molecular pathogenesis of human hypertension remains elusive. This has not, however, prevented the development of safe, effective pharmacological therapy for hypertension. The therapy of obesity has lagged behind that of other cardiovascular risk factors, but effective drugs for obesity are now becoming available. In this issue of the journal, Sharma and Golay [9] present a meta-analysis of data from five controlled clinical studies of the effects of the anti-obesity drug orlistat on arterial pressure and body weight in obese hypertensive patients. We will comment on this meta-analysis, and then take the opportunity to offer a provocative perspective on the future of pharmacotherapy for obesity, drawing on lessons from large-scale clinical trials in hypertension. Current pharmacotherapy of obesity Currently, licensed therapies for weight loss include orlistat and sibutramine. Orlistat is a non-absorbed intestinal lipase inhibitor that reduces fat absorption by approximately 30%. Randomized trials have shown that patients receiving orlistat have a weight loss of approximately 10% over a 12-month period, compared to 5% weight reduction with placebo [10,11]. Weight loss is sustained for at least 2 years with continued therapy. In addition to inducing weight loss, orlistat lowers low-density lipoprotein (LDL) by approximately 6%, although this is not accompanied by an increase in high-density lipoprotein (HDL) cholesterol [10,11]. These changes presumably reflect weight loss and decreased absorption of both saturated and unsaturated fats. Orlistat also reduces the risk of developing diabetes by approximately two-thirds in at-risk obese subjects [12], and lowers glycolysated haemoglobin by approximately 0.5% in obese patients with type 2 diabetes [13]. In a substantial minority of patients, orlistat causes gastrointestinal symptoms, which are related to the presence of non-absorbed fat in the colon and stool. In their meta-analysis, Sharma and Golay [9] document that patients treated with orlistat lose more weight and have greater decreases in blood pressure compared to patients treated with placebo [9]. Compared to lifestyle interventions alone, systolic pressure was reduced by approximately 5 mmHg and diastolic pressure by approximately 2 mmHg. A reduction in blood pressure of this magnitude by anti-hypertensive therapy would be expected to reduce major cardiovascular events by 10–20%, so this effect is potentially important [14]. However, the authors fail to emphasize an important point: for a given amount of weight loss, the fall in blood pressure was no greater in patients treated with orlistat than in patients who lost weight on placebo. Thus, there is no evidence that orlistat lowers blood pressure except by promoting weight loss. The clear, if unspoken, intent of their study is to contrast the effects of orlistat-induced weight loss and sibutramine-induced weight loss on blood pressure. As we will note, weight loss induced by sibutramine is not accompanied by the expected lowering of blood pressure. The other licensed drug for treating obesity is sibutramine, which blocks norepinephrine, serotonin and dopamine reuptake in the central nervous system. Sibutramine causes a placebo-corrected 5% long-term weight loss, similar to that observed with orlistat [15]. However, despite weight loss, sibutramine does not decrease arterial pressure [15], and some obese hypertensive patients develop marked hypertension on sibutramine. In contrast to orlistat, sibutramine does not decrease LDL, but does increase HDL by approximately 4% [15]. Sibutramine reduces glycolysated haemoglobin by approximately 0.5% in obese diabetic patients [16]. Headache, dry mouth and constipation occur in approximately 10% of sibutramine-treated patients [15]. One other drug that has weight-reducing actions is metformin, and this has been used in non-diabetic obese patients to induce a weight loss of approximately 3–5% [17,18], with accompanying decreases in LDL and insulin, without hypoglycaemia. However, metformin is not currently licensed for the treatment of obesity in the absence of diabetes mellitus. The challenge of lifestyle interventions Because the current epidemic of obesity is undoubtedly fueled by environmental factors (increased availability of low-cost foods and an increasingly sedentary lifestyle), and because of a lack of safe, dramatically effective pharmacotherapy, attention has focused on lifestyle and behavioural modification. These efforts have largely been disappointing despite claims and hopes to the contrary. Even if initially effective, these behavioural therapies are difficult to sustain, and there is little evidence of their long-term efficacy. In addition, there is evidence that ‘weight cycling’ due to non-sustained weight loss may have undesirable long-term effects on weight and morbidity [19]. If the results of dietary salt restriction for hypertension and of dietary cholesterol restriction for hypercholesterolemia are any indication, then lifestyle modification for prevention and treatment of obesity will continue to prove disappointing. Reluctantly, therefore, we believe that meaningful progress in the treatment of obesity will await safe, effective pharmacotherapy, just as dramatic progress in treatment of hypertension and hypercholesterolemia awaited effective anti-hypertensive and cholesterol-lowering drugs, respectively. Prospects for pharmacotherapy in obesity We stand today at the dawn of effective pharmacotherapy for obesity, just as we did 50 years ago in the treatment of essential hypertension. At that time, the drugs for treatment of hypertension had multiple and troublesome side-effects and were difficult to administer and regulate. Insights into the mechanisms regulating arterial pressure were just emerging. Finally, there was no definite evidence that treatment favourably impacted mortality and major morbid events. This is now history. Landmark outcome trials proved the benefit and safety of pharmacological treatment of essential hypertension [20,21]. The ensuing decades witnessed advances in understanding the regulation of arterial pressure and the development of multiple classes of safe, effective anti-hypertensive drugs. Although various monotherapies proved effective in lowering arterial pressure, the value of combination therapies became apparent. Pharmacotherapy has become the mainstay in the treatment of human hypertension. Rightly or wrongly, dietary sodium restriction is no longer a linchpin in the treatment of human hypertension. Essentially the same story can be told about the treatment of hypercholesterolemia over the last 30 years. We predict that obesity will follow the same path over the next two decades. We believe that recent discoveries of factors regulating appetite and metabolism will lead to the introduction of safe, effective drugs for the treatment of obesity, and that these will become the mainstay of the treatment of obesity, probably often in combination therapy. These might include ghrelin antagonists, melanocortin agonists or leptin sensitizers. There are several important issues that need to be addressed in considering the pharmacotherapy of obesity. First, as with hypertension and hypercholesterolemia, drug therapy for obesity will need to be sustained in almost all patients. The old idea that short-term therapy would be successful was anachronistic and based more on a fear of habituation with amphetamines. With more recent medications, such as orlistat, sibutramine, fenfluramine and phentermine, there is proof principle that sustained pharmacological therapy can both promote and sustain weight loss. Second, after the optimism following the initial promise of fenfluramine and phentermine, we have entered a period of despair. This despair began with the withdrawal of fenfluramine and dexfenfluramine because of an association with valvular heart disease, and this has been reinforced with concerns about increases in arterial pressure with sibutramine. Perhaps most discouraging is evidence that parenteral administration of leptin does not produce ‘clinically’ effective decreases in adiposity in patients with common obesity, presumably because of partial leptin resistance. Leptin therapy is dramatically effective in the rare patients with congenital leptin deficiency and in patients with lipodystrophy, and may yet offer meaningful results in small subsets of patients with common obesity. Nevertheless, it has not proved to be clinically effective in most patients with obesity, presumably because they are leptin resistant. The disappointment of leptin therapy in polygenic common obesity should not dim our optimism. Previous and current drugs for the treatment of obesity were not based on the ‘new biology’ of obesity. Except for leptin, most of the recent advances in the biology of obesity are just beginning to enter the realm of experimental therapeutics, and there is an increasing understanding of the molecular pathophysiology of obesity. We believe that there will be ‘gold in those hills'. Just as the discovery of the factors regulating arterial pressure (the renin–angiotensin–aldosterone system; adrenergic receptors; and calcium channels) led to the development of effective anti-hypertensive therapy, so it is likely that the discovery of the factors regulating appetite and metabolism will lead to the discovery of effective therapy for obesity. Third, what evidence is needed to establish the value of pharmacological therapy for the treatment of obesity? We anticipate that common concensus is that it must sustain as well as promote weight loss. It should minimize the adverse consequences of obesity, such as hypertension, dyslipidemia and insulin resistance. It should not produce serious or annoying adverse effects. However, we submit that it is not enough to demonstrate that pharmacotherapy produces sustained weight loss, reduces risk factors, and is safe. The time has come for large-scale, randomized, controlled clinical trials of the effects of drug(s) on mortality and major morbidity in obesity (i.e. outcome trials). Why are such trials important to the future treatment of obesity? While there is evidence that weight loss decreases arterial pressure and improves diabetes, we simply do not know if sustained weight loss appreciably reduces mortality and major morbidity in obesity. Until we have persuasive evidence that this is the case, physicians will not be convinced that it is worthwhile to treat obesity aggressively, particularly with drugs. While most physicians accept that obesity increases health risks, they are not convinced that the benefits of drug treatment outweigh the risks of obesity and the frustration in treating it. This was true with hypertension before the Veterans Administration Cooperative trials proved the value of anti-hypertensive drug therapy, and it was largely true with hypercholesterolemia until the Scandinavian Simvastatin Survival Study trial demonstrated that aggressive treatment with the statins was even more beneficial than had been anticipated by the proponents of cholesterol lowering [22]. Given that there are now relatively safe drugs that produce appreciable and sustained weight loss, we urgently need a large-scale clinical trial to determine the overall benefit of effective, sustained pharmacological treatment of obesity. Fourth, in evaluating the benefits of therapy for human obesity, it will be important to recognize that obesity has a diverse phenotype or expression. This is true for all diseases, but it is particularly striking for obesity, and this has potentially important implications for treatment. There is a growing realization (based substantially on imaging studies in both rodents and humans) that body mass index (BMI) is an insensitive and crude measure of adiposity and its regional distribution. Upper body and particularly visceral obesity is associated with more adverse consequences than is lower body and subcutaneous obesity [23,24]. The effect of body fat distribution on the adverse consequences of obesity has important implications for the design of clinical trials. We believe that clinical trials for treatment of obesity should at least stratify by the presence of abdominal/visceral obesity. It seems logical that patients with visceral obesity may derive greater benefit from treatment than will patients with peripheral or subcutaneous obesity. Fifth, why is it not enough to treat the risk factors of obesity with proven therapies? In general, it is more difficult to treat risk factors such as hypertension and dyslipidemia in the presence of significant and worsening obesity. Focusing on risk factors in obese patients is treating the consequences rather than cause. In any case, pharmacological induction of weight loss improves cardiovascular risk factors. Although the changes in individual risk factors may appear modest with current drugs for obesity, a 10% decrease in LDL : HDL ratio, a 5 mmHg decrease in systolic pressure, and 0.5% reduction in glycolysated haemoglobin could reduce risk of major cardiovascular events by 15–30% [25,26]. Perhaps, most importantly, obesity has adverse effects on cardiovascular death and events that are independent of hypertension, dyslipidemia and diabetes. In the nurses health study, a BMI above 29 was associated with a 50% increased risk of death compared to subjects with a BMI of under 27, even after allowing for other risk factors [4]. Outcome trials in obesity We believe that a definitive randomized, controlled outcome study in obesity has several prerequisites. It needs to have sufficient statistical power to demonstrate statistically robust reductions in major cardiovascular events (myocardial infarction, stroke, revascularization procedures and cardiovascular death). The sample size should also be sufficient to exclude a deleterious effect on non-cardiovascular mortality, or alternatively demonstrate a reduction in total mortality. This should not be difficult given the substantial lowering of overall cardiovascular risk with even modest weight loss. High-risk obese patients should be recruited, such as those with established atherosclerosis or multiple risk factors that confer an equivalent coronary risk. Entry should not be restricted to patients with just one risk factor or severe obesity, because this would limit the generalizability of the results. Most importantly, the ideal outcome trial in obesity would include randomization to immediate pharmacotherapy or placebo and would not be dependent on failure of lifestyle interventions. Why do we not recommend testing aggressive lifestyle interventions? Because although non-pharmacological treatment has some effects in obesity, these are often fleeting. In addition, most physicians or health care systems do not have the resources available to offer widespread access to the intense, multidisciplinary and sustained interventions that can produce even modest weight loss. Thus, the inclusion of aggressive lifestyle interventions as an essential component of a pharmacological trial might limit the applicability of the results of such a trial. What pharmacological intervention(s) should be tested? Both orlistat and sibutramine have shown sustained reductions in weight, are licensed for weight loss and could be considered. The adverse effect profiles of these drugs would need to be considered. Just as in the treatment of hypertension, combination therapy offers the possibility of more substantial effects. In addition, combination therapy may prevent symptomatic side-effects (by allowing lower doses) and have synergistic effects to minimize adverse effects on risk factors such as blood pressure and HDL (i.e. using sibutramine and orlistat combination). Another possible agent to use, even in non-diabetic patients, would be metformin. The control group should have standard interventions (i.e. physician advice), but not complex, severe lifestyle interventions. The National Institutes of Health is sponsoring the LOOK AHEAD trial to evaluate the benefit of weight reduction in overweight diabetic patients. This 12-year study started recruiting patients in 2002. While this is an important proof of principle study, it has several characteristics that will limit its applicability to clinical practice. First, LOOK AHEAD is recruiting only obese patients with type 2 diabetes, even though most patients with obesity do not have diabetes. Thus, it is a study of obesity-related type 2 diabetes and not of obesity per se. Second, it is not powered to demonstrate a reduction in total mortality, or a convincing neutral effect on non-cardiovascular mortality. Third, LOOK AHEAD is based on the premise that lifestyle interventions are, and will be, the mainstay of obesity treatment, with the use of pharmacotherapy only after patients have failed to lose sufficient weight over the first 6 months. While the intensive and aggressive lifestyle interventions being used in LOOK AHEAD (weekly counselling, behavioural therapy, provision of diets, exercise interventions, etc.) may induce weight loss, these are unlikely to be successfully translated to or sustained in general clinical practice. The limited success of dietary sodium or saturated fat restriction in treating hypertension or hypercholesterolemia offers a salutary lesson. Thus, LOOK AHEAD will provide valuable data on the benefit of aggressive lifestyle modification on obesity-induced type 2 diabetes, but it is not a study of the treatment of obesity per se. We submit that clinical trials of obesity using pharmacotherapy as the principal treatment should begin soon and not await the results of LOOK AHEAD. Conclusions The current epidemic of obesity likely underlies the increasing incidence of type 2 diabetes and the slowing decline in cardiovascular mortality. While intensive lifestyle interventions can reduce weight in some patients, their effects are brief and they require a commitment of resources that most health care providers cannot achieve. The treatment of hypertension and hyperlipidemia was revolutionized by the proof that pharmacological interventions could reduce major cardiovascular events. We now have relatively safe and effective drugs for weight loss that attenuate the adverse cardiovascular risk factors associated with obesity. We submit that it is a public health imperative to prove that pharmacotherapy, even in the absence of vigorous lifestyle interventions, reduces cardiovascular events and mortality in obesity.