Context: Although commercial weight loss programs provide treatment to millions of clients, their efficacy has not been evaluated in rigorous long-term trials.Objective: To compare weight loss and health benefits achieved and maintained through self-help weight loss vs with a structured commercial program.Design and Setting: A 2-year, multicenter randomized clinical trial with clinic visits at 12, 26, 52, 78, and 104 weeks conducted at 6 academic research centers in the United States between January 1998 and January 2001.Participants: Overweight and obese men (n = 65) and women (n = 358) (body mass index, 27-40) aged 18 to 65 years.Intervention: Random assignment to either a self-help program (n = 212) consisting of two 20-minute counseling sessions with a nutritionist and provision of self-help resources or to a commercial weight loss program (n = 211) consisting of a food plan, an activity plan, and a cognitive restructuring behavior modification plan, delivered at weekly meetings.Main Outcome Measures: Weight change was the primary outcome measure. Secondary outcomes included waist circumference, body mass index, blood pressure, serum lipids, glucose, and insulin levels.Results: At 2 years, 150 participants (71%) in the commercial group and 159 (75%) in the self-help group completed the study. In the intent-to-treat analysis, mean (SD) weight loss of participants in the commercial group was greater than in the self-help group at 1 year (−4.3 [6.1] kg vs −1.3 [6.1] kg, respectively; P<.001) and at 2 years (−2.9 [6.5] kg vs −0.2 [6.5] kg, respectively; P<.001). Waist circumference (P = .003) and body mass index (P<.001) decreased more in the commercial group. Changes in blood pressure, lipids, glucose, and insulin levels were related to changes in weight in both groups, but between-group differences in biological parameters were mainly nonsignificant by year 2.Conclusion: The structured commercial weight loss program provided modest weight loss but more than self-help over a 2-year period.

Reproductive hormonal dynamics were assessed in 10 massively obese men, 200–380% of ideal body weight (percentage ideal body weight) and 11 similarly-aged controls who were 85–135% of ideal body weight. The mean serum testosterone of the obese group was significantly lower than normal (223.1 ± 26.9 (sem) ng/dl vs. 599.2 ± 58.1 ng/dl, P < 0.001). Despite their reduced serum testosterone levels, the obese subjects had normal secondary sexual characteristics except for slightly decreased facial hair and normal sized testes. The mean sex-hormone-binding-globulin level of the obese group was also lower than normal (0.247 ± 0.037 (sem) μg dihydrotestosterone bound/dl vs. 0.672 ±0.125 μg/dl, P < 0.01), while their mean per cent free testosterone, determined by equilibrium dialysis, was higher than normal (4.19 ± 0.29 (SEM) % vs. 2.04 ± 0.08%, P < 0.001). Though the mean free testosterone was not significantly different in the 2 groups (obese 9.5 ± 1.3 (SEM) ng/dl, normal 12.1 ± 1.1 ng/dl), within the obese group there were significant negative correlations between total serum testosterone and percentage ideal body weight (r = −0.85, P < 0.01), as well as between free testosterone and percentage ideal body weight (r = −0.70, P < 0.05). Two of the most obese subjects (wt > 220 kg) had free testosterone concentrations more than two standard deviations below the normal mean. Within the obese group, there was no significant correlation of sex-hormone-binding-globulin with total serum testosterone, free testosterone, or percentage ideal body weight. Baseline serum LH and FSH were normal in 9 obese subjects, including the 2 with low free testosterone, and elevated in one whose free testosterone was normal. The increases in serum LH after LHRH were not subnormal in the obese group, and the 2 subjects with low free testosterone did not have supranormal responses. Increases in serum LH and FSH after clomiphene were normal in the obese group. The serum testosterone of the obese group increased by a mean of 190% after clomiphene and by a further 120% (mean) after HCG, with all subjects attaining a serum testosterone over 600 ng/dl, thus indicating substantial testicular reserve. We conclude that, in massively obese men, 1) serum testosterone and sex-hormone-binding-globulin are low, 2) total serum testosterone and free testosterone correlate negatively with weight but do not correlate significantly with sex-hormone-binding-globulin, 3) responses to LHRH, HCG, and clomiphene indicate substantial reproductive hormonal axis reserve, and 4) a subpopulation (2/10) of the most massively obese subjects may have a defect in the hypothalamic-pituitary axis as suggested by its low free testosterone in the absence of elevated gonadotropins or hyper-response to LRH.

Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro‐opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo‐controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of β‐endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.