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Morbid obesity is associated with increased estradiol production as a result of aromatase-dependent conversion of testosterone to estradiol. The elevated serum estradiol levels may inhibit pituitary LH secretion to such extent that hypogonadotropic hypogonadism can result. Normalization of the disturbed estradiol-testosterone balance may be beneficial to reverse the adverse effects of hypogonadism.To examine whether aromatase inhibition with Letrozole can normalize serum testosterone levels in severely obese men with hypogonadotropic hypogonadism.Ten severely obese men, mean age 48.2 ± 2.3 (s.e.) years and body mass index 42.1 ± 2.6 kg/m2, were treated with Letrozole for 6 weeks in doses ranging from 7.5 to 17.5 mg per week.Six weeks of treatment decreased serum estradiol from 120 ± 20 to 70 ± 9 pmol/l (p = 0.006). None of the subjects developed an estradiol level of less than 40 pmol/l. LH increased from 4.5 ± 0.8 to 14.8 ± 2.3 U/l (p < 0.001). Total testosterone rose from 7.5 ± 1.0 to 23.8 ± 3.0 nmol/l (p < 0.001) without a concomitant change in sex hormone-binding globulin level. Those treated with Letrozole 17.5 mg per week had an excessive LH response.Short-term Letrozole treatment normalized serum testosterone levels in all obese men. The clinical significance of this intervention remains to be established in controlled, long-term studies. [ABSTRACT FROM AUTHOR]

It has been suggested that diazoxide (DZX)-mediated insulin suppression may be useful to promote weight loss in obese subjects.To assess the DZX-dose range that is safe to use in obese hyperinsulinaemic men.Assessment of DZX efficacy and safety was based on plasma glucose and insulin responses to a standardized 500-kcal breakfast, taken on the sixth day of treatment. Basic information regarding the potential efficacy of DZX treatment was first evaluated in an open-label study in five non-obese men. Subsequently, a double-blind, randomized, placebo-controlled study was performed in 12 obese but otherwise healthy men, comparing placebo treatment with DZX in doses of 50, 75 and 100 mg three times daily for 6 days.In non-obese subjects, DZX 50 mg decreased peak insulin levels by±28% and raised peak glucose concentration from 7.1 ± 0.6 to 7.8 ± 0.6 mmol/l (p < 0.05). DZX 100 mg reduced peak insulin levels by 45% and caused a rise in peak glucose levels from 7.1 ± 0.6 to 9.0 ± 0.9 mmol/l (p < 0.05). In obese men, the 50 and 75 mg doses had no significant effects on glucose or insulin levels. DZX 100 mg reduced the peak insulin levels and insulin area under the curve by±20% (p < 0.05) but did not affect fasting or postprandial glucose levels. The relatively limited insulin-suppressive effects in obese subjects were attributed to the low plasma DZX levels that were achieved in this group. For comparable doses, plasma DZX levels were about 30% lower in obese than in non-obese men. Plasma DZX levels were highly dependent on dose (p < 0.001) and body weight (p < 0.001). Ninety-two percent of the total variability in DZX levels was explained by these two parameters.DZX-mediated insulin suppression is dose dependent in normal and in obese men. However, the efficacy of DZX is much less in obese than in non-obese subjects. This is attributed to weight-dependent differences in distribution volume that lead to markedly lower plasma DZX levels in obese subjects. Weight-adjusted doses will be needed to achieve biologically effective plasma DZX levels. Extrapolation of the data suggests that effective insulin suppression in obese men will at least require a daily dose of 3.2–4.2 mg/kg. [ABSTRACT FROM AUTHOR]