Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.

Introduction Clomiphene citrate is employed off-label in men who have low testosterone and for the restoration of sperm counts in men who have used exogenous testosterone. Clomiphene is a mixture of two diastereoisomers: zuclomiphene and enclomiphene. We evaluated enclomiphene citrate in men with secondary hypogonadism. Aim Our aim was to compare oral enclomiphene citrate as an alternative to topical testosterone. Main Outcome Measures Blood levels of total testosterone (TT), estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin, thyroid stimulation hormone, prolactin, and insulin-like growth factor 1 IGF-1 were measured at certain times after treatment with each agent. Sperm parameters were determined at the same visits. Free testosterone (FT) was calculated. Methods This was a proof-of-principle, randomized, open-label, fixed dose, active-control, two-center phase IIB study in 12 men with secondary hypogonadism treated previously with topical testosterone. Results After discontinuation of topical testosterone, morning TT values averaged 165 ± 66 pg/dL. After 3 months, there was a significant rise in men receiving enclomiphene citrate and gel that was sustained for 3 months. At 6 months, TT levels were 545 ± 268 and 525 ± 256 pg/dL for groups receiving the gel and enclomiphene citrate, respectively. Only men in the enclomiphene citrate group demonstrated increased LH and FSH. TT decreased one month posttreatment to pretreatment values. Enclomiphene citrate elevated sperm counts in seven out of seven men at 3 months and six out of six men at 6 months with sperm concentrations in the 75–334 × 106/mL range. The gel was ineffective in raising sperm counts above 20 × 106/mL for all five men at 3 months and raised counts in only two or five men at 6 months. At follow-up, only enclomiphene citrate treatment was associated with elevated sperm counts. Conclusions Enclomiphene citrate increased testosterone and sperm counts. Concomitant changes in LH and FSH suggest normalization of endogenous testosterone production and restoration of sperm counts through the hypothalamic–pituitary–testicular axis.

Of 589 men who underwent RP, subjects reported use of at least one erectile aid at 2 years. Frequency of use, and effectiveness of erectile aids, is summarized in Table 1. Factors associated with responsiveness to ED treatment included age, number of comorbidities, baseline PSA, prostate volume, and D'Amico risk stratification. Effectiveness of oral PDE5i was the best predictor of erection quality, defined as erection firm enough for penetration, and sexual satisfaction two years after RP. Of the 140 men in whom PDE5i were ineffective, 35, 39, and 39 subjects tried IA, ICI, and/or VED, respectively; there was no significant difference in the effectiveness of these three aids in this subset of men. Only 4/140 subjects reported achieving an erection firm enough for penetration using these three aids. CONCLUSIONS: Almost all men seeking treatment for ED try PDE5i following surgery. Over 50% of these men report effectiveness of PDE5i 2 years following RP. In cases where PDE5i are ineffective, IA, ICI, and VED may be used for treatment of ED, but erection quality remains poor despite the use of these erectile aids.

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