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This review examines the most common male sexual dysfunction, premature ejaculation (PE). The prevalence, classification, neurophysiology, neuropharmacology, and psychological studies that offer evidence useful for understanding and clinically evaluating PE are reviewed. It is proposed that there are two basic kinds of PE: biogenic and psychogenic. Studies reporting pharmacological aspects of ejaculation offer some suggestions regarding the mechanisms of ejaculation as well as possible pharmacologic aid for some premature ejaculators. The traditional assumption among sex therapists that PE is almost universally caused by psychological features, and easily treated with sex therapy behavioral techniques, is drawn into question. Based on the limited available results from systematic investigations, behavioral treatments for PE remain beneficial to only a minority of men three years after treatment ends, suggesting that this male dysfunction is difficult to treat effectively. The mediocre results reported in treatment outcome studies may be due, in part, to reports on heterogeneous groups of premature ejaculators, for whom treatment has been generalized rather than targeted to the specific type of PE. We propose a biological and psychological etiology. With more discriminating assessment and more specific diagnosis of PE, and with treatment designed to address the particular type of PE, long-term outcome should improve for this common sexual dysfunction.

As dominant regulators of osteoclastogenesis and bone resorption, receptor activator of NFKB (RANK), receptor activator of NFKB ligand, and OPG have been identified as ideal drug targets for the treatment of metabolic bone disease. One concern regarding the therapeutic use of RANK signaling inhibitors is their effect on fracture healing. Therefore we tested if uncoupling and osteoclast depletion via RANK blockade affects callus formation, maturation and matrix remodeling, as well as union rates in a mouse tibia fracture model. Low dose (1 mg/kg i.p.) RANK:Fc therapy had no effect on callus formation, matrix maturation and remodeling, and resulted in 100'%1 bony union by day 28. High dose RANK:Fc treatment (10 mgikg i.p.) effectively eliminated osteoclasts at the fracture site on day 14, with no significant effects on fracture healing. When therapy was discontinued, normal numbers of osteoclasts were observed at the fracture site by day 28. However. continuous therapy resulted in a large osteopetrotic callus consisting of both mineralized and unmineralized matrix that was void of osteoclasts, but bony union was unaffected at day 28. We also evaluated this process in the complete absence of RANK signaling using RANK -/-mice. These animals exhibited significant radiographic and histologic evidence of callus formation, indicating that RANK signaling is not required for fracture callus formation. However, only 33% of RANK 4-animals formed bony unions compared to 100'%1 of the osteopetrotic control mice. This defect was most likely a result of decreased blood flow, as evidenced by fewer blood vessels in the RANK 4-animals.Together, these data imply that osteoclast depletion via inhibition of RANK signaling is a viable option for the treatment of pathological bone loss since no adverse effects on fracture healing are observed when therapy is discontinued.

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