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Miki Bloch, MD; David R. Rubinow, MD; Kate Berlin, BA; Karl R. Kevala, MSC; Hee-Yong Kim, MD; Peter J. Schmidt, MD

Arch Gen Psychiatry. 2006;63:450-456.

Context  Although the behavioral effects of high-dose androgen administration may involve alterations in serotonergic activity, few studies have investigated the impact of androgen withdrawal on the central nervous system in humans.

Objective  To examine the effects of pharmacologically induced hypogonadism on several cerebrospinal fluid (CSF) systems that could mediate the behavioral concomitants of hypogonadism.

Design  Double-blind assessment of the effects of the short-term induction of hypogonadism and subsequent replacement with testosterone and placebo in a crossover design.

Setting  National Institutes of Health, Bethesda, Md.

Participants  Twelve healthy male volunteers.

Interventions  We administered the gonadotropin-releasing hormone agonist leuprolide acetate (7.5 mg intramuscularly every 4 weeks) to the healthy male volunteers, creating a hypogonadal state, and then either replaced testosterone (200 mg intramuscularly) or administered a placebo every 2 weeks for 1 month.

Main Outcome Measures  Mood and behavioral symptoms were monitored with daily self-ratings, and lumbar punctures were performed during both hypogonadal (placebo) and testosterone-replaced conditions for CSF levels of steroids and monoamine metabolites.

Results  The CSF testosterone, dihydrotestosterone, and androsterone levels were significantly lower during hypogonadism (P=.002, .04, and .046, respectively), but no significant changes were observed in CSF measures of 5-hydroxyindoleacetic acid, homovanillic acid, dehydroepiandrosterone, or pregnenolone. Decreased sexual interest was observed during the hypogonadal state compared with both baseline and testosterone replacement (P=.009) and correlated significantly with CSF measures of androsterone during both hypogonadism and testosterone replacement (r = –0.76 and –0.81, respectively; P<.01). Moreover, the change in severity of decreased sexual interest correlated significantly with the change in CSF androsterone levels between testosterone replacement and hypogonadism (r = –0.68; P<.05). The CSF 5-hydroxyindoleacetic acid and homovanillic acid levels did not correlate significantly with any behavioral or CSF measure.

Conclusion  These data suggest that the neurosteroid androsterone contributes to the regulation of sexual function in men.

Author Affiliations: Behavioral Endocrinology Branch, National Institute of Mental Health (Drs Bloch, Rubinow, and Schmidt and Ms Berlin), and National Institute of Alcohol Abuse and Alcoholism (Mr Kevala and Dr Kim), National Institutes of Health, Bethesda, Md.

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