Monoamines and neurosteroids in sexual function during induced hypogonadism in healthy men.

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.

The passage of 5 alpha-dihydrotestosterone from serum into cerebrospinal fluid and LH negative feedback in castrated rhesus monkeys.

Seven castrated monkeys were given either 50 or 100 micrograms 5 alpha-dihydrotestosterone (DHT) propionate/kg per day. There was no correlation between serum and cerebrospinal fluid (CSF) levels of DHT, which remained very low in the CSF (0.3-0.6% of blood levels) despite the presence of high, supraphysiological amounts in the circulation. There was also no relation between unbound DHT in the blood and the CSF, in which all DHT is unbound. These results differ from previous work on testosterone, the metabolic precursor of DHT. 5 alpha-Dihydrotestosterone propionate at the higher dose maintained suppressed levels of serum LH; LH in two out of four monkeys treated at the lower dose increased to levels observed in castrated, untreated rhesus monkeys. There was no predictable relationship between the amount of DHT in the CSF and levels of LH in the blood: by contrast, DHT in the blood was correlated with serum levels of LH. Levels of LH rose in monkeys in which total blood DHT fell below about 68 nmol/l and, even more obviously, if unbound DHT decreased to less than about 2 nmol/l. Differences between the distribution of testosterone and DHT between blood and CSF cannot be explained by serum binding, lipid solubility or clearance from the brain, and suggest that there may be some mechanism for excluding DHT from the CSF. Though DHT reaches the CSF from the blood in small amounts, levels there do not relate predictably to those in the vascular compartment. It seems unlikely, therefore, that levels of intracerebral DHT are controlled by changes in those of the blood.

Studies on the transfer of steroid hormones across the blood-cerebrospinal fluid barrier in the rhesus monkey. II.

The movement of progesterone (P), cortisol (F) and 17-hydroxyprogesterone (17-OHP) across the blood-cerebrospinal fluid (CSF) barrier was determined using six adult male rhesus monkeys with indwelling canulae in the lateral ventricles of their brains. Tritiated steroids were given iv as a bolus followed by a constant 6 h infusion with continuous collection of CSF and periodic sampling of blood before and during the infusion. The amounts of authentic steroid in the plasma and CSF were determined by recrystallization to constant isotopic ratio and the amount of free plasma steroid was determined by equilibrium dialysis against Ringer's solution. Tritiated progesterone was undetectable in the pooled samples of CSF. The average concentration of tritiated 17-OHP in the CSF was 10.3% of the concurrent plasma level while the concentration of tritiated F was 22.5% of the concurrent plasma level. Plasma free steroid was found to be 2.2% for P, 6.3% for 17-OHP and 22.3% for F, showing a rough correlation between steroid entry into the CSF and free steroid concentration in plasma.