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,
From the * Department of Urology, Suleyman Demirel
University Faculty of Medicine, Isparta, Turkey; and the Departments of
Urology and
Biochemistry, Boston University School of
Medicine, Boston, Massachusetts.
| Correspondence to: Abdulmaged M. Traish, Institute for Sexual Medicine, Department of Urology, Boston University School of Medicine, 700 Albany St., Rm. W607D, Boston, Massachusetts 02118 (e-mail: atraish{at}bu.edu). |
| Received for publication August 22, 2005; accepted for publication January 20, 2006. |
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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1.9 nM), as determined by standard radioimmunoassay.
In the second study, a more sensitive enzyme-linked immunoassay was used to
measure the lower testosterone levels. Using this assay, intact rats had a
mean plasma testosterone concentration of 2.02 ± 0.59 ng/mL.
Intracavernosal pressure measurements indicated that orchiectomy resulted in a
significant reduction in erectile function, when compared to intact animals,
whereas testosterone infusion restored erectile function to varying degrees.
Erectile function was maintained by a wide range of systemic testosterone
levels as low as 10%–12% of normal physiological plasma concentrations.
Below these concentrations, erectile function was significantly and positively
correlated with testosterone plasma levels in a dose-dependent manner.
Interestingly, prostate tissue mass was positively correlated to plasma
testosterone levels across all concentrations examined. Protein expression of
neural nitric oxide synthase (nNOS) and phosphodiesterase type 5 (PDE 5) was
reduced in penile tissue from orchiectomized animals and increased in
testosterone-infused animals, as assessed by Western blot analyses. We suggest
that testosterone at levels approaching one-tenth normal physiological plasma
concentration may represent a threshold value, below which erectile function
declines in a dose-dependent fashion. However, different androgen-dependent
tissues may exhibit varying sensitivities to circulating testosterone with
regard to growth and function.
Key words: Androgens, erection, neural NOS, phosphodiesterase type 5, prostate
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Trachtenberg (1985) evaluated the dose–response relationship between serum testosterone and growth of the prostate, seminal vesicles, and prostate tumors in the rat. The growth of the prostate and seminal vesicles correlated positively with serum testosterone levels. In addition, it was noted that a threshold level of testosterone existed at which prostate, seminal vesicles, and tumor growth was inhibited, but sexual activity was maintained. These observations suggest that different androgen target organs exhibit physiological responses that require varying threshold values of plasma androgens. Unfortunately, in the above study, instead of the actual serum levels of testosterone, only the length of the silastic implants containing testosterone were reported. This did not permit assessment of the minimum level of testosterone required to maintain normal sexual activity in this animal model. Heyns et al (1978) also demonstrated a direct dose relationship between testosterone levels, prostate growth, and prostatic binding protein. Fielder et al (1989) examined the doses of testosterone required to restore normal ventral prostate and testis weights and mating behavior in medically castrated rats (GnRH agonist treatment). The testosterone levels in the plasma needed to maintain scent marking and mating behaviors were lower than that required to maintain prostate and testes weight. These findings suggest that sexual and nonsexual behaviors in the male rat have different testosterone dose requirements, especially those for maintaining spermatogenesis and fertility. Davidson et al (1982) suggested that some aspects of sexual function are maintained by androgen levels that are not optimal for maintaining the metabolic function of other target organs. Although considerable evidence suggests the existence of a threshold value for testosterone in maintaining sexual activity, no values have been reported for erectile function in the animal model.
In men, erectile function, sexual activity, and feelings were restored by relatively low plasma testosterone levels. Studies by Bagatell et al (1994a) suggest that plasma testosterone levels needed for sexual function are lower than that of the pretreatment baseline. However, increasing testosterone levels in eugonadal men had no influence on sexual function (Bagatell et al, 1994b). These observations may explain why some partially hypogondal men continue to have normal sexual function. Studies by Bhasin et al (2000, 2001) suggested that changes in circulating testosterone concentrations, induced by GnRH agonist and testosterone readministration, are associated with testosterone-dependent changes in fat-free mass, muscle size, strength and power, fat mass, hemoglobin, HDL cholesterol, and IGF-I levels, in conformity with a single linear dose–response relationship. However, different androgen-dependent processes have different testosterone dose–response relationships. These data are supported by a recent finding (Gray et al, 2005) in which the relationships between testosterone dose and its effects on sexual function, mood, and visuospatial cognition were investigated in older men. Medical castration by administration of a long-acting GnRH agonist suppressed endogenous testosterone production. Administration of testosterone enanthate was carried out at several doses (25, 50, 125, 300, and 600 mg) weekly for 20 weeks. Changes in overall sexual function and waking erections differed by dose. The free testosterone levels were directly correlated with overall sexual function, waking erections, spontaneous erections, and libido, but not with intercourse frequency or masturbation frequency. The authors suggested that different aspects of male behavior respond differently to testosterone levels. Foresta et al (2003, 2004) suggested that nocturnal penile tumescence (NPT) are androgen dependent even though the threshold value of testosterone required for this physiological response is not yet determined. However, other investigators suggest that there is no relationship between plasma testosterone levels and erectile function in humans (Handelsman and Liu, 2005; Rhoden et al, 2002a,b). Jannini et al (1999) suggested that hypogonadism is a rare cause of impotence and that sexual activity after nonhormonal therapy increases testosterone levels in humans. The authors further postulated that impotence causes a reduction in testosterone levels. The present study was undertaken to determine the dose–response relationship between plasma testosterone levels and erectile response in a castrated rat model, as determined by changes in the intracavernosal pressure, subsequent to electrical stimulation of the cavernosal nerve.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Assessment of Erectile Function
In both study 1 and 2, erectile function was assessed 2 weeks after pump
implantation. Rats were anesthetized with intramuscular injections of ketamine
(50 mg/kg) and xylazine (8 mg/kg). Anesthetized rats were secured in the
supine position and a 2-cm midline neck incision was fashioned to access the
carotid artery and expose the external jugular vein. To continuously monitor
systemic blood pressure, a 24-gauge angiocatheter was introduced into the
carotid artery and connected to a pressure transducer (Transpac IV; Abbott
Laboratories, North Chicago, Ill). A 2-cm lower abdominal midline incision was
fashioned to expose the cavernosal nerve. Exposure was maximized using a Scott
retractor (Lonestar Retractor System, Lone Star Medical Products, Houston,
Tex). Under direct vision, a bipolar platinum wire electrode was carefully
positioned onto the cavernosal nerve. Unilateral nerve stimulation was
accomplished with a Grass S9 stimulator set at normal polarity and repeat mode
to generate a 30-second train of square waves with 6-volt pulse amplitude and
0.8-millisecond pulse duration at various frequencies (2–8 Hz). Correct
placement of the electrode was verified by visual inspection of the penile
shaft during nerve stimulation. To monitor intracavernosal pressure, a
23-gauge needle filled with heparinized saline was inserted into a cavernosal
body near the base of the penis and connected to a second pressure transducer.
Intracavernosal and systemic arterial pressure were continuously recorded by
means of pressure channel amplifiers in the Transonic BLF21D flowmeter
(Transonic Systems, Inc, Ithaca, NY) and Windaq software (Dataq Instruments,
Akron, Ohio).
Determination of Tissue Wet Weight and Plasma Hormone Concentration
After in vivo studies were concluded, blood was collected from each animal
and plasma was frozen for later analysis. The animals were then euthanized and
the prostate tissue was removed. Tissues were cleaned and weighed to obtain
wet weights. Plasma samples were sent to the Endocrinology Laboratory, Animal
Health Diagnostic Center at the Cornell University College of Veterinary
Medicine (Ithaca, NY) for determination of testosterone levels. For both
studies 1 and 2, free testosterone was measured directly in rat plasma with no
further extraction or processing. Samples were diluted if testosterone
concentrations were above the limits of detection. For study 1, a solid-phase
radioimmunoassay (RIA) with Coat-A-Count reagents (Diagnostic Products Corp,
Los Angeles, Calif) was used, as previously described by Reimers et al
(1991). The interassay
variation for this RIA was 6%–11% and the intra-assay variation of
replicate samples was 5% for the medium to high range of concentrations. For
study 2, testosterone was measured using a more sensitive enzyme-linked
immunoassay (EIA; Diagnostic Systems Laboratories, Inc, Webster, Tex). Both
assays are highly specific for testosterone with extremely low (<0.3%) or
nondetectable cross-reactivity for other sex steroid hormones, including
19-nortestosterone, 17
-methyltestosterone, androstenedione,
androstenediol, 5-dihydrotestosterone, dehydroepiandrosterone,
progesterone, and estradiol.
Western Blot Analysis of Neural Nitric Oxide Synthase and Phosphodiesterase Type 5 Protein Expression
Rat penile tissue was frozen in liquid nitrogen and pulverized with a
Bessman tissue pulverizer (Spectrum Laboratories, Rancho Dominguez, Calif)
cooled on dry ice. Tissue powder from each treatment group was pooled and
combined (1 g/4 mL) with ice cold buffer (20 mM HEPES, pH 7.4, 1 mM EDTA, 0.25
M sucrose). After the addition of phenylmethylsulfonylfluoride (PMSF; 0.5 mM)
and mammalian protease inhibitor cocktail (1 mM AEBSF, 0.08 µM aprotinin,
20 µM leupeptin, 40 µM bestatin, 15 µM pepstatin A, and 14 µM
E-64; Sigma Chemical Co, St Louis, Mo), tissue powder was homogenized on ice
using a Brinkmann PT3000 polytron with 10-second bursts and 30-second cooling
intervals. The homogenate was centrifuged at 100 000 x g for 30
minutes and the resulting supernatant was transferred to a new tube and stored
at –80°C until further assay. Soluble protein was determined by the
method of Lowry. Aliquots of penile tissue extract (200 µg/lane) were
electrophoresed on 7.5% polyacrylamide/10% SDS gels under denaturing
conditions and transferred to nitrocellulose membranes. Membranes were
incubated for 1 hour in blocking buffer and then incubated at 4°C for
16–20 hours in primary antibody on a rocking platform. Antibody to
neural NOS (mouse IgG2a, clone 16) was obtained from BD Transduction
Laboratories (Franklin Lanes, NJ) and used at 1:1000 dilution. Rabbit
polyclonal antibody to phosphodiesterase type 5 was made and characterized in
our laboratory and used at 1:5000 dilution (Kim et al, unpublished data).
Membranes were washed and incubated with horseradish peroxidase-linked
anti-mouse or anti-rabbit IgG (Pierce Chemical Co, Rockford, Ill). After
washing, membranes were developed with an enhanced chemiluminescence (ECL) kit
(Pierce Chemical Co, Rockford, Ill) and exposed to autoradiographic film.
Data Analysis
For erectile function studies, the intracavernosal pressure (ICP) was
normalized to the systemic arterial pressure (SAP) by determining the ratio of
ICP/SAP. Using these normalized response curves, peak ICP/SAP, duration and
area-under-the-curve (AUC) were determined for each response using Microsoft
Excel and Windaq software. Smaller elevations in ICP exhibited much slower
decay times (ie, the time to return to baseline pressure) and inaccurately
skewed the parameters of erectile function. To normalize this effect, duration
and AUC were determined at the point when the ICP/SAP response curve decayed
to 50% of the peak ICP/SAP. All data were expressed as mean ± SEM (n =
5 per group for study 1; n = 7 per group for study 2), unless otherwise
indicated. At each independent frequency of nerve stimulation, statistical
comparisons between groups were accomplished by one-way analysis of variance
(ANOVA). If the ANOVA P value was less than .05, post-hoc comparisons
to control were performed using Dunnett's test. Means were considered
significantly different for P values less than .05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1.9 nM),
whereas castrated rats infused with vehicle had plasma testosterone values
that were below the accurate detection limit of the assay (<0.05 ng/mL).
Because the growth of prostate and penile tissues are known to be
androgen-dependent, we determined the wet weights of these target organs in
each animal. Owing to the sensitivity limits of the testosterone assay,
tissues from animals with levels below 0.05 ng/mL were subjected to separate
correlation analyses. As shown in Figure
1, there was a significant positive correlation between plasma
testosterone concentration and prostate weight, whereas penile weights
exhibited a modest correlation that did not reach statistical
significance.
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Castration markedly reduced erectile function in response to cavernosal nerve stimulation (Figure 2), as assessed by the ratio between the peak intracavernosal pressure and systemic arterial pressure (ICP/SAP). This reduction was evident at all frequencies tested. Administration of testosterone at varying doses (44–440 µg/d) resulted in restoration of nerve-stimulated erection. Surprisingly, castrated animals infused with the lowest dose of testosterone (44 µg/d) exhibited erectile activity that was not significantly different from intact animals, despite having plasma testosterone concentrations (0.06 ± 0.01 ng/mL = 0.2 nM) that were one tenth of those detected in intact control animals. Analyses of the data by determining the area under the response curve (AUC) produced similar profiles, suggesting that low plasma testosterone levels are sufficient to maintain erectile response to cavernosal nerve stimulation, when compared to that of castrated animals infused with vehicle. No statistically significant differences were noted in the duration of the erectile response between the various treatment groups (mean response duration = 39.15 ± 1.02 seconds).
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Within each treatment group, including the intact controls, we noted a wide range in plasma testosterone values. Thus, to further examine the relationship between testosterone and erectile function, we plotted the response AUC for each animal as a function of the plasma testosterone concentration (Figure 3). As with tissue weights, two separate correlation analyses were performed, dependent upon plasma testosterone values. Although we observed a moderate correlation between AUC and plasma testosterone concentration, none of the correlations reached statistical significance, further confirming the observation that castrated animals receiving the lowest dose of testosterone maintained similar erectile function as the intact animals.
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7.0 nM) and 15 ± 4 pg/mL in castrated rats infused with vehicle.
On average, a 9%–14% reduction in body weight was observed in castrated
animals, relative to intact controls. However, within the range of
testosterone doses used in the follow-up study, no significant correlation was
observed between testosterone concentration and body weight. In contrast to
the higher range of testosterone replacement doses used in study 1,
significant, dose-dependent differences were observed for all
androgen-sensitive tissues examined (penis, prostate, and seminal vesicle;
Figure 5). Correlation of
tissue weights with plasma testosterone concentrations of individual animals
suggested that the seminal vesicles have the greatest sensitivity to changes
in androgen levels among the tissues examined, followed by the prostate and
then the penis (Figure 6).
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0.9 nM),
which is approximately 12% of the mean value measured in intact animals.
Similar trends were observed when erectile function was assessed by peak
ICP/SAP. Response duration was significantly correlated to testosterone
concentration (P = .018) at the lowest stimulation frequency (2 Hz),
but not at higher stimulation frequencies. Despite the different methods for
determination of plasma testosterone levels in intact animals using the normal
versus the sensitive assay, both studies (study 1 and 2) included a group
infused with 44 µg of testosterone per day (group T4). Plasma testosterone
concentrations in this group were 10% (study 1) and 12% (study 2) of the
intact control group in each respective study. This indicates that each assay
adequately quantified the relative differences in plasma testosterone within
each study and suggests that erectile function is most sensitive to plasma
testosterone at concentrations below 10%–12% of normal physiological
levels.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In other studies, examination of the effects of androgen on regrowth of the
prostate in castrated animals indicated that a threshold of testosterone must
be attained before significant growth was observed. The threshold for
testosterone was two- to threefold greater than that for the high affinity
androgen, 5-DHT (Wright et al,
1999; Vanderschueren et al,
2000). In the rat, a marked decrease in prostate and seminal
vesicle weight was noted after castration, whereas administration of moderate
doses of testosterone (serum levels of 0.38 ng/mL) to orchiectomized rats
resulted in partial maintenance of prostate (45%) and seminal vesicle (52%)
weights (Vanderschueren et al,
2000). Higher doses of testosterone (0.92–2.5 ng/mL)
completely prevented loss of prostate and seminal vesicle tissue weights, as
compared to untreated, castrated rats. The higher dose (2.5 ng/mL) was
considered supraphysiological and was associated with tissue hypertrophy. In
contrast, the suboptimal dose of testosterone (0.38 ng/mL) completely
prevented the loss of bone mineral content and bone mineral density observed
in orchiectomized animals that were not treated with testosterone. Higher
doses of testosterone caused changes similar to the lower dose, suggesting
that the threshold for changes in bone mineral density and content is lower
than that needed to maintain prostate and seminal vesicle growth
(Vanderschueren et al,
2000).
In castrated rhesus monkeys, Mangat (1979) reported that the dose of exogenous testosterone needed to maintain the weight of the accessory reproductive organs, varied significantly between organs. Fjosne et al (1992) demonstrated that induction of ornithine decarboxylase and S-adenosyl-methionine decarboxylase in the accessory reproductive organs of castrated rats exhibited a dose–response relationship with varying threshold values. Similar observations were reported by Yamanaka et al (1975). Furthermore, the androgen threshold to activate copulation in male rats, prenatally exposed to alcohol, stress, or both, increased significantly compared to control animals (Ward et al, 1999). Copulatory behavior and penile reflexes are also shown to exhibit different responses to testosterone doses (Hlinak et al, 1979; Hart et al, 1983). These observations support the notion that different physiological responses have different androgen threshold requirements. It should be noted that several experimental variables can contribute to the assessment of the threshold value of testosterone in erectile function. In the animal model, it is possible that the length of the period postcastration and of androgen administration may be relevant to nerve and tissue remodeling and recovery of the erectile response (Clark et al, 1995). Also, once the administration of hormone is commenced and the treatment is continued for several days, the dose of androgen required to maintain specific physiological function may become independent of the response (Brooks, 1979). We believe that additional time course studies will be necessary to fully address these issues with regard to the effects of the postcastration period and the duration of testosterone replacement on erectile function.
Analysis of the literature clearly indicates that androgen modulation of erectile function exists. In laboratory studies, androgens have been shown to modulate penile tissue innervation (Giuliano et al, 1993), structure and function of penile trabecular smooth muscle (Traish et al, 1999, 2005), penile endothelial function, as well as the fibroelastic properties of the penile corpus cavernosum (Rogers et al, 2003; Shen et al, 2003). Yet, the physiological role of androgens in human penile erection is a subject of constant debate and remains controversial. Amar et al (2005) noted that an association in aging men between the progressive decline in circulating androgen levels and erectile dysfunction has not been clearly demonstrated. Buena et al (1993) suggested that changes in testosterone levels within the normal range had no effect on sexual function. It has been suggested that hypogonadal men with low plasma androgens continue to maintain sexual activity (Handelsman and Liu, 2005) and that testosterone treatment is not warranted. Others, however, have suggested that sexual activity is maintained by androgens and erectile function in older men is dependent on plasma androgen levels (Amar et al, 2005; Bancroft, 2005; Basar et al, 2005; Carani et al, 1990; Davidson et al, 1982; Gray et al, 2005; Harman, 2003; Morelli et al, 2005; Tsitouras et al, 1982; Wang et al, 2004). A recent meta-analysis of clinical studies examining testosterone and sexual function concluded that testosterone treatment results in an improvement of erectile function and that this effect was inversely related to the mean baseline testosterone concentration before treatment (Isidori et al, 2005). Also, testosterone replacement therapy may improve the response of androgen deficient patients to phosphodiesterase inhibitors (Giuliano et al, 2004; Aversa et al, 2003).
Other recent clinical studies have documented that a dose–response relationship exists between plasma testosterone levels and various androgen-dependent functions in target tissues. More specifically, overall sexual function and waking and spontaneous erections were positively correlated with free testosterone in a small cohort of healthy men aged 60–75 years (Gray et al, 2005). Carani et al (1990) suggested that different threshold levels of androgens may be required for sexual function. The authors suggested the presence of a minimum free testosterone threshold, lying near the lower normal range, which determines male sexual function. Moreover, free testosterone levels in serum are a more sensitive index than total testosterone for identifying men with erectile dysfunction who can be successfully treated with androgens. Further, the threshold of testosterone may be lower than that needed to maintain other biological functions such as fertility, muscle mass, or bone mass. Kelleher et al (2004a,b) investigated blood testosterone threshold for androgen deficiency symptoms in men and concluded that despite a wide range in individual thresholds for androgen deficiency symptoms, the mean blood testosterone threshold corresponded to the lower end of the eugonadal reference range for young men. Granata et al (1997) suggested that the threshold for serum testosterone required to maintain sleep related erections is lower than the low end of the normal laboratory male range and is about 200 ng/dL.
It is not clear why sexual function and in particular erectile function requires a lower threshold of testosterone than those needed for the physiological function of other target tissues, such as the accessory reproductive organs. One possibility is discussed by Giuliano et al (1993) in which they proposed that the site of androgen action is the major pelvic ganglion and that androgen regulation of the erectile response is a neuroendocrine process that alters signaling of the pelvic nerve. This, however, remains to be established. We suggest that erectile function is an androgen-dependent physiological process and is maintained by androgens at threshold values that may be far below those required to maintain the function of other target organs.
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Footnotes |
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P < .01 vs T5; n = 7 rats per treatment group.
