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,
,
From the Departments of * Biochemistry and
Urology and the
Institute of Sexual Medicine, Boston
University School of Medicine, Boston, Massachusetts.
| Correspondence to: Dr Abdulmaged M. Traish, Institute for Sexual Medicine, Boston University School of Medicine, 700 Albany St, Room W607, Boston, MA 02118 (e-mail: atraish{at}bu.edu). |
| Received for publication August 18, 2004; accepted for publication November 4, 2004. |
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Abstract |
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Key words: Trabecular smooth muscle, veno-occlusion, fat-containing cells
It is generally accepted that androgens play an important role in the development, growth, and maintenance of function of male secondary sexual characteristics (Dorfman and Shipley, 1956). However, the role of androgens in erectile function remains controversial and poorly understood. Several studies in the rat model have reported that androgen deprivation results in reduction of nitric oxide synthase (NOS) expression and activity (Chamness et al, 1995; Garban et al, 1995; Lugg et al, 1995, 1996; Zvara et al, 1995; Penson et al, 1996; Schirar et al, 1997). However, these observations were not confirmed in the rabbit corpus cavernosum (Holmquist et al, 1994; Traish et al, 1999, 2003), suggesting species differences in NOS regulation by steroid hormones.
Mills et al (1998) suggested that androgen deprivation alters penile blood outflow in the rat, resulting in reduced erectile function (veno-occlusive dysfunction). Rogers et al (2003) showed that castrated rats exhibit depressed expression of NOS, reduced smooth muscle content, and altered dorsal nerve structure and endothelial morphology. These animals display venogenic erectile dysfunction as assessed by intracavernosal pressure (ICP) monitoring and blood flow studies. Testosterone replacement induced vascular smooth muscle growth and restored erectile function. We have demonstrated that androgen deprivation in the animal model by surgical or medical castration resulted in loss of trabecular smooth muscle and increase in deposition of extracellular matrix, producing diffuse fibrosis and erectile dysfunction (Traish et al, 1999, 2003). The androgen-dependent loss of erectile response is restored by androgen administration but not restored by administration of phosphodiesterase type-5 inhibitor (Traish et al, 2003). Because androgens are reported to inhibit differentiation of stroma progenitor cells into adipocytes and to promote differentiation into smooth muscle (Bhasin et al, 2003), we hypothesize that, in the corpus cavernosum, androgens regulate differentiation of progenitor cells into smooth muscle cells and inhibit differentiation into adipocytes. Thus, castration would favor accumulation of adipocytes in the corpus cavernosum and alter its function. The goal of this study was to investigate the hypothesis that androgen depletion favors adipogenic lineage and increases accumulation of fat-containing cells in the corpus cavernosum in vivo.
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Materials and Methods |
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Measurement of Plasma Testosterone
Blood samples were drawn before orchiectomy and then again on the day of
assessment of erectile function. Plasma was processed from each sample,
extracted with ether, and used in a commercially available enzyme-linked
immunosorbent assay kit (Assay Designs Inc, Ann Arbor, Mich) to determine
plasma testosterone levels.
Measurements of Systemic Arterial Pressure and ICP
Animals were anesthetized with intramuscular injection of ketamine (35
mg/kg) and xylazine (5 mg/kg). Anesthesia was maintained with 0.2-mL
intravenous bolus injections of pentobarbital (25 mg/mL) as needed. A 20-gauge
angiocatheter was placed into the carotid artery for measurement of systemic
arterial blood pressure (SAP). A 21-gauge minicatheter was placed near the
base of the penis for measurement of ICP. A midline abdominal incision was
made to expose the perivesical space. The internal pudendal artery was
identified, and the distal branch to the prostate, bladder neck, and
cavernosal bodies was localized. The cavernosal nerve bears relation to the
cavernosal artery on the posterolateral surface of the prostate. With the use
of platinum wire electrodes, we electrically stimulated the cavernosal nerve
at frequencies of 2.5 or 4 Hz with a train of square waves at 10 V and a pulse
width of 8 milliseconds for a total duration of 30 seconds.
Determination of Penile Wet Weight
Animals were euthanized by intravenous administration of sodium
pentobarbital (50 mg/kg). The penis was removed in its entirety by dissecting
along the shaft to the crura and separating each crus from its point of
attachment at the ischial tuberosity. The skin overlying the penile shaft, the
surrounding skeletal muscle, and the corpus spongiosum were removed. The
remaining corpus cavernosum, tunica albuginea, Bucks fascia, and glans of each
penis was weighed on an analytical balance.
Histological Evaluation of Corpus Cavernosum Tissue
Cross sections (3-5 mm thick) from the medial region of the penile shaft
were fixed in 10% formalin buffered with 75 mM phosphate for staining with
hematoxylin and eosin or Masson's trichrome.
Masson's Trichrome Staining of Tissue Sections
Tissue staining by Masson's trichrome was carried out as described
previously (Nehra et al, 1996;
Traish et al, 1999). Briefly,
fixed tissues were embedded in paraffin, sectioned (6 µm), and placed on
Colorfrost Plus glass slides (Fisher Scientific, Pittsburgh, Pa). Tissue
sections were deparaffinized with CitriSolv (Fisher Scientific) and rehydrated
in graded ethanol solutions (100%-70%). Sections were then placed in Bouin's
fixative for 1 hour at room temperature, transferred to 4% ferric ammonium
sulfate for 5 minutes at 50°C, and rapidly rinsed with distilled water at
50°C. Sections were stained with 1% hematoxylin at 50°C for 30 to 60
seconds and destained in 2% ferric ammonium sulfate at room temperature until
only nuclei retained stain. After washing in running water for 10 minutes,
slides were immersed in 0.1% acid fuchsin for 1 minute and gently rinsed by
repeatedly immersing in water 5 times. The slides were then placed in 1%
phosphomolybdic acid for 10 minutes and then stained for 90 seconds in 0.25%
aniline blue/0.5% phosphomolybdic acid. The slides were washed in water until
the rinses became clear and then dehydrated in graded ethanol, cleared with
CitriSolv, and coverslipped with Permount (Fisher Scientific).
Staining of Fat-Containing Cells With Osmium Tetroxide
Penile tissues were fixed in 4.3% glutaraldehyde in 0.03 M Palade's veronal
acetate buffer (pH 7.4) containing 0.07 M KCl and postfixed with 1% osmium
tetroxide. Penile tissues were then embedded in epoxy, and semithin sections
(1-2 µm) were stained with Toluidine blue by adding several drops of
filtered aqueous 1% Toluidine blue/1% borax solution and heated at 70°C to
80°C for 45 seconds. After incubation, the slides were rinsed thoroughly
with water.
Data Analysis
Plasma testosterone data for orchiectomized animals were analyzed by paired
t test. Comparison of hemodynamic data between control and
orchiectomized animals was analyzed by unpaired t test. Comparisons
were considered to be significantly different at P less than or equal
to .05.
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Results |
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Effects of Androgen Deprivation on Penile Corpus Cavernosum Morphology
Histologic examination of hematoxylin and eosin-stained penile tissue
sections from intact (sham-operated control) animals showed normal tissue
morphology with a characteristic network of cavernosal spaces (sinusoids) and
trabecular smooth muscle bundles surrounded by the tunica albuginea
(Figure 1A). In contrast,
penile tissue sections from orchiectomized animals exhibited clusters of
"empty" cellular structures in the subtunical region of the corpus
cavernosum that were distinct from cavernous spaces
(Figure 1B). These hollow cells
resembled adipocytes. When penile tissue was subjected to Masson's trichrome
staining, these hollow cells were consistently present in tissue from
orchiectomized animals but absent in tissue from control animals
(Figure 2).
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Because normal processing of paraffin-embedded tissue with organic solvents results in removal of fat droplets, we fixed penile tissue in glutaraldehyde and postfixed with osmium tetroxide, which binds to unsaturated lipids and results in a brown or gray-black stain. Tissues were then embedded in epoxy resin to verify that the hollow cells were indeed adipocytes. Epoxy-embedded tissue sections were then stained with Toluidine blue to visualize the remaining cellular structures. Although not all cells retained their lipid content, this fixation and staining procedure confirmed the presence of fat globules in a majority of the hollow cells that were observed in paraffin-embedded tissue sections (Figure 3). Interestingly, a few fat cells were always present in the penile tissue of control animals. However, the quantity and distribution of fat-containing cells was greatly increased in tissue sections from orchiectomized animals (Figure 3B).
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Effect of Androgen Deprivation on Erectile Function
In intact animals, the mean baseline ICP/SAP ratio was 0.16 ± 0.10.
Pelvic nerve stimulation at 2.5 and 4 Hz caused a marked increase in the
ICP/SAP ratio in intact animals, with values increasing to 0.48 ± 0.14
at 2.5 Hz and 0.69 ± 0.11 at 4 Hz
(Figure 4). In orchiectomized
animals, the mean baseline ICP/SAP value was 0.19 ± 0.02 and was not
significantly different from that of intact animals. However, as shown in
Figure 4, a marked decrease in
erectile function was observed in orchiectomized animals. The ICP/SAP ratios
were 0.18 ± 0.02 at 2.5 Hz and 0.32 ± 0.11 at 4 Hz for this
group. Androgen deprivation via surgical castration did not result in
significant changes in mean systemic blood pressure (73.8 ± 1.4 mm Hg
in the orchiectomized group vs 72.8 ± 2.4 mm Hg in the control
group).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Several hypotheses have been put forth to explain the decline in erectile function after orchiectomy. These include reduced NO synthesis from decreased expression of NOS isoforms (Chamness et al, 1995; Garban et al, 1995; Lugg et al, 1995, 1996; Zvara et al, 1995; Penson et al, 1996; Schirar et al, 1997) and changes in responsiveness of the vascular smooth muscle to neurotransmitters. Alternatively, we previously proposed that orchiectomy results in an increased extracellular matrix with a concomitant decrease in smooth muscle content (Traish et al, 1999, 2003). These changes contribute to a reduced compliance of the cavernosal bodies that prevents engagement of the veno-occlusive mechanism.
Along with the previously noted histopathologic changes in smooth muscle and connective tissue content, the most striking observation made in this study is the accumulation of fat-containing cells in the corpus cavernosum. These alterations in cavernosal tissue composition and structure are accompanied by a reduced erectile response to pelvic nerve stimulation. It is interesting to note that because veno-occlusion depends on the compression of the subtunical venules to impede blood outflow during sexual stimulation, it is possible that the presence of fat cells in the subtunical region of the corpus cavernosum might contribute to venous leakage in the orchiectomized animal.
Previous studies in the intact rabbit have noted that administration of the endocrine disrupters bisphenol A and tetrachlorodibenzodioxin (TCDD) resulted in an abnormal deposition of fat-containing cells in the subtunical region of the corpus cavernosum (Moon et al, 2001, 2004). However, these reports noted an increase in the trabecular smooth muscle content and thickening of the tunica albuginea. The increase in smooth muscle content is in contrast to that observed with castrated animals (Traish et al, 1999, 2003). Organ bath studies that use cavernosal tissue from bisphenol A and TCDD-treated animals showed a reduced relaxation response to nitroprus-side and acetylcholine. However, no hemodynamic studies were presented to demonstrate the effects of these agents on the erectile response. Interestingly, neonatal rats exposed to the estrogen receptor agonist diethylstilbestrol also showed accumulation of fat-containing cells in the penile corpus cavernosum, whereas animals treated with vehicle exhibited no fat-containing cells (Goyal et al, 2004a,b). The authors suggested that estrogen treatment coupled with low plasma androgen levels contributed to alterations in penile morphology, infertility, and potentially erectile dysfunction (Goyal et al, 2004a,b). However, no hemodynamic or organ bath studies were presented to document that these changes in erectile tissue morphology are related to the erectile response in the estrogen-treated rats.
Masson's trichrome staining of penile tissue confirmed our previous observations that the area occupied by the smooth muscle cells (stained red) was decreased and that of connective tissue (stained blue-purple) increased as a result of orchiectomy (Traish et al, 1999, 2003). Furthermore, the data presented in this study suggest that additional histopathologic changes in the subtunical region of the corpus cavernosum in which fat-containing cells accumulated might interfere with the veno-occlusive mechanism and contribute to erectile dysfunction. It is possible that androgens might modulate the differentiation of the progenitor stroma cells into the myogenic lineage and that androgen deficiency (after orchiectomy) shifts this differentiation into the adipogenic lineage, contributing to accumulation of fat cells in the penis.
Bhasin et al (2003) proposed
that androgens promote the commitment of pluripotent stem cells into a muscle
lineage, whereas androgen deprivation promotes differentiation of pluripotent
stem cells into an adipocyte lineage. In a recent study, Singh et al
(2003) showed that
differentiation of pluripotent cells C3H10T1/2 is androgen dependent. Both
testosterone and dihydrotestosterone decreased the number of adipocytes and
down-regulated the expression of the adipogenic markers PPAR-
-2 and
C/EBP
. However, these mechanisms have yet to be investigated in tissue
or cells from the corpus cavernosum. It is possible that pluripotent stem
cells are present in the corpus cavernosum and that these cells respond to
androgen deprivation by differentiation to an adipogenic lineage.
Another possibility is the dedifferentiation of the corpus cavernosum
trabecular smooth muscle cells into other phenotypes. In several experimental
systems, vascular smooth muscle was shown to undergo dedifferentiation into
other phenotypes (Johnson et al,
2001; Ruker-Martin et al, 2002). Interestingly, Corradi et al
(2004) showed that inhibition
of 5-reductase activity induces stromal remodeling and smooth muscle
dedifferentiation in the prostate. Because 5-reductase converts
testosterone to 5-dihydrotestosterone (5-DHT), these data
suggest that 5-DHT deficiency promotes smooth muscle dedifferentiation.
However, there is no data in the literature on the dedifferentiation of the
trabecular smooth muscle in the corpus cavernosum. Future studies that use
expression of muscle biochemical markers, as well as changes in ultrastructure
as determined by electron microscopy, will be needed to test this possibility
in the corpus cavernosum under androgen deprivation and supplementation.
The role of androgens in erectile function is highly controversial. Although the prevalence of erectile dysfunction increases with age (Feldman et al, 1994), it is not clear whether an association exists between the progressive decrease in the circulating levels of androgens in aging males and erectile dysfunction. Rhoden et al (2002a,b) suggested that although erectile dysfunction showed a clear association with aging, there was no consistent correlation with total plasma testosterone. In men, bioavailable and free testosterone levels decline by about 1.0% and 1.2% per year, respectively, after the age of 40. Clinical symptoms associated with aging and androgen insufficiency are characterized by decreased muscle mass and strength, increased fat mass, loss of libido, erectile dysfunction, impaired cognitive function, and depression. Testosterone supplementation has been shown to be effective in improving androgen deficiency in the hypogonadal older male (Aversa et al, 2000, 2003).
Clinical studies have suggested that surgical or medical castration results in loss of libido and erectile function (Ellis and Grayhack, 1963; Peters and Walsh, 1987; Rousseau et al, 1988; Eri et al, 1994a,b; Greenstein et al, 1995; Hirshkowitz et al, 1997; Marumo et al, 1999). A meta-analysis of 16 studies on the usefulness of androgen replacement therapy for erectile dysfunction by Jain et al (2000) found a statistically significant difference in favor of testosterone over placebo, implying a role for testosterone supplementation in select groups. Recently, Aversa et al (2000) studied 52 men with erectile dysfunction without vascular risk factors in a double-blind correlation analysis. They noted a direct correlation between cavernosal artery resistive index values and free testosterone, a relationship that was maintained after adjusting for age, sex hormone-binding globulin, and estradiol. They concluded that men with erectile dysfunction and low free testosterone might have impaired relaxation of penile smooth muscle, thus providing clinical evidence for the importance of androgen in regulating erectile function. Subsequently, Aversa et al (2003) performed a perspective, randomized, placebo-controlled study in 20 men with erectile dysfunction who failed sildenafil treatment (100 mg dose) on 6 consecutive attempts and had free testosterone in the lower quartile of the lower range. One month after treatment with transdermal testosterone and sildenafil on demand, they found significantly increased scores in the erectile function domain of the International Index of Erectile Function. These data suggest a critical role for testosterone in erectile physiology. Several clinical studies have indicated that the majority of patients undergoing luteinizing hormone-releasing hormone agonist treatment suffer complete or partial loss of erectile function (Peters and Walsh, 1987; Rousseau et al, 1988; Eri et al, 1994a,b; Marumo et al, 1999).
Several lines of evidence for a role of androgens in erectile function are also suggested from animal studies. Baba et al (2000a,b) demonstrated that the ICP decreased significantly in castrated animals (vs control) after both pelvic nerve stimulation or intracavernosal papaverine injection. More importantly, testosterone replacement restored penile hemodynamics. Rogers et al (2003) demonstrated that castrated animals developed venous leakage and veno-occlusive dysfunction and that testosterone treatment restored erectile function. The authors noted a decrease in smooth muscle content and degeneration of trabecular smooth muscle morphology. In the rat model, Mills et al (1992, 1994, 1996, 1998, 1999) and Reilly et al (1997a,b,c) proposed that androgens are critical for maintaining erectile function and might act specifically to support the responsiveness of the vascular smooth muscle to vasoactive agents, maintaining both the inflow and the outflow of blood from the cavernous spaces during erection. Other studies in the rat model have suggested that androgens modulate erectile function by up-regulating NOS activity in the corpus cavernosum (Muller et al, 1988; Lugg et al, 1995; Zvara et al, 1995; Penson et al, 1996). We have reported that androgen insufficiency in the rabbit animal model produced significant loss of trabecular smooth muscle and increased connective tissue deposition but had little effect on neural NOS expression or activity (Traish et al, 1999, 2003).
The effects of androgens on erectile physiology are complex, and androgens modulate various cellular components. We suggest that in the corpus cavernosum, androgens affect 1) smooth muscle cell content and smooth muscle reactivity to vasodilators, 2) connective tissue metabolism, and 3) the differentiation of progenitor stroma cells into myogenic and lipogenic lineages. Thus, androgen deprivation results in erectile dysfunction by altering penile corpus cavernosum structural and functional integrity at multiple cellular components.
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Footnotes |
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 H. O. Goyal, T. D. Braden, C. S. Williams, P. Dalvi, M. Mansour, and J. W. Williams Estrogen-Induced Abnormal Accumulation of Fat Cells in the Rat Penis and Associated Loss of Fertility Depends upon Estrogen Exposure during Critical Period of Penile Development Toxicol. Sci., September 1, 2005; 87(1): 242 - 254. [Abstract] [Full Text] [PDF]
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