Effects of Androgen on the Expression of Vascular Endothelial Growth Factor in the Penile Corpus Cavernosum

doi:10.1016/j.urology.2011.01.036

Urology

Volume 77, Issue 6, June 2011, Pages 1381-1386

https://doi.org/10.1016/j.urology.2011.01.036 Get rights and content

Objectives

To investigate the effect of orchiectomy and androgen replacement on the expression of vascular endothelial growth factor (VEGF) in rat penile tissue.

Material and Methods

Adult male Sprague-Dawley rats (12 weeks old) were left intact (control) or surgically castrated. Orchiectomized rats were left untreated or received testosterone propionate (TP) for 7 days, beginning 1 or 2 weeks after castration. Erectile function was assessed by measuring intracavernosal pressure in response to cavernous nerve stimulation, and the expression of VEGF protein and mRNA was determined by immunohistochemistry, Western blot analysis, and reverse transcriptase–polymerase chain reaction. Serum testosterone values were measured in each animal by radioimmunoassay.

Results

Serum androgen levels decreased significantly in castrated animals, whereas TP injection normalized the serum levels of testosterone. Intracavernosal pressure was significantly decreased in untreated castrated rats (31.3 ± 15.7% at 2 weeks postcastration; 18.6 ± 4.6% at 3 weeks postcastration) compared with intact controls (58.0 ± 11.4% and 58.9 ± 8.2%, respectively). Erectile function was normalized in androgen-replaced rats, irrespective of treatment was initiation 1 or 2 weeks after orchiectomy. The expression of VEGF protein and mRNA was decreased in the corpus cavernosum of castrated animals compared with controls, whereas androgen replacement normalized the expression of VEGF. These results were consistently observed by all 3 methods of assessment.

Conclusions

These data suggest that androgen regulates the expression of VEGF in rat penile corpus cavernosum and confirms the importance of androgens in the maintenance of erectile function.

Section snippets

Animal Subjects and Treatment Protocol

Sixty adult male Sprague-Dawley rats (12 weeks old) were used in the current study. The rats were separated into 2 groups by time after surgery (group I [n = 30], 1 week; and group II [n = 30], 2 weeks). Each group was then into a control (n = 10), surgical castration (n = 10), and castration with androgen replacement subgroup (n = 10). The control subgroup was sham-operated. Rats were castrated under ketamine anesthesia (35 mg/kg intraperitoneal [ip]) and androgen replacement was achieved by

Serum Testosterone and DHT

Serum testosterone and dihydrotestosterone (DHT) levels were significantly decreased after 1 week of castration (2.20 ± 0.85, 0.10 ± 0.15 ng/mL), which was restored to the control level (3.48 ± 0.76, 0.48 ± 0.11 ng/mL) after testosterone replacement, respectively (P <.05). The mean body weights were not significantly different between any of the treatment groups (Table 1).

Erectile Function Studies

Pelvic nerve stimulation in the castrated group elicited significantly decreased erectile responses compared with those in

Comment

There have been limited studies investigating the effects of various growth factors on nerve regeneration and cavernosal tissue remodeling and function. Given that androgens have been shown to be critical in maintaining erectile tissue structure and function in animals, we examined the relationship between androgens and growth factor expression. Because the corpus cavernosum is a vascular tissue, VEGF served as a suitable candidate that might mediate some of the effects of androgens.

VEGF acts

Conclusions

Our data further reinforce the concept that androgens are important for the maintenance of erectile function and suggest that the VEGF production is androgen-dependent. Androgen deficiency may cause downregulation of VEGF, resulting in an imbalance in connective tissue synthesis and deposition, which leads to cavernosal tissue fibrosis and erectile dysfunction. Further animal model studies are needed for the development of growth factor therapy as a novel treatment for erectile dysfunction.

Acknowledgment

This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and family Affairs, Republic of Korea (A084869).

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Vcsa1 expression and its gene product, sialorphin, increased with testosterone supplementation after castration.28 Vascular endothelial growth factor protein and mRNA decrease in the corpora cavernosa of castrated rats and androgen replacement returned vascular endothelial growth factor to baseline expression.88 RhoA and Rho-kinase protein increased with castration, resulting in a depressed erectile response.55
The biological importance of testosterone is generally accepted by the medical community; however, controversy focuses on its relevance to sexual function and the sexual response, and our understanding of the extent of its role in this area is evolving.
To provide scientific evidence examining the role of testosterone at the cellular and molecular levels as it pertains to normal erectile physiology and the development of erectile dysfunction and to assist in guiding successful therapeutic interventions for androgen-dependent sexual dysfunction.
In this White Paper, the Basic Science Committee of the Sexual Medicine Society of North America assessed the current basic science literature examining the role of testosterone in sexual function and dysfunction.
Testosterone plays an important role in sexual function through multiple processes: physiologic (stimulates activity of nitric oxide synthase), developmental (establishes and maintains the structural and functional integrity of the penis), neural (development, maintenance, function, and plasticity of the cavernous nerve and pelvic ganglia), therapeutically for dysfunctional regulation (beneficial effect on aging, diabetes, and prostatectomy), and phosphodiesterase type 5 inhibition (testosterone supplement to counteract phosphodiesterase type 5 inhibitor resistance).
Despite controversies concerning testosterone with regard to sexual function, basic science studies provide incontrovertible evidence for a significant role of testosterone in sexual function and suggest that properly administered testosterone therapy is potentially advantageous for treating male sexual dysfunction.
Androgen supplementation in rats increases the inflammatory response and prolongs urethral healing
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The peak in VEGFα level in the T+ rats is observed earlier compared with noncastrated rats,11 which suggests a testosterone-mediated induction of this cytokine in urethral healing. Indeed, a recent report showed expression of VEGF in rat corpora cavernosa in response to testosterone.25 The phases of urethral wound healing in the T+ rats were also extended compared with noncastrated rats without preoperative testosterone surge in which the inflammatory phase extended until approximately day 4 and the proliferative phase until day 8,11 supporting a role of increased androgen levels in this process.
To describe the effects of androgens on urethral wound healing, we compared the urethral healing process in castrated Sprague-Dawley rats with and without testosterone supplementation.
Of 30 castrated male Sprague-Dawley rats, 15 received testosterone cypionate (3 mg/kg; T+ rats). All rats underwent an urethroplasty procedure and were sacrificed at postoperative days 5, 10, and 20. Neutrophils, macrophages, vessels, myofibroblasts, Ki67+ cells, collagen, and cytokines were quantified with immunofluorescence and real-time polymerase chain reaction.
Penile length was significantly increased in T+ rats (21.8 vs 13.25 mm; P <.001) and operative time decreased (20.8 vs 23.3 minutes; P <.017). On day 5, T+ rats showed elevated neutrophil (727.4 vs 30.75 per high power field; P = .051) and macrophage counts (1295.8 vs 481.5 per high power field; P = .051) compared with those of T− rats. This elevation persisted throughout day 10 (291.7 vs 34; P = .002 and 1283.7 vs 110.2; P = .005) and day 20 (252.7 vs 12.2; P <.001 and 1672.7 vs 115.2; P <.001) reflecting increased and prolonged inflammation. Myofibroblasts were decreased in T+ rats on day 5 (215.7 vs 808.3; P <.001) and increased by day 10 (1490.1 vs 263.0; P = .001) and day 20 (1964.0 vs 210.0; P <.001) consistent with a delayed onset but with prolongation of the proliferative phase. Limitations include the use of castrated rats, which may have been exposed to androgens before castration.
Testosterone supplementation leads to an increased inflammatory response and myofibroblast proliferation accompanied by prolonged inflammatory and proliferative phases. These novel findings suggest a delayed and possibly impaired urethral healing in the presence of excessive androgens.
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There is evidence that these mechanisms may be disturbed if testosterone is lacking. Thus, animal studies have shown that castration can cause apoptosis of the erectile tissue and endothelium in the penis [22-25]. These changes resulted in veno‐occlusive dysfunction, which proved to be reversible upon subsequent testosterone substitution.
Androgen deprivation therapy (ADT) is commonly used in men with prostate cancer, either as primary therapy or as salvage therapy. The treatment has a range of side effects including sexual dysfunction.
To review available literature on sexual dysfunction in men undergoing ADT and to discuss the management of this dysfunction.
A literature review was performed regarding androgens' role in sexual function and on sexual dysfunction in men receiving ADT.
To describe the prevalence and nature of ADT‐related sexual dysfunction and to give clinical recommendations on the evaluation and treatment of the problem.
Most men experience reductions in both sexual desire and erectile function with ADT. However, approximately 20% of the patients maintain some degree of libido and sexual function. In addition, partner considerations, maintenance of intimacy, and maintaining a sense of masculinity may all be reasons for attempting to uphold a sex life. When counseling and treating patients undergoing ADT, it is important to include partners and to listen to the couples' needs. The patients' choices regarding continued sexual activity should be respected and those who desire to maintain some kind of sexual relationship should be helped in doing so. Treatments may include normal erectogenic aids (phosphodiesterase 5 enzyme inhibitors, intraurethral alprostadil, vacuum erection devices, injection therapy, and penile implants), sexual counseling, and instruction in alternative sexual practices. Management of expectations and partner involvement are crucial.
Sexual function is severely affected in most men undergoing ADT. However, it is important to be aware that a sexual desire may be preserved in some patients. Likewise, it is important to respect that sexual activity is not solely driven by a man's libido. Therefore, issues relating to sexuality should be routinely dealt with in men undergoing ADT. Fode M and Sønksen J. Sexual function in elderly men receiving androgen deprivation therapy (ADT). Sex Med Rev 2014;2:36–46.
Erectile Dysfunction in Inflammaging
2013, Inflammation, Advancing Age and Nutrition: Research and Clinical Interventions
In the current era, it is known that as life expectancy improves, men are seeking to preserve their sexuality and sexual potency into old age. While the appreciation of sexuality persists with aging, a decline in sexual activity is typically seen with, and can be attributed to, both general health problems as well as specific sexual dysfunctions. Erectile dysfunction is the most frequently diagnosed sexual dysfunction in the older male population. This chapter provides an overview of the epidemiology, pathophysiology, assessment, and treatment of erectile dysfunction and the relation of this prevalent sexual dysfunction to the aging process.
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View full text

Male Sexual DysfunctionEffects of Androgen on the Expression of Vascular Endothelial Growth Factor in the Penile Corpus Cavernosum

Objectives

Material and Methods

Results

Conclusions

Section snippets

Animal Subjects and Treatment Protocol

Serum Testosterone and DHT

Erectile Function Studies

Comment

Conclusions

Acknowledgment

J Urol

J Urol

J Sex Med

J Urol

J Urol

J Urol

Eur Urol

J Urol

Mol Cell Endocrinol

J Urol

Biochem Biophys Res Commun

Ann Anat

Ann Anat

Erectile dysfunction

N Engl J Med

Are androgens critical for penile erections in humans?Examining the clinical and preclinical evidence

J Sex Med

Male Sexual Dysfunction
Effects of Androgen on the Expression of Vascular Endothelial Growth Factor in the Penile Corpus Cavernosum