Open access peer-reviewed chapter

Testosterone and Erectile Function: A Review of Evidence from Basic Research

Written By

Tomoya Kataoka and Kazunori Kimura

Submitted: 01 August 2017 Reviewed: 06 December 2017 Published: 20 December 2017

DOI: 10.5772/intechopen.72935

From the Edited Volume

Sex Hormones in Neurodegenerative Processes and Diseases

Edited by Gorazd Drevenšek

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Androgens are essential for male physical activity and normal erectile function. Hence, age-related testosterone deficiency, known as late-onset hypogonadism (LOH), is considered a risk factor for erectile dysfunction (ED). This chapter summarizes relevant basic research reports examining the effects of testosterone on erectile function. Testosterone affects several organs and is especially active on the erectile tissue. The mechanism of testosterone deficiency effects on erectile function and the results of testosterone replacement therapy (TRT) have been well studied. Testosterone affects nitric oxide (NO) production and phosphodiesterase type 5 (PDE-5) expression in the corpus cavernosum through molecular pathways, preserves smooth muscle contractility by regulating both contraction and relaxation, and maintains the structure of the corpus cavernosum. Interestingly, testosterone deficiency has relationship to neurological diseases, which leads to ED. Testosterone replacement therapy is widely used to treat patients with testosterone deficiency; however, this treatment might also induce some problems. Basic research suggests that PDE-5 inhibitors, L-citrulline, and/or resveratrol therapy might be effective therapeutic options for testosterone deficiency-induced ED. Future research should confirm these findings through more specific experiments using molecular tools and may shed more light on endocrine-related ED and its possible treatments.


  • testosterone
  • erectile dysfunction
  • endothelial function
  • testosterone replacement therapy
  • basic science

1. Introduction

Androgens are essential for male physical activity and normal erectile function [1, 2, 3, 4, 5]. Thus, age-related androgen deficiency, known as late-onset hypogonadism (LOH), is a risk factor for erectile dysfunction (ED) [1, 2]. Several studies have reported that androgen replacement therapy mitigates the symptoms of LOH and ED. In this context, bioidentical or synthetic testosterone facilitates erectile function by maintaining an adequate supply of nitric oxide (NO), penile structure, and the endothelial functioning of the corpus cavernosum. Thus, reduced NO bioavailability is believed to be the main cause of ED in individuals with testosterone deficiency [6]; however, the pathophysiological mechanisms underlying this process remain unclear and require further study. This chapter summarizes relevant basic research reports examining the effects of testosterone on erectile function.


2. Testosterone and erectile function

Androgens are well established as being essential for erectile function, and their deficiency is considered a risk factor for ED. LOH is a result of the normal aging process and is responsible for androgen deficiency [7, 8]. In recent years, epidemiologic studies have suggested that metabolic syndrome and diabetes mellitus are also associated with the development of androgen deficiency [9, 10, 11, 12].

Erectile function is regulated by complex mechanisms [13]. When sexual stimulation occurs, NO is released in the penis, causing corporal smooth muscle relaxation through the activation of the cGMP/protein kinase G signaling cascade. ED results when the relaxant system is weakened; therefore, many studies have focused on smooth muscle relaxation. In contrast, in the flaccid state, corporal smooth muscle contraction is controlled by constrictors such as noradrenaline. Recent studies have indicated that the balance between smooth muscle relaxation and contraction is disturbed by abnormal activation of the RhoA/Rho-kinase signaling pathway. In some syndromes causing ED, such as diabetes mellitus or metabolic syndrome, the RhoA/Rho-kinase signaling pathway is enhanced [14, 15, 16]. Additionally, enhancement of the RhoA/Rho-kinase signaling pathway is known to occur in aged individuals, and a Rho-kinase inhibitor (Y-27632) has been shown to improve erectile function in aged rats [17, 18]. As contractility may play a significant role in erectile function, its role in ED should be considered along with contraction. Thus, the balance between smooth muscle contraction and relaxation is important for normal erectile function.


3. Testosterone deficiency and ED

Most animal studies have shown that castration causes ED by reducing arterial inflow [19]. Further, endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) are important in erectile functioning. In castrated animals, testosterone administration restores the erectile response and NOS expression in the penis [20]. Li et al. showed that testosterone deficiency decreases eNOS activity (phosphor-eNOS/eNOS ratio) by upregulating reactive oxygen species production [21], and the decreased eNOS activity decreases cGMP levels in the penis.

Some studies found that testosterone changes phosphodiesterase type 5 (PDE-5) expression in the penis. Traish et al. showed that castration decreased PDE-5 activity in rabbit penises [22], whereas Zhang et al. showed that testosterone deficiency decreased PDE-5 expression in the rat penis and that testosterone administration increased PDE-5 expression [23]. These results suggest that testosterone is essential not only for regulating eNOS activity but also for regulating PDE-5 activity. Traish et al. also suggested that while these actions may seem paradoxical, in which androgens are upregulating both signal initiators (NOS) and signal terminators (PDE-5), they may be interpreted to be part of a homeostatic mechanism that maintains a relatively constant ratio of critical pathway enzymes [3]. They also postulated that PDE-5 expression may be controlled by NO. Androgen-mediated upregulation of NOS may lead to increased NO synthesis, which may then upregulate PDE-5 expression and activity. Conversely, androgen deprivation-mediated NOS downregulation also results in the downregulation of PDE-5 expression and activity. More studies are needed to define this delicate and crucial mechanism of testosterone action.

Testosterone also affects the smooth muscle of the corpus cavernosum. Reilly et al. showed that castration reduced the number of α-adrenergic-1 receptors on smooth fascia [24]. They also showed that testosterone modulated the adrenergic response of the corpus cavernosum vascular smooth muscle [25]. Their results indicate that when testosterone levels decrease, smooth muscle contractility also decreases. On the other hand, Wingard et al. showed that castration increased the levels of Rho-A and Rho-kinase proteins in rats. RhoA, a small monomeric GTPase, activates the Rho-associated protein kinase, a serine/threonine kinase, which phosphorylates the myosin-binding subunit of myosin light chain phosphatase, thereby deactivating it and promoting contraction [26]. Their results indicate that when testosterone levels decline, smooth muscle contractility increases, leading not only to the development of ED but also to the hypertension. Thus, although testosterone deficiency might increase contraction, additional research is required to fully elucidate its impact on smooth muscle contraction.

Interestingly, testosterone also directly affects smooth muscle relaxation. Yue et al., using an isometric tension study, showed that testosterone relaxed the smooth muscle of rabbit coronary arteries and aortas [27]. Others also showed that testosterone induces the relaxation of isolated human corpora cavernosa strips by activating smooth muscle ATP-sensitive K+ channels [28]. These findings suggest that testosterone, in addition to its known endothelial action, might regulate erectile function locally by acting on human corpus cavernosum smooth muscle. These results indicate that testosterone might affect both the genomic and nongenomic actions of erectile function.

Some studies demonstrated that testosterone also impacts the structure of the penis. One group showed that castrated rats show smooth muscle loss and fibrosis [29], and another group reported that castration increases the collagen content of the internal pudendal arteries and decreases α-actin expression [30]. These testosterone effects suggest that testosterone deprivation results in programmed trabecular smooth muscle cell death (apoptosis) and increased development of extracellular matrix [22]. Traish et al. also proposed that testosterone deprivation is associated with the accumulation of fat-containing cells (fibroblasts or preadipocyte-like cells), especially in the subtunical region of the corpus cavernosum, contributing to impaired veno-occlusion [31]. Interestingly, Wang et al. showed that castration attenuates erectile function and induces corporeal fibrosis by inhibiting autophagy and promoting apoptosis of the corpus cavernosum smooth muscle cells in rats [32]. Their study has limitations, but they highlighted the important role of androgens in maintaining the structural integrity and functioning of the corpus cavernosum. This resulted from androgens mediating the counter-regulation of autophagy and apoptosis through regulation of the BECN 1-Bcl-2 (key dual regulators of autophagy and apoptosis) interaction [33, 34].


4. Testosterone and neurogenic factors

ED has relationships between not only cardiovascular diseases but also neurological diseases. Yang et al. found the hazard risk for Alzheimer’s disease and non-Alzheimer dementia to be greater in patients with ED [35]. They also found that log-rank test revealed that patients with ED had significantly higher cumulative incidence rates of dementia than those without. Yang et al. found the incidence density rate of Parkinson’s disease (PD) was higher in the ED cohort than in the non-ED cohort [36]. Balsamo et al. reported that men with multiple sclerosis had high risk of ED [37]. Interestingly, testosterone deficiency is often observed in these neurological disease patients relative to age-matched controls [38, 39, 40].

In basic study, there are some reports on the relationship between testosterone deficiency and neurogenic factors. Baba et al. reported the mean number of NOS-containing nerve fibers in the corpora cavernosa and in both dorsal nerves of castrated rats [41]. Others also showed that castration decreased nNOS protein expression in the corpus cavernosum [32]. However, reports regarding nNOS responses differ significantly; some studies show increased activity but no change in protein expression [42] in rats, whereas others report no effects in rabbits [43]. Thus, more research into the relationship between nNOS and testosterone is required.

On the other hand, Suzuki et al. measured the ICP during electrical stimulation of the preoptic area and cavernous nerve in castrated male rats with and without testosterone replacement [44]. They showed the actions of testosterone and its metabolites on both the central and peripheral neural pathways are crucial for maintaining and restoring erectile capacity. Syme et al. reported that castration resulted in a decreased erectile response to electrostimulation following nerve grafting due to decreased graft neuronal nitric oxide synthase-positive axonal regeneration [45]. Armagan et al. indicated that testosterone had a neuroprotective role in the nerve fibers of the dorsal nerve and testosterone deficiency led to different forms of nerve degeneration resulting in anatomic alterations [46]. Baba et al. also reported that castration decreased the number of nicotinamide adenine dinucleotide phosphate diaphorase-staining nerve fibers not only in corpus cavernosum but also in dorsal nerve [47]. These results indicate that testosterone deficiency would cause neurogenic dysfunction of erectile tissues; however, future study needs to unravel the mechanism of testosterone action to the nerve systems.


5. Testosterone and metabolic syndrome

Obesity has become a major public health issue that is associated with increased mortality primarily due to increased risks of cardiovascular disease and type 2 diabetes mellitus (T2DM) [1, 48, 49]. Obesity is also considered a strong risk factor for ED [4, 5]. In men, visceral adipose tissue causes arteriosclerosis and vessel endothelial dysfunction [12]. Therefore, men with T2DM have a high incidence of ED [5, 48, 50, 51].

In recent years, epidemiologic studies have suggested that obesity is also associated with multiple alterations in the gonadal endocrine system, including low testosterone levels [1, 48, 52, 53]. Low testosterone levels have also been reported in animals with T2DM, including two seminal research papers that reported testosterone replacement therapy (TRT) in such animal models [54, 55]. Davis et al. administered TRT to obese Zucker rats, resulting in improved cholesterol parameters and insulin sensitivity [54]. On the other hand, others administered TRT to rabbits with high-fat diet-associated hypogonadotropic hypogonadism [55]. TRT partially ameliorated the animals’ blood glucose levels and improved CC sensitivity to acetylcholine and eNOS.

We also reported that T2DM increased inflammatory biomarker (inducible NO synthase, interleukin-6, and tumor necrosis factor alpha) mRNA expression levels in the CC, but TRT decreased them [56]. Ota et al. reported an in vitro study that demonstrated testosterone prevented inflammation caused by hydrogen peroxide in blood vessel cells by upregulating the sirtuin-1 (Sirt1)/eNOS pathway [57, 58]. In one of our studies, testosterone administration upregulated Sirt1 and eNOS mRNA transcription, possibly preventing CC inflammation in T2DM rats (Figures 1 and 2). Interestingly, serum asymmetric dimethylarginine (ADMA) levels were also increased in T2DM rats, and rats receiving TRT were observed to have decreased ADMA levels. ADMA is an endogenous arginine compound that rises in individuals demonstrating some disease states [59]; in particular, several reports have suggested a potential relationship between ADMA levels and ED [60, 61]. ADMA has NOS inhibitory activity, and the elevation of ADMA levels contributes to decreased NO bioactivity and decreased endothelial functioning of vessel tissues. Zhang et al. also reported that testosterone treatment improved nNOS activity using streptozotocin-induced diabetic rat [62].

Figure 1.

The mechanism of erectile dysfunction caused by T2DM.

Figure 2.

The mechanism of ART for T2DM.


6. TRT limitations

TRT is widely used to effectively treat patients with testosterone deficiencies. It has also been applied to animal models for investigating the mechanisms of testosterone action. However, Burns-Cox et al. pointed out that testosterone (testosterone enanthate) injections cause extremely high levels of testosterone after a few days [63]. Similarly, we injected testosterone enanthate into rats, and the animals demonstrated serum testosterone level increases that rose in a dose-dependent manner (Figure 3).

Figure 3.

Testosterone levels after testosterone injection in rat.

Amano et al. reported that the therapeutic administration of testosterone ointment to patients with LOH successfully kept testosterone at normal levels [64]. We administered low-dose testosterone (similar to applying testosterone ointment) to rats, as previous report [65], 4 weeks after castration. Interestingly, this TRT did not improve erectile functioning over the first 4 weeks of administration. However, after 8 weeks of TRT, partial ED improvements were observed (Figure 4). Baba et al. reported that delayed TRT improved ED, in rats, for 4 weeks [41]. However, they used high-dose testosterone administrations and the testosterone levels were ≥10 times normal. These results suggest that low-dose testosterone treatments may require longer treatment periods to overcome testosterone deficiency. Currently, testosterone undecanoate, a drug that is applied over a long period (about 3 months), is widely used in European countries. The medication has been shown to be a safe and effective treatment for patients with testosterone deficiencies [66]. However, some countries have not approved the medication, and there are no basic science reports addressing its use. These results demonstrate the need to investigate differences between various testosterone administration methods.

Figure 4.

Different effects of TRT periods for delayed treatment.

Erectile functioning is a complex process, with an underlying mechanism that is affected by several factors [4, 67, 68, 69]. Recent studies have suggested that one of these factors may be endogenous estrogen levels [70, 71, 72, 73, 74, 75, 76, 77]. For example, Baser et al. suggested that serum estrogen levels are correlated with aging in men and that estrogen may, therefore, play an important role in the expression of the symptoms of aging [70]. Further, Greco et al. reported that tadalafil treatment suppresses estrogen levels in some obese men and improved their erectile function domain scores [71]. Another group reported high estrogen levels in elderly patients with ED and sexual disinterest; therefore, they suggested that pathophysiological estrogen-testosterone imbalance is involved in these conditions among elderly men [72, 73]. In a basic study, Goyal et al. reported that estrogen caused developmental disorders of the rat penis and that it decreased penile testosterone levels [74, 75]. Others reported that estrogen caused pathophysiological changes in the corpus cavernosum and a decline in erectile function in rats [76]. These authors also reported that estrogen induction enhanced corpus cavernosum smooth muscle contraction and decreased smooth muscle relaxation in rabbits [77]. We reported the use of TRT in a rat model of testosterone deficiency induced by estrogen injections. Interestingly, TRT is not an effective ED treatment in the high-estrogen level model [78]. Thus, attention needs to be given not only to the testosterone levels but also to the levels of other hormones.


7. New approaches for testosterone deficiency treatment

Although TRT is an effective treatment for testosterone deficiency, some reports have reported a new treatment approach based on the use of testosterone deficiency models that consider the mechanism of testosterone action on erectile function. PDE-5 inhibitors are the first choice for ED patients, but they are not always effective in patients with testosterone deficiencies [7980]. One of the reasons for the lack of efficacy might be the PDE-5 expression changes induced by testosterone. A combination therapy involving both testosterone and PDE-5 inhibitors is one choice, but it is the one that is being vigorously debated, with strong reasons being presented for and against its use. PDE-5 inhibitors are also effective, but regardless of their pharmacokinetics or the regimen used, none has been shown to cure ED [2].

Moody et al. showed that L-arginine administration also improves ED in castrated rats [81]. Similarly, we demonstrated that L-citrulline supplementation improves erectile function and penile structure in castrated rats [82]. L-arginine and L-citrulline are amino acids present in free form in the human body. When L-citrulline is orally administered, it is converted to L-argininosuccinate and, subsequently, to L-arginine by renal argininosuccinate lyase [83]. L-arginine is then converted to NO and L-citrulline by NOS [84]. Orally administered L-arginine is known to be extensively metabolized by autochthonous gut bacteria and by arginases in the gut and liver [3]. However, oral L-citrulline administrations were shown to avoid such metabolism [85]. Accordingly, oral L-citrulline supplementation was reported to increase L-arginine levels more efficiently than oral L-arginine administration; L-citrulline also increased NO production [86]. In addition, we conducted a similar study using an acute arteriogenic ED model [87]. In that study, oral L-citrulline supplementation improved erectile function and increased NO production, without side effects (e.g., decreased mean arterial pressure) [87].

Fukuhara et al. showed that resveratrol and vardenafil improved erectile responses in rats with streptozotocin-induced diabetes [88]. Recently, Dalaklioglu et al. also reported that resveratrol improved sildenafil-induced corpus cavernosum relaxation in both diabetic and nondiabetic aged rats, probably by potentiating NOS activity [89]. Oral supplementation might improve the vasculogenic condition, considering our previous study, though this is just speculation and needs to be examined.


8. Conclusions

Testosterone levels affect several organs, including the functioning of male erectile tissue. Many studies have described the mechanism of testosterone deficiency effects on erectile function as well as the impact of TRT. Testosterone affects NO production and PDE-5 expression in the corpus cavernosum through molecular pathways. It also preserves smooth muscle contractility by regulating both contraction and relaxation. Further, testosterone maintains the structure of the corpus cavernosum. TRT is widely used to treat patients with testosterone deficiencies; however, the present discussion has also documented some problems associated with this therapeutic approach. Basic research has also identified other potentially effective therapeutic methods for treating testosterone deficiency. Among these, PDE-5 inhibitors, L-citrulline, and resveratrol might be options for treating testosterone deficiency-induced ED. Future research should confirm these findings in more specific experiments that use molecular tools. Such additional research may shed more light on possible treatments for endocrine-mediated ED and its treatment.


Conflict of interest

The authors declare no conflict of interest.


  1. 1. Meldrum DR, Gambone JC, Morris MA, Esposito K, Giugliano D, Ignarro LJ. Lifestyle and metabolic approaches to maximizing erectile and vascular health. International Journal of Impotence Research. 2012;24:61-68
  2. 2. Isidori AM, Buvat J, Corona G, Goldstein I, Jannini EA, Lenzi A, Porst H, Salonia A, Traish AM, Maggi M. A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment: A systematic review. European Urology. 2014;65:99-112
  3. 3. Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: From basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. European Urology. 2007;52:54-70
  4. 4. Shamloul R, Ghanem H. Erectile dysfunction. The Lancet. 2013;381:153-165
  5. 5. Buvat J, Maggi M, Guay A, Torres LO. Testosterone deficiency in men: Systematic review and standard operating procedures for diagnosis and treatment. The Journal of Sexual Medicine. 2013;10:245-284
  6. 6. Maiorino MI, Bellastella G, Esposito K. Lifestyle modifications and erectile dysfunction: What can be expected? Asian Journal of Andrology. 2015;17:5-10
  7. 7. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC. Investigation, treatment and monitoring of late-onset hypogonadism in males. European Journal of Endocrinology. 2008;159:507-514
  8. 8. Morales A, Buvat J, Gooren LJ, Guay AT, Kaufman JM, Tan HM, Torres LO. Endocrine aspects of sexual dysfunction in men. The Journal of Sexual Medicine. 2004;1:69-81
  9. 9. Diaz-Arjonilla M, Schwarcz M, Swerdloff RS, Wang C. Obesity, low testosterone levels and erectile dysfunction. International Journal of Impotence Research. 2009;21:89-98
  10. 10. Yassin A, Saad F, Gooren LJ. Metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone. Andrologia. 2008;40:259-264
  11. 11. Corona G, Mannucci E, Fisher AD, Lotti F, Petrone L, Balercia G, Bandini E, Forti G, Maggi M. Low levels of androgens in men with erectile dysfunction and obesity. The Journal of Sexual Medicine. 2008;5:2454-2463
  12. 12. Shabsigh R, Arver S, Channer KS, Eardley I, Fabbri A, Gooren L, Heufelder A, Jones Z, Meryn S, Zitzmann M. The triad of erectile dysfunction, hypogonadism and the metabolic syndrome. International Journal of Clinical Practice. 2008;62:791-798
  13. 13. Andersson KE, Wagner G. Physiology of penile erection. Physiological Reviews. 1995;75:191-236
  14. 14. Wingard C, Fulton D, Husain S. Altered penile vascular reactivity and erection in the Zucker obese-diabetic rat. The Journal of Sexual Medicine. 2007;4:348-363
  15. 15. Morelli A, Chavalmane AK, Filippi S, Fibbi B, Silvestrini E, Sarchielli E, Zhang XH, Vignozzi L, Vannelli GB, Forti G, Maggi M. Atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced RhoA/Rho-kinase signaling hyperactivation. The Journal of Sexual Medicine. 2009;6:91-106
  16. 16. Wingard CJ, Moukdar F, Prasad RY, Cathey BL, Wilkinson L. Reversal of voltage-dependent erectile responses in the Zucker obese-diabetic rat by rosuvastatin-altered RhoA/Rho-kinase signaling. The Journal of Sexual Medicine. 2009;6:269-278
  17. 17. Rajasekaran H, White S, Baquir A, Wilkes N. Rho-kinase inhibition improves erectile function in aging male Brown-Norway rats. Journal of Andrology. 2005;26:182-188
  18. 18. Jin L, Liu T, Lagoda GA, Champion HC, Bivalacqua TJ, Burnett AL. Elevated RhoA/Rho-kinase activity in the aged rat penis: Mechanism for age-associated erectile dysfunction. The FASEB Journal. 2006;20:536-538
  19. 19. Mills TM, Lewis RW, Stopper VS. Androgenic maintenance of inflow and veno-occlusion during erection in the rat. Biology of Reproduction. 1998;59:1413-1418
  20. 20. Armagan A, Kim NN, Goldstein I, Traish AM. Dose-response relationship between testosterone and erectile function: Evidence for the existence of a critical threshold. Journal of Andrology. 2006;27:517-526
  21. 21. Li R, Meng X, Zhang Y, Wang T, Yang J, Niu Y, Cui K, Wang S, Liu J, Rao K. Testosterone improves erectile function through inhibition of reactive oxygen species generation in castrated rats. PeerJ. 2016;4:e2000
  22. 22. Traish AM, Park K, Dhir V, Kim NN, Moreland RB, Goldstein I. Effects of castration and androgen replacement on erectile function in a rabbit model. Endocrinology. 1999;140:1861-1868
  23. 23. Zhang XH, Morelli A, Luconi M, Vignozzi L, Filippi S, Marini M, Vannelli GB, Mancina R, Forti G, Maggi M. Testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum. European Urology. 2005;47:409-416
  24. 24. Reilly CM, Stopper VS, Mills TM. Androgens modulate the alphaadrenergic responsiveness of vascular smooth muscle in the corpus cavernosum. Journal of Andrology. 1997;18:26-31
  25. 25. Reilly CM, Lewis RW, Stopper VS, Mills TM. Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway. Journal of Andrology. 1997;18:588-594
  26. 26. Sopko NA, Hannan JL, Bivalacqua TJ. Understanding and targeting the Rho kinase pathway in erectile dysfunction. Nature Reviews. Urology. 2014;11:622-628
  27. 27. Yue P, Chatterjee K, Beale C, Poole-Wilson PA, Collins P. Testosterone relaxes rabbit coronary arteries and aorta. Circulation. 1995;91:1154-1160
  28. 28. Han DH, Chae MR, Jung JH, So I, Park JK, Lee SW. Effect of testosterone on potassium channel opening in human corporal smooth muscle cells. The Journal of Sexual Medicine. 2008;5:822-832
  29. 29. Dai YT, Stopper V, Lewis R, Mills T. Effects of castration and testosterone replacement on veno-occlusion during penile erection in the rat. Asian Journal of Andrology. 1999;1:53-59
  30. 30. Alves-Lopes RU, Neves KB, Silva MA, Olivon VC, Ruginsk SG, Antunes-Rodrigues J, Ramalho LN, Tostes RC, Carneiro FS. Functional and structural changes in internal pudendal arteries underlie erectile dysfunction induced by androgen deprivation. Asian Journal of Andrology. 2017;19:526-532
  31. 31. Traish AM, Toselli P, Jeong SJ, Kim NN. Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: A potential mechanism for veno-occlusive dysfunction in androgen deficiency. Journal of Andrology. 2005;26:242-248
  32. 32. Wang XJ, Xu TY, Xia LL, Zhong S, Zhang XH, Zhu ZW, Chen DR, Liu Y, Fan Y, Xu C, Zhang MG, Shen ZJ. Castration impairs erectile organ structure and function by inhibiting autophagy and promoting apoptosis of corpus cavernosum smooth muscle cells in rats. International Urology and Nephrology. 2015;47:1105-1115
  33. 33. Lian J, Karnak D, Xu L. The Bcl-2-Beclin 1 interaction in (−)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Autophagy. 2010;6:1201-1203
  34. 34. Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death and Differentiation. 2011;18:571-580
  35. 35. Yang CM, Shen YC, Weng SF, Wang JJ, Tien KJ. Increased risk of dementia in patients with erectile dysfunction: A population-based, propensity score-matched, longitudinal follow-up study. Medicine (Baltimore). 2015;94:e990
  36. 36. Yang Y, Liu H, Lin T, Kuo Y, Hsieh T. Relationship between erectile dysfunction, comorbidity, and Parkinson’s disease: Evidence from a population-based longitudinal study. Journal of Clinical Neurology. 2017;13:250-258
  37. 37. Balsamo R, Arcaniolo D, Stizzo M, Illiano E, Autorino R, Natale F, Costantini E, Damiano R, De Sio M. Increased risk of erectile dysfunction in men with multiple sclerosis: An Italian cross-sectional study. Central European Journal of Urology. 2017;70:289-295
  38. 38. Barron AM, Pike CJ. Sex hormones, aging, and Alzheimer’s disease. Frontiers in Bioscience (Elite Edition). 2012;4:976-997
  39. 39. Okun MS, McDonald WM, DeLong MR. Refractory nonmotor symptoms in male patients with Parkinson disease due to testosterone deficiency: A common unrecognized comorbidity. Archives of Neurology. 2002;59:807-811
  40. 40. Bove R, Musallam A, Healy BC, Raghavan K, Glanz BI, Bakshi R, Weiner H, De Jager PL, Miller KK, Chitnis T. Low testosterone is associated with disability in men with multiple sclerosis. Multiple Sclerosis. 2014;20:1584-1592
  41. 41. Baba K, Yajima M, Carrier S, Morgan DM, Nunes L, Lue TF, Iwamoto T. Delayed testosterone replacement restores nitric oxide synthase-containing nerve fibres and the erectile response in rat penis. BJU International. 2000;85:953-958
  42. 42. Lugg J, Ng C, Rajfer J, Gonzalez-Cadavid N. Cavernosal nerve stimulation in the rat reverses castration-induced decrease in penile NOS activity. The American Journal of Physiology. 1996;271:E354-E361
  43. 43. Giuliano F, Rampin O, Schirar A, Jardin A, Rousseau JP. Autonomic control of penile erection: Modulation by testosterone in the rat. Journal of Neuroendocrinology. 1993;5:677-683
  44. 44. Suzuki N, Sato Y, Hisasue S, Kato R, Suzuki K, Tsukamoto T. Effect of testosterone on intracavernous pressure elicited with electrical stimulation of the medial preoptic area and cavernous nerve in male rats. Journal of Andrology. 2007;28:218-222
  45. 45. Syme DB, Corcoran NM, Bouchier-Hayes DM, Morrison WA, Costello AJ. The effect of androgen status on the structural and functional success of cavernous nerve grafting in an experimental rat model. The Journal of Urology. 2007;177:390-394
  46. 46. Armagan A, Hatsushi K, Toselli P. The effects of testosterone deficiency on the structural integrity of the penile dorsal nerve in the rat. International Journal of Impotence Research. 2008;20:73-78
  47. 47. Baba K, Yajima M, Carrier S, Akkus E, Reman J, Nunes L, Lue TF, Iwamoto T. Effect of testosterone on the number of NADPH diaphorase-stained nerve fibers in the rat corpus cavernosum and dorsal nerve. Urology. 2000;56:533-538
  48. 48. Buvat J, Maggi M, Gooren L, Guay AT, Kaufman J, Morgentaler A, Schulman C, Tan HM, Torres LO, Yassin A, Zitzmann M. Endocrine aspects of male sexual dysfunctions. The Journal of Sexual Medicine. 2010;7:1627-1656
  49. 49. García-Cruz E, Leibar-Tamayo A, Romero J, Piqueras M, Luque P, Cardeñosa O, Alcaraz A. Metabolic syndrome in men with low testosterone levels: Relationship with cardiovascular risk factors and comorbidities and with erectile dysfunction. The Journal of Sexual Medicine. 2013;10:2529-2538
  50. 50. Esposito K, Giugliano F, Martedì E, Feola G, Marfella R, D’Armiento M, Giugliano D. High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care. 2005;28:1201-1203
  51. 51. Ryan JG, Gajraj J. Erectile dysfunction and its association with metabolic syndrome and endothelial function among patients with type 2 diabetes mellitus. Journal of Diabetes and its Complications. 2012;26:141-147
  52. 52. Wang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, Swerdloff RS, Traish A, Zitzmann M, Cunningham G. Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care. 2011;34:1669-1675
  53. 53. Zhang XH, Melman A, Disanto ME. Update on corpus cavernosum smooth muscle contractile pathways in erectile function: A role for testosterone? The Journal of Sexual Medicine. 2011;8:1865-1879
  54. 54. Davis DD, Ruiz AL, Yanes LL, Iliescu R, Yuan K, Moulana M, Racusen LC, Reckelhoff JF. Testosterone supplementation in male obese Zucker rats reduces body weight and improves insulin sensitivity but increases blood pressure. Hypertension. 2012;59:726-731
  55. 55. Filippi S, Vignozzi L, Morelli A, Chavalmane AK, Sarchielli E, Fibbi B, Saad F, Sandner P, Ruggiano P, Vannelli GB, Mannucci E, Maggi M. Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5 inhibitors in an animal model of male metabolic syndrome. The Journal of Sexual Medicine. 2009;6:3274-3288
  56. 56. Kataoka T, Hotta Y, Maeda Y, Kimura K. Assessment of androgen replacement therapy for erectile function in rats with type 2 diabetes mellitus by examining nitric oxide-related and inflammatory factors. The Journal of Sexual Medicine. 2014;11:920-929
  57. 57. Ota H, Akishita M, Akiyoshi T, Kahyo T, Setou M, Ogawa S, Iijima K, Eto M, Ouchi Y. Testosterone deficiency accelerates neuronal and vascular aging of SAMP8 mice: Protective role of eNOS and SIRT1. PLoS One. 2012;7:e29598
  58. 58. Yu J, Akishita M, Eto M, Ogawa S, Son BK, Kato S, Ouchi Y, Okabe T. Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: Role of phosphatidylinositol 3-kinase/akt pathway. Endocrinology. 2010;151:1822-1828
  59. 59. Bełtowski J, Kedra A. A symmetric dimethylarginine (ADMA) as a target for pharmacotherapy. Pharmacological Reports. 2006;58:159-178
  60. 60. Ioakeimidis N, Vlachopoulos C, Rokkas K, Aggelis A, Terentes-Printzios D, Samentzas A, Alexopoulos N, Stefanadis C. Relationship of asymmetric dimethylarginine with penile Doppler ultrasound parameters in men with vasculogenic erectile dysfunction. European Urology. 2011;59:948-955
  61. 61. Paroni R, Barassi A, Ciociola F, Dozio E, Finati E, Fermo I, Ghilardi F, Colpi GM, Corsi MM, Melzi d’Eril GV. Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and L-arginine in patients with arteriogenic and non-arteriogenic erectile dysfunction. International Journal of Andrology. 2012;35:660-667
  62. 62. Zhang XH, Filippi S, Morelli A, Vignozzi L, Luconi M, Donati S, Forti G, Maggi M.Testosterone restores diabetes-induced erectile dysfunction and sildenafil responsiveness in two distinct animal models of chemical diabetes. The Journal of Sexual Medicine. 2006;3:2535-2545
  63. 63. Burns-Cox N, Gingell JC. Erectile dysfunction: Endocrinological therapies risks and benefits of treatment. In: Carson CC, Kirby RS, editors. Textbook of Erectile Dysfunction. Oxford: Isis Medical Media; 1999. pp. 327-344
  64. 64. Amano T, Imao T, Takemae K, Iwamoto T, Yamakawa K, Baba K, Nakanome M, Sugimori H, Tanaka T, Yoshida K, Katabami T, Tanaka M. Profile of serum testosterone levels after application of testosterone ointment (Glowmin) and its clinical efficacy in late-onset hypogonadism patients. The Journal of Sexual Medicine. 2008;5:1727-1736
  65. 65. Kataoka T, Hotta Y, Maeda Y, Kimura K. Testosterone deficiency causes endothelial dysfunction via elevation of asymmetric dimethylarginine (ADMA) and oxidative stress in castrated rats. The Journal of Sexual Medicine. 2017;14:1540-1548
  66. 66. Yassin AA, Nettleship J, Almehmadi Y, Salman M, Saad F. Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: Real-life experience from an observational registry study. Andrologia. 2016;48:793-799
  67. 67. Keller J, Chen YK, Lin HC. Hyperthyroidism and erectile dysfunction: A population-based case-control study. International Journal of Impotence Research. 2012;24:242-246
  68. 68. Andersen ML, Santos-Silva R, Bittencourt LR, Tufik S. Prevalence of erectile dysfunction complaints associated with sleep disturbances in Sao Paulo, Brazil: A population-based survey. Sleep Medicine. 2010;11:1019-1024
  69. 69. Shaeer O, Shaeer K. The global online sexuality survey (GOSS): The United States of America in 2011. Chapter I: Erectile dysfunction among English-speakers. The Journal of Sexual Medicine. 2012;9:3018-3027
  70. 70. Basar MM, Aydin G, Mert HC, Keles I, Caglayan O, Orkun S, et al. Relationship between serum sex steroids and aging male symptoms score and international index of erectile function. Urology. 2005;66:597-601
  71. 71. Greco EA, Pili M, Bruzziches R, Corona G, Spera G, Aversa A. Testosterone:estradiol ratio changes associated with long-term tadalafil administration: A pilot study. The Journal of Sexual Medicine. 2006;3:716-722
  72. 72. Srilatha B, Adaikan PG, Chong YS. Relevance of oestradiol-testosterone balance in erectile dysfunction patients’ prognosis. Singapore Medical Journal. 2007;48:114-118
  73. 73. Srilatha B, Adaikan PG. Endocrine milieu and erectile dysfunction: Is oestradiol-testosterone imbalance, a risk factor in the elderly? Asian Journal of Andrology. 2011;13:569-573
  74. 74. Goyal HO, Braden TD, Williams CS, Williams JW. Estrogen-induced developmental disorders of the rat penis involve both estrogen receptor (ESR)- and androgen receptor (AR)-mediated pathways. Biology of Reproduction. 2009;81:507-516
  75. 75. Simon L, Avery L, Braden TD, Williams CS, Okumu LA, Williams JW, et al. Exposure of neonatal rats to anti-androgens induces penile mal-developments and infertility comparable to those induced by oestrogens. International Journal of Andrology. 2012;35:364-376
  76. 76. Adaikan PG, Srilatha B. Oestrogen-mediated hormonal imbalance precipitates erectile dysfunction. International Journal of Impotence Research. 2003;15:38-43
  77. 77. Srilatha B, Adaikan PG. Estrogen and phytoestrogen predispose to erectile dysfunction: Do ER-alpha and ER-beta in the cavernosum play a role? Urology. 2004;63:382-386
  78. 78. Kataoka T, Hotta Y, Ohno M, Maeda Y, Kimura K. Limited effect of testosterone treatment for erectile dysfunction caused by high-estrogen levels in rats. International Journal of Impotence Research. 2013;25:201-205
  79. 79. Boloña ER, Uraga MV, Haddad RM, Tracz MJ, Sideras K, Kennedy CC, Caples SM, Erwin PJ, Montori VM. Testosterone use in men with sexual dysfunction: A systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic Proceedings. 2007;82:20-28
  80. 80. Mäkinen JI, Huhtaniemi I. Androgen replacement therapy in late-onset hypogonadism: Current concepts and controversies—A mini-review. Gerontology. 2011;57:193-202
  81. 81. Moody JA, Vernet D, Laidlaw S, Rajfer J, Gonzalez-Cadavid NF. Effects of long-term oral administration of L-arginine on the rat erectile response. The Journal of Urology 1997;158:942-947
  82. 82. Hotta Y, Shiota A, Kataoka T, Motonari M, Maeda Y, Morita M, Kimura K. Oral L-citrulline supplementation improves erectile function and penile structure in castrated rats. International Journal of Urology. 2014;21:608-612
  83. 83. Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Bénazeth S, Cynober L. Almost all about citrulline in mammals. Amino Acids. 2005;29:177-205
  84. 84. Morris SM Jr. Enzymes of arginine metabolism. The Journal of Nutrition. 2004;134:2743S-2747S
  85. 85. Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Böger RH. Pharmacokinetic and pharmacodynamic properties of oral l-citrulline and l-arginine: Impact on nitric oxide metabolism. British Journal of Clinical Pharmacology. 2008;65:51-59
  86. 86. Wijnands KA, Vink H, Briedé JJ, van Faassen EE, Lamers WH, Buurman WA, Poeze M. Citrulline a more suitable substrate than arginine to restore NO production and the microcirculation during endotoxemia. PLoS One 2012;7:e37439
  87. 87. Shiota A, Hotta Y, Kataoka T, Morita M, Maeda Y, Kimura K. Oral l-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction. The Journal of Sexual Medicine. 2013;10:2423-2429
  88. 88. Fukuhara S, Tsujimura A, Okuda H, Yamamoto K, Takao T, Miyagawa Y, Nonomura N, Okuyama A. Vardenafil and resveratrol synergistically enhance the nitric oxide/cyclic guanosine monophosphate pathway in corpus cavernosal smooth muscle cells and its therapeutic potential for erectile dysfunction in the streptozotocin-induced diabetic rat: Preliminary findings. The Journal of Sexual Medicine. 2011;8:1061-1071
  89. 89. Dalaklioglu S, Bayram Z, Tasatargil A, Ozdem S. Resveratrol reverses diabetes-related decrement in sildenafil-induced relaxation of corpus cavernosum in aged rats. Aging Clinical and Experimental Research. 2017;29:345-351

Written By

Tomoya Kataoka and Kazunori Kimura

Submitted: 01 August 2017 Reviewed: 06 December 2017 Published: 20 December 2017