J Sex Med. 2014 Apr;11(4):920-9.

Assessment of androgen replacement therapy for erectile function in rats with type 2 diabetes mellitus by examining nitric oxide-related and inflammatory factors.
 

Kataoka T, Hotta Y, Maeda Y, Kimura K.

Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.

 

ABSTRACT:

Introduction: Type 2 diabetes mellitus (T2DM) has become a major public health issue and is considered a risk factor for erectile dysfunction (ED). T2DM is also associated with androgen deficiency. However, there have been few basic studies on androgen replacement therapy (ART) for ED treatment in T2DM animal models, and the mechanism underlying the effect of ART on T2DM-induced ED is unclear.

Aim: To investigate the effect of ART on ED in T2DM rats by examining inflammatory and nitric oxide (NO)-related factors.

Methods: Otsuka Long-Evans Tokushima Fatty (OLETF) rats and their controls, Long-Evans Tokushima Otsuka (LETO) rats, were distributed into 3 groups: LETO, OLETF, and ART. In the ART group, OLETF rats were treated daily with testosterone (3 mg/kg/day, subcutaneously) from 20–25 weeks of age; LETO and OLETF rats received vehicle only.

Main outcome measures: We measured erectile function by using intracavernosal pressure (ICP)/mean arterial pressure (MAP) measurements following electrical stimulation of the cavernous nerve and by evaluating the endothelial function of the corpus cavernosum in an isometric tension study. Expression of endothelial NO synthase (eNOS), inducible NOS (iNOS), sirtuin-1 (Sirt1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) mRNA was detected using polymerase chain reaction.

Results: The ICP/MAP ratio in the OLETF group was significantly decreased and that in the ART group was significantly improved (P < 0.01). The response to acetylcholine was significantly decreased in the OLETF group and improved in the ART group (P < 0.01). Although expression of eNOS and Sirt1 mRNA was decreased and that of iNOS, IL-6, and TNF-α mRNA was increased in the OLETF group, ART improved mRNA expression.

Conclusions: ART-suppressed inflammation in rats with T2DM and metabolic disorders and improved their endothelial and erectile functions. ART could be effective for T2DM-induced ED and may be considered a potential ED treatment method. © 2014 International Society for Sexual Medicine.

KEYWORDS: Androgen Replacement Therapy; Endothelial Dysfunction; Erectile Dysfunction; Inflammation; Obesity; Testosterone; Type 2 Diabetes Mellitus

PMID: 24467772

 

SUPPLEMENT:

Obesity has become a major public health issue and is associated with increased mortality, primarily due to the increased risk of cardiovascular disease and type 2 diabetes mellitus (T2DM). Obesity is also considered a strong risk factor for erectile dysfunction (ED). In recent years, epidemiologic studies have suggested that obesity is associated with multiple alterations in the gonadal endocrine system and with low testosterone levels [1].

  World-biomedical-frontiers-Fig1

 

Patients with androgen deficiency are usually diagnosed with late-onset hypogonadism, and androgen replacement therapy (ART) is attempted. However, there is little evidence to support the benefit of ART in obese and T2DM animal models with ED, as published studies on ART for ED treatment in T2DM animal models have been somewhat basic. The mechanism underlying the effect of ART on T2DM-induced ED has not been sufficiently investigated to date, and thus the mechanism remains unclear. The aim of the present study was to investigate the effect of ART on ED in T2DM rats by examining nitric oxide (NO)-related and inflammatory factors.

 

World-biomedical-frontiers-Fig2

 

T2DM is an independent risk factor for ED because it up-regulates oxidative stress and causes inflammation in the corpus cavernosum (CC). It also causes endothelial dysfunction and tissue damage. In the present study, T2DM increased inflammatory biomarkers (inducible NO synthase [iNOS), interleukin-6 [IL-6), and tumor necrosis factor alpha [TNF-α) mRNA expression) in the CC, but ART decreased them. Ota et al. reported the results of an in vitro study that demonstrated that testosterone prevents inflammation caused by H2O2 in blood vessel cells by upregulating the sirtuin-1 (Sirt1)/endothelial NO synthase (eNOS) pathway [2, 3]. In the current study, ART upregulated Sirt1 and eNOS mRNA transcription, possibly preventing CC inflammation in T2DM rats.

Interestingly, serum asymmetric dimethylarginine (ADMA) levels were increased in T2DM rats, while ART rats were observed to have decreased levels. ADMA is an endogenous arginine compound that is increased in some disease states [4]; in particular, several reports have suggested a potential relationship between ADMA levels and ED [5, 6]. ADMA has NOS inhibitory effects, and elevated ADMA levels contribute to decreased NO bioactivity and endothelial function in vessel tissues.

The results of this study indicate that ART suppressed inflammation in T2DM rats and improved their tissue damage and endothelial dysfunction because ED was improved. Therefore, we believe that ART could be effective for T2DM-induced ED and may be considered a potential ED treatment.

 

REFERENCES

  1. Buvat J, Maggi M, Guay A, Torres LO. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med 2013;10:245-284.
  2. 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.
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  5. 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. Eur Urol 2011;59:948-955.
  6. 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. Int J Androl 2012;35:660-667.

 

Contact

Kazunori Kimura, PhD

Professor

Department of Clinical Pharmaceutics, Graduate School of Medical Sciences, Nagoya City University, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.

E-mail: kkimura@med.nagoya-cu.ac.jp

 
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