Altered circulating hormone levels, endothelial function and vascular reactivity in the testicular feminised mouse

Jones, Rhiannon; Pugh, PJ; Hall, Jennifer; Channer, KS; Jones, T. H.

doi:10.1530/eje.0.1480111

Cited by 77 publications

(63 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Testosterone concentrations in sham-operated Tfm mice were 89% (data not shown), a result also reported by Jones et al (15). Testosterone therapy restored physiological testosterone levels in castrated and Tfm mice, and finally, oxidative damage that occurred in cardiomyocytes after testosterone deficiency and testosterone therapy was observed.…”

Section: Discussionsupporting

confidence: 84%

“…Tfm mice exhibit an X-linked, single-base-pair deletion in the gene encoding the AR. This deletion results in premature termination of AR protein synthesis, which in turn leads to a non-functional AR (14,15). In addition, circulating levels of testosterone are reduced in the Tfm mouse, reportedly 10-fold lower compared to its male littermate (15).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Testosterone suppresses oxidative stress via androgen receptor-independent pathway in murine cardiomyocytes

Xing¹

2011

Mol Med Report

View full text Add to dashboard Cite

Abstract. Evidence supports that oxidative stress exerts significant effects on the pathogenesis of heart dysfunction. On the other hand, the presence of specific androgen receptor (AR) in mammalian cardiomyocytes implies that androgen plays a physiological role in cardiac function, myocardial injury and the regulation of the redox state in the heart. This study used the testicular feminized (Tfm) and castrated male mice to investigate the effects of testosterone deficiency, physiological testosterone therapy and AR on oxidative stress in cardiomyocytes. Tfm mice have a non-functional AR and reduced circulating testosterone levels. Male littermates and Tfm mice were separated into 5 experimental groups: non-castrated littermate controls, castrated littermates, sham-operated Tfm, testosterone-treated castrated littermates and testosteronetreated sham-operated Tfm mice. Cardiomyocytes that were isolated from the left ventricle were used for determination of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) enzyme activities, and malondialdehyde (MDA) levels. Additionally, mitochondrial DNA (mtDNA) deletion mutations were detected by nested PCR. The SOD and GSH-Px enzyme activities of cardiomyocytes were decreased, and the MDA levels and the proportion of mtDNA mutations were increased in castrated and sham-operated Tfm mice compared to control mice. However, an increase was observed in the activities of SOD and GSH-Px enzyme as well as a decrease in MDA levels and the proportion of mtDNA mutations in the mice that had received testosterone therapy. These changes were statistically similar in castrated and sham-operated Tfm mice after testosterone therapy. In conclusion, it is testosterone deficiency that induces oxidative stress in cardiomyocytes. Physiological testosterone therapy is able to suppress oxidative stress mediated via the AR-independent pathway.

show abstract

Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Testosterone suppresses oxidative stress via androgen receptor-independent pathway in murine cardiomyocytes

Xing¹

2011

Mol Med Report

View full text Add to dashboard Cite

show abstract

“…Animal and human studies also suggest direct vasoactive properties. Dose-dependent vasodilatory effects are observed in the presence of androgen receptor (AR) antagonists and in testicular feminised mice (40,41). Alternatively, some of the favourable effects attributed to testosterone may be at least partly due to oestradiol, which is also thought to have beneficial actions.…”

Section: Discussionmentioning

confidence: 99%

Elevated LH predicts ischaemic heart disease events in older men: the Health in Men Study

Hyde

Norman

Flicker

et al. 2011

European Journal of Endocrinology

View full text Add to dashboard Cite

Context: Hypogonadism in men is associated with insulin resistance, elevations in pro-inflammatory cytokines and fibrinogen, and an atherogenic lipid profile. However, it is uncertain whether the age-related decline in testosterone is associated with ischaemic heart disease (IHD) events. Objective: To determine whether testosterone and its associated hormones, sex hormone-binding globulin (SHBG) and LH, predict IHD events in older men. Design: Prospective cohort study. Methods: Between 2001 and 2004, 3637 community-dwelling men aged 70-88 years underwent a clinical assessment of cardiovascular risk factors and biochemical assessment of testosterone, SHBG and LH. Free testosterone was calculated using mass action equations. Participants were followed until December 2008 using electronic record linkage to capture IHD events (hospital admission or death). Results: Mean follow-up was 5.1 years. During this period, 618 men (17.0%; 95% confidence interval (CI) 15.8, 18.3%) experienced an event, of which 160 were fatal. Men with higher baseline total or free testosterone levels experienced fewer IHD events (hazard ratio (HR)Z0.89; 95% CI 0.82, 0.97 and HRZ0.86; 95% CI 0.79, 0.94 for each one S.D. increase in total and free testosterone respectively). These associations were maintained after adjustment for age and waist:hip ratio but did not persist after adjustment for prevalent IHD or other cardiovascular risk factors. SHBG was not associated with IHD events. In contrast, higher LH levels were associated with reduced event-free survival in both univariate (HRZ1.15; 95% CI 1.08, 1.22) and adjusted analyses (HRZ1.08; 95% CI 1.01, 1.15). Conclusions: Dysregulation of the hypothalamic-pituitary-gonadal axis may be a risk factor for IHD. Further studies of men with either elevated LH or low testosterone are warranted.

show abstract

“…Tfm male mice have significantly less endogenous T compared to their wt siblings (Jones et al, 2003), while Tfm male rats have circulating T levels in the high male range (Rosseli et al, 1987). In this regard, the Tfm rat resembles untreated humans with CAIS, who also have circulating T levels in the high-male range (Vague, 1983).…”

mentioning

confidence: 99%

The role of androgen receptors in the masculinization of brain and behavior: What we've learned from the testicular feminization mutation

Zuloaga

Puts

Jordan

et al. 2008

Hormones and Behavior

210

156

View full text Add to dashboard Cite

Many studies demonstrate that exposure to testicular steroids such as testosterone early in life masculinizes the developing brain, leading to permanent changes in behavior. Traditionally, masculinization of the rodent brain is believed to depend on estrogen receptors (ERs) and not androgen receptors (ARs). According to the aromatization hypothesis, circulating testosterone from the testes is converted locally in the brain by aromatase to estrogens, which then activate ERs to masculinize the brain. However, an emerging body of evidence indicates that the aromatization hypothesis cannot fully account for sex differences in brain morphology and behavior, and that androgens acting on ARs also play a role. The testicular feminization mutation (Tfm) in rodents, which produces a nonfunctional AR protein, provides an excellent model to probe the role of ARs in the development of brain and behavior. Tfm rodent models indicate that ARs are normally involved in the masculinization of many sexually dimorphic brain regions and a variety of behaviors, including sexual behaviors, stress response and cognitive processing. We review the role of ARs in the development of the brain and behavior, with an emphasis on what has been learned from Tfm rodents as well as from related mutations in humans causing complete androgen insensitivity. Keywordscomplete androgen insensitivity syndrome -CAIS; vasopressin; anxiety; spatial memory; bed nucleus; medial amygdala; SDN-POA; sexual behavior; aggression; VMH Exposure to testicular steroids such as testosterone (T) early in life masculinizes the developing brain, leading to permanent changes in behavior in a wide variety of animal models (Morris et al., 2004). According to the aromatization hypothesis, T is converted by aromatase into 17-β estradiol (E2), which then acts on estrogen receptors (ERs) to masculinize the brain (Naftolin et al., 1975). Traditionally, aromatization is believed to be the mechanism by which the rodent brain becomes masculinized and defeminized. Some sexually dimorphic regions within the hypothalamus adhere well to this hypothesis, including the sexually dimorphic nucleus of the preoptic area (SDN-POA) and anteroventral periventricular nucleus (AVPV). T spares neuronsCorresponding author: Damian Zuloaga, Neuroscience Program, 108 Giltner Hall, Michigan State University, East Lansing, MI 48824, Phone: Fax: (517) 432-2744, Email: E-mail: zuloagad@msu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript from death in the SDN-POA...

show abstract

Altered circulating hormone levels, endothelial function and vascular reactivity in the testicular feminised mouse

Cited by 77 publications

References 40 publications

Testosterone suppresses oxidative stress via androgen receptor-independent pathway in murine cardiomyocytes

Testosterone suppresses oxidative stress via androgen receptor-independent pathway in murine cardiomyocytes

Elevated LH predicts ischaemic heart disease events in older men: the Health in Men Study

The role of androgen receptors in the masculinization of brain and behavior: What we've learned from the testicular feminization mutation

Contact Info

Product

Resources

About