The Possible Role of Sex Hormones
in the Development of
Testicular Cancer

E, Rajpert-De Meyts; Ne, Skakkebaek

doi:10.1159/000474570

Cited by 103 publications

(56 citation statements)

References 27 publications

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“…The progression of CIS to malignancy is associated with puberty, as seen by a sharp rise in the age-specific incidence of germ cell tumors following puberty (Rajpert-De Meyts & Skakkebaek 1993). The dramatic change in testicular hormone production is a likely trigger for this malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

et al. 2009

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Activin is a pleiotropic growth factor belonging to the transforming growth factor-b (TGFB) superfamily of signaling molecules. Regulated activin signaling is known to influence several steps in rodent male gamete differentiation. TGFB ligand isoforms, TGFB1-B3, also influence germ cell survival in the rodent testis at the onset of spermatogenesis and around the time of puberty. Given the importance of regulated activin and TGFB signaling in testis development and function, we sought to investigate the cellular production sites of activin/TGFB-signaling modulators in normal and dysfunctional adult human testes samples. Signaling transducers phosphorylated SMAD2/3, and signaling modulators SMAD6, MAN-1, inhibin a (INHA), and b-glycan were detected in Bouins fixed, paraffin-embedded adult human testis sections using immunohistochemistry. Additional samples examined were from testicular cancer patients and from normal men subjected to gonadotropin suppression with androgen-based contraceptives. Our findings identify distinct differences between normal and gonadotropin-deprived human testis in the expression and cellular localization of activin/TGFB-signaling modulators. The presence of a nuclear phosphorylated SMAD2/3 signal in all analyzed seminoma specimens indicated active activin/TGFB signaling. Moreover, a subset of seminoma specimens exhibited selective enhanced expression of b-glycan (4 out of 28 seminoma tumors), INHA (6 out of 28), and MAN-1 (6 out of 28), highlighting potential functional differences between individual tumors in their capacity to regulate activin/TGFB signaling. Within the heterogenous nonseminomas, expression of signaling modulators was variable and reflected the degree of somatic differentiation. Thus, synthesis of activin and TGFB-signaling modulators may be affected by spermatogenic disruption and altered hormone levels in the testis. Reproduction (2009) 138 801-811

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Section: Discussionmentioning

confidence: 99%

Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

et al. 2009

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“…Recently, other suggestions of a genetic basis for TC (Chemes et al 2003, Skakkebaek et al 2003 have been made; however, specific genetic alterations including genetic susceptibility to endocrine disruption are still unknown. Although definitive proof is still lacking, it is generally assumed that the development of TC is under endocrine control (Rajpert-De Meyts et al 1993). In particular, alterations in the pituitary-testicular hormonal axis and/or alterations in gonadotrophin and sex steroid action, are believed to be involved in the development of this tumour and in the progression from the pre-invasive carcinoma in situ stage to invasive tumour (Skakkebaek et al 1987, Rajpert-De Meyts et al 1993.…”

Section: Discussionmentioning

confidence: 99%

“…Although definitive proof is still lacking, it is generally assumed that the development of TC is under endocrine control (Rajpert-De Meyts et al 1993). In particular, alterations in the pituitary-testicular hormonal axis and/or alterations in gonadotrophin and sex steroid action, are believed to be involved in the development of this tumour and in the progression from the pre-invasive carcinoma in situ stage to invasive tumour (Skakkebaek et al 1987, Rajpert-De Meyts et al 1993. This is supposed by clinical observations showing a main peak of TC incidence early after puberty (Prener & Østerlind 1985).…”

Section: Discussionmentioning

confidence: 99%

Molecular analysis of the androgen receptor gene in testicular cancer

Garolla

Ferlin²,

Vinanzi³

et al. 2005

Endocr Relat Cancer

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Testicular cancer (TC) is the most common solid tumour in white males aged 20-34 years, and its incidence has doubled over the past 40 years. Some risk factors for TC have been proposed, such as cryptorchidism, infertility and testicular dysgenesis. However, the causes of TC remain still largely unknown. Recently a genetic basis for TC has been proposed, but specific genetic alterations have not been identified. The risk of TC is markedly increased in subjects with androgen insensitivity and some authors have suggested that mutations in the androgen receptor (AR) gene or disorders of CAG and GGC repeats could be related to TC. However, definitive data have not been produced. In this study, we analysed the AR gene for mutations and CAG and GGC triplets in exon 1 in 123 patients affected by TC. In three patients (2.3%) we found a mutation in the AR gene, two of which represent a novel mutation. Evaluation of CAG and GGC repeat numbers showed no difference with respect to controls when these variables were analysed separately. However, when joint distributions of CAG and GGC were considered, we found that the combination CAG=20/ GGC=17 was significantly more frequent in TC patients (8.1%) with respect to controls (1.7%, P<0.05). Furthermore, we observed that in TC subjects, differently from controls, the joint analysis of CAG and GGC showed a statistically significant dependence among these variable repeats. In conclusion, our data show for the first time a high prevalence of AR gene mutations in patients affected by TC and suggest that some CAG/GGC combinations might be more frequently associated with an increased risk of TC.Endocrine-Related Cancer (2005) 12 645-655

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“…While androgen insensitivity is an important risk factor for TGCTs, especially demonstrated in patients with DSD, 28 an increased androgen signalling during development may, in theory, decrease the risk. 49 Given that the length of the effect, it is likely that mutations in spermatogenic candidate genes will be involved only in those patients who have reduced sperm count. Up to now no specific screening for mutations in spermatogenesis candidate genes has been performed in large enough group of selected cases with impaired spermatogenesis.…”

Section: Other Polymorphismsmentioning

confidence: 99%

Genetic aspects of testicular germ cell tumors

Krausz

Looijenga²

2008

Cell Cycle

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Testicular Germ Cell Tumor (TGCT) is the most common malignant tumor in young Caucasian men with an annual increase of 3-6% in the past 50 years. Data in the literature indicate that both environmental and genetic factors acting on the primordial gonocyte/gonocyte are implicated in the etiopathogenesis of this tumour. Genetic linkage and genome-wide analyses did not reveal a major gene effect so far, implying that multiple loci must contribute to the development of TGCTs. Only one significant genetic risk factor has been reported, the so called "gr/gr" deletion of the Y chromosome which still request further confirmation by independent studies. On the other side, the analysis of somatic genetic changes through mutation and genome imbalance analyses and expression profiling has just began to unravel the complex interaction of multiple pathways involved in TGCTs. This review focuses on genetic factors (both genomic and somatic) involved in the etiology, progression and treatment sensitivity of TGCTs.

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The Possible Role of Sex Hormones in the Development of Testicular Cancer

Cited by 103 publications

References 27 publications

Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

Molecular analysis of the androgen receptor gene in testicular cancer

Genetic aspects of testicular germ cell tumors

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