Estrogen receptor α single nucleotide polymorphism modifies the risk of azoospermia in childhood cancer survivors

Romerius, Patrik; Giwercman, Aleksander; Relander, Thomas; Cavallin‐Ståhl, Eva; Wiebe, Thomas; Halldén, Christer; Giwercman, Yvonne Lundberg

doi:10.1097/fpc.0b013e328343a132

Cited by 22 publications

(23 citation statements)

References 28 publications

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“…36 Genetic polymorphisms could be associated with decreased therapeutic activity (decreased drug activation) or increased toxicity (accelerated drug activation) after treatment with alkylating agents. 37 Other factors that could affect our findings include the use of tobacco, alcohol, or recreational drugs, unreported use of anabolic steroids (participants reporting use of anabolic steroids were excluded from the analysis), obesity, unrecognised or undiagnosed genitourinary abnormalities (eg, varicoceles), and other unknown factors.…”

Section: Discussionmentioning

confidence: 99%

Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

Green

Liu

Kutteh

et al. 2014

The Lancet Oncology

286

197

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Summary Background Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer. Methods We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01–20·3] at diagnosis, 29·0 years [18·4–56·1] at assessment, and a median of 21·0 years [10·5–41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling. Findings Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m2 were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=–0·37, p<0·0001). Mean CED was 10 830 mg/m2 (SD 7274) in patients with azoospermia, 8480 mg/m2 (4264) in patients with oligospermia, and 6626 mg/m2 (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m2 CED for azoospermia (OR 1·22, 95% CI 1·11–1·34), and for oligospermia (1·14, 1·04–1·25), but age at diagnosis and age at assessment were not. Interpretation Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m2. Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services.

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Section: Discussionmentioning

confidence: 99%

Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

Green

Liu

Kutteh

et al. 2014

The Lancet Oncology

286

197

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“…However, another option is that polymorphisms in the SNP rs2207396 , changes the secondary structure of the ESR1 mRNA, possibly leading to changes in mRNA synthesis, splicing, maturation, transport, translation, or degradation [29]. The importance of this SNP is stressed by the fact that same variation in the ESR1 was previously reported to determine the risk of azoospermia in men who during childhood underwent cancer treatment [20].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that G to A substitution in SNP rs2207396, situated in intron 6, of the ESR1 was associated with higher risk of developing azoospermia in childhood cancer survivors [20], pointing to a functional role of this polymorphism. With respect to rs1256049 SNP in ESR2, a synonymous substitution of GTG to GTA in, exon 5 was first shown to be associated with ovulatory dysfunction in women of Chinese origin [21] and later also with male infertility in Caucasian patients [22].…”

Section: Introductionmentioning

confidence: 93%

Estrogen receptor alpha single nucleotide polymorphism as predictor of diabetes type 2 risk in hypogonadal men

et al. 2013

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Estrogen receptor alpha single nucleotide polymorphism as predictor of diabetes type 2 risk in hypogonadal men.Linnér, Carl; Svartberg, Johan; Giwercman, Aleksander; Giwercman, Yvonne Lundberg Link to publication Citation for published version (APA): Linnér, C., Svartberg, J., Giwercman, A., & Giwercman, Y. L. (2013). Estrogen receptor alpha single nucleotide polymorphism as predictor of diabetes type 2 risk in hypogonadal men. The Aging Male, 16(2), 52-57. DOI: 10.3109/13685538.2013.772134 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal AbstractEstradiol (E2) is apart from its role as a reproductive hormone also important for cardiac function and bone maturation in both genders. It has also been shown to play a role in insulin production, energy expenditure and in inducing lipolysis. The aim of the study was to investigate if low circulating testosterone or E2 levels in combination with variants in the estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2) genes were of importance for the risk of type-2 diabetes.The single nucleotide polymorphisms rs2207396 and rs1256049, in ESR1 and ESR2, respectively, were analysed by allele specific PCR in 172 elderly men from the population based Tromsø study. The results were adjusted for age.In individuals with low total (≤11 nmol/L) or free testosterone (≤0.18 nmol/L) being carriers of the variant A-allele in ESR1 was associated with 7.3 and 15.9 times, respectively increased odds ratio of being diagnosed with diabetes mellitus type 2 (p = 0.025 and p = 0.018, respectively).Lower concentrations of E2 did not seem to increase the risk of being diagnosed with diabetes.In conclusion, in hypogonadal men, the rs2207396 variant in ESR1 predicts the risk of type 2 diabetes.3

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“…Regarding the estrogen receptors, it was demonstrated that polymorphisms in ERα are associated with azoospermia (Romerius et al, 2011) and are more likely to be associated with the risk of seminoma and metastasis (Brokken et al, 2012); whereas polymorphisms in ERβ are more likely to be link to altered spermatogenesis (Aschim et al, 2005) and with risk of TGCC. New to this, polymorphisms in 17-β hydroxydehydrogenase-4 which convert androgen and estrogen to weaker hormones were associated with TGCC (Chia et al, 2010; Ferlin et al, 2010).…”

Section: Testicular Cancersmentioning

confidence: 99%

Epigenetic: a molecular link between testicular cancer and environmental exposures

Véga¹,

Baptissart²,

Caira³

et al. 2012

Front. Endocrin.

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In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the testicular dysgenesis syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations. Furthermore, infertility has been stated as a risk factor for testicular cancer (TC). The incidence of TC has been increasing over the past decade. Most of testicular germ cell cancers develop through a pre-invasive carcinoma in situ from fetal germ cells (primordial germ cell or gonocyte). During their development, fetal germ cells undergo epigenetic modifications. Interestingly, several lines of evidence have shown that gene regulation through epigenetic mechanisms (DNA and histone modifications) plays an important role in normal development as well as in various diseases, including TC. Here we will review chromatin modifications which can affect testicular physiology leading to the development of TC; and highlight potential molecular pathways involved in these alterations in the context of environmental exposures.

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Estrogen receptor α single nucleotide polymorphism modifies the risk of azoospermia in childhood cancer survivors

Abstract: Use of genetic markers of high risk of posttreatment azoospermia may, in the future, prove an important clinical tool in selection of boys to whom preservation of testicular tissue before cancer therapy should be offered.

Cited by 22 publications

References 28 publications

Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study

Estrogen receptor alpha single nucleotide polymorphism as predictor of diabetes type 2 risk in hypogonadal men

Epigenetic: a molecular link between testicular cancer and environmental exposures

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