&lt;i&gt;EGR4&lt;/i&gt; Is a Master Gene Responsible for Fertility in Cryptorchidism

Hadžiselimović, Faruk; Hadziselimovic, Nils; Demougin, Philippe; Krey, Gunthild; Hoecht, B; Oakeley, E. J.

doi:10.1159/000249147

Cited by 47 publications

(66 citation statements)

References 48 publications

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“…Whole genome expression analysis strongly supports the theory that impaired mini-puberty is responsible for azoospermia and adult infertility in cryptorchidism [49]. Multiple differences in gene expression between high- and low-infertility risk groups underscore the importance of an intact hypothalamus-pituitary-testicular axis in fertility development.…”

Section: Resultsmentioning

confidence: 67%

“…Multiple differences in gene expression between high- and low-infertility risk groups underscore the importance of an intact hypothalamus-pituitary-testicular axis in fertility development. Molecular biological observations support LH deficiency, with EGR4 as a master gene over Leydig cell dysgenesis as the reason for impaired mini-puberty [49]. …”

Section: Resultsmentioning

confidence: 99%

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Opinion: Comment on Evaluation and Treatment of Cryptorchidism: AUA/AAP and Nordic Consensus Guidelines

Hadžiselimović¹

2016

Urol Int

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The ultimate goal in the treatment of cryptorchidism is to achieve normal fertility. However, in a substantial number of cryptorchid males, early and apparently successful orchidopexy does not improve fertility as it does not address the underlying pathophysiological cause, namely, the impaired transformation of gonocytes into Ad spermatogonia. It is important to realize that over half the patients presenting with unilateral cryptorchidism and the majority of those presenting with bilateral cryptorchidism have abnormal spermiogram which indicates that unilateral cryptorchidism is in fact a bilateral disease and therefore a serious andrological problem. More importantly, only testicular biopsy can nowadays determine which patient should benefit from hormonal therapy. This means that the rationale behind testicular biopsy is both diagnostic and therapeutic, particularly since LH-RHa hormonal therapy is a worthwhile solution to this andrological problem. In boys with a high risk of azoospermia development, adequate treatment with low doses of LH-RHa allowed 86% of subjects to achieve a normal sperm count. This strongly contrasts with the results of the ‘surgery-only' group where not a single patient had a normal spermiogram and 20% suffered from azoospermia. Testicular biopsy is all the more justified that it allowed the detection of in situ carcinoma in 0.6% of all the cryptorchid boys studied. Even if hormonal pre-treatment only achieves successful epididymo-testicular descent in 20% of cases, this treatment should remain the first therapeutic choice because it may avoid resorting to surgery. In addition, it has no adverse effect on fertility and, in unsuccessful cases, facilitates orchidopexy and considerably helps reduce the incidence of post-surgical testicular atrophy, whether unilateral or, and this is a much more serious event, bilateral.

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Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Opinion: Comment on Evaluation and Treatment of Cryptorchidism: AUA/AAP and Nordic Consensus Guidelines

Hadžiselimović¹

2016

Urol Int

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“…Furthermore, analyzing the whole genome expression profiling of testicular tissue, we found that cryptorchid boys lacking Ad spermatogonia had decreased expression of most of the genes essential for hypothalamo-pituitary-testicular axis function ( table 1 ). In particular, EGR4 , which is involved in regulating the secretion of luteinizing hormone, was virtually silent in the HAZR group [Hadziselimovic et al, 2009].…”

Section: Discussionmentioning

confidence: 99%

“…cDNAs were synthesized with the Reverse Transcriptase Core Kit (Eurogentec, cat# RT-RTCK-03) using random primers [Hadziselimovic et al, 2009]. Real-time PCR runs were performed using SYBR Fast Kit (Kapa Biosystems, cat# KK4602) with each gene-specific primer at 200 n M final concentration in a total volume of 17.5 l. Wave lengths for source and detection were set at 470 and 510 nm, respectively.…”

Section: Statistical Analysis and Interpretation Of Microarray Datamentioning

confidence: 99%

Testicular Gene Expression in Cryptorchid Boys at Risk of Azoospermia

Hadžiselimović¹,

Hadziselimovic

Demougin

et al. 2011

Sex Dev

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Despite timely and successful surgery, 32% of patients with bilateral and 10% with unilateral cryptorchidism will develop azoospermia. Cryptorchid boys at risk of azoospermia display a typical testicular histology of impaired mini-puberty at the time of the orchidopexy. During mini-puberty increased gonadotropin and testosterone secretion stimulate transformation of gonocytes into Ad spermatogonia. In the azoospermia risk group this transformation is to a great extent impaired. This study aimed to analyze data on whole genome expression signatures of undescended testes at risk of developing azoospermia. Twenty-three testicular biopsies from 22 boys were analyzed (19 testes from 18 boys with cryptorchidism and 4 contralateral descended testes from patients with testicular agenesis). Expression profiling identified 483 genes not or under-expressed in the azoospermia risk group compared with the control and low risk for azoospermia (LAZR) groups. Annotated loci were associated with spermatogenesis. Other significant genes were cellular defense response genes and hormone-controlled loci involved in spermatogenesis. Some genes transcribed in normal adult meiotic and post-meiotic germ cells are activated in healthy juvenile Ad spermatogonia. Thus, molecular events initiating the testicular expression program at the onset of puberty and maintaining it during adulthood occur very early in prepubertal testes. This molecular event is to a great extent impaired in the high risk for azoospermia (HAZR) group lacking Ad spermatogonia (stem cells for spermatozoa) indicating impaired mini-puberty.

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“…In those for whom this minipuberty is blunted or non-existent, the risk of being azoospermic in adulthood is high. 12 Hadziselimovic et al 13 has demonstrated that EGR4 is a critical, master gene of sorts responsible for the regulation of LH secretion and, as such, for the initiation of the minipuberty. Therefore, cryptorchidism, either unilateral or bilateral, whether corrected early or later, is an important risk factor for azoospermia.…”

Section: The Medical and Surgical History: What Clues Might It Reveal?mentioning

confidence: 99%

Evaluation of the azoospermic male

2008

Fertility and Sterility

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When presented with an azoospermic patient, a thorough history and careful, considered physical examination often leads to a definite or presumptive diagnosis. An algorithmic, logical thought process is important to have in mind when embarking on the evaluation. Adjunctive laboratory tests, such as hormonal assays or genetic studies, are often complementary and/or additive and allow a very precise determination to be made as to the etiologies, either genetic or acquired. It is only with this information that a therapeutic plan can be made for the patient. As will be discussed, a targeted approach to testing is far more satisfying and cost-effective than a blind, shotgun approach. INTRODUCTIONIn most circumstances, azoospermia is diagnosed when no spermatozoa are detected upon microscopic evaluation of two centrifuged semen samples. As will be seen below, certain conditions only require a single semen specimen when coupled with history, physical examination or both. Azoospermia is found in approximately 1% of all men and up to 15% of infertile men, depending upon the demographic nature of the infertile cohort. 1 Aspermia is defined as a complete absence of seminal fluid during orgasm. Men with azoospermia should be evaluated in an effort to discover the underlying etiology of their condition, which will guide the formulation of a therapeutic plan. 2 A complete history and physical examination is mandatory, while measurement of reproductive hormones (testosterone, folliclestimulating hormone (FSH), luteinizing hormone (LH), prolactin and estradiol) are potentially helpful. Depending upon the certain or suspected diagnosis, a Y chromosomal microdeletion assay, a karyotype, cystic fibrosis mutation analysis, transrectal ultrasonography and renal ultrasonography may be helpful. There should be no single 'azoospermia panel' where all of these studies are ordered in a shotgun approach with no regard to the likely diagnosis. These adjunctive tests are ordered in a targeted way-only those that are necessary based upon the presumptive diagnosis are obtained. This presumptive diagnosis is arrived at by the evaluating clinician with a combination of the mind (what do the history, the semen analysis and the hormonal data suggest), the eyes (what does the patient's appearance suggest) and the fingers (what does the genital physical examination suggest). To be clear in one's thoughts, though, it requires a way of thinking about azoospermia, a process to focus on and an algorithm to follow.

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<i>EGR4</i> Is a Master Gene Responsible for Fertility in Cryptorchidism

Cited by 47 publications

References 48 publications

Opinion: Comment on Evaluation and Treatment of Cryptorchidism: AUA/AAP and Nordic Consensus Guidelines

Opinion: Comment on Evaluation and Treatment of Cryptorchidism: AUA/AAP and Nordic Consensus Guidelines

Testicular Gene Expression in Cryptorchid Boys at Risk of Azoospermia

Evaluation of the azoospermic male

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