Postnatal Germ Cell Development during Mini-Puberty in the Mouse Does Not Require Androgen Receptor: Implications for Managing Cryptorchidism

Li, Ruili; Vannitamby, Amanda; Meijer, Jorien; Southwell, Bridget R.; Hutson, John M.

doi:10.1016/j.juro.2014.10.024

Cited by 26 publications

(6 citation statements)

References 26 publications

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“…25 Recently, it has also been reported that androgen receptors are not required for gonocyte migration and transformation into spermatogonial stem cells in the first 10 days after birth in androgen receptor knockout mice. 26 This is consistent with prior studies on androgen insensitive mice and mice lacking gonadotropin-releasing hormone (GnRH) as well as mice with a deletion of the FSH receptor. 13 Concerns have, however, been raised over speciesspecific differences in the physiology of minipuberty in mice versus humans.…”

Section: Normal Germ Cell Development In the Postnatal Testissupporting

confidence: 90%

Hormonal Aspects of the Pathogenesis and Treatment of Cryptorchidism

2016

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A normal functioning hypothalamic-pituitary-testicular axis is required for normal testicular descent. The percentage of cases that result from a disturbance in this axis remains controversial. Much has yet to be learnt about cryptorchidism, but is seems that the existence of A dark spermatogonia (Ad spermatogonia) is essential for later fertility. Bilateral cryptorchid patients have a high risk of later infertility, even though they undergo early surgery for cryptorchidism. It is possible today to distinguish-to a certain extent-between three different groups of cryptorchid patients based on testicular histology, gonadotropins, and inhibin B at the time of early surgery: Group 1, patients suspected of prepubertal transient hypothalamic-pituitary-testicular hypofunction and a high risk of later infertility; Group 2, patients with hypergonadotropic hypogonadism and a primary testicular dysfunction; and Group 3, patients with normal histology and normal serum levels of inhibin B and gonadotropins at the time of early surgery and a low risk of later infertility. Given the potential adverse effects of hormonal treatment, attention should be directed toward small doses of adjuvant gonadotropin-releasing hormone (GnRH) treatment for those who might benefit the most, that is, bilateral cryptorchid boys at early surgery without evidence of normal maturation of gonocytes into Ad spermatogonia. Optimally, gonadotropin levels in such patients should be measured to ensure that levels are not compensatory elevated, thereby supporting the suspicion of hypothalamic-pituitary-testicular hypofunction. Studies of GnRH-supplementary treatment should include testicular biopsy at surgery and at follow-up in childhood as well as examinations of fertility potential in adulthood.

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Section: Normal Germ Cell Development In the Postnatal Testissupporting

confidence: 90%

Hormonal Aspects of the Pathogenesis and Treatment of Cryptorchidism

2016

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“…Furthermore, Li et al performed immunofluorescence histochemistry to detect the proliferation marker, Ki67, the Sertoli cell marker, AMH, and the germ-cell marker, DDX4. They did not observe any differences in gonocyte migration from the center to the tubular basement membrane, or in spermatogonial stem cell transformation [ 66 ]. Thus, they concluded that gonocyte transition to Ad spermatogonia and gonocyte migration towards the basement membrane were androgen-independent processes in both mouse and human.…”

Section: Discussionmentioning

confidence: 99%

Curative GnRHa treatment has an unexpected repressive effect on Sertoli cell specific genes

Gegenschatz‐Schmid¹,

Verkauskas²,

Demougin³

et al. 2018

Basic Clin. Androl.

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BackgroundFollicle stimulating hormone and testosterone stimulate Sertoli cells to support germ cell function and differentiation. During mini-puberty, when gonadotropin (GnRH) stimulates increases in plasma luteinizing hormone (LH) and testosterone levels, gonocytes are transformed into Ad spermatogonia. In cryptorchidism, impaired gonadotropin secretion during mini-puberty results in insufficient LH and testosterone secretion, impaired gonocyte transition to Ad spermatogonia, and perturbed Sertoli cell proliferation. Treatment with a gonadotropin-releasing hormone agonist (GnRHa/Buserelin) induced gonocytes to differentiate into Ad spermatogonia and rescued fertility. The present study evaluated the impact of low LH secretion on Sertoli cell function by comparing differential gene expression data between testes with low LH that lacked Ad spermatogonia (Ad-) and testes that completed mini-puberty (Ad+). Furthermore, we analyzed changes in the transcription of selected Sertoli cell specific genes in response to GnRHa treatment.ResultsAd- testes showed reduced expression of nine out of 40 selected Sertoli cell specific genes compared to Ad+ testes. GnRHa treatment repressed most of the Sertoli cell specific genes, including the inhibins, but it increased the expression of genes that regulate apoptosis (FASLG) and proliferation (GDNF).ConclusionsImpaired-minipuberty with decreased LH and testosterone levels affected Ad and Sertoli cell development through positive and negative regulation of morphoregulatory and apoptotic genes. GnRHa treatment had a repressive effect on most Sertoli cell specific genes, which suggested that Sertoli cells underwent a cellular rearrangement. We propose that gonadotropin-dependent increases in FASLG and GDNF expression drove Sertoli cell proliferation and germ cell self-renewal and supported the transition of gonocytes to Ad spermatogonia, independent of inhibins.

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“…Immunohistochemistry was performed after paraffin sections (5 μm) were dewaxed and underwent antigen retrieval in 0.01 M citric buffer (pH 7) in a microwave oven followed by 3% H 2 O 2 (v/v) in 0.1% Triton X-100/PBS for 10 min as described previously [Li et al, 2015a]. Primary antibodies mouse vasa homologue (MVH, germ cell marker; Abcam, ab13840, 1: 10,000 dilution) or promyelocytic leukaemia zinc-factor (PLZF, undifferentiated SSC or type A spermatogonia marker; Santa Cruz, sc-22839, 1: 400 dilution) were incubated at 4 ° C overnight.…”

Section: Methodsmentioning

confidence: 99%

Bcl2-Associated X (BAX) Knockout in Mice Resulted in Persistence of Neonatal Testicular Germ Cells (Gonocytes)

Kaur

et al. 2019

Sex Dev

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During early testicular development, neonatal gonocytes transform into spermatogonial stem cells (SSC), and any untransformed gonocytes are thought to undergo apoptosis. In human cryptorchidism, persisting gonocytes may lead to seminoma. Using Bcl2-associated X knockout (BAXKO) mice, we investigated apoptosis in gonocyte development during mouse minipuberty. Testes from BAXKO, heterozygous (HET), and wild-type (WT) littermates were collected on postnatal days 1, 3, 6, and 9 (<i>n</i> = 6/group), labelled with antibodies against mouse vasa homologue (MVH, germ cell marker) or promyelocytic leukaemia zinc-factor (PLZF, SSC marker) and imaged for cell counting. Total germ cells/tubule, i.e., the number of germ cells on and off the basement membrane (BM), were counted using Image J followed by 2-way ANOVA analysis with Prism. Total PLZF+ germ cells/tubule, PLZF+ germ cells/tubule off BM, total MVH+ germ cells/tubule, and MVH+ germ cells off BM/tubule were significantly higher at day 9 in BAXKO compared to WT and HET mice (<i>p </i>< 0.01). In conclusion, knockout of BAX in mouse leads to gonocytes persisting at the centre of the tubules after minipuberty, which failed to migrate and transform into SSC, indicating the important role of apoptosis is to eliminate undifferentiated gonocytes during transformation. Failed apoptosis in gonocytes may be the cause of malignancy in humans with cryptorchidism.

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Postnatal Germ Cell Development during Mini-Puberty in the Mouse Does Not Require Androgen Receptor: Implications for Managing Cryptorchidism

Cited by 26 publications

References 26 publications

Hormonal Aspects of the Pathogenesis and Treatment of Cryptorchidism

Hormonal Aspects of the Pathogenesis and Treatment of Cryptorchidism

Curative GnRHa treatment has an unexpected repressive effect on Sertoli cell specific genes

Bcl2-Associated X (BAX) Knockout in Mice Resulted in Persistence of Neonatal Testicular Germ Cells (Gonocytes)

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