scholarly journals Temporal Role of Sertoli Cell Androgen Receptor Expression in Spermatogenic Development

2013 ◽  
Vol 27 (1) ◽  
pp. 12-24 ◽  
Author(s):  
Rasmani Hazra ◽  
Lisa Corcoran ◽  
Mat Robson ◽  
Kirsten J. McTavish ◽  
Dannielle Upton ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Sertoli Cell ◽  
Serum Testosterone ◽  
Receptor Expression ◽  
Testicular Development ◽  
Testis Size ◽  
Age Related ◽  
Regulated Expression ◽  
Tubular Lumen

Sertoli cell (SC) androgen receptor (AR) activity is vital for spermatogenesis. We created a unique gain-of-function transgenic (Tg) mouse model to determine the temporal role of SCAR expression in testicular development. The SC-specific rat Abpa promoter directed human Tg AR [Tg SC-specific AR (TgSCAR)] expression, providing strong premature postnatal AR immunolocalized to SC nuclei. Independent Tg lines revealed that TgSCAR dose dependently reduced postnatal and mature testis size (to 60% normal), whereas androgen-dependent mature seminal vesicle weights and serum testosterone levels remained normal. Total SC numbers were reduced in developing and mature TgSCAR testes, despite normal or higher Fshr mRNA and circulating FSH levels. Postnatal TgSCAR testes exhibited elevated levels of AR-regulated Rhox5 and Spinlw1 transcripts, and precocious SC function was demonstrated by early seminiferous tubular lumen formation and up-regulated expression of crucial SC tight-junction (Cldn11 and Tjp1) and phagocytic (Elmo1) transcripts. Early postnatal Amh expression was elevated but declined to normal levels in peripubertal-pubertal TgSCAR vs. control testes, indicating differential age-related regulation featuring AR-independent Amh down-regulation. TgSCAR induced premature postnatal spermatogenic development, shown by increased levels of meiotic (Dmc1 and Spo11) and postmeiotic (Capza3 and Prm1) germ cell transcripts, elevated meiotic-postmeiotic germ:Sertoli cell ratios, and accelerated spermatid development. Meiotic germ:Sertoli cell ratios were further increased in adult TgSCAR mice, indicating predominant SCAR-mediated control of meiotic development. However, postmeiotic germ:Sertoli cell ratios declined below normal. Our unique TgSCAR paradigm reveals that atypical SC-specific temporal AR expression provides a direct molecular mechanism for induction of precocious testicular development, leading to reduced adult testis size and decreased postmeiotic development.

scholarly journals Sertoli Cell Androgen Receptor Expression Regulates Temporal Fetal and Adult Leydig Cell Differentiation, Function, and Population Size

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3410-3422 ◽  
Author(s):  
Rasmani Hazra ◽  
Mark Jimenez ◽  
Reena Desai ◽  
David J. Handelsman ◽  
Charles M. Allan
Keyword(s):  
Androgen Receptor ◽  
Population Size ◽  
Sertoli Cell ◽  
Serum Testosterone ◽  
Absolute Number ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Adult Type ◽  
Dependent Relationship ◽  
Regulated Expression

We recently created a mouse model displaying precocious Sertoli cell (SC) and spermatogenic development induced by SC-specific transgenic androgen receptor expression (TgSCAR). Here we reveal that TgSCAR regulates the development, function, and absolute number of Leydig cells (LCs). Total fetal and adult type LC numbers were reduced in postnatal and adult TgSCAR vs control testes, despite normal circulating LH levels. Normal LC to SC ratios found in TgSCAR testes indicate that SC androgen receptor (SCAR)-mediated activity confers a quorum-dependent relationship between total SC and LC numbers. TgSCAR enhanced LC differentiation, shown by elevated ratios of advanced to immature LC types, and reduced LC proliferation in postnatal TgSCAR vs control testes. Postnatal TgSCAR testes displayed up-regulated expression of coupled ligand-receptor transcripts (Amh-Amhr2, Dhh-Ptch1, Pdgfa-Pdgfra) for potential SCAR-stimulated paracrine pathways, which may coordinate LC differentiation. Neonatal TgSCAR testes displayed normal T and dihydrotestosterone levels despite differential changes to steroidogenic gene expression, with down-regulated Star, Cyp11a1, and Cyp17a1 expression contrasting with up-regulated Hsd3b1, Hsd17b3, and Srd5a1 expression. TgSCAR males also displayed elevated postnatal and normal adult serum testosterone levels, despite reduced LC numbers. Enhanced adult-type LC steroidogenic output was revealed by increased pubertal testicular T, dihydrotestosterone, 3α-diol and 3β-diol levels per LC and up-regulated steroidogenic gene (Nr5a1, Lhr, Cyp11a1, Cyp17a1, Hsd3b6, Srd5a1) expression in pubertal or adult TgSCAR vs control males, suggesting regulatory mechanisms maintain androgen levels independently of absolute LC numbers. Our unique gain-of-function TgSCAR model has revealed that SCAR activity controls temporal LC differentiation, steroidogenic function, and population size.

scholarly journals Elevated expression of the Sertoli cell androgen receptor disrupts male fertility

2016 ◽  
Vol 311 (2) ◽  
pp. E396-E404 ◽  
Author(s):  
Rasmani Hazra ◽  
Dannielle Upton ◽  
Reena Desai ◽  
Omar Noori ◽  
Mark Jimenez ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Male Fertility ◽  
Leydig Cells ◽  
Cell Function ◽  
Pubertal Development ◽  
Receptor Expression ◽  
Testis Size

Recently, we created a unique gain-of-function mouse model with Sertoli cell-specific transgenic androgen receptor expression (TgSCAR) showing that SCAR activity controls the synchronized postnatal development of somatic Sertoli and Leydig cells and meiotic-postmeiotic germ cells. Moderate TgSCAR (TgSCARm) expression reduced testis size but had no effect on male fertility. Here, we reveal that higher TgSCAR expression (TgSCARH) causes male infertility. Higher SCAR activity, shown by upregulated AR-dependent transcripts ( Rhox5, Spinw1), resulted in smaller adult TgSCARH testes (50% of normal) despite normal or elevated circulating and intratesticular testosterone levels. Unlike fertile TgSCARm males, testes of adult TgSCARH males exhibited focal regions of interstitial hypertrophy featuring immature adult Leydig cells and higher intratesticular dihydrotestosterone and 5α-androstane 3α,17β-diol levels that are normally associated with pubertal development. Mature TgSCARH testes also exhibited markedly reduced Sertoli cell numbers (70%), although meiotic and postmeiotic germ cell/Sertoli cell ratios were twofold higher than normal, suggesting that elevated TgSCAR activity supports excessive spermatogenic development. Concurrent with the higher germ cell load of TgSCARH Sertoli cells were increased levels of apoptotic germ cells in TgSCARH relative to TgSCARm testes. In addition, TgSCARH testes displayed unique morphological degeneration that featured accumulated cellular and spermatozoa clusters in dilated channels of rete testes, consistent with reduced epididymal sperm numbers. Our findings reveal for the first time that excessive Sertoli cell AR activity in mature testes can reach a level that disturbs Sertoli/germ cell homeostasis, impacts focal Leydig cell function, reduces sperm output, and disrupts male fertility.

scholarly journals Enhanced Sexual Behaviors and Androgen Receptor Immunoreactivity in the Male Progesterone Receptor Knockout Mouse

Endocrinology ◽  
2005 ◽  
Vol 146 (10) ◽  
pp. 4340-4348 ◽  
Author(s):  
Johanna S. Schneider ◽  
Carly Burgess ◽  
Nicole C. Sleiter ◽  
Lydia L. DonCarlos ◽  
John P. Lydon ◽  
...  
Keyword(s):  
Sexual Behavior ◽  
Androgen Receptor ◽  
Progesterone Receptor ◽  
Sexual Behaviors ◽  
Gene Deletion ◽  
Biological Significance ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Testicular Development ◽  
Testicular Weight

Reproductive and behavioral functions of progesterone receptors (PRs) in males were assessed by examining consequences of PR gene deletion. Basal hormone levels were measured in male progesterone receptor knockout (PRKO) mice and compared to wild-type (WT) counterparts. RIA of serum LH, testosterone, and progesterone levels revealed no significant differences. Levels of FSH were moderately but significantly lower and inhibin levels were higher in PRKOs; these differences were not accompanied by gross differences in testicular weight or morphology. PRKOs exhibited significant alterations in sexual behavior. In initial tests PRKOs exhibited reduced latency to mount, compared with WT. In second sessions, PRKOs again showed a significantly reduced latency to mount and increased likelihood of achieving ejaculation. RU486 treatment in WT produced increased mount and intromission frequency and decreased latency to intromission. In anxiety-related behavior tests, PRKO mice exhibited intermediate anxiety levels, compared with WT, suggesting that enhanced sexual behavior in PRKOs is not secondary to reduced anxiety. Immunohistochemical analysis revealed significantly enhanced androgen receptor expression in the medial preoptic nucleus and bed nucleus of the stria terminalis of PRKO. We conclude that testicular development and function and homeostatic regulation of the hypothalamic-pituitary testicular axis are altered to a lesser extent by PR gene deletion. In contrast, PR appears to play a substantial role in inhibiting the anticipatory/motivational components of male sexual behavior in the mouse. The biological significance of this inhibitory mechanism and the extent to which it is mediated by reduced androgen receptor expression remain to be clarified.

scholarly journals Prognostic Role of Androgen Receptor Expression in Surgically Resected Early Breast Cancer Patients

2020 ◽  
Vol 23 (2) ◽  
pp. 182 ◽  
Author(s):  
Yaewon Yang ◽  
Ahrum Min ◽  
Kyung-Hun Lee ◽  
Han Suk Ryu ◽  
Tae-Yong Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cancer Patients ◽  
Early Breast Cancer ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Breast Cancer Patients ◽  
Prognostic Role

scholarly journals Androgen receptor expression predicts breast cancer survival: the role of genetic and epigenetic events

BMC Cancer ◽  
2012 ◽  
Vol 12 (1) ◽  
Author(s):  
Kate M Peters ◽  
Stacey L Edwards ◽  
Shalima S Nair ◽  
Juliet D French ◽  
Peter J Bailey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cancer Survival ◽  
Breast Cancer Survival ◽  
Receptor Expression ◽  
Androgen Receptor Expression ◽  
Epigenetic Events

Role of mammalian Y chromosome in sex determination

1988 ◽  
Vol 322 (1208) ◽  
pp. 63-72 ◽  
Keyword(s):  
Cell Differentiation ◽  
Sex Determination ◽  
Y Chromosome ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Sex Reversal ◽  
Testicular Development ◽  
Chimeric Mouse ◽  
Embryonic Gonad

It has long been assumed that the mammalian Y chromosome either encodes, or controls the production of, a diffusible testis-determining molecule, exposure of the embryonic gonad to this molecule being all that is required to divert it along the testicular pathway. My recent finding that Sertoli cells in XX ↔ XY chimeric mouse testes are exclusively XY has led me to propose a new model in which the Y acts cell-autonomously to bring about Sertoli-cell differentiation. I have suggested that all other aspects of foetal testicular development are triggered by the Sertoli cells without further Y-chromosome involvement. This model thus equates mammalian sex determination with Sertoli-cell determination. Examples of natural and experimentally induced sex reversal are discussed in the context of this model.

scholarly journals Deficient testosterone levels in men above 45 years with major depressive disorder - an age-matched case control study

2007 ◽  
Vol 13 (3) ◽  
pp. 5
Author(s):  
A M Dikobe ◽  
C W Van Staden ◽  
S Reif ◽  
M Bornman
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Treatment Options ◽  
Serum Testosterone ◽  
Control Group ◽  
Major Depressive ◽  
Age Related ◽  
Appropriate Treatment ◽  
Matched Case

<p><strong>Background.</strong> Symptoms of partial androgen deficiency in ageing men (PADAM) overlap considerably with those of major depressive disorder. The relationship between these conditions is complicated by the usual age-related decline in serum testosterone concentrations.</p><p><strong>Objectives.</strong> To test the hypothesis that depressed men above 45 years of age have lower serum testosterone concentrations than age-matched controls.</p><p><strong>Method.</strong> Serum testosterone fractions of 20 men above the age of 45 years suffering from a major depressive disorder were compared with those of 20 healthy men. An age-matched controlled design was used to account for the usual age-related decline in serum testosterone concentrations.</p><p><strong>Results.</strong> Testosterone concentrations of men suffering from a major depressive disorder were statistically significantly lower than those of an age-matched control group without depression. Conclusion. The role of testosterone deficiency in depressed men needs to be examined further in order for appropriate treatment options to be developed.</p>

Testicular responsiveness to hCG during infancy measured by salivary testosterone

1990 ◽  
Vol 123 (6) ◽  
pp. 633-636 ◽  
Author(s):  
Leo Dunkel ◽  
Ilpo Huhtaniemi
Keyword(s):  
Serum Testosterone ◽  
Maximal Level ◽  
Salivary Testosterone ◽  
Non Invasive ◽  
Basal Serum ◽  
Age Related ◽  
Invasive Method ◽  
Prepubertal Boys ◽  
The Mean

Abstract. To investigate the role of gonadotropins in postnatal testicular activation, testosterone responsiveness to human chorionic gonadotropin was studied in 11 male infants (aged 5-180 days). The boys were given a single im injection of 5000 IU/1.7m2 hCG, and serum and salivary testosterone responses were then measured for 7 days. The results were compared with the serum testosterone responses of 8 older prepubertal boys (aged 1.7-10.4 years) studied with the same protocol. The mean (±sem) basal serum testosterone levels were 2.67±1.27 nmol/l in the infants and 0.09±0.02 nmol/l in the prepubertal boys (p<0.05). Both groups gave a significant response to hCG stimulation (p<0.001, ANOVA, one-way). The stimulated concentrations of serum testosterone were higher in the infants than in the prepubertal boys (p<0.001). The mean basal level of salivary testosterone was 30.5 ±7.0 and the mean maximal level was 97± 10.3 pmol/l in the infants (p<0.001). No age-related changes were observed in either basal or hCG-stimulated levels. In infants the mean (±sem) maximal hCG-stimulated increase was 25 ± 10-fold in serum and 8±4-fold in saliva (p=0.13). A clear stimulatory effect of hCG on testicular testosterone production was found, suggesting that the postnatal increase in serum testosterone concentration in male infants is gonadotropin-mediated. Salivary testosterone concentrations can be increased by hCG, indicating that measurements of salivary testosterone may provide an optional, non-invasive method for assessing gonadal function in children.

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