Non-classical mechanisms of steroid sensing in the ovary: Lessons from the bovine oxytocin model

Ivell, Richard; Dai, Yanzhenzi; Mann, Navdeep; Anand‐Ivell, Ravinder

doi:10.1016/j.mce.2013.04.016

Cited by 11 publications

(4 citation statements)

References 56 publications

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“…This is not surprising given the profile of ambient steroids present in the adult testis. Together with the lack of canonical steroid responsive elements in the INSL3 gene promoter, this suggests that steroid action is less likely to be via classical regulatory mechanisms acting directly on INSL3 gene transcription, but more likely to be indirect by influencing other aspects of cell metabolism or differentiation, or using non-classical signaling pathways (Ivell et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, follicular fluid accumulates high levels of steroids from both GC and TC, which govern the environment of the oocyte as well as the follicular somatic cells. Steroid concentrations may be very high, in the region of 10 −7 to 10 −6 molar or even greater (Ivell et al, 2014 ). This is a concentration which is well above the dynamic range for conventional nuclear steroid receptors (10 −10 to 10 −8 molar) but nevertheless appears to regulate important ovarian functions such as follicle transition and maturation (Kezele and Skinner, 2003 ; Yang and Fortune, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

“…This is a concentration which is well above the dynamic range for conventional nuclear steroid receptors (10 −10 to 10 −8 molar) but nevertheless appears to regulate important ovarian functions such as follicle transition and maturation (Kezele and Skinner, 2003 ; Yang and Fortune, 2006 ). It seems likely that such follicular steroids are making use of non-classical receptor mechanisms, which may operate in a dynamic range with 10 to 100-fold less sensitivity than for classical steroid receptor systems (Ivell et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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Theca Cell INSL3 and Steroids Together Orchestrate the Growing Bovine Antral Follicle

2017

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Insulin-like peptide 3 (INSL3) and its specific receptor RXFP2 are both expressed by theca interna cells of the growing antral follicle where they form an essential regulatory element in the production of the steroid precursor androstenedione. Using primary cultures of bovine theca cells from the mid follicular phase together with steroid agonists and antagonists we have examined how ovarian steroids modulate INSL3 expression. Transcript analysis shows that these cells express estrogen receptors α and β, androgen and progesterone receptors, besides the orphan nuclear receptors SF1 and nur77. Whereas, exogenous androgens have little or no effect, the androgen antagonist bicalutamide stimulates INSL3 production. In contrast, estrogen receptor agonists, as also progesterone, are stimulatory. Importantly, estrogen receptor signaling is convergent with the protein kinase A signaling pathway activated by LH, such that the estrogen receptor antagonist can inhibit the mild stimulatory effect of LH, and vice versa the PKA antagonist H89 blocks stimulation by estradiol. A significant finding is that the major steroid metabolite androstenedione appears to act predominantly as an estrogen and not an androgen in this system. Transfection of INSL3 gene promoter-reporter constructs together with various steroid receptor expression plasmids supports these findings and shows that steroid action uses non-classical pathways not requiring canonical steroid-responsive elements in the proximal promoter region. Together, the results indicate that increasing estrogens in the follicular phase stimulate a feedforward loop driving INSL3 signaling and thereby promoting steroidogenesis in the growing antral follicle until the LH surge which effectively switches off INSL3 expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Theca Cell INSL3 and Steroids Together Orchestrate the Growing Bovine Antral Follicle

2017

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“…It is also recognized that the inhibitory transcription factor COUP-TF may also bind to an SFRE and compete with SF1 to control the up- or down-regulation of a gene ( 58 ); and it is now established that COUP-TF may play an important role in the differentiation and development of the fetal testis ( 59 ) as well as in regulating the INSL3 gene ( 60 ). However, it has also been shown that several nuclear steroid receptors may also influence gene expression using SFREs, probably in a non-classical manner which does not involve direct interaction with the responsive element in the DNA itself ( 61 ). Both rodent and bovine INSL3 promoter-reporter constructs can be stimulated in vitro by activated estrogen and androgen receptors ( 56 , 62 ), though whether via classical or non-classical mechanisms is not clear.…”

Section: The Regulation Of Insl3 and Rxfp2mentioning

confidence: 99%

Expression and Role of INSL3 in the Fetal Testis

et al. 2022

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Insulin-like peptide 3 (INSL3) is a small peptide hormone of the insulin-relaxin family which is produced and secreted by the fetal Leydig cells in the testes only. It appears to be undetectable in female fetuses. In the human fetus INSL3 synthesis begins immediately following gonadal sex determination at weeks 7 to 8 post coitum and the peptide can be detected in amniotic fluid 1 to 2 weeks later. INSL3 acts through a unique G-protein-coupled receptor, called RelaXin-like Family Peptide receptor 2 (RXFP2), which is expressed by the mesenchymal cells of the gubernacular ligament linking the testes to the inguinal wall. The role of INSL3 in the male fetus is to cause a thickening of the gubernaculum which then retains the testes in the inguinal region, while the remainder of the abdominal organs grow away in an antero-dorsal direction. This represents the first phase of testis descent and is followed later in pregnancy by the second inguino-scrotal phase whereby the testes pass into the scrotum through the inguinal canal. INSL3 acts as a significant biomarker for Leydig cell differentiation in the fetus and may be reduced by maternal exposure to endocrine disrupting chemicals, such as xenoestrogens or phthalates, leading to cryptorchidism. INSL3 may have other roles within the fetus, but as a Leydig cell biomarker its reduction acts also as a surrogate for anti-androgen action.

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The Ovarian Follicle of Cows as a Model for Human

Sirard¹

2017

Animal Models and Human Reproduction

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Non-classical mechanisms of steroid sensing in the ovary: Lessons from the bovine oxytocin model

Cited by 11 publications

References 56 publications

Theca Cell INSL3 and Steroids Together Orchestrate the Growing Bovine Antral Follicle

Theca Cell INSL3 and Steroids Together Orchestrate the Growing Bovine Antral Follicle

Expression and Role of INSL3 in the Fetal Testis

The Ovarian Follicle of Cows as a Model for Human

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