scholarly journals Effect of the spatial–temporal specific theca cell Cyp17 overexpression on the reproductive phenotype of the novel TC17 mouse

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Christian Secchi ◽  
Martina Belli ◽  
Tracy N. H. Harrison ◽  
Joseph Swift ◽  
CheMyong Ko ◽  
...  
Keyword(s):  
Mouse Model ◽  
Polycystic Ovary ◽  
Ovarian Follicle ◽  
Expression System ◽  
Androgen Excess ◽  
Steroid Synthesis ◽  
Sex Assignment ◽  
Ovarian Morphology ◽  
Versatile Tool ◽  
Essential Enzyme

Abstract Background In the ovarian follicle, the Theca Cells (TCs) have two main functions: preserving morphological integrity and, importantly, secreting steroid androgen hormones. TCs express the essential enzyme 17α-hydroxylase/17,20-desmolase (CYP17), which permits the conversion of pregnenolone and progesterone into androgens. Dysregulation of CYP17 enzyme activity due to an intrinsic ovarian defect is hypothesized to be a cause of hyperandrogenism in women. Androgen excess is observed in women with polycystic ovary syndrome (PCOS) resulting from excess endogenous androgen production, and in transgender males undergoing exogenous testosterone therapy after female sex assignment at birth. However, the molecular and morphological effects of Cyp17 overexpression and androgen excess on folliculogenesis is unknown. Methods In this work, seeking a comprehensive profiling of the local outcomes of the androgen excess in the ovary, we generated a transgenic mouse model (TC17) with doxycycline (Dox)-induced Cyp17 overexpression in a local and temporal manner. TC17 mice were obtained by a combination of the Tet-dependent expression system and the Cre/LoxP gene control system. Results Ovaries of Dox-treated TC17 mice overexpressed Cyp17 specifically in TCs, inducing high testosterone levels. Surprisingly, TC17 ovarian morphology resembled the human ovarian features of testosterone-treated transgender men (partially impaired folliculogenesis, hypertrophic or luteinized stromal cells, atretic follicles, and collapsed clusters). We additionally assessed TC17 fertility denoting a perturbation of the normal reproductive functions (e.g., low pregnancy rate and numbers of pups per litter). Finally, RNAseq analysis permitted us to identify dysregulated genes (Lhcgr, Fshr, Runx1) and pathways (Extra Cellular Matrix and Steroid Synthesis). Conclusions Our novel mouse model is a versatile tool to provide innovative insights into study the effects of Cyp17 overexpression and hyperandrogenism in the ovary.

scholarly journals Contemporary approaches to the management of polycystic ovary syndrome

2018 ◽  
Vol 9 (4) ◽  
pp. 123-134 ◽  
Author(s):  
Renato Pasquali
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Review Article ◽  
Metabolic Abnormalities ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Ovulatory Dysfunction ◽  
Ovarian Morphology

Polycystic ovary syndrome (PCOS) is a common disorder in women in their reproductive years and is characterized by androgen excess, ovulatory dysfunction, and polycystic ovarian morphology. It is also associated with several metabolic abnormalities, particularly insulin resistance and obesity, which play an important role in the pathophysiology of PCOS and, in particular, negatively influence ovarian function and fertility. This review article summarizes the available treatment for women with PCOS. Specifically, current and potentially new therapies are discussed.

scholarly journals Regulatory Functions of L-Carnitine, Acetyl, and Propionyl L-Carnitine in a PCOS Mouse Model: Focus on Antioxidant/Antiglycative Molecular Pathways in the Ovarian Microenvironment

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 867
Author(s):  
Giovanna Di Emidio ◽  
Francesco Rea ◽  
Martina Placidi ◽  
Giulia Rossi ◽  
Domenica Cocciolone ◽  
...  
Keyword(s):  
Mouse Model ◽  
Molecular Mechanisms ◽  
Polycystic Ovary ◽  
Ovarian Follicle ◽  
Oocyte Quality ◽  
Molecular Pathways ◽  
Type Iv ◽  
Estrous Cyclicity ◽  
Anti Oxidant ◽  
Regulatory Functions

Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with female infertility. Based on energy and antioxidant regulatory functions of carnitines, we investigated whether acyl-L-carnitines improve PCOS phenotype in a mouse model induced by dehydroepiandrosterone (DHEA). CD1 mice received DHEA for 20 days along with two different carnitine formulations: one containing L-carnitine (LC) and acetyl-L-carnitine (ALC), and the other one containing also propionyl-L-carnitine (PLC). We evaluated estrous cyclicity, testosterone level, ovarian follicle health, ovulation rate and oocyte quality, collagen deposition, lipid droplets, and 17ß-HSD IV (17 beta-hydroxysteroid dehydrogenase type IV) expression. Moreover, we analyzed protein expression of SIRT1, SIRT3, SOD2 (superoxide dismutase 2), mitochondrial transcriptional factor A (mtTFA), RAGE (receptor for AGEs), GLO2 (glyoxalase 2) and ovarian accumulation of MG-AGEs (advanced glycation end-products formed by methylglyoxal). Both carnitine formulations ameliorated ovarian PCOS phenotype and positively modulated antioxidant molecular pathways in the ovarian microenvironment. Addition of PLC to LC-ALC formulation mitigated intraovarian MG-AGE accumulation and increased mtTFA expression. In conclusion, our study supports the hypothesis that oral administration of acyl-L-carnitines alleviates ovarian dysfunctions associated with this syndrome and that co-administration of PLC provides better activity. Molecular mechanisms underlying these effects include anti-oxidant/glycative activity and potentiation of mitochondria.

scholarly journals SUN-012 Role of Leptin-Receptor Expressing Cells in the Pathogenesis of Polycystic Ovary Syndrome (PCOS)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Alexandra Cara ◽  
Laura Lynn Burger ◽  
Martin Grosvenor Myers ◽  
Karel De Gendt ◽  
Sue Moenter ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Mouse Model ◽  
Leptin Receptor ◽  
Polycystic Ovary ◽  
Central Regulation ◽  
Polycystic Ovaries ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Cycle Number ◽  
Female Mice

Abstract Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, and is characterized by hyperandrogenism, oligo/anovulation, and/or polycystic ovaries. Many women with PCOS also suffer from adverse metabolic phenotypes, including central adiposity, insulin resistance, and glucose intolerance, which can exacerbate reproductive dysfunction. Androgens can act upon androgen receptors (AR), which are expressed in many reproductive and metabolic tissues, and contribute to the pathogenesis of PCOS. AR are highly expressed in the neuroendocrine hypothalamus in areas which regulate the hypothalamic-pituitary-gonadal axis and contribute to the central regulation of metabolism. Many phenotypes of PCOS can be modelled in rodents by administration of the non-aromatizable androgen dihydrotestosterone (DHT) during critical periods of development. Neuronal AR is key in the development of PCOS, as female mice with neuronal AR deletion who are exposed to androgen excess are protected against development of anovulation, polycystic ovaries, and metabolic abnormalities. Yet it is not known which populations of neurons confers this protection. We hypothesize that leptin-receptor (LepR) neurons participate in the pathogenesis of PCOS, as sub-populations of LepR neurons co-express AR in the hypothalamus, and LepR neurons are critical in the central regulation of energy homeostasis, and exert permissive actions on puberty and fertility. We have pre-natally androgenized (PNA) a mouse model of AR deletion specifically in LepR cells (LepRΔAR) and are conducting reproductive and metabolic phenotyping. As previously demonstrated, control PNA females show long periods of acyclicity, whereas LepRΔAR PNA female mice show a similar number of days in each stage of the estrous cycle, number of cycles, and cycle length as vehicle treated LepRΔAR females. Our findings indicate that a subpopulation of AR/LepR cells mediate the effects of prenatal androgen excess on female estrous cycles in a mouse model of PCOS-like phenotype.

scholarly journals Inositols’ Importance in the Improvement of the Endocrine–Metabolic Profile in PCOS

2019 ◽  
Vol 20 (22) ◽  
pp. 5787 ◽  
Author(s):  
Anna Wojciechowska ◽  
Adam Osowski ◽  
Marcin Jóźwik ◽  
Ryszard Górecki ◽  
Andrzej Rynkiewicz ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Physiological Properties ◽  
Ovarian Morphology ◽  
Common Causes ◽  
Symptom Formation

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility and metabolic problems among women of reproductive age. The mechanism of PCOS is associated with concurrent alterations at the hormonal level. The diagnosis assumes the occurrence of three interrelated symptoms of varying severity, namely ovulation disorders, androgen excess, or polycystic ovarian morphology (PCOM), which all require a proper therapeutic approach. The main symptom seems to be an increased androgen concentration, which in turn may contribute to different metabolic disorders. A number of papers have demonstrated the significant role of inositol therapy in PCOS. However, there is a lack of detailed discussion about the importance of myo-inositol (MI) and d-chiro-inositol (DCI) in reference to particular symptoms. Thus, the aim of this review is to present the effectiveness of MI and DCI treatment for PCOS symptoms. Moreover, the review is focused on analyzing the use of inositols, taking into account their physiological properties, together with the mechanism of individual PCOS symptom formation.

scholarly journals A Novel Mouse Model for Studying the Effects of Cyp17 Overexpression in a Temporal- and Spatial-Specific Manner

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A762-A763
Author(s):  
Christian Secchi ◽  
Martina Belli ◽  
Dwayne Stupack ◽  
Shunichi Shimasaki
Keyword(s):  
Mouse Model ◽  
Polycystic Ovary ◽  
Expression System ◽  
Follicular Development ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Active Transcription ◽  
And Function ◽  
Dose Dependent

Abstract Background: Cyp17 plays a key role in theca cells (TCs) to produce androgens, which, in turn, are converted to estrogens in granulosa cells. Intrinsic alterations in ovarian steroidogenesis contribute to excessive ovarian androgen production that characterizes polycystic ovary disease (PCOS)1,2. Hyperandrogenism has been associated with higher levels of Cyp17 in TCs, and correlate with increased numbers of antral follicles3. While androgen excess is one of the hallmark features of PCOS, its putative role in the follicular development and function remains poorly known. Most efforts have used androgen administration or Cyp19 blockade approach to study how androgens prolong folliculogenesis4. Although some insights have been made, it is not clear if these models accurately address the cascade of effects that follow ovarian hyperandrogenism. Aim: Here, we aim to study the specific effects of hyperandrogenemia on ovarian morphology, follicle function and fertility with a new transgenic (TG) mouse model expressing elevated Cyp17 levels exclusively in TCs. Methods: We generated a breeding line of triple TG mice using a combination of the Tet-dependent expression system and the Cre/LoxP gene control system. Specifically, we used Cyp17 promoter-iCre mice crossed with trans-activator mice (R26-STOP-rtTA-IRES-EGFP transgene, Jackson Lab) and with a responder mouse carrying the TRE-Cyp17 transgene. Cyp17 promoter-iCre mice were used to ensure rtTA/EGFP is expressed specifically in TCs of secondary follicles. After the DNA segment between the two LoxP sites is excised by Cyp17iCre specifically in TCs, the R26-STOP-rtTA gene remains activated in all daughter TCs. Only upon treatment with Doxycycline (DOX) can suppression be relieved and active transcription of TRE-Cyp17 be induced in a dose-dependent manner. Results: Cyp17 mRNA expression levels in TCs of TG mice treated with 20, 100 or 200 mg/Kg DOX compared with corresponding untreated control mice showed a modulation in a dose-dependent manner (P=0.01 ANOVA). Confocal and RNAscope analysis validated (i) the effective combination of the Cyp17iCre/rtTA expression system visualizing the rtTA/EGFP specifically expressed in ovarian TCs and (ii) the DOX-induced increase of Cyp17 expression compared with the WT mice. DOX treated TG females were acyclic, being mostly arrested in diestrus. Analysis of estrous cycle stages revealed that treated TG females spent significantly more time in diestrus than control females (P=0.007, ANOVA). Conclusions: Our new in vivo model is the first that analyzes androgen impact independent of any extraovarian source of androgen, complementing current clinical efforts to study the occurrences of TCs elevated androgen levels in normal and PCOS women. 1 Rosenfield, R. L. et al. Endocr Rev (2016)2 Azziz, R. et al. Nat Rev Dis Primers (2016)3 Comim, F. V., et al. Hum Reprod (2013)4 Stener-Victorin, E. et al. Endocr Rev (2020)

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