scholarly journals Role of androgens in normal and pathological ovarian function

Reproduction ◽  
2015 ◽  
Vol 149 (4) ◽  
pp. R193-R218 ◽  
Author(s):  
K A Walters
Keyword(s):  
Animal Models ◽  
Ovarian Function ◽  
Female Fertility ◽  
Female Reproduction ◽  
Mediated Effects ◽  
Reproductive Disorder ◽  
Pharmacological Studies ◽  
And Function ◽  
Ovarian Syndrome

Androgens mediate their actions via the androgen receptor (AR), a member of the nuclear receptor superfamily. AR-mediated androgen action is essential in male reproductive development and function; however, only in the last decade has the suspected but unproven role for AR-mediated actions in female reproduction been firmly established. Deciphering the specific roles and precise pathways by which AR-mediated actions regulate ovarian function has been hindered by confusion on how to interpret results from pharmacological studies using androgens that can be converted into oestrogens, which exert actions via the oestrogen receptors. The generation and analysis of global and cell-specific femaleArknockout mouse models have deduced a role for AR-mediated actions in regulating ovarian function, maintaining female fertility, and have begun to unravel the mechanisms by which AR-mediated androgen actions regulate follicle health, development and ovulation. Furthermore, observational findings from human studies and animal models provide substantial evidence to support a role for AR-mediated effects not only in normal ovarian function but also in the development of the frequent ovarian pathological disorder, polycystic ovarian syndrome (PCOS). This review focuses on combining the findings from observational studies in humans, pharmacological studies and animal models to reveal the roles of AR-mediated actions in normal and pathological ovarian function. Together these findings will enable us to begin understanding the important roles of AR actions in the regulation of female fertility and ovarian ageing, as well as providing insights into the role of AR actions in the androgen-associated reproductive disorder PCOS.

scholarly journals Subfertility in androgen-insensitive female mice is rescued by transgenic FSH

2017 ◽  
Vol 29 (7) ◽  
pp. 1426 ◽  
Author(s):  
K. A. Walters ◽  
M. C. Edwards ◽  
M. Jimenez ◽  
D. J. Handelsman ◽  
C. M. Allan
Keyword(s):  
Androgen Receptor ◽  
Litter Size ◽  
Ovarian Function ◽  
Reproductive Function ◽  
Antral Follicle ◽  
Female Fertility ◽  
Wild Type ◽  
Female Reproduction ◽  
Androgen Insensitivity ◽  
Female Mice

Androgens synergise with FSH in female reproduction but the nature of their interaction in ovarian function and fertility is not clear. In the present study, we investigated this interaction, notably whether higher endogenous FSH can overcome defective androgen actions in androgen receptor (AR)-knockout (ARKO) mice. We generated and investigated the reproductive function of mutant mice exhibiting AR resistance with or without expression of human transgenic FSH (Tg-FSH). On the background of inactivated AR signalling, which alone resulted in irregular oestrous cycles and reduced pups per litter, ovulation rates and antral follicle health, Tg-FSH expression restored follicle health, ovulation rates and litter size to wild-type levels. However, Tg-FSH was only able to partially rectify the abnormal oestrous cycles observed in ARKO females. Hence, elevated endogenous FSH rescued the intraovarian defects, and partially rescued the extraovarian defects due to androgen insensitivity. In addition, the observed increase in litter size in Tg-FSH females was not observed in the presence of AR signalling inactivation. In summary, the findings of the present study reveal that FSH can rescue impaired female fertility and ovarian function due to androgen insensitivity in female ARKO mice by maintaining follicle health and ovulation rates, and thereby optimal female fertility.

scholarly journals Salt-inducible Kinases Are Critical Determinants of Female Fertility

Endocrinology ◽  
2020 ◽  
Vol 161 (7) ◽  
Author(s):  
Marah Armouti ◽  
Nicola Winston ◽  
Osamu Hatano ◽  
Elie Hobeika ◽  
Jennifer Hirshfeld-Cytron ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Follicle Stimulating Hormone ◽  
Female Fertility ◽  
Camp Signaling ◽  
Follicle Development ◽  
Pharmacological Modulation ◽  
Ovarian Granulosa Cells ◽  
Different Levels

Abstract Follicle development is the most crucial step toward female fertility and is controlled mainly by follicle-stimulating hormone (FSH). In ovarian granulosa cells (GCs), FSH activates protein kinase A by increasing 3′,5′-cyclic adenosine 5′-monophosphate (cAMP). Since cAMP signaling is impinged in part by salt-inducible kinases (SIKs), we examined the role of SIKs on the regulation of FSH actions. Here, we report that SIKs are essential for normal ovarian function and female fertility. All SIK isoforms are expressed in human and rodent GCs at different levels (SIK3>SIK2>SIK1). Pharmacological inhibition of SIK activity potentiated the stimulatory effect of FSH on markers of GC differentiation in mouse, rat, and human GCs and estradiol production in rat GCs. In humans, SIK inhibition strongly enhanced FSH actions in GCs of patients with normal or abnormal ovarian function. The knockdown of SIK2, but not SIK1 or SIK3, synergized with FSH on the induction of markers of GC differentiation. SIK inhibition boosted gonadotropin-induced GC differentiation in vivo, while the genomic knockout of SIK2 led to a significant increase in the number of ovulated oocytes. Conversely, SIK3 knockout females were infertile, FSH insensitive, and had abnormal folliculogenesis. These findings reveal novel roles for SIKs in the regulation of GC differentiation and female fertility, and contribute to our understanding of the mechanisms regulated by FSH. Furthermore, these data suggest that specific pharmacological modulation of SIK2 activity could be of benefit to treat ovulatory defects in humans and to increase the propagation of endangered species and farm mammals.

Dicarbonyl stress and glyoxalases in ovarian function

2014 ◽  
Vol 42 (2) ◽  
pp. 433-438 ◽  
Author(s):  
Carla Tatone ◽  
Ursula Eichenlaub-Ritter ◽  
Fernanda Amicarelli
Keyword(s):  
Ovarian Function ◽  
Reproductive Age ◽  
Oocyte Competence ◽  
Reproductive Age Women ◽  
Glycation End Products ◽  
Lower Fertility ◽  
Main Regulator ◽  
Ovarian Syndrome ◽  
New Strategies

The ovary is the main regulator of female fertility. Changes in maternal health and physiology can disrupt intraovarian homoeostasis thereby compromising oocyte competence and fertility. Research has only recently devoted attention to the involvement of dicarbonyl stress in ovarian function. On this basis, the present review focuses on clinical and experimental research supporting the role of dicarbonyl overload and AGEs (advanced glycation end-products) as key contributors to perturbations of the ovarian microenvironment leading to lower fertility. Particular emphasis has been given to oocyte susceptibility to methylglyoxal, a powerful glycating agent, whose levels are known to increase during aging and metabolic disorders. According to the literature, the ovary and the oocyte itself can rely on the glyoxalase system to counteract the possible dicarbonyl overload such as that which may occur in reproductive-age women and patients with PCOS (polycystic ovarian syndrome) or diabetes. Overall, although biochemical methods for proper evaluation of dicarbonyl stress in oocytes and the ovarian microenvironment need to be established, AGEs can be proposed as predictive markers and/or therapeutic targets in new strategies for improving reproductive counselling and infertility therapies.

Potential role of microRNAs in mammalian female fertility

2017 ◽  
Vol 29 (1) ◽  
pp. 8 ◽  
Author(s):  
Dawit Tesfaye ◽  
Dessie Salilew-Wondim ◽  
Samuel Gebremedhn ◽  
Md Mahmodul Hasan Sohel ◽  
Hari Om Pandey ◽  
...  
Keyword(s):  
Embryo Development ◽  
Oocyte Maturation ◽  
Potential Role ◽  
Mammalian Species ◽  
Female Fertility ◽  
Conditional Knockout ◽  
Female Reproduction ◽  
Extracellular Mirnas ◽  
Mammalian Female

Since the first evidence for the involvement of microRNAs (miRNAs) in various reproductive processes through conditional knockout of DICER, several studies have been conducted to investigate the expression pattern and role of miRNAs in ovarian follicular development, oocyte maturation, embryo development, embryo–maternal communication, pregnancy establishment and various reproductive diseases. Although advances in sequencing technology have fuelled miRNA studies in mammalian species, the presence of extracellular miRNAs in various biological fluids, including follicular fluid, blood plasma, urine and milk among others, has opened a new door in miRNA research for their use as diagnostic markers. This review presents data related to the identification and expression analysis of cellular miRNA in mammalian female fertility associated with ovarian folliculogenesis, oocyte maturation, preimplantation embryo development and embryo implantation. In addition, the relevance of miRNAs to female reproductive disorders, including polycystic ovary syndrome (PCOS), endometritis and abnormal pregnancies, is discussed for various mammalian species. Most importantly, the mechanism of release and the role of extracellular miRNAs in cell–cell communication and their potential role as non-invasive markers in female fertility are discussed in detail. Understanding this layer of regulation in female reproduction processes will pave the way to understanding the genetic regulation of female fertility in mammalian species.

scholarly journals Ovary Development: Insights From a Three-Dimensional Imaging Revolution

2021 ◽  
Vol 9 ◽  
Author(s):  
Bikem Soygur ◽  
Diana J. Laird
Keyword(s):  
Ovarian Function ◽  
3D Visualization ◽  
Three Dimensional ◽  
Ovary Development ◽  
3D Analysis ◽  
Female Reproduction ◽  
Tissue Clearing ◽  
Hormonal Cycle ◽  
Size Discrepancy ◽  
And Function

The ovary is an indispensable unit of female reproduction and health. However, the study of ovarian function in mammals is hindered by unique challenges, which include the desynchronized development of oocytes, irregular distribution and vast size discrepancy of follicles, and dynamic tissue remodeling during each hormonal cycle. Overcoming the limitations of traditional histology, recent advances in optical tissue clearing and three-dimensional (3D) visualization offer an advanced platform to explore the architecture of intact organs at a single cell level and reveal new relationships and levels of organization. Here we summarize the development and function of ovarian compartments that have been delineated by conventional two-dimensional (2D) methods and the limits of what can be learned by these approaches. We compare types of optical tissue clearing, 3D analysis technologies, and their application to the mammalian ovary. We discuss how 3D modeling of the ovary has extended our knowledge and propose future directions to unravel ovarian structure toward therapeutic applications for ovarian disease and extending female reproductive lifespan.

Role of cAMP/PKA/CREB pathway and β-arrestin 1 in LH induced luteolysis in pregnant rats

Reproduction ◽  
2021 ◽  
Vol 162 (1) ◽  
pp. 21-31
Author(s):  
Akshi Vashistha ◽  
H Rahaman Khan ◽  
Medhamurthy Rudraiah
Keyword(s):  
Pregnancy Loss ◽  
Map Kinases ◽  
Repeated Administration ◽  
Luteal Cell ◽  
Female Reproduction ◽  
Pregnant Rats ◽  
Mammalian Female ◽  
And Function ◽  
Creb Pathway

Luteal dysfunction in pregnant women is associated with early pregnancy loss, making the study of structure and function of the corpus luteum (CL) critical. Luteinizing hormone (LH) plays a crucial role in the mammalian female reproduction majorly by regulating luteal development. In rats, the luteotropic roles of LH have been widely investigated but its role in the process of luteolysis has received little attention. In this study, we explored the luteolytic actions of LH during different stages of pregnancy in rats. Repeated administration of LH during the late and mid-stages of pregnancy led to functional luteolysis during both stages, while structural luteolysis was observed only during the late-stage. We analyzed the involvement of cAMP/PKA/CREB pathway, MAP kinases and β-arrestins to elucidate the molecular mechanism of LH-mediated luteolysis. The results indicate that the repeated administration of LH causes LH/CGR desensitization along with an increase in β-arrestin 1 expression, while luteal expression of MAP kinases remained unaffected. Further, siRNA-mediated depletion of β-arrestin 1 in primary luteal-cell cultures prevents initiation of the luteolysis process to some extent during both the stages of pregnancy, underscoring its role in LH mediated-luteolysis. In conclusion, the luteolytic actions of LH appear to involve more than one signaling pathway and cAMP/PKA/CREB pathway appears to be the key regulator. This is the first report to show a positive correlation between β-arrestin 1 and 20α-hsd expression. These findings have implications for our understanding of the molecular pathways that regulate luteolysis.

Tocotrienol preserves ovarian function in cyclophosphamide therapy

2015 ◽  
Vol 34 (10) ◽  
pp. 946-952 ◽  
Author(s):  
HS Saleh ◽  
E Omar ◽  
GRA Froemming ◽  
RM Said
Keyword(s):  
Ovarian Function ◽  
Corn Oil ◽  
Concurrent Administration ◽  
Treatment Groups ◽  
Ovarian Protection ◽  
Normal Mean ◽  
Ovarian Size ◽  
And Function

Introduction: Cyclophosphamide (CPA) chemotherapy leads to ovarian failure and infertility. Tocotrienol (T3) is an antioxidant and anti-inflammatory agent. The role of T3 in ovarian protection throughout chemotherapy remains unclear. Aim: To investigate the role of T3 in the preservation of female fertility in CPA treatment. Method: Sixty female mice were divided into five treatment groups, namely, normal saline, corn oil only, T3 only, CPA and CPA + T3. The treatment was given for 30 days, followed by administration of gonadotrophin to induce ovulation. After killing, both ovaries were collected and examined histologically. Results: There was significant reduction in ovarian size in the CPA group compared with the normal group (CPA versus normal, mean area ± SD; 0.118 ± 0.018 vs. 0.423 ± 0.024 cm2; p ≤ 0.005), whilst concurrent administration of T3 with CPA leads to conservation of ovarian size (CPA + T3 vs. CPA, mean area ± SD; 0.285 ± 0.032 vs. 0.118 ± 0.018 cm2; p ≤ 0.005). Ovaries in CPA group showed abnormal folliculogenesis with accompanied reduced ovulation rate, follicular oedema, increased vascularity and inflammatory cell infiltration. These changes were reversed by concurrent T3 administration. Conclusion: Co-administration of T3 with CPA confers protection of ovarian morphology and function in vivo. These findings contribute to the further elucidation of CPA effect on ovary and suggest the potential of T3 use in preserving fertility in chemotherapy.

scholarly journals Therapeutic Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Female Reproductive Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhiqi Liao ◽  
Chang Liu ◽  
Lan Wang ◽  
Cong Sui ◽  
Hanwang Zhang
Keyword(s):  
Extracellular Vesicles ◽  
Current Knowledge ◽  
Polycystic Ovary ◽  
Female Reproduction ◽  
Reproductive Disorders ◽  
Reproductive Disorder ◽  
Critical Issues ◽  
Underlying Mechanisms ◽  
Multiple Molecules

Reproductive disorders, including intrauterine adhesion (IUA), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS), are great threats to female reproduction. Recently, mesenchymal stem cells derived–extracellular vesicles (MSC-EVs) have presented their potentials to cure these diseases, not only for the propensity ability they stemmed from the parent cells, but also for the higher biology stability and lower immunogenicity, compared to MSCs. EVs are lipid bilayer complexes, functional as mediators by transferring multiple molecules to recipient cells, such as proteins, microRNAs, lipids, and cytokines. EVs appeared to have a therapeutic effect on the female reproductive disorder, such as repairing injured endometrium, suppressing fibrosis of endometrium, regulating immunity and anti-inflammatory, and repressing apoptosis of granulosa cells (GCs) in ovaries. Although the underlying mechanisms of MSC-EVs have reached a consensus, several theories have been proposed, including promoting angiogenesis, regulating immunity, and reducing oxidate stress levels. In the current study, we summarized the current knowledge of functions of MSC-EVs on IUA, POI, and PCOS. Given the great potentials of MSC-EVs on reproductive health, the critical issues discussed will guide new insights in this rapidly expanding field.

scholarly journals A Phosphotyrosine Switch in Estrogen Receptor β Is Required for Mouse Ovarian Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Bin Yuan ◽  
Jing Yang ◽  
Louis Dubeau ◽  
Yanfen Hu ◽  
Rong Li
Keyword(s):  
Breast Cancer Cells ◽  
Target Genes ◽  
Ovarian Function ◽  
Physiological Role ◽  
Molecular Evidence ◽  
Wild Type ◽  
Female Mice ◽  
Mutant Female ◽  
And Function

The two homologous estrogen receptors ERα and ERβ exert distinct effects on their cognate tissues. Previous work from our laboratory identified an ERβ-specific phosphotyrosine residue that regulates ERβ transcriptional activity and antitumor function in breast cancer cells. To determine the physiological role of the ERβ phosphotyrosine residue in normal tissue development and function, we investigated a mutant mouse model (Y55F) whereby this particular tyrosine residue in endogenous mouse ERβ is mutated to phenylalanine. While grossly indistinguishable from their wild-type littermates, mutant female mice displayed reduced fertility, decreased ovarian follicular cell proliferation, and lower progesterone levels. Moreover, mutant ERβ from female mice during superovulation is defective in activating promoters of its target genes in ovarian tissues. Thus, our findings provide compelling genetic and molecular evidence for a role of isotype-specific ERβ phosphorylation in mouse ovarian development and function.

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