SIK2 and SIK3 Differentially Regulate Mouse Granulosa Cell Response to Exogenous Gonadotropins In Vivo.

Salt-inducible kinases (SIKs), a family of serine/threonine kinases, were found to be critical determinants of female fertility. SIK2 silencing results in increased ovulatory response to gonadotropins. In contrast, SIK3 knockout results in infertility, gonadotropin insensitivity, and ovaries devoid of antral and preovulatory follicles.

Molecular crosstalk between insulin-like growth factors and follicle-stimulating hormone in the regulation of granulosa cell function.

Background: The last phase of folliculogenesis is driven by follicle-stimulating hormone (FSH) and locally produced insulin-like growth factors (IGFs), both essential for forming preovulatory follicles.

Methods: This review discusses the molecular crosstalk of the FSH and IGF signaling pathways in regulating follicular granulosa cells (GCs) during the antral-to-preovulatory phase.

Main Findings: IGFs were considered co-gonadotropins since they amplify FSH actions in GCs.

Salt-inducible kinases regulate androgen synthesis in theca cells by enhancing CREB signaling.

Ovulation is the pinnacle of folliculogenesis, a process that requires an interplay between the oocyte, the granulosa cells, and the theca cells (TCs). TCs are the only source of ovarian androgens, which play a vital role in female fertility. However, abnormally elevated androgen levels reduce fertility.

Insulin-like growth factor 1 enhances follicle-stimulating hormone-induced phosphorylation of GATA4 in rat granulosa cells.

Preovulatory granulosa cell (GC) differentiation is essential for the maturation and release of oocytes from the ovary. We have previously demonstrated that follicle-stimulating hormone (FSH) and insulin-like growth factors (IGFs) closely interact to control GC function. Similarly, we showed that GATA4 mediates FSH actions and it is required for preovulatory follicle formation.

Mechanism of negative modulation of FSH signaling by salt-inducible kinases in rat granulosa cells.

The optimal development of preovulatory follicles needs follicle-stimulating hormone (FSH). Recent findings revealed that salt-inducible kinases (SIKs) inhibit FSH actions in humans and rodents. This report seeks to increase our understanding of the molecular mechanisms controlled by SIKs that participate in the inhibition of FSH actions in primary rat granulosa cells (GCs).

Oocyte-secreted factors strongly stimulate sFRP4 expression in human cumulus cells.

Secreted frizzled-related protein-4 (SFRP4) belongs to a family of soluble ovarian-expressed proteins that participate in female reproduction, particularly in rodents. In humans, SFRP4 is highly expressed in cumulus cells (CCs). However, the mechanisms that stimulate SFRP4 in CCs have not been examined.

Salt-inducible Kinases Are Critical Determinants of Female Fertility.

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.

Regulation of Insulin-Like Growth Factor 2 by Oocyte-Secreted Factors in Primary Human Granulosa Cells.

Context: Human granulosa cells (hGCs) produce and respond to insulin-like growth factor 2 (IGF2) but whether the oocyte participates in IGF2 regulation in humans is unknown.

Objective: To determine the role of oocyte-secreted factors (OSFs) such as growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) in IGF2 production by hGCs.

Design: Primary human cumulus GCs in culture.

Sp1 regulates steroidogenic genes and LHCGR expression in primary human luteinized granulosa cells.

Luteinizing hormone and human chorionic gonadotropin (hCG) bind to the luteinizing hormone/chorionic gonadotropin receptor (LHCGR). LHCGR is required to maintain corpus luteum function but the mechanisms involved in the regulation of LHCGR in human luteal cells remain incompletely understood. This study aimed to characterize the expression of LHCGR mRNA in primary human luteinized granulosa cells (hLGCs) obtained from patients undergoing in vitro fertilization and to correlate LHCGR expression with the response of hLGCs to hCG by assessing the expression of genes known to be markers of hCG actions.

Oocyte-Secreted Factors Synergize With FSH to Promote Aromatase Expression in Primary Human Cumulus Cells.

Context: The role of growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) on aromatase regulation is poorly understood in humans.

Objective: Determine GDF9 and BMP15 effects on FSH stimulation of estradiol production in primary human cumulus granulosa cells (GCs). We hypothesized that the combination of GDF9 and BMP15 potentiates FSH-induced aromatase expression.

GATA Regulation and Function During the Ovarian Life Cycle.

GATA4 and GATA6 are the sole GATA factors expressed in the ovary during embryonic development and adulthood. Up today, GATA4 and GATA6 are the only transcription factors that have been conditionally deleted during ovarian development and at each major stage of follicle maturation. The evidence from these transgenic mice revealed that GATA4 and GATA6 are crucial for follicles assembly, granulosa cell differentiation, postnatal follicle growth, and luteinization.

Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells.

The regulation of AMH production by follicular cells is poorly understood. The purpose of this study was to determine the role of the oocyte-secreted factors, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), on AMH production in primary human cumulus cells. Cumulus cells from IVF patients were cultured with a combination of GDF9, BMP15, recombinant FSH and specific signaling inhibitors.

IGF1R Expression in Ovarian Granulosa Cells Is Essential for Steroidogenesis, Follicle Survival, and Fertility in Female Mice.

Folliculogenesis is a lengthy process that requires the proliferation and differentiation of granulosa cells (GCs) for preovulatory follicle formation. The most crucial endocrine factor involved in this process is follicle-stimulating hormone (FSH). Interestingly, previous in vitro studies indicated that FSH does not stimulate GC proliferation in the absence of the insulinlike growth factor 1 receptor (IGF1R).

Genome-wide interactions between FSH and insulin-like growth factors in the regulation of human granulosa cell differentiation.

Study Question: Is the genome-wide response of human cumulus cells to FSH and insulin-like growth factors (IGFs) comparable to the response observed in undifferentiated granulosa cells (GCs)?

Summary Answer: FSH actions in human cumulus cells mimic those observed in preantral undifferentiated GCs from laboratory animals, and approximately half of the regulated genes are dependent on the simultaneous activation of the IGF1 receptor (IGF1R).

What Is Known Already: Animal studies have shown that FSH and the IGFs system are required for follicle growth and maturation. In humans, IGF levels in the follicular fluid correlate with patients' responses to IVF protocols.

GATA4 and GATA6 Knockdown During Luteinization Inhibits Progesterone Production and Gonadotropin Responsiveness in the Corpus Luteum of Female Mice.

The surge of luteinizing hormone triggers the genomic reprogramming, cell differentiation, and tissue remodeling of the ovulated follicle, leading to the formation of the corpus luteum. During this process, called luteinization, follicular granulosa cells begin expressing a new set of genes that allow the resulting luteal cells to survive in a vastly different hormonal environment and to produce the extremely high amounts of progesterone (P4) needed to sustain pregnancy. To better understand the molecular mechanisms involved in the regulation of luteal P4 production in vivo, the transcription factors GATA4 and GATA6 were knocked down in the corpus luteum by crossing mice carrying Gata4 and Gata6 floxed genes with mice carrying Cre recombinase fused to the progesterone receptor.

FSH Regulates IGF-2 Expression in Human Granulosa Cells in an AKT-Dependent Manner.

Context: IGF-2 is highly expressed in the granulosa cells of human dominant ovarian follicles; however, little is known about the regulation of the IGF-2 gene or the interaction of IGF-2 and FSH during follicle development.

Objective: To examine the mechanisms involved in the regulation of the IGF-2 gene by FSH and the interplay between FSH and IGF-2 during granulosa cell differentiation. Design, Setting, Patients, and Interventions: Cumulus granulosa cells were separated from cumulus-oocyte complexes isolated from the follicular aspirates of in vitro fertilization patients and cultured for in vitro studies.

IGF1R signaling is necessary for FSH-induced activation of AKT and differentiation of human Cumulus granulosa cells.

Context: FSH is routinely administered to in vitro fertilization patients to induce follicle maturation. During this process, granulosa cells differentiate and acquire specific functional characteristics that are required to coordinate ovulation and oocyte maturation.

Objective: The objective of the study was to gain insight into the molecular mechanisms regulating human granulosa cell differentiation.

GATA4 and GATA6 silencing in ovarian granulosa cells affects levels of mRNAs involved in steroidogenesis, extracellular structure organization, IGF-I activity, and apoptosis.

Knockdown of the transcription factors GATA4 and GATA6 in granulosa cells (GCs) impairs folliculogenesis and induces infertility. To investigate the pathways and genes regulated by these factors, we performed microarray analyses on wild-type GCs or GCs lacking GATA4, GATA6, or GATA4/6 (G4(gcko), G6(gcko), and G4/6(gcko)) after in vivo treatment with equine chorionic gonadotropin. GATA4 deletion affected a greater number of genes than GATA6, which correlates with the subfertility observed in G4(gcko) mice and the normal reproductive function found in G6(gcko) animals.

Testosterone-dependent interaction between androgen receptor and aryl hydrocarbon receptor induces liver receptor homolog 1 expression in rat granulosa cells.

Androgens play a major role in the regulation of normal ovarian function; however, they are also involved in the development of ovarian pathologies. These contrasting effects may involve a differential response of granulosa cells to the androgens testosterone (T) and dihydrotestosterone (DHT). To determine the molecular pathways that mediate the distinct effects of T and DHT, we studied the expression of the liver receptor homolog 1 (LRH-1) gene, which is differentially regulated by these steroids.

IGF-I signaling is essential for FSH stimulation of AKT and steroidogenic genes in granulosa cells.

FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes.

Abruption-induced preterm delivery is associated with thrombin-mediated functional progesterone withdrawal in decidual cells.

Plasma progesterone levels remain elevated throughout human pregnancy, suggesting that reduced reproductive-tract progesterone receptor (PR) initiates labor. Placental abruption and excess thrombin generation elicit preterm delivery (PTD). PR, glucocorticoid receptor (GR), and total and p-ERK1/2 in decidual cells (DCs) and interstitial trophoblasts (IT) were assessed via immunohistochemical staining in abruption-associated PTD versus gestational-age matched control placentas, and in cultured DCs incubated with estradiol (E2) ± medroxyprogesterone acetate (MPA) ± thrombin.

Loss of GATA-6 and GATA-4 in granulosa cells blocks folliculogenesis, ovulation, and follicle stimulating hormone receptor expression leading to female infertility.

Single GATA-6 (G6(gcko)), GATA-4 (G4(gcko)), and double GATA-4/6 (G4/6(gcko)) granulosa cell-specific knockout mice were generated to further investigate the role of GATA transcription factors in ovarian function in vivo. No reproductive defects were found in G6(gcko) animals. G4(gcko) animals were subfertile as indicated by the reduced number of pups per litter and the release of significantly fewer oocytes at ovulation.

The long and short of the prolactin receptor: the corpus luteum needs them both!

In this issue of , Le et al. examine the role of the long form of the prolactin receptor in ovarian function by developing mice expressing only this isoform of the receptor either ubiquitously or specifically in the corpus luteum.

Tissue physiology and pathology of aromatase.

Aromatase is expressed in multiple tissues, indicating a crucial role for locally produced oestrogens in the differentiation, regulation and normal function of several organs and processes. This review is an overview of the role of aromatase in different tissues under normal physiological conditions and its contribution to the development of some oestrogen-related pathologies.