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Reproductive Biology and Endocrinology... Nov 2003The synthesis of progesterone by the corpus luteum is essential for the establishment and maintenance of early pregnancy. Regulation of luteal steroidogenesis can be... (Review)
Review
The synthesis of progesterone by the corpus luteum is essential for the establishment and maintenance of early pregnancy. Regulation of luteal steroidogenesis can be broken down into three major events; luteinization (i.e., conversion of an ovulatory follicle), luteal regression, and pregnancy induced luteal maintenance/rescue. While the factors that control these events and dictate the final steroid end products are widely varied among different species, the composition of the corpus luteum (luteinized thecal and granulosa cells) and the enzymes and proteins involved in the steroidogenic pathway are relatively similar among all species. The key factors involved in luteal steroidogenesis and several new exciting observations regarding regulation of luteal steroidogenic function are discussed in this review.
Topics: Animals; Biological Transport; Cholesterol; Corpus Luteum; Female; Humans; Phosphoproteins; Progesterone; Steroids
PubMed: 14613534
DOI: 10.1186/1477-7827-1-90 -
Human steroidogenesis: implications for controlled ovarian stimulation with exogenous gonadotropins.Reproductive Biology and Endocrinology... Dec 2014In the menstrual cycle, the mid-cycle surge of gonadotropins (both luteinising hormone [LH] and follicle-stimulating hormone [FSH]) signals the initiation of the... (Review)
Review
In the menstrual cycle, the mid-cycle surge of gonadotropins (both luteinising hormone [LH] and follicle-stimulating hormone [FSH]) signals the initiation of the periovulatory interval, during which the follicle augments progesterone production and begins to luteinise, ultimately leading to the rupture of the follicle wall and the release of an oocyte. The administration of gonadotropins in controlled ovarian stimulation (COS) leads to supraphysiological steroid concentrations of a very different profile compared with those seen during natural cycles. It has been suggested that these high steroid concentrations cause alterations in endometrial development, affecting oocyte viability in assisted reproductive technology. Furthermore, it has been proposed that elevated progesterone levels have a negative effect on the reproductive outcome of COS. This may arise from an asynchrony between embryo stage and endometrium status at the window of implantation. The regulation of progesterone production by the developing follicles during COS is a complicated interplay of hormonal systems involving the theca and granulosa cells, and the effect of the actions of both LH and FSH. The present paper reviews current knowledge of the regulation of progesterone in the human ovary during the follicular phase and highlights areas where knowledge remains limited. In this review, we provide in-depth information outlining the regulation and function of gonadotropins in the complicated area of steroidogenesis. Based on current evidence, it is not clear whether the high levels of progesterone produced during COS have detrimental effects on fertility.
Topics: Animals; Evidence-Based Medicine; Female; Follicle Stimulating Hormone, Human; Humans; Infertility, Female; Luteinizing Hormone; Models, Biological; Ovary; Ovulation; Ovulation Induction; Progesterone; Recombinant Proteins
PubMed: 25543693
DOI: 10.1186/1477-7827-12-128 -
Obstetrics & Gynecology Science Mar 2014Dynamic changes in steroidogenesis occur in ovarian granulosa cells during ovulation after the LH surge. The ovulatory LH surge induces rapid up-regulation of...
Dynamic changes in steroidogenesis occur in ovarian granulosa cells during ovulation after the LH surge. The ovulatory LH surge induces rapid up-regulation of steroidogenic acute regulatory (StAR) protein and rapid down-regulation of aromatase (Cyp19a1) in granulosa cells undergoing luteinization during ovulation. These rapid changes in StAR and Cyp19a1 gene expression after the LH surge efficiently facilitate progesterone production, which plays a crucial role in ovulation and the following luteinization. Recently, it has become clear that epigenetic regulation such as histone modifications and DNA methylation play a key role in gene expression through the chromatin remodeling of the promoter region. This study reports the in vivo evidence that epigenetic mechanisms including histone modifications, DNA methylation and chromatin remodeling are involved in the rapid changes of StAR and Cyp19a1 gene expression in granulosa cells undergoing luteinization during ovulation.
PubMed: 24678481
DOI: 10.5468/ogs.2014.57.2.93 -
Science Advances Mar 2022Anti-Müllerian hormone (AMH) is produced by growing ovarian follicles and provides a diagnostic measure of reproductive reserve in women; however, the impact of AMH on...
Anti-Müllerian hormone (AMH) is produced by growing ovarian follicles and provides a diagnostic measure of reproductive reserve in women; however, the impact of AMH on folliculogenesis is poorly understood. We cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and downstream single-cell RNA sequencing of granulosa and theca/stroma cell fractions. A total of 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals (>10 weeks). In the context of exogenous AMH, follicles exhibited a decreased ratio of primordial to growing follicles and antral follicles of increased diameter. Transcriptomic analysis and immunolabeling revealed a marked increase in factors typically noted at more advanced stages of follicle maturation, with granulosa and theca/stroma cells also displaying molecular hallmarks of luteinization. These results suggest that superphysiologic AMH alone may contribute to ovulatory dysfunction by accelerating maturation and/or luteinization of antral-stage follicles.
Topics: Animals; Anti-Mullerian Hormone; Endothelial Cells; Female; Heterografts; Humans; Luteinization; Mice; Ovarian Follicle
PubMed: 35263130
DOI: 10.1126/sciadv.abi7315 -
Seminars in Reproductive Medicine Jan 2008Human follicle development requires the recruitment of primordial follicles into a cohort of growing follicles from which one follicle is selected to ovulate a mature... (Review)
Review
Human follicle development requires the recruitment of primordial follicles into a cohort of growing follicles from which one follicle is selected to ovulate a mature oocyte. During this developmental process, complex endocrine and intraovarian paracrine signals create a changing intrafollicular hormonal milieu. With this microenvironment, appropriate cumulus cell-oocyte signaling governs oocyte developmental competence, defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. Many of these mechanisms are perturbed in polycystic ovary syndrome (PCOS), a heterogeneous syndrome characterized by ovarian hyperandrogenism, hyperinsulinemia from insulin resistance, and reduced fecundity. In addition to these endocrinopathies, PCOS also is characterized by paracrine dysregulation of follicle development by intraovarian proteins of the transforming growth factor-beta family. Consequently, PCOS patients undergoing ovarian stimulation for in vitro fertilization are at increased risks of impaired oocyte developmental competence, implantation failure, and pregnancy loss. Recent data demonstrate links between endocrine/paracrine factors and oocyte gene expression in PCOS and suggest that new clinical strategies to optimize developmental competence of PCOS oocytes should target correction of the entire follicle growth and oocyte development process.
Topics: Female; Humans; Hyperandrogenism; Hyperinsulinism; Luteinization; Oocytes; Oogenesis; Ovarian Follicle; Polycystic Ovary Syndrome; Transforming Growth Factor beta
PubMed: 18181083
DOI: 10.1055/s-2007-992925 -
PloS One 2022Reactivation of the hypothalamic-pituitary-ovarian (HPO) axis triggered by the decline in serum progesterone in mid-gestation is an uncommon trait that distinguishes the...
Reactivation of the hypothalamic-pituitary-ovarian (HPO) axis triggered by the decline in serum progesterone in mid-gestation is an uncommon trait that distinguishes the vizcacha from most mammals. Accessory corpora lutea (aCL) developed upon this event have been proposed as guarantors of the restoration of the progesterone levels necessary to mantain gestation. Therefore, the steroidogenic input of primary CL (pCL) vs aCL was evaluated before and after HPO axis-reactivation (BP and AP respectively) and in term pregnancy (TP). Nonpregnant-ovulated females (NP) were considered as the pCL-starting point group. In BP, the ovaries mainly showed pCL, whose LH receptor (LHR), StAR, 3β-HSD, 20α-HSD, and VEGF immunoexpressions were similar or lower than those of NP. In AP, luteal reactivity increased significantly compared to the previous stages, and the pool of aCL developed in this stage represented 20% of the ovarian structures, equaling the percentage of pCL. Both pCL and aCL luteal cells shared similar histological features consistent with secretory activity. Although pCL and aCL showed equivalent labeling intensity for the luteotropic markers, pCL were significantly larger than aCL. Towards TP, both showed structural disorganization and loss of secretory characteristics. No significant DNA fragmentation was detected in luteal cells throughout gestation. Our findings indicate that the LH surge derived from HPO axis-reactivation targets the pCL and boost luteal steroidogenesis and thus progesterone production. Because there are many LHR-expressing antral follicles in BP, they also respond to the LH stimuli and luteinize without extruding the oocyte. These aCL certainly contribute but it is the steroidogenic restart of the pCL that is the main force that restores progesterone levels, ensuring that gestation is carried to term. Most importantly, the results of this work propose luteal steroidogenesis reboot as a key event in the modulation of vizcacha pregnancy and depict yet another distinctive aspect of its reproductive endocrinology.
Topics: Animals; Corpus Luteum; Female; Luteal Cells; Luteinizing Hormone; Pregnancy; Progesterone; Receptors, LH; Rodentia
PubMed: 35802690
DOI: 10.1371/journal.pone.0271067 -
Cell and Tissue Research May 2022L-lactate acts as a signaling molecule in bovine granulosa cells (GCs). The initiated alterations depend on the transport of L-lactate into the cells via monocarboxylate...
L-lactate acts as a signaling molecule in bovine granulosa cells (GCs). The initiated alterations depend on the transport of L-lactate into the cells via monocarboxylate transporters. In the present study, we further elucidated the intracellular actions of L-lactate and tested whether the PKA signaling pathway is involved. Therefore, we treated cultured bovine GCs with L-lactate and PKA inhibitors H-89 and KT5720, and with an activator of PKA, 6-Bnz-cAMP. L-lactate treatment resulted in decreased estradiol production and downregulation of CYP19A1, FSHR, and LHCGR as well as in the upregulation of the markers of early luteinization PTX3, RGS2, and VNN2. These specific L-lactate effects were almost completely abolished by pre-treatment of the GCs with both inhibitors of PKA signaling. In addition, also the L-lactate-induced upregulation of LDHA and of the monocarboxylate transporters SLC16A1 and SLC16A7 was abolished after PKA inhibition. An activation of the PKA with 6-Bnz-cAMP revealed similar effects on the gene expression like L-lactate alone. In summary, the presented data demonstrate that L-lactate-induced effects on GCs are mediated via PKA signaling thus supporting the role of L-lactate as signaling molecule during the folliculo-luteal transition.
Topics: Animals; Cattle; Cells, Cultured; Female; Granulosa Cells; Lactic Acid; Luteinizing Hormone; Signal Transduction
PubMed: 34985545
DOI: 10.1007/s00441-021-03569-7 -
Reproductive Medicine and Biology Mar 2011The gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), are of particular importance in ovarian physiology. However, FSH receptors and LH... (Review)
Review
The gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), are of particular importance in ovarian physiology. However, FSH receptors and LH receptors are not expressed until the secondary follicle stage, indicating that initiation of follicular growth is independent of the gonadotropins. Among many intra-ovarian growth factors, many studies have shown that bone morphogenetic proteins (BMPs) play pivotal roles in regulating the early phases of follicular growth. The BMP system induces the gonadotropin system by modulating gonadotropin receptors in early-stage follicles. Interestingly, the BMP system also prevents precocious maturation of the follicle by suppressing luteinization. Signals provoked by the preovulatory LH surge eliminate BMPs, enabling luteinization to progress. Thus, the BMP system and the gonadotropin system seem to cooperate in regulating follicular development, maturation, and luteinization.
PubMed: 29699076
DOI: 10.1007/s12522-010-0072-3 -
Journal of Neuroendocrinology Mar 2009The best characterised oestrogen receptors (ERs) that are responsible for membrane-initiated oestradiol signalling are the classic ERs, ERalpha and ERbeta. When in the... (Review)
Review
The best characterised oestrogen receptors (ERs) that are responsible for membrane-initiated oestradiol signalling are the classic ERs, ERalpha and ERbeta. When in the nucleus, these proteins are oestradiol activated transcription factors but, when trafficked to the cell membrane, ERalpha and ERbeta rapidly activate protein kinase pathways, alter membrane electrical properties, modulate ion flux and can mediate long-term effects through gene expression. To initiate cell signalling, membrane ERs transactivate metabotropic glutamate receptors (mGluRs) to stimulate Gq signalling through pathways using PKC and calcium. In this review, we discuss the interaction of membrane ERalpha with metabotropic glutamate receptor 1a (mGluR1a) to initiate rapid oestradiol cell signalling and its critical roles in female reproduction: sexual behaviour and oestrogen positive feedback of the luteinising hormone (LH) surge. Although long considered to be regulated by the long-term actions of oestradiol on gene transcription, recent results indicate that membrane oestradiol cell signalling is vital for a full display of sexual receptivity. Similarly, the source of pre-ovulatory progesterone necessary for initiating the LH surge is hypothalamic astrocytes. Oestradiol rapidly amplifies progesterone synthesis through the release of intracellular calcium stores. The ERalpha-mGluR1a interaction is necessary for critical calcium flux. These two examples provide support for the hypothesis that membrane ERs are not themselves G-protein receptors; rather, they use mGluRs to signal.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Astrocytes; Calcium; Cell Membrane; Estradiol; Estrogen Receptor alpha; Female; Hypothalamus; Luteinizing Hormone; Ovulation; Preoptic Area; Progesterone; Receptors, Metabotropic Glutamate; Receptors, Opioid, mu; Sexual Behavior, Animal; Signal Transduction
PubMed: 19207814
DOI: 10.1111/j.1365-2826.2009.01833.x -
Frontiers in Endocrinology 2019Anovulation is a major cause of infertility, and it is the major leading reproductive disorder in mammalian females. Without ovulation, an oocyte is not released from... (Review)
Review
Anovulation is a major cause of infertility, and it is the major leading reproductive disorder in mammalian females. Without ovulation, an oocyte is not released from the ovarian follicle to be fertilized and a corpus luteum is not formed. The corpus luteum formed from the luteinized somatic follicular cells following ovulation, vasculature cells, and immune cells is critical for progesterone production and maintenance of pregnancy. Follicular theca cells differentiate into small luteal cells (SLCs) that produce progesterone in response to luteinizing hormone (LH), and granulosa cells luteinize to become large luteal cells (LLCs) that have a high rate of basal production of progesterone. The formation and function of the corpus luteum rely on the appropriate proliferation and differentiation of both granulosa and theca cells. If any aspect of granulosa or theca cell luteinization is perturbed, then the resulting luteal cell populations (SLC, LLC, vascular, and immune cells) may be reduced and compromise progesterone production. Thus, many factors that affect the differentiation/lineage of the somatic cells and their gene expression profiles can alter the ability of a corpus luteum to produce the progesterone critical for pregnancy. Our laboratory has identified genes that are enriched in somatic follicular cells and luteal cells through gene expression microarray. This work was the first to compare the gene expression profiles of the four somatic cell types involved in the follicle-to-luteal transition and to support previous immunofluorescence data indicating theca cells differentiate into SLCs while granulosa cells become LLCs. Using these data and incorporating knowledge about the ways in which luteinization can go awry, we can extrapolate the impact that alterations in the theca and granulosa cell gene expression profiles and lineages could have on the formation and function of the corpus luteum. While interactions with other cell types such as vascular and immune cells are critical for appropriate corpus luteum function, we are restricting this review to focus on granulosa, theca, and luteal cells and how perturbations such as androgen excess and inflammation may affect their function and fertility.
PubMed: 31849844
DOI: 10.3389/fendo.2019.00832