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Distribution of the type I inositol trisphosphate receptor in the human metaphase I stage oocyte. Optical sections are passing through the equatorial ( A , B , F ); subcortical ( C , E ) and cortical planes ( D ). Green fluorescent (FITC) signal depicts the receptor. Red fluorescent (propidium iodide) signal in ( A ) indicates the chromosome metaphase plate. Bar ϭ 50 μ m.
Source publication
We studied the presence and distribution of the intracellular calcium channel regulating type I inositol 1,4,5-trisphosphate receptors (IP3R) in human immature and mature oocytes, pronuclear zygotes and cleaved embryos using a specific antibody. Two approaches were used: (i) fluorescence immunocytochemistry using a confocal laser scanning microscop...
Contexts in source publication
Context 1
... six MI oocytes were positive for the FITC fluorescence. The pattern of receptor distribution changed from the diffuse, patchy type into a more reticular type (Figure 2A-F). However, in the centre of the MI oocytes, there were certain zones with patches of diffuse staining. ...
Context 2
... in the centre of the MI oocytes, there were certain zones with patches of diffuse staining. Furthermore, the receptor was now also noted to be concentrated in the cortex forming a peripheral rim ( Figure 2A, B and F). Three-dimensional reconstructed images did not reveal any new findings other than those seen in the optical sections. ...
Citations
... A higher concentration of PLCζ results in a higher frequency of calcium oscillations, which will cause cleavage stage arrest, while a appropriate concentration of PLCζ leads to a appropriate frequency of calcium oscillations, which will activate embryonic development to the blastocyst stage [33,34]. The calcium-binding proteins in the human endoplasmic reticulum and intracellular calcium channels that regulate inositol 1,4,5-trisphosphate receptors (IP3Rs) play an important role in the regulation of calcium signaling during oocyte maturation, fertilization and early embryo development as calcium signaling is a key factor in early embryonic cleavage [35,36]. Taken together, calcium oscillations may be an essential element of early embryonic division [37]. ...
Background
Artificial oocyte activation (AOA) is used to improve fertilization rate following fertilization failure after intracytoplasmic sperm injection (ICSI). Several studies have also shown that AOA may be involved in embryo development. Women with poor ovarian response are more likely to encounter in vitro fertilization (IVF) failure due to poor embryo quality. The aim of this study was to investigate whether AOA could improve embryo quality in older patients with diminished ovarian reserve undergoing IVF-ICSI cycles.
Methods
The retrospective cohort study consisted of 308 patients who fulfilled the POSEIDON Group 4 criteria and received IVF-ICSI cycles. The study group included 91 patients receiving AOA with calcium ionophores following ICSI. A total of 168 patients in the control group underwent ICSI without AOA. The baseline and cycle characteristics and embryo quality were compared between the two groups.
Results
At baseline, there were more IVF attempts, greater primary infertility, higher basal FSH levels and lower anti-Müllerian hormone (AMH) levels in the AOA group than in the non-AOA group. In terms of embryo quality, there were higher cleavage rates and top-quality Day 3 embryo (TQE) rates, as well as higher percentages of more than 1 TQE and TQE rates ≥50 in the AOA group than in the non-AOA group. The multivariate analysis revealed that AOA was positively associated with more than 1 TQE (adjusted OR 3.24, 95% CI 1.63–6.45, P = 0.001) and a TQE rate ≥ 50 (adjusted OR 2.14, 95% CI 1.20–3.80, P = 0.010). When the study population was divided into 2 subgroups based on the age of 40 years old, the beneficial effects of AOA on embryo quality were only observed in the subgroup of age ≥ 40 years old.
Conclusions
Our data suggest that AOA with calcium ionophores may improve embryo quality in older patients with diminished ovarian reserve undergoing IVF-ICSI cycles, especially in women aged ≥40 years.
... A higher concentration of PLCζ results in a higher frequency of calcium oscillations, which will cause cleavage stage arrest, while a appropriate concentration of PLCζ leads to a appropriate frequency of calcium oscillations, which will activate embryonic development to the blastocyst stage [31,32]. The calcium-binding proteins in the human endoplasmic reticulum and intracellular calcium channels that regulate inositol 1,4,5-trisphosphate receptors (IP3Rs) play an important role in the regulation of calcium signaling during oocyte maturation, fertilization and early embryo development as calcium signaling is a key factor in early embryonic cleavage [33,34]. Taken together, calcium oscillations may be an essential element of early embryonic division [35]. ...
Background
Artificial oocyte activation (AOA) is used to improve fertilization rate following fertilization failure after intracytoplasmic sperm injection (ICSI). Several studies have also shown that AOA may be involved in embryo development. Women with poor ovarian response are more likely to encounter in vitro fertilization (IVF) failure due to poor embryo quality. The aim of this study was to investigate whether AOA could improve embryo quality in older patients with diminished ovarian reserve undergoing IVF-ICSI cycles.
Methods
The retrospective cohort study consisted of 308 patients who fulfilled the POSEIDON Group 4 criteria and received IVF-ICSI cycles. The study group included 91 patients receiving AOA with calcium ionophores following ICSI. A total of 168 patients in the control group underwent ICSI without AOA. The baseline and cycle characteristics and embryo quality were compared between the two groups.
Results
At baseline, there were more IVF attempts, greater primary infertility, higher basal FSH levels and lower anti-Müllerian hormone (AMH) levels in the AOA group than in the non-AOA group. In terms of embryo quality, there were higher cleavage rates and top-quality Day 3 embryo (TQE) rates, as well as higher percentages of more than 1 TQE and TQE rates ≥ 50 in the AOA group than in the non-AOA group. The multivariate analysis revealed that AOA was positively associated with more than 1 TQE (adjusted OR 3.24, 95% CI 1.63–6.45, P = 0.001) and a TQE rate ≥ 50 (adjusted OR 2.14, 95% CI 1.20–3.80, P = 0.010). When the study population was divided into 2 subgroups based on the age of 40 years old, the beneficial effects of AOA on embryo quality were only observed in the subgroup of age ≥ 40 years old.
Conclusions
Our data suggest that AOA with calcium ionophores may improve embryo quality in older patients with diminished ovarian reserve undergoing IVF-ICSI cycles, especially in women aged ≥ 40 years.
... Kane and Chiu stated in their studies that high concentrations of myo-inositol in human follicular fluid play a role in follicle maturation and cause the development of oocytes with good quality (14,15). Goud also showed that myo-inositol had a positive effect on the growth of mature oocytes (16). In a clinical trial aimed to compare the effect of myo-inositol supplementation and D-chiroinositol on the oocytes quality of patients with PCOS the results showed that myo-inositol was able to improve oocytes quality instead of D-chiroinositol (17). ...
Objective. Polycystic ovary syndrome is a disorder in women
of reproductive age and it is one of the pathological factors that
play a role in the failure of laboratory fertilization (IVF). The
aim of this study was to determine the effect of inofolic supplementation on women with polycystic ovary syndrome (PCOS).
Material and methods. This clinical trial study was performed
on 70 infertile women aged 20 to 40 years with polycystic ovary syndrome referred to the Sanandaj Besat Hospital infertility
center in 2019. Patients were randomly divided into intervention and control groups. Patients in the intervention group took
Clomiphene and inofolic supplement for 3 months and patients
in the control group received only Clomiphene for 3 months.
Various parameters such as fasting sugar, LDL, HDL, cholesterol, triglyceride and testosterone level were also measured.
Results. LDL (96.6 ± 19.4 vs 105.2 ± 10.1, p = 0.02), cholesterol
(158.2 ± 10.4 vs 79.8 ± 14.4, p = 0.0001) and triglycerides levels
(140.1 ± 30.3 vs 160.3 ± 22.0, p = 0.002) was significantly lower
in the intervention group than in the control group. The mean
HDL level in the intervention group was higher than the control group (47.3 ± 7.5 vs 43.2 ± 5.1, p = 0.009). The frequency
of follicles (+ 2) in the intervention group (85.7%) was higher
than in the control group (37.1%) (p = 0.001). The frequency of
clinical pregnancies, pregnancies leading to live births, miscarriages, and preterm births in the two groups did not differ
significantly and were almost similar (P > .05).
Conclusions. Inofolic supplementation improved fat profile
status, fetal quality and reduced miscarriage and also increased follicles in women with polycystic ovary syndrome
... МИ является вторичным мессенджером фолликулостимулирующего гормона (ФСГ) и непосредственно участвует в фолликуло-и оогенезе [29]. Он регулирует пролиферацию и созревание гранулезных клеток в яичниках [30,31], опосредует ФСГ-индуцированную выработку антимюллерова гормона (АМГ), модулируя чувствительность фолликулов к ФСГ [32], поддерживает структуру и объем фолликулов [17], играет ключевую роль в развитии зрелых ооцитов, в том числе за счет вовлечения внутриклеточного кальция [33,34], а также ускоряет транспорт ооцитов в маточной трубе [35]. Вследствие высокой востребованности МИ репродуктивными органами женщины концентрация МИ в фолликулярной жидкости значительно выше, чем в сыворотке крови [15], и служит потенциальным маркером качества ооцитов. ...
The article presents key data on the physiology of inositols in the body, their pathogenetic role in the development of polycystic ovary syndrome, and the possibilities of myo-inositol and D-chiro-inositol in the restoration of ovarian function, metabolic parameters, and overcoming of infertility.
... 11 In addition, inositol 3 fosfat (IP3) plays a role in intracellular calcium regulation and induces oocyte maturation with its effects during the stages of oogenesis. 12 Studies have reported that oocyte maturation increases with the secretion of calcium by MI and IP3 supplementation and the acceleration of meiosis in oogenesis. 13,14 MI/DCI ratio decreased from 100:1 in healthy women to 0.2:1 in PCOS women. ...
Aim:
To investigate the effectiveness of myo-inositol and d-chiro-inositol (MI:DCI) (40:1) treatment in normal-weight polycystic ovary syndrome (PCOS) patients without insulin resistance.
Methods:
This retrospective case-control study included PCOS patients without insulin resistance who were diagnosed in the gynecology and obstetrics clinic of Başkent University Konya Practice and Research Hospital between January 2016 and October 2019 and received at least 6 months of MI:DCI (40:1) treatment. The patients were divided into two groups according to body mass index (BMI). Twenty-nine anovulatory patients without insulin resistance with a BMI of 18-25 were included in group 1 (normal-weight group), whereas 17 patients without insulin resistance with BMI > 25 were included in group 2 (obese/overweight group). Ovulation status of both groups was compared after MI:DCI treatment.
Results:
Ovulation was detected in 23 of 29 patients in the normal-weight group, whereas it was detected only in 5 of 17 patients in the obese/overweight group; this difference was statistically significant (P < 0.001) (Table 2, Figure 1). Post-treatment progesterone levels of both groups were compared and in the normal-weight PCOS group was significantly higher than the obese/overweight group (P < 0.001) (Table 2, Figure 2). In addition, spontaneous pregnancy following treatment was observed in six of the seven (85.7%) patients in the normal-weight group who wanted to conceive, whereas it was observed in only two of the six (33.3%) patients in the obese/overweight group who wanted to conceive.
Conclusion:
Our results showed that MI:DCI (40:1) treatment may be a first-line treatment in normal-weight PCOS patients without insulin resistance.
... Within the ovary, the binding of InsP3 to its receptor 1 (IP3-R1) seems to be mandatory for oocyte maturation, especially in the final stages of development that are tightly calcium dependent [21]. Interestingly, accumulating evidence from animal models suggests that exogenous injection of InsP3 stimulates Ca 2+ release from the ovary, thus allowing orderly oogenesis [22]. ...
... The role of calcium in cell mitosis and embryo cleavage is well established (25,26). Thus, it is logical that calcium ionophore treatment may have a positive effect on ICSI success rates. ...
... It is established that calcium initially drives mitotic division (25,27). However, the identification and localization of calcium-binding proteins within human endoplasmic reticulum and IP 3 -receptors found to be associated with Ca 2þ release in human embryos further emphasizes that Ca 2þ also plays a critical role in subsequent cleavages (26,28). Calcium plays an important role in a number of cell cycle checkpoints (29,30). ...
... Calcium plays an important role in a number of cell cycle checkpoints (29,30). For example, spontaneous Ca 2þ spikes accompany resumption of meiosis in maturing oocytes (26,31). ...
Objective:
To study the effect, if any, of calcium ionophore as a method of artificial oocyte activation (AOA) on pregnancy outcomes and fertilization rates.
Design:
Meta-analysis of randomized controlled trials, prospective observational and retrospective trials, case reports, and a case-control trial.
Setting:
University-affiliated teaching hospital.
Patient(s):
Infertile couples undergoing fertilization treatment.
Intervention(s):
Use of calcium ionophore during AOA.
Main outcome measure(s):
Odds ratio (OR) as the summary statistic for binary variables was used. Both a fixed and random effects model were applied. Subgroup analysis using quantitative methodology (risk of bias, metaregression) and graphical comparison (funnel plot) assessed statistical heterogeneity.
Result(s):
Fourteen studies were selected. AOA with calcium ionophore increased the overall clinical pregnancy rate (per ET; OR = 3.48; 95% confidence interval [CI], 1.65-7.37) and the live birth rate (OR = 3.33; 95% CI, 1.50-7.39). This effect of adding calcium ionophore was further demonstrated with fertilization, cleavage, blastocyst, and implantation rates. Subgroup analysis further supported our findings (studies where n > 10 in both arms; random and fixed effects models). A metaregression (beta = -.145) found that as the quality of the study increases, the effect of calcium ionophore is significantly more pronounced with regards to overall pregnancy rate.
Conclusion(s):
AOA with calcium ionophore treatment after intracytoplasmic sperm injection (ICSI) results in a statistically significant improvement in fertilization, cleavage, blastulation, and implantation rates, as well as overall pregnancy and live-birth rates. The conclusion of this systematic review, demonstrating a strong effect of calcium ionophore use, is reassuring and promising, particularly for couples for whom ICSI alone yields poor fertilization rates.
... Upon fertilisation, IP 3 R1 is present in the centre and periphery at the two-to fourcell stage embryos, but redistributes to a pattern across the entire cytosol in six-to eight-cell embryos. These localisation changes occur concomitant with an increase in the levels of this receptor (Goud et al. 1999). Therefore, these data collectively show the relevance of this receptor in the signalling processes underlying oocyte maturation, activation and embryo development. ...
This chapter intends to summarise the importance of sperm- and oocyte-derived factors in the processes of sperm–oocyte binding and oocyte activation. First, we describe the initial interaction between sperm and the zona pellucida, with particular regard to acrosome exocytosis. We then describe how sperm and oocyte membranes fuse, with special reference to the discovery of the sperm protein IZUMO1 and its interaction with the oocyte membrane receptor JUNO. We then focus specifically upon oocyte activation, the fundamental process by which the oocyte is alleviated from metaphase II arrest by a sperm-soluble factor. The identity of this sperm factor has been the source of much debate recently, although mounting evidence, from several different laboratories, provides strong support for phospholipase C ζ (PLCζ), a sperm-specific phospholipase. Herein, we discuss the evidence in support of PLCζ and evaluate the potential role of other candidate proteins, such as post-acrosomal WW-binding domain protein (PAWP/WBP2NL). Since the cascade of downstream events triggered by the sperm-borne oocyte activation factor heavily relies upon specialised cellular machinery within the oocyte, we also discuss the critical role of oocyte-borne factors, such as the inositol trisphosphate receptor (IP3R), protein kinase C (PKC), store-operated calcium entry (SOCE) and calcium/calmodulin-dependent protein kinase II (CaMKII), during the process of oocyte activation. In order to place the implications of these various factors and processes into a clinical context, we proceed to describe their potential association with oocyte activation failure and discuss how clinical techniques such as the in vitro maturation of oocytes may affect oocyte activation ability. Finally, we contemplate the role of artificial oocyte activating agents in the clinical rescue of oocyte activation deficiency and discuss options for more endogenous alternatives.
... Myoinositol is a molecule that belongs to the vitamin B family. Myoinositol enhances the developmental competence of maturing oocytes (Goud et al. 1999). In a prospective-controlled randomized trial, the effects of myoinositol among women with PCOS who were scheduled for ovulation induction and ICSI were examined. ...
Physiological levels of reactive oxygen species (ROS) are required for proper functioning of the male and female reproductive system. However, imbalances between ROS production and antioxidant systems induce oxidative stress, which can jeopardize the quality of the gamete and the developing embryo and cause many pregnancy disorders, such as spontaneous abortion, recurrent pregnancy loss, preeclampsia, fetal embryopathies, and intrauterine growth restriction. This review discusses the adverse effect of ROS-induced oxidative stress in assisted reproductive technologies (ART) outcome, ROS generated in vitro by gametes and embryos, and ROS generated by external sources in the in vitro fertilization (IVF) laboratory and the protocols used, including gamete/embryo handling, composition and pH of culture media, temperature and oxygen concentration during incubation, centrifugation and freeze-thaw protocols, as well as visible light. Studies on oral supplementation of enzymatic and nonenzymatic antioxidants are discussed. Although there is no one antioxidant that is considered the best choice for improving ART outcomes, some antioxidants show promising results. Additional well-designed trials are needed to determine the appropriate type(s) and concentration of antioxidant(s) that would be helpful to infertile patients with various etiologies. Studies are also warranted in the improvement of ART protocols to minimize ROS formation during assisted reproduction.
... Furthermore, IP3 collaborates in regulating intracellular Ca 2+ release from mitochondria. In oocytes, this mechanism involves a specific receptor subtype (IP3-R1) [50], deemed to play a pivotal role in oocyte maturation, namely during the final stages of oogenesis, when oocyte sensitivity to calcium fluctuations reaches the maximal value. Indeed, oocyte maturation in rat is triggered by calcium release after IP3 injection [51]. ...
Polycystic ovary syndrome (PCOS), a relevant cause of infertility, is a heterogeneous, endocrine disorder affecting up to 10–15% of women in reproductive age. Besides hyperandrogenism, insulin resistance (IR) plays a key role in such syndrome. Insulin-sensitizing drugs, such as Metformin, are effective in treating hyper-insulinemic PCOS patients. Recently, inositols – myo-inositol (MI) and D-chiro-inositol (DCI) – have shown to be an efficient and safe alternative in PCOS management, as both inositol isoforms are able to counteract downstream consequences of insulin resistance. Yet, whereas DCI contributes in mediating insulin activity mainly on non-ovarian tissues, MI displays specific effects on ovary, chiefly by modulating glucose metabolism and FSH-signaling. Moreover, MI may also improve ovarian functions by modulating steroid metabolism through non-insulin-dependent pathways. As DCI and MI activity likely involves different biological mechanisms, both inositol isoforms can be synergistically integrated according to a multitargeted design, by combining MI and DCI in a ratio corresponding to their physiological plasma relative amount (40:1). New experimental and clinical evidence with MI plus DCI evidenced the suitability of such integrated approach, and provided promising results. Further studies need to investigate thoroughly the molecular mechanism and confirm such preliminary data.
