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Background: Growth hormone (GH) could improve the outcomes of in vitro fertilization and embryo transfer (IVF-ET) in patients with decreased ovarian reserve (DOR), but which age group will benefit the most has remained controversial. This study aims to explore the outcome of IVF-ET among differently aged patients with DOR treated with GH. Methods: A total of 846 patients with DOR undergoing IVF-ET from May 2018 to June 2023 at the Reproductive Medicine Center of Sichuan Provincial Women's and Children's Hospital were prospectively enrolled. The patients were divided into group A (< 35 year old, n = 399), group B (35 ~ 40 year old, n = 286), and group C (> 40 year old, n = 161). Each group was sub-divided into the GH part and the control part, with the former receiving pretreatment with GH 4 IU/day on day 2 of the previous menstrual cycle before the injection of gonadotrophin (Gn) until the trigger day. The ovarian stimulation protocol was gonadotrophin-releasing hormone antagonist (GnRH-A) or long-acting GnRH agonist protocol. The quality of oocytes and embryos and the outcome of pregnancy were compared. Results: In group B, the number (1.16 ± 0.12 vs. 0.74 ± 0.09) and rate (34.27% vs. 23.90%) of high-quality cleavage embryos, rate of implantation (32.37% vs. 22.35%), clinical pregnancy (48.98% vs. 33.67%), and live birth (44.90% vs. 29.59%) were significantly higher, whereas the canceled oocyte retrieval rate was significantly lower (1.49% vs. 6.58%) in the GH part than those of the control part (P < 0.05). In group B, the duration and dose of Gn, number of oocyte retrieved, and rates of normal fertilization, cleavage embryo, blastocyst, high-quality blastocyst, and early miscarriage were not significantly different between the GH and control parts (P > 0.05). In groups A and C, no significant difference was detected in the quality of embryos and outcomes of embryo transfer with or without pretreatment (P > 0.05). Conclusion: GH could improve the quality of embryos and live birth rate for patients with DOR aged 35–40 years old. [ABSTRACT FROM AUTHOR]

Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BackgroundGrowth hormone (GH) could improve the outcomes of in vitro fertilization and embryo transfer (IVF-ET) in patients with decreased ovarian reserve (DOR), but which age group will benefit the most has remained controversial. This study aims to explore the outcome of IVF-ET among differently aged patients with DOR treated with GH.MethodsA total of 846 patients with DOR undergoing IVF-ET from May 2018 to June 2023 at the Reproductive Medicine Center of Sichuan Provincial Women’s and Children’s Hospital were prospectively enrolled. The patients were divided into group A (< 35 year old, n = 399), group B (35 ~ 40 year old, n = 286), and group C (> 40 year old, n = 161). Each group was sub-divided into the GH part and the control part, with the former receiving pretreatment with GH 4 IU/day on day 2 of the previous menstrual cycle before the injection of gonadotrophin (Gn) until the trigger day. The ovarian stimulation protocol was gonadotrophin-releasing hormone antagonist (GnRH-A) or long-acting GnRH agonist protocol. The quality of oocytes and embryos and the outcome of pregnancy were compared.ResultsIn group B, the number (1.16 ± 0.12 vs. 0.74 ± 0.09) and rate (34.27% vs. 23.90%) of high-quality cleavage embryos, rate of implantation (32.37% vs. 22.35%), clinical pregnancy (48.98% vs. 33.67%), and live birth (44.90% vs. 29.59%) were significantly higher, whereas the canceled oocyte retrieval rate was significantly lower (1.49% vs. 6.58%) in the GH part than those of the control part (P < 0.05). In group B, the duration and dose of Gn, number of oocyte retrieved, and rates of normal fertilization, cleavage embryo, blastocyst, high-quality blastocyst, and early miscarriage were not significantly different between the GH and control parts (P > 0.05). In groups A and C, no significant difference was detected in the quality of embryos and outcomes of embryo transfer with or without pretreatment (P > 0.05).ConclusionGH could improve the quality of embryos and live birth rate for patients with DOR aged 35–40 years old.

Background: This study was designed to explore the effects of flaxseed oil on the metaphase II (MII) oocyte rates in women with decreased ovarian reserve (DOR). Methods: The women with DOR were divided into a study group (n = 108, flaxseed oil treatment) and a control group (n = 110, no treatment). All patients were treated with assisted reproductive technology (ART). Subsequently, the ART stimulation cycle parameters, embryo transfer (ET) results, and clinical reproductive outcomes were recorded. The influencing factors affecting the MII oocyte rate were analyzed using univariate analysis and multivariate analysis. Results: Flaxseed oil reduced the recombinant human follicle-stimulating hormone (r-hFSH) dosage and stimulation time and increased the peak estradiol (E2) concentration in DOR women during ART treatment. The MII oocyte rate, fertilization rate, cleavage rate, high-quality embryo rate, and blastocyst formation rate were increased after flaxseed oil intervention. The embryo implantation rate of the study group was higher than that of the control group (p = 0.05). Additionally, the female age [odds ratio (OR): 0.609, 95% confidence interval (CI): 0.52-0.72, p < 0.01] was the hindering factor of MII oocyte rate, while anti-Müllerian hormone (AMH; OR: 100, 95% CI: 20.31-495, p < 0.01), peak E2 concentration (OR: 1.00, 95% CI: 1.00-1.00, p = 0.01), and the intake of flaxseed oil (OR: 2.51, 95% CI: 1.06-5.93, p = 0.04) were the promoting factors for MII oocyte rate. Conclusion: Flaxseed oil improved ovarian response and the quality of oocytes and embryos, thereby increasing the fertilization rate and high-quality embryo rate in DOR patients. The use of flaxseed oil was positively correlated with MII oocyte rate in women with DOR. Clinical trial number: https://www.chictr.org.cn/, identifier ChiCTR2300073785 [ABSTRACT FROM AUTHOR]

Abstract Background Declining oocyte quality in women with advanced age has been a major impediment to assisted reproductive treatments’ (ART) success rate. However, aging is often accompanied by a diminished ovarian reserve (DOR). Cumulus cells (CCs) are known to play an important role in the development and maturation of oocytes, and the quality of CCs actually reflects the quality of the oocyte. In this study, CCs were used to investigate the real reasons for the decline in oocyte quality in older women. Methods Ninety-nine CC samples were subdivided into 4 different groups according to the different age and ovarian reserve status. Other than clinical ART results, transcriptional expression profiles were performed in CCs to detect the differences. Results The results were that DOR, no matter in young or advanced age group, was found to be significantly associated with adverse ART outcomes. Of note, there were no statistically significant changes in ART outcomes in the group at advanced age with normal ovarian reserve (NOR), compared to the young with NOR. DOR induced a series of transcriptional variations in CCs commonly enriched in oxygen metabolism. Conclusion Our results revealed that the ART outcomes in advanced patients were attributable to the DOR. The oxygen metabolic changes may interfere with CCs’ function of supporting oocytes. This study can provide guidance for ART practice that not age but ovarian reserve status is the main predictor for ART outcomes, and ovarian reserve status should be timely assessed when the clinical manifestations are still mild in elderly women.

Objective To explore the protein differences between decreased ovarian reserve (DOR), premature ovarian failure (POF), and the normal control group using proteomic technology; and Additionally, to analyze the differential proteins to further elucidate the possible mechanisms of ovarian reserve decline and premature ovarian failure. Methods DOR model mice were prepared by a single intraperitoneal injection of 60 mg/kg cyclophosphamide combined with 6 mg/kg busulfan, while POF model mice were prepared by a single intraperitoneal injection of 120 mg/kg cyclophosphamide combined with 12 mg/kg busulfan. The mice′s estrous cycles were continuously observed after drug administration to determine the success of the modeling. After successful modeling, differential proteins were screened, and bioinformatics methods were used for functional annotation and enrichment analysis of the identified differential proteins to analyze their possible mechanisms. Results A total of 148 differential proteins with fold changes of more than 1.2 were screened in the DOR group, and 149 differential proteins were identified in the POF group. Enrichment analysis showed that the differentially expressed proteins in the DOR group were mainly involved in biological processes such as vitamin B6 metabolism, pyridoxal phosphate synthesis, and oxidative stress, and they were enriched in pathways such as vitamin B6 metabolism, α-linolenic acid metabolism, and PPAR signaling. On the other hand, the differentially expressed proteins in the POF group were mainly involved in biological processes such as lipid metabolism and inflammatory response, and they were enriched in pathways such as glycosphingolipid biosynthesis, arachidonic acid metabolism, and ribosome. Conclusion The pathogenesis of DOR and POF is complex, involving processes like oxidative stress and inflammatory response. The α-linolenic acid signaling pathway may be an important pathway involved in the occurrence of DOR, and HIST1 H1 C, CA3, and FABP4 may be important targets for its occurrence. The arachidonic acid metabolism signaling pathway may be an important pathway involved in the occurrence of POF, and HIST1 H1 C, D2 HGDH, and CYP4 F3 may be important targets for its occurrence. [ABSTRACT FROM AUTHOR]

Background: Declining oocyte quality in women with advanced age has been a major impediment to assisted reproductive treatments' (ART) success rate. However, aging is often accompanied by a diminished ovarian reserve (DOR). Cumulus cells (CCs) are known to play an important role in the development and maturation of oocytes, and the quality of CCs actually reflects the quality of the oocyte. In this study, CCs were used to investigate the real reasons for the decline in oocyte quality in older women. Methods: Ninety-nine CC samples were subdivided into 4 different groups according to the different age and ovarian reserve status. Other than clinical ART results, transcriptional expression profiles were performed in CCs to detect the differences. Results: The results were that DOR, no matter in young or advanced age group, was found to be significantly associated with adverse ART outcomes. Of note, there were no statistically significant changes in ART outcomes in the group at advanced age with normal ovarian reserve (NOR), compared to the young with NOR. DOR induced a series of transcriptional variations in CCs commonly enriched in oxygen metabolism. Conclusion: Our results revealed that the ART outcomes in advanced patients were attributable to the DOR. The oxygen metabolic changes may interfere with CCs' function of supporting oocytes. This study can provide guidance for ART practice that not age but ovarian reserve status is the main predictor for ART outcomes, and ovarian reserve status should be timely assessed when the clinical manifestations are still mild in elderly women. [ABSTRACT FROM AUTHOR]

Women with Triple X syndrome (TXS) appear to be at increased risk for decreased ovarian reserve; however, available data are limited. We present an asyndromic adult female with features of recurrent pregnancy loss and decreased ovarian reserve detected with mosaic Triple X syndrome (TXS). The patient was initially evaluated by a low-cost peripheral blood (PB) conventional karyotyping using standard cytogenetic protocols. Interphase fluorescence in situ hybridisation was performed to confirm the diagnosis. Chromosomal microarray, which is a more expensive test, substantiated the presence of additional X chromosomes but failed to detect the presence of low level of mosaicism. Our case study emphasised the recommendation of performing a strategy-based cost-effective cytogenetic evaluation of all cases of decreased ovarian reserve or low anti-Müllerian hormone levels in a resource-constrained setting. It also highlighted the need for additional research to understand the natural history of ovarian function in TXS affected women throughout their lifespans.

Background: Human papillomavirus (HPV) infection has been considered an important involved factor for infertility. Since one of the causes of decreased ovarian reserve is oophoritis due to viral infections, this study aimed to evaluated the association between HPV infection and ovarian reserve. Methods: This case‐control study was performed on 219 women aged 25–35 years who were referred to the gynecologic oncology clinic during 2019–2020. The positive or negative HPV infection was confirmed by cervical biopsy and polymerase chain reaction (PCR) test. Cervical lesions or abnormalities in the cervix were assessed by colposcopy and histopathological analysis. Serum anti‐Mullerian hormone (AMH) levels were measured for all participants to assess ovarian reserve. Results: The results of this study showed that in patients who were HPV positive, decreased ovarian reserve was more common than in the HPV negative group (p = 0.0001). Also, there was a significant difference between Cervical intraepithelial neoplasia (CIN) I and CIN III sub‐groups in AMH level (p = 0.0001). Conclusions: Traces of HPV have been observed in various aspects of infertility, but no study has been performed on its association with ovarian reserve. According to the results of this study, decreased ovarian reserve was more common in patients who were HPV positive. [ABSTRACT FROM AUTHOR]

Abstract Background Human papillomavirus (HPV) infection has been considered an important involved factor for infertility. Since one of the causes of decreased ovarian reserve is oophoritis due to viral infections, this study aimed to evaluated the association between HPV infection and ovarian reserve. Methods This case‐control study was performed on 219 women aged 25–35 years who were referred to the gynecologic oncology clinic during 2019–2020. The positive or negative HPV infection was confirmed by cervical biopsy and polymerase chain reaction (PCR) test. Cervical lesions or abnormalities in the cervix were assessed by colposcopy and histopathological analysis. Serum anti‐Mullerian hormone (AMH) levels were measured for all participants to assess ovarian reserve. Results The results of this study showed that in patients who were HPV positive, decreased ovarian reserve was more common than in the HPV negative group (p = 0.0001). Also, there was a significant difference between Cervical intraepithelial neoplasia (CIN) I and CIN III sub‐groups in AMH level (p = 0.0001). Conclusions Traces of HPV have been observed in various aspects of infertility, but no study has been performed on its association with ovarian reserve. According to the results of this study, decreased ovarian reserve was more common in patients who were HPV positive.

Women with Triple X syndrome (TXS) appear to be at increased risk for decreased ovarian reserve; however, available data are limited. We present an asyndromic adult female with features of recurrent pregnancy loss and decreased ovarian reserve detected with mosaic Triple X syndrome (TXS). The patient was initially evaluated by a low-cost peripheral blood (PB) conventional karyotyping using standard cytogenetic protocols. Interphase fluorescence in situ hybridisation was performed to confirm the diagnosis. Chromosomal microarray, which is a more expensive test, substantiated the presence of additional X chromosomes but failed to detect the presence of low level of mosaicism. Our case study emphasised the recommendation of performing a strategy-based cost-effective cytogenetic evaluation of all cases of decreased ovarian reserve or low anti-Müllerian hormone levels in a resource-constrained setting. It also highlighted the need for additional research to understand the natural history of ovarian function in TXS affected women throughout their lifespans. [ABSTRACT FROM AUTHOR]

Ovarian dysfunction, including premature ovarian insufficiency and decreased ovarian reserve, affects the ovarian reserve and is one of the leading causes of female infertility. More and more cases of ovarian dysfunction are associated with genetic factors. Here, we identified eight potential variants in five genes (MSH4, HFM1, SYCE1, FSHR, and C14orf39) from six independent families by exome sequencing. The splice‐site variants in SYCE1 and MSH4 affected canonical splicing isoforms, leading to missing protein domains or premature termination. Our findings expand the mutational spectrum of ovarian dysfunction and provide potential biomarkers for future genetic counseling and for more personalized treatments. Exome sequencing was shown to be a useful tool to better dissect the genetic basis for ovarian dysfunction and yielded a genetic diagnosis in about 5.0% (6/124) of cases in a cohort of 124 patients with ovarian dysfunction. [ABSTRACT FROM AUTHOR]

Decreased ovarian reserve (DOR) is defined as a decrease in the quality and quantity of oocytes, which reduces ovarian endocrine function and female fertility. The impaired follicular development and accelerated follicle atresia lead to a decrease in the number of follicles, while the decline of oocyte quality is related to the disorder of DNA damage-repair, oxidative stress, and the dysfunction of mitochondria. Although the mechanism of DOR is still unclear, recent studies have found that long non-coding RNA (lncRNA) as a group of functional RNA molecules participate in the regulation of ovarian function, especially in the differentiation, proliferation and apoptosis of granulosa cells in the ovary. LncRNAs participate in the occurrence of DOR by affecting follicular development and atresia, the synthesis and secretion of ovarian hormones. This review summarizes current research on lncRNAs associated with DOR and reveals the potential underlying mechanisms. The present study suggests that lncRNAs could be considered as prognostic markers and treatment targets for DOR. [ABSTRACT FROM AUTHOR]

The authors have described a clinical case of a spontaneous pregnancy in a patient with decreased ovarian reserve, secondary infertility and a history of an in vitro fertilization failure. Based on literature data and their own experience, the authors believe that intraovarian administration of platelet-rich plasma can increase the ovarian reserve and improve reproductive potential.

Objective To analyze the association between oocyte quality and decreased ovarian reserve (DOR) markers in young women undergoing controlled ovarian stimulation (COS). Methods This retrospective study included 49 patients classified as having DOR based on anti-Müllerian hormone (AMH) levels, follicle-stimulating hormone (FSH) levels, or antral follicle counts (AFCs;

Objective: To explore and analyze the effect of Bushen Tiaojing Decoction combined with B-ultrasound on embryo quality in assisted reproductive technology in patients with poor ovarian reserve (DOR). Methods: A total of 58 infertile patients with reduced ovarian reserve who were treated in our hospital from August 2018 to January 2021 were selected as the research subjects. According to the principle of 1:1 random allocation, the patients were divided into a decoction group and a control group with 29 cases in each. The control group was given estradiol valerate tablets combined with dydrogesterone tablets for treatment, the decoction group was given the oral treatment of Bushen Tiaojing Decoction on the basis of the treatment of the control group, and the treatment was observed for 3 menstrual cycles. Results: After treatment, the total effective rate of decoction group was 96.6%, which was higher than 75.9% of control group (P<0.05). All patients had no adverse reactions during treatment. The levels of serum luteinizing hormone (LH) and estradiol (E2) in the two groups after treatment were lower than those before treatment, and those in the decoction group were lower than those in the control group (P<0.05). After treatment, the ovarian artery peak systolic velocity (PSV) and ovarian artery end-diastolic velocity (EDV) in the two groups were higher than those before treatment, and the decoction group was higher than the control group (P<0.05). The number of antral follicles in the two groups after treatment was higher than that before treatment, and that in the decoction group was higher than that in the control group (P<0.05). All patients were followed up for 1 year after treatment. The 1-year pregnancy rate in the decoction group was 72.4%, which was higher than that in the control group (27.6%) (P<0.05). Conclusion: The application of Bushen Tiaojing Decoction in patients with poor ovarian reserve can promote the increase of the number of antral follicles in B-ultrasound, increase the blood flow rate of the ovarian artery, facilitate the normal secretion of sex hormones, improve the quality of embryos, exert the overall therapeutic effect, and is conducive to promoting The patient is pregnant. [ABSTRACT FROM AUTHOR]

Copyright of Progress in Modern Biomedicine is the property of Publishing House of Progress in Modern Biomedicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Despite the great advances in Assisted Reproductive Technologies (ART), management of poor responders has remained a great challenge. Gonadotropin releasing hormone antagonist (GnRH-ant) has been offered as a patient friendly protocol. In the literature, conflicting data exists about the effect of the GnRH-ant starting day on cycle outcomes. Aim: The aim of this study is to evaluate the effect of GnRH-ant starting day on cycle outcomes of patients with poor ovarian response defined by Bologna criteria. Setting and Design: This retrospective cohort study was conducted at an ART clinic of a tertiary hospital. Materials and Methods: A total of 361 cycles using flexible GnRH-ant, 195 in Group A (GnRH-ant administered before day 6 of stimulation) and 166 cycles in Group B (GnRH-ant started on or after day 6), were selected retrospectively for the study. Statistical analysis: Statistical analysis of data was carried out using using IBM SPSS Statistics Software (20.0, SPSS Inc., Chicago, IL, USA). Independent samples t-test and Mann–Whitney U test were used to analyze the variables. Results: Total antral follicle count was significantly higher in Group A compared to Group B (P = 0.009). Duration of stimulation was significantly shorter (P < 0.01) and total dose of gonadotropin used was lower in Group A when compared to Group B (P < 0.01). While higher number of oocytes was retrieved from Group A (P = 0.037), no between-group differences were observed in number of mature oocytes, fertilized oocytes, clinical pregnancy rate or ongoing pregnancy rate (OPR) per embryo transfer (P > 0.05). Conclusion: Early GnRH-ant start may point out a favourable response to ovarian stimulation in poor responders. However, clinical or OPRs were not different from the late GnRH-ant start group.

Genome-wide association study (GWAS) is a field of biomedical research related to the study of associations between genomic variants and phenotypic traits. GWAS is to identify genetic risk factors in order to make a reasonable prediction of susceptibility to the disease, as well as to identify the biological basis of susceptibility to the disease to develop new strategies for prevention and treatment. It is known that 1,0-3,7% of the female population suffers from premature ovarian failure (POF) under the age of 40 and 0.1% under 30. Due to the fact that the etiology of most cases of POF is unclear, and a few decades ago few specific genetic causes of POF were known, the aim of this study was to collect data on full-genomic studies of associations of premature ovarian failure. Based on the analysis of the literature, the following generalizations can be made: GWAS is a modern powerful tool in identifying the causes of diseases, including POF, which require a personalized medical approach. Studies of this type usually compare the genomes of a group of sick people with different phenotypes with the genomes of the control group, which includes similar in age, sex and other characteristics of healthy people. With the help of GWAS it is possible to compare not only the genomes of patients, but also healthy people with different manifestations of the same phenotypic trait. The material for the study are DNA samples of the genome of each participant in the study, in which using microchips look for single nucleotide polymorphisms. If it is possible to identify variants of genomes (more precisely, a set of alleles), which are probably more common in people with this disease, it is said that this variant is associated (or associated) with the disease. Unlike methods that test one or more specific regions of the genome, GWAS uses the complete DNA sequence of the patient. It should be noted that this approach to research does not detect mutations that cause the disease, but only a greater or lesser significant correlation with the disease or other symptom. Today, due to the limited, as a rule, sample size, it is difficult to identify probable genetic candidates for POF. However, this type of research is developing rapidly in the world, its cost will decrease, and the possibility of using such research in medical practice in the near future for individual and accurate approach to the diagnosis of POF should be considered. Currently, the GWAS of the genome of patients with POF in Ukraine is relevant for the detection of known mutations in genes associated with this disease. Given the growing number of women worldwide with premature ovarian failure, the involvement of genomic DNA (GWAS) research from individuals representing major regions of Ukraine will provide data for medical research in a large, little-studied population

Background: Despite the great advances in Assisted Reproductive Technologies (ART), management of poor responders has remained a great challenge. Gonadotropin releasing hormone antagonist (GnRH-ant) has been offered as a patient friendly protocol. In the literature, conflicting data exists about the effect of the GnRH-ant starting day on cycle outcomes. Aim: The aim of this study is to evaluate the effect of GnRH-ant starting day on cycle outcomes of patients with poor ovarian response defined by Bologna criteria. Setting and Design: This retrospective cohort study was conducted at an ART clinic of a tertiary hospital. Materials and Methods: A total of 361 cycles using flexible GnRH-ant, 195 in Group A (GnRH-ant administered before day 6 of stimulation) and 166 cycles in Group B (GnRH-ant started on or after day 6), were selected retrospectively for the study. Statistical analysis: Statistical analysis of data was carried out using using IBM SPSS Statistics Software (20.0, SPSS Inc., Chicago, IL, USA). Independent samples t-test and Mann–Whitney U test were used to analyze the variables. Results: Total antral follicle count was significantly higher in Group A compared to Group B (P = 0.009). Duration of stimulation was significantly shorter (P < 0.01) and total dose of gonadotropin used was lower in Group A when compared to Group B (P < 0.01). While higher number of oocytes was retrieved from Group A (P = 0.037), no between-group differences were observed in number of mature oocytes, fertilized oocytes, clinical pregnancy rate or ongoing pregnancy rate (OPR) per embryo transfer (P > 0.05). Conclusion: Early GnRH-ant start may point out a favourable response to ovarian stimulation in poor responders. However, clinical or OPRs were not different from the late GnRH-ant start group. [ABSTRACT FROM AUTHOR]

Objectives: Data regarding whether the assisted reproductive technologies (ART) outcome of patients with decreased ovarian reserve (DOR) secondary to an endometrioma surgery differs from that of patients with DOR secondary to other etiologies is limited. The aim of this study was to compare the ART outcomes of DOR patients diagnosed by Bologna criteria secondary to a previous endometrioma surgery with DOR patients without a history of an endometrioma surgery. Methods: This retrospective cohort study was conducted in the assisted reproduction unit of a tertiary research and education hospital. Medical records of the patients with DOR were reviewed retrospectively. Group I included 23 cycles of DOR patients secondary to a previous endometrioma surgery and Group II consisted of 260 cycles of DOR patients without a history of endometrioma surgery. Results: No significant difference was demonstrated between groups regarding demographic features except for the age (32 (24–41) in Group I vs 35 (23–47) in Group II, p = 0.031). The data comparing the controlled ovarian stimulation parameters and ART outcomes showed similar results in both groups. No statistically significant difference was found between groups regarding pregnancy rates per transfer (23% vs 22.2 %) and per cycle (13% vs 15.4%) (p > 0.05). Conclusion: Cycle outcomes of DOR patients secondary to an endometrioma surgery did not differ from that of DOR without an endometrioma surgery history. [ABSTRACT FROM AUTHOR]

Background: Premature luteinization (PL) is defined as a premature rise in serum progesterone concentration on or before the day of ovulation trigger with human chorionic gonadotropin. The incidence of PL varies between 5% and 30% during in vitro fertilization and embryo transfer (IVF-ET). Materials and Methods: The prospective observational study comprising 380 patients undergoing IVF-ET. Blood samples were collected for serum progesterone level estimation on the day of ovulation trigger. Ovum pickup was done 36 h later and serum progesterone levels were correlated with IVF-ET outcome. Study Outcome: To correlate serum progesterone level on the day of ovulation trigger during IVF and its effect on treatment outcome. Results: Mean serum progesterone level in the positive pregnancy group and negative pregnancy group was 0.892 ± 0.752 ng/ml and 0.91 ± 0.688 ng/ml, respectively (P = 0.961). The overall incidence of PL was 12.8% with 12.7% and 13.6% in the agonist and antagonist protocol respectively (P = 0.9001). PL incidence was 13.5% and 13.4% in positive pregnancy and negative pregnancy group (P = 0.223). Conclusion: PL has been associated with 12.8% of the IVF cycles. There was no statistically significant difference observed in the incidence of PL between different IVF stimulation protocols. PL does not seem to affect IVF outcome.

Background: Empty follicle syndrome (EFS) is a condition in which no oocytes are retrieved from normally growing ovarian follicles after ovarian stimulation. It is a rare and frustrating condition of obscure etiology. Objective: The objective of this study was to estimate the incidence of EFS and study factors related to it. Design: This was a retrospective study. Setting: This study was conducted in hospital-based research center. Methods: In 1968 in vitro fertilization cycles from January 2010 to August 2016 were studied. Agonist, antagonist, and miniflare protocols were used for the stimulation. Results: The incidence of EFS is 2.38% (47/1968 cycles). Antagonist protocol group (76.59%, n = 36) had highest incidence of EFS (6.69%). Literature on EFS depicts decreased ovarian reserve (DOR) as the main cause, but only 4.25% of patients had DOR in our study. Interestingly, polycystic ovary syndrome and unexplained infertility were found in 31.9% of the cases. Serum anti-Müllerian hormone (AMH) levels (mean ± standard deviation [SD]) were 4.47 ± 3.54 ng/ml, and antral follicle count (AFC) was 15.30 ± 8.07 (mean ± SD) emphasizing that diminished ovarian reserve is not the main factor for EFS. All patients (n = 95) who underwent ovum pickup on day when any patient had EFS were taken as control. Patients with EFS were compared with controls. A statistically significant difference was not observed in serum AMH (P = 0.38) and AFC (P = 0.52). Conclusion: EFS is an uncommon event. Antagonist cycles have higher chances of empty follicle at ovum pickup. Looking at the profile of patients in this study, we conclude that EFS is not a manifestation of DOR.

Background: Nearly 0.6%-7% of patients undergoing in vitro fertilization embryo transfer (IVF ET) will not be able to yield any oocyte despite successful ovarian stimulation and this condition is called as empty follicular syndrome (EFS). EFS is a dreadful situation for clinicians as well as patients, seems to be an unavoidable clinical condition despite a proper ovarian stimulation. Materials and Methods: This was a retrospective observational study conducted at a tertiary hospital; 1103 patients who underwent IVF ET between January 2016 and May 2017 were included in the study. Study Outcome: To estimate the incidence of empty follicle syndrome (EFS) and to study the associated factors. Results: There were 53 (4.8%) cases of EFS out of 1103 cycles of IVF ET; 43 (3.9%) cases were false EFS and 10 (0.9%) cases were genuine EFS. Mean age of EFS group and oocyte retrieved group was 30.17 years and 29.12 years respectively. Recurrence rate of EFS during the next IVF cycle was 36.8%. Decreased ovarian reserve was associated with an increased chance of EFS (54.7%) with a recurrence rate as high as 57%. Conclusion: The incidence of EFS is not an uncommon clinical scenario; it depends upon ovarian reserve to a great extent. Young age is not immune for the occurrence of EFS as there is a similar incidence in comparatively younger age group in our study. EFS is seen in all etiological groups of infertility, but only respite is that there is a chance of about 63.2% oocyte retrieval during repeat IVF cycle. [ABSTRACT FROM AUTHOR]

Aim: In this prospective study, we aimed to compare the patients scheduled for in vitro fertilization (IVF) with poor ovarian reserve to patients with unexplained infertility in the same age group in terms of sexual dysfunction. Material and Methods: In this prospective study, a total of 146 patients admitted to the IVF center of Ondokuz Mayıs University between June 2018 and December 2018 were included in the study. Fourty-eight of these patients had poor ovarian reserve and 98 were scheduled for IVF due to unexplained infertility. In these patients, the female sexual function index (FSFI) scores were calculated for the diagnosis of sexual dysfunction prior to treatment. In addition, ovarian reserve tests such as cyclic follicle stimulating hormone (FSH) and anti mullerian hormone (AMH) at the beginning of the menstrual cycle were recorded. Results: The mean age of the female patients in the study was 30.2+-5 years. The mean FSFI score was 22.36 +-3.31 and 22.44+- 3.53 in the group with poor ovarian reserve and with unexplained infertility, respectively. The prevalence of sexual dysfunction (FSFI score <26.55) in the poor ovarian reserve group was 89.6% (n=48) compared to the unexplained infertility group, which was 93.9% (n=98). The analysis of domains revealed no statistically significant difference between the two groups (p=0,356). Conclusion: Sexual dysfunction is frequently observed in patients scheduled for IVF. Our study showed that there was no difference in sexual dysfunction between the two groups. Interestingly, it was revealed that there was a correlation between FSH levels and satisfaction and pain. It was also interesting that the rate of sexual dysfunction was extremely high in both groups. [ABSTRACT FROM AUTHOR]

Background: Empty follicle syndrome (EFS) is a condition in which no oocytes are retrieved from normally growing ovarian follicles after ovarian stimulation. It is a rare and frustrating condition of obscure etiology. Objective: The objective of this study was to estimate the incidence of EFS and study factors related to it. Design: This was a retrospective study. Setting: This study was conducted in hospital-based research center. Methods: In 1968 in vitro fertilization cycles from January 2010 to August 2016 were studied. Agonist, antagonist, and miniflare protocols were used for the stimulation. Results: The incidence of EFS is 2.38% (47/1968 cycles). Antagonist protocol group (76.59%, n = 36) had highest incidence of EFS (6.69%). Literature on EFS depicts decreased ovarian reserve (DOR) as the main cause, but only 4.25% of patients had DOR in our study. Interestingly, polycystic ovary syndrome and unexplained infertility were found in 31.9% of the cases. Serum anti-Müllerian hormone (AMH) levels (mean ± standard deviation [SD]) were 4.47 ± 3.54 ng/ml, and antral follicle count (AFC) was 15.30 ± 8.07 (mean ± SD) emphasizing that diminished ovarian reserve is not the main factor for EFS. All patients (n = 95) who underwent ovum pickup on day when any patient had EFS were taken as control. Patients with EFS were compared with controls. A statistically significant difference was not observed in serum AMH (P = 0.38) and AFC (P = 0.52). Conclusion: EFS is an uncommon event. Antagonist cycles have higher chances of empty follicle at ovum pickup. Looking at the profile of patients in this study, we conclude that EFS is not a manifestation of DOR. [ABSTRACT FROM AUTHOR]

In the context of assisted reproduction, the term ovarian aging is often used to refer to declining potential of ovaries to produce oocytes in adequate number or quality in response to controlled ovarian stimulation (COS). Different aspects of COS have been modified with the intention to increase the number and quality of oocytes obtained for in vitro fertilization. In the setting of ovarian aging, suppression of the luteinizing hormone (LH) surge with gonadotropin-releasing hormone (GnRH) antagonist or short GnRH agonist protocol and stimulation with a daily gonadotropin dosage of ≤300 IU/day seem to be appropriate first choices, and there is a strong need for well-designed randomized controlled trials investigating effects of addition of LH activity, estradiol priming, transdermal testosterone administration, and growth hormone supplementation. Given the lack of high-quality evidence showing effectiveness of one approach over another, other factors such as duration of stimulation, total gonadotropin consumption and cost of medication, patient friendliness, and possible side effect profiles must be considered in tailoring the COS protocol according to each individual's needs and desires. [ABSTRACT FROM AUTHOR]

Objective: To investigate the dynamics of anti-Mullerian hormone (AMH) and inhibin B (INHB) levels during controlled ovarian hyperstimulation (COH) in women with decreased ovarian reserve (DOR), and assess the effect of these dynamic changes on the prediction of clinical outcome in in-vitro fertilization (IVF). Methods: A total of 124 women undergoing IVF cycles were divided into normal ovarian reserve (NOR) and DOR groups. AMH and INHB levels were measured in serum on menstrual cycle day 2 or 3 (D2/3), day 5 of stimulation (D5), hCG day (D-hCG) and follicular fluid (FF) on oocyte retrieval day. Results: Serum AMH levels were gradually decreased while INHB levels were gradually increased from D2/3 to D-hCG during the COH in both groups. Serum AMH, INHB levels on D2/3 and FF AMH, INHB levels were highly positively correlated with AFC and oocytes retrieval. Multivariate logistic regression analysis revealed that clinical pregnancy did not directly correlate with serum and FF AMH and INHB levels. Conclusion: Serum AMH and INHB levels were not directly related to clinical pregnancy, dynamic serum AMH and IHNB levels were positively correlated with COH outcomes. [ABSTRACT FROM AUTHOR]

Background: To compare the pregnancy rates of patients experiencing cleavage stage versus blastocyst single embryo transfer (ET) with regard to ovarian reserve. Methods: This study was conducted with analysis of 200 ICSIET cycles performed in our IVF Center. A total of 78 ICSI- ET cycles down-regulated with GnRH antagonists were included in the study and the etiology of infertility was as follows: tubal factor (n=8), decreased ovarian reserve (n=29), and unexplained infertility (n=41). The population was divided into two groups according to the number of retrieved oocytes (NRO). The groups were compared for the parameters of ET day, embryo quality, grade1 embryo rate, pregnancy rate and implantation rate. Results: The 78 women were divided into two groups as follows: poor responders (NRO <8, n=40) and normoresponders (NRO=8-12, n=38). The mean age, body mass index (BMI), 3-day FSH, and estradiol levels of study population were 31.5±5.2 years, 24.9±5.3 kg/m2, 6.9±3.4 IU/mL and 40.4±16.6 pg/mL, respectively. In poor responders, the great extent of ET (67.5%) was performed at cleavage stage, but in normoresponders the majority of ET (86.8%) was performed at blastocyst stage (p<0.01). There was no significant difference between the groups for the parameters of grade1 embryo rate, fertilization rate, pregnancy rate, and implantation rate. Conclusion: Our results indicate that the poor responder patients with good grade cleavage stage embryo have no disadvantage in ICSI-ET cycles compared to normoresponders with blastocyst embryo. [ABSTRACT FROM AUTHOR]

Background: Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase. Methods: We analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied. Results: Two normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p. Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a second trimester-abortion in the other. WRN-mutated fibroblasts showed oxidative stress, increased lamin B1 expression, nuclear dysmorphies and premature senescence. Conclusions: We show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Increased expression of lamin B1 with altered lamina architecture observed in WRN-mutated fibroblasts could contribute to premature cellular senescence. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy of three different GnRH agonist (GnRH-a) stimulation regimens to improve ovarian response in poor responders undergoing IVF. Design: Retrospective cohort study. Setting: Center for Reproductive Health at the University of Cincinnati Medical Center. Patient(s): Women diagnosed as poor responders who presented consecutively from January 1999 to January 2004. Intervention(s): Patients underwent three different stimulation regimens during IVF cycles: [1] stop protocol: GnRH-a 500 μg/d administered from the midluteal phase to the start of menses, then gonadotropins from day 2 of cycle, [2] microdose flare: GnRH-a 20 μg administered twice daily with gonadotropins from day 2 to the day of hCG administration, or [3] regular dose flare: gonadotropins beginning with GnRH-a on day 2 at 1 mg/d for 3 days, followed by 250 μg/d until the day of hCG administration. Main Outcome Measure(s): Ovarian response, implantation rates, clinical pregnancy and delivery rates. Result(s): Sixty-one IVF cycles were included in the study. None of the comparisons reached statistical significance; however, the microdose group demonstrated a trend toward a higher completed pregnancy rate. Conclusion(s): The microdose flare protocol for poor responders demonstrated a trend toward higher delivery rates. A larger prospective study would need to be performed to determine whether this trend leads to a significant finding in this patient population. [Copyright &y& Elsevier]

Objective: Moxibustion, a common therapy in traditional Chinese medicine, has potential benefits for treating decreased ovarian reserve (DOR). The present study investigates the protective effect of moxibustion in a rat model of DOR and explores the possible mechanisms., Methods: Sixty-four female Sprague-Dawley rats were randomly divided into four groups: control, DOR, moxibustion (MOX), and hormone replacement therapy (HRT). The DOR rat model was established by intragastric administration of 50 mg/kg Tripterygium glycoside suspension (TGS), once daily for 14 days. MOX and HRT treatments were given from the day TGS administration was initiated. The ovarian reserve function was evaluated by monitoring the estrus cycle, morphological changes in ovaries, levels of serum estradiol (E 2 ), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-Mullerian hormone (AMH), pregnancy rate and embryo numbers. Terminal-deoxynucleotidyl transferase-mediated nick-end-labeling staining was used to identify ovarian granulosa cell apoptosis, while the protein and mRNA expressions of Bax, B-cell lymphoma-2 (Bcl-2), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in ovarian tissues were examined by immunohistochemistry, Western blot and quantitative reverse transcription-polymerase chain reaction., Results: Compared with the DOR group, MOX improved the disordered estrous cycle, promoted follicular growth, reduced the number of atresia follicles, increased the concentrations of serum E 2 and AMH, and decreased serum FSH and LH concentrations. More importantly, the pregnancy rate and embryo numbers in DOR rats were both upregulated in the MOX treatment group, compared to the untreated DOR model. Further, we found that the MOX group had reduced apoptosis of ovarian granulosa cells, increased Bcl-2 expression and reduced expression of Bax. Furthermore, the PI3K/AKT signaling pathway was triggered by the moxibustion treatment., Conclusion: Moxibustion improved ovarian function and suppressed apoptosis of ovarian granulosa cells in a rat model of DOR induced by TGS, and the mechanism may involve the PI3K/AKT signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

Infertility has long-term effects beyond the inability to conceive. Infertility may be a harbinger of future disease and altered longevity. Understanding the mechanisms of how fertility is a window to health opens new avenues of important investigation addressing interdependent physiologic processes. Identification of healthy persons at risk for future cardiovascular disease, diabetes, or cancer could allow a change in reproductive medical care by altering long-term surveillance and reduction of risk. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of sequential therapy for kidney-tonifying via traditional Chinese medicine (TCM) on improving the fecundity and quality of life (QOL) of women with decreased ovarian reserve (DOR)., Methods: A prospective and randomized controlled study was conducted, in which 80 infertile patients with DOR were selected in our hospital and randomly divided into the test group (n=40) and the control group (n=40). The control group was given sequential therapy of artificial menstrual cycle via administration of estrogen and progesterone, and the test group received sequential therapy for kidney-tonifying via TCM. Then, Kupperman indices, hormone levels, ovarian reserve functions, menopause specific quality of life questionnaire (MENQOL) scores, as well as the pregnancy rates within one year before and after treatment were compared between the two groups., Results: Compared with the control group, the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and resistance index (RI) of ovarian stroma were significantly decreased in the test group (all P<0.001), while the levels of estradiol (E2), anti-Mullerian hormone (AMH), mid-luteal phase E2, progesterone, antral follicular count (AFC), and ovarian diameter (OVD) of patients were notably increased in the test group (all P<0.001). After treatment, the Kupperman indices and MENQOL scores of the test group were considerably lower than those of the control group (P<0.001). No adverse effects were observed in the test group, whereas the incidence of adverse effects in the control group was 12.50%, although without significant difference between the two groups (P>0.05). The pregnancy rate within one year in the test group was significantly higher than that of the control group (47.50% vs. 25.00%) (P<0.05)., Conclusion: Sequential therapy for kidney-tonifying via TCM could effectively improve the clinical symptoms, hormone levels, and ovarian function, increase ovulation quality and pregnancy rate, and improve the QOL of DOR patients., Competing Interests: None., (AJTR Copyright © 2021.)

The emergence of autologous platelet-rich plasma (PRP) therapy reflects a break-through for infertile patients with premature ovarian failure. To study the efficacy of intra-ovarian infusion of autologous PRP on the improvement of ovarian reserve parameters and the subsequent artificial reproductive technique (ART) cycle outcomes in infertile women with poor ovarian reserve or premature ovarian insufficiency, a systematic search in electronic databases like Medline (through PubMed), Embase, Scopus, Web of Science, and Cochrane was done using relevant search terms. Except for case series, case reports, and review articles, all other types of studies, those evaluated for the effects of intra-ovarian infusion of PRP in subfertile women for decreased ovarian reserve (DOR) or premature ovarian insufficiency (POI) were included in our systematic review. The data were extracted from each eligible study and cross-checked by two authors. Intra-ovarian PRP infusion appears to be effective in ovarian rejuvenation, and the results of the subsequent intracytoplasmic sperm injection (ICSI) cycle are encouraging. PRP intervention was found to be beneficial in terms of an improvement in ovarian reserve parameters (increase in serum anti-mullerian hormone or antral follicle count or decrease in serum follicular stimulating hormone). ICSI cycle performance in terms of the total number of oocytes retrieved, number of two-pronuclei embryos, fertilization rate, number of cleavage stage embryos, number of good quality embryos, and cycle cancellation rate were found to be improved after intra-ovarian PRP infusion as compared to their previous cycle without PRP infusion., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Panda et al.)

Objective: This study aimed to evaluate whether exposure to bisphenol A (BPA) affects the ovarian reserve., Methods: Follicular fluid (FF) was collected from diminished ovarian reserve (DOR) and non-DOR patients who underwent in vitro fertilization or intracytoplasmic sperm injection. ELISA was used to detect the BPA and hormones levels in 54 cases of DOR and 67 cases of non-DOR. A total of 64, five-week-old SPF C57BL/6 mice were randomly divided into four groups, of which three were exposed to 5, 50, and 500 µg/kg/day of BPA solution, and one was exposed to con oil only as the control. The weight and estrus of each mouse were recorded daily, and the E2 hormone and anti-Müllerian hormone (AMH) in the serum were detected by ELISA. The expression levels of AMH mRNA and protein were also detected., Results: The BPA levels in the FF of DOR patients were significantly higher than those of non-DOR patients (234.048±81.736 ng/L vs. 193.300±67.225 ng/L, P<0.01); The AMH and E2 levels in the FF of DOR patients were lower than those of non-DOR patients ([555.689+74.224] pg/ml vs. [587.178+77.731] pg/ml, P<0.05, [209.720+31.556] pg/ml vs. [221.845+32.632] pg/ml, P<0.05). The BPA concentration was correlated with the AMH and E2 levels in the FF (r BPA & AMH =-0.312, P<0.05; r BPA & E2 =-0.290, P<0.05); in the animal experiment, the levels of serum AMH and E2 as well as the expression levels of the AMH gene and protein in the BPA treatment group displayed downward trends. The concentrations of the 5 and 500 µg/kg/day groups decreased significantly (P<0.05)., Conclusion: The increased BPA in the FF may promote the pathogenesis of DOR. BPA did not present a single-dose effect on the mouse ovary. Sub-chronic exposure to a low dose of BPA can reduce the ovarian reserve in female mice., Competing Interests: None., (IJCEP Copyright © 2018.)

Objective: To determine whether infertile women have lower antral follicle counts (AFC) than age-matched normal women. Design: Case-control. Setting: Academic center. Patient(s): A total of 881 infertile women and 771 women from the community. Intervention(s): Antral follicle count and basal hormone measurements. Main Outcome Measure(s): Median AFCs and FSH levels were compared between the two groups within 5-year age strata by using the median test. A subanalysis was performed by identifying women in the control group with a history of attempting conception without success (subfertile group) and with a spontaneous conception in fewer than 12 months resulting in a live birth (fertile group). Age-specific AFC percentiles were calculated and compared within strata determined by age at the time of attempted conception. Result(s): AFCs were significantly lower in infertile women than in control women across age groups up to 40 years of age. Average FSH levels were significantly higher in the younger-age infertile group versus the community. AFC percentiles differ significantly between fertile and subfertile women within the community up to 40 years of age. Conclusion(s): Decreased AFC in infertile women suggests that factors affecting the size of the remaining follicle pool in younger women also affect oocyte quality and the likelihood of conception. [Copyright &y& Elsevier]

Objective: To present the a case of decreased ovarian reserve in a patient with a balanced 13;21 translocation. Design: Case report. Setting: Reproductive endocrinology and infertility practice in a university teaching hospital. Patient(s): A 33-year-old caucasian woman with primary infertility. Intervention(s): Laboratory evaluation, hysterosalpingogram, karyotype analysis, semen analysis. Main Outcome Measure(s): Endocrinologic evaluation and genetic analysis. Result(s): A diagnosis of decreased ovarian reserve based upon laboratory evaluation with concomitant findings of a balanced translocation between the long arms of chromosomes 13 and 21. Conclusion(s): A diagnosis of primary infertility secondary to decreased ovarian reserve of unknown etiology, but with karyotype evidence of a balanced autosomal translocation and a familial history of early menopause, suggested possible roles of autosomal genes in mechanisms of ovarian follicular attrition. [Copyright &y& Elsevier]