A cross sectional study on serum homocysteine levels in women with unexplained infertility at rural hospital setup and its correlation with ovulation

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Unexplained infertility is a challenging clinical entity, with a limited understanding of its underlying mechanisms in resource-constrained healthcare settings. The study will include women between 21 and 45 years of age, diagnosed with unexplained infertility, who have not received any prior fertility treatments. Data will be collected through blood samples to measure serum homocysteine levels, and ovulation assessments using hormonal analysis and ultrasound monitoring of the menstrual cycle. Descriptive statistics will summarize participants’ characteristics, while comparison tests will be employed to assess the association between serum homocysteine levels and unexplained infertility. Correlation analysis will explore the relationship between serum homocysteine levels and ovulation parameters. Furthermore, multiple regression analysis will identify independent associations between serum homocysteine levels and ovulation, controlling for potential confounding variables. This study aims to provide valuable insights into the role of serum homocysteine in unexplained infertility and its potential impact on ovulation patterns in women in a rural healthcare setup. The findings may contribute to understanding the pathophysiology of unexplained infertilities and pave the way for targeted therapeutic interventions. Ethical considerations will ensure participant privacy, and all data will be managed with the utmost confidentiality. The study’s results will be reported transparently, adhering to ethical guidelines, to offer evidence-based guidance for managing unexplained infertility in rural healthcare settings." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-141", "name": "A cross sectional study on serum homocysteine levels in women with..." } } ] } Home Browse A cross sectional study on serum homocysteine levels in women with... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Shukla S and Shrivastava D. A cross sectional study on serum homocysteine levels in women with unexplained infertility at rural hospital setup and its correlation with ovulation [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :141 ( https://doi.org/10.12688/f1000research.140685.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol A cross sectional study on serum homocysteine levels in women with unexplained infertility at rural hospital setup and its correlation with ovulation [version 1; peer review: 1 not approved] Swasti Shukla https://orcid.org/0009-0007-9765-7744 1 , Deepti Shrivastava 1 Swasti Shukla https://orcid.org/0009-0007-9765-7744 1 , Deepti Shrivastava 1 PUBLISHED 23 Feb 2024 Author details Author details 1 Department of Obstetrics and Gynaecology, Acharya Vinoba Bhave Rural Hospital, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, Maharashtra, 442001, India Swasti Shukla Roles: Conceptualization, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Deepti Shrivastava Roles: Methodology, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Datta Meghe Institute of Higher Education and Research collection. Abstract This cross-sectional study aims to investigate the serum homocysteine levels in women diagnosed with unexplained infertility at a rural hospital setup and its correlation with ovulation patterns. Unexplained infertility is a challenging clinical entity, with a limited understanding of its underlying mechanisms in resource-constrained healthcare settings. The study will include women between 21 and 45 years of age, diagnosed with unexplained infertility, who have not received any prior fertility treatments. Data will be collected through blood samples to measure serum homocysteine levels, and ovulation assessments using hormonal analysis and ultrasound monitoring of the menstrual cycle. Descriptive statistics will summarize participants’ characteristics, while comparison tests will be employed to assess the association between serum homocysteine levels and unexplained infertility. Correlation analysis will explore the relationship between serum homocysteine levels and ovulation parameters. Furthermore, multiple regression analysis will identify independent associations between serum homocysteine levels and ovulation, controlling for potential confounding variables. This study aims to provide valuable insights into the role of serum homocysteine in unexplained infertility and its potential impact on ovulation patterns in women in a rural healthcare setup. The findings may contribute to understanding the pathophysiology of unexplained infertilities and pave the way for targeted therapeutic interventions. Ethical considerations will ensure participant privacy, and all data will be managed with the utmost confidentiality. The study’s results will be reported transparently, adhering to ethical guidelines, to offer evidence-based guidance for managing unexplained infertility in rural healthcare settings. READ ALL READ LESS Keywords Unexplained infertility, Serum homocysteine levels, Ovulation patterns, Rural healthcare setup, Demographic characteristics, Correlation analysis, Therapeutic interventions Corresponding Author(s) Swasti Shukla ( [email protected] ) Close Corresponding author: Swasti Shukla Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2024 Shukla S and Shrivastava D. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Shukla S and Shrivastava D. A cross sectional study on serum homocysteine levels in women with unexplained infertility at rural hospital setup and its correlation with ovulation [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :141 ( https://doi.org/10.12688/f1000research.140685.1 ) First published: 23 Feb 2024, 13 :141 ( https://doi.org/10.12688/f1000research.140685.1 ) Latest published: 23 Feb 2024, 13 :141 ( https://doi.org/10.12688/f1000research.140685.1 ) Introduction Infertility is a distressing global health issue that affects millions of couples, causing significant emotional, psychological, and social burdens. While advancements in reproductive medicine have improved the diagnosis and treatment of specific infertility causes, a substantial portion of cases remain unexplained despite comprehensive investigations. Unexplained infertility is a challenging clinical entity characterized by the absence of identifiable factors that could explain the failure to conceive. 1 – 3 Recent research has suggested that unexplained infertility may be attributed to subtle and complex dysregulations in various biological pathways, including hormonal imbalances, oxidative stress, and inflammation. 4 , 5 One emerging area of interest in investigating unexplained infertility is the role of serum homocysteine levels. Homocysteine, a non-protein amino acid, is a central player in the one-carbon metabolism pathway and is involved in DNA methylation, the synthesis of purines and pyrimidines, and the generation of glutathione. Elevated homocysteine levels have been associated with adverse reproductive outcomes been implicated in vascular dysfunction, oxidative stress, and endocrine disturbances. 6 Despite the growing body of evidence suggesting a potential link between serum homocysteine levels and infertility, particularly in unexplained cases, research on this topic still needs to be improved, especially in resource-constrained rural healthcare setups. Understanding the relationship between serum homocysteine levels and ovulation in women with unexplained infertility in such settings could have important clinical implications. 7 , 8 This study protocol aims to address this knowledge gap by conducting a prospective observational study to assess serum homocysteine levels in women diagnosed with unexplained infertility at a rural hospital setup. Additionally, the study seeks to investigate the potential correlation between serum homocysteine levels and ovulation in these women. By elucidating the potential role of homocysteine in unexplained infertility and its association with ovulation patterns, the findings of this study may contribute valuable insights into the pathophysiology of unexplained infertility and open avenues for targeted therapeutic interventions. Moreover, the study’s focus on a rural healthcare setup enhances its significance, as it addresses the specific needs and challenges faced by underserved populations in accessing infertility care. Aim The aim of this study is to investigate the association between serum homocysteine levels and ovulation patterns in women diagnosed with unexplained infertility at a rural hospital setup. Objective 1. To assess the level of serum homocysteine in infertile women seeking the advanced fertility treatment at rural hospital. 2. To correlate different serum values of homocysteine with ovulation pattern in infertile group women. 3. To assess the level of serum homocysteine level in fertile women of similar demographic characteristics attending rural hospital for any other indications and willing to participate in the study. 4. To compare the value of serum homocysteine in both fertile and infertile group women. Methods Study design The study will employ a cross sectional study to investigate the serum homocysteine levels in women with unexplained infertility at an Acharya Vinoba Bhave Rural Hospital setup 2023-2024 of period and its correlation with ovulation. Study population The study population will consist of women between the ages of 21 and 45 years who have been diagnosed with unexplained infertility. These women will be recruited from the patient population attending a rural hospital or clinics that serve as a primary healthcare center for the surrounding rural community. Place of study The current research will be carried out at the Department of Obstetrics and Gynecology within the rural hospital setup of Datta Meghe Institute of Higher Education and Research (DMIHER). Inclusion criteria 1. Women aged between 21 and 45 years. 2. A documented diagnosis of unexplained infertility, defined as the absence of identifiable causes of infertility after thorough investigations, including normal semen analysis in their male partners. 3. Women who have not undergone any fertility treatments before enrolment in the study. Exclusion criteria 1. Women with known causes of infertility, such as tubal factor infertility, male factor infertility, endocrine disorders ( e.g. , polycystic ovary syndrome), and other reproductive abnormalities. 2. Women with a history of recurrent pregnancy loss. 3. Women with significant medical conditions that may affect fertility, such as thyroid disorders, diabetes, or autoimmune diseases. 4. Women with a history of hormonal treatments or medications that could influence ovulation or homocysteine levels. Bias The potential for selection bias exists due to the recruitment of participants from a single rural hospital setup, possibly limiting the broader applicability of the study’s findings. To address this concern, proactive measures will be taken to enhance the diversity and representation of the study sample. These efforts will include reaching out to multiple healthcare centres and collaborating with different geographic regions to ensure a more comprehensive inclusion of women with unexplained infertility. By expanding the participant recruitment process beyond the confines of a single hospital, we aim to mitigate the impact of potential selection bias on the validity and generalizability of the study’s outcomes. Enrollment Participants meeting the specified inclusion criteria will be selected for the study. On Day two of the menstrual cycle, hormonal assessments will be conducted for the infertile group, and ovulation will be monitored through follicular scans until Day 20 of the cycle. Serum estradiol and serum LH levels will be measured when the follicular size reaches or exceeds 18mm. Ovulation signs will be assessed using transvaginal sonography, looking for the disappearance of the dominant follicle and/or the presence of free fluid in the paraovarian fossa (pouch of Douglas). Physical and obstetrical examinations, along with laboratory findings, will be recorded. Various investigations, including complete blood count, liver profile test, kidney function test, and thyroid profile, will be conducted. Data collection Fasting blood samples, essential for the investigation, will be meticulously collected in accordance with standardized protocols. To ensure comprehensive reproducibility, we provide a detailed outline of the data collection procedures. 1. Biological sample collection : Fasting blood samples of 2 milliliters will be collected from the arms and drawn into plain Vacutainer tubes, ensuring the precise preservation of sample integrity. This vital procedure will be carried out by proficient healthcare professionals to maintain uniformity. Subsequently, the samples will be promptly conveyed to the laboratory within a 30-minute timeframe, thereby minimizing the risk of any potential degradation. 2. Biological sample storage : The storage of biological samples will adhere to established guidelines to safeguard the quality of the samples. Collected blood samples will be immediately centrifuged to obtain plasma, which will then be aliquoted and stored at the recommended temperature and conditions. Detailed records of the storage process will be meticulously maintained, ensuring the traceability and reliability of the stored samples. 3. Laboratory analysis : For the quantification of maternal serum homocysteine levels, we will employ the Enzyme-Linked Immunosorbent Assay (ELISA) method. This well-established technique 9 guarantees accurate and consistent results. The laboratory analyses will be executed by skilled technicians with expertise in ELISA methodology, further enhancing the precision and reliability of the data obtained. 4. Ovulation pattern assessment : The study of ovulation patterns in infertile women will encompass two integral aspects: transvaginal ultrasound and endocrinal assessments. Transvaginal ultrasound will allow for detailed monitoring of follicular development and ovulation, providing essential insights into the participants’ reproductive cycles. Simultaneously, endocrinal assessments will involve meticulous hormonal analysis, including serum progesterone levels, to comprehensively characterize the participants’ ovulation patterns. Sample size Formula using mean difference are: n 1 = n 2 = 2 Z α + Z β 2 σ 2 δ 2 Z α = 1.96 α = Type I error at 5% at both sides two tailed Z β = 1.28 = Power at 90% Primary Variable = Serum homocysteine level (Mean ± SD) serum homocysteine level in fertile group = 13.46 ± 5.05 (As per reference article 10 ). (Mean± SD) serum homocysteine level in infertile group = 9.87 ± 4.84 Mean difference =3.59 Pooled standard deviation = 5.05 + 4.84 / 2 = 4.945 Sample size N = n 1 = n 2 = 2 1.96 + 1.28 2 3.59 2 4.945 2 = 40 per group Considering 20% drop out = 8 Total sample size required = 40 + 8 = 48 per group . Statistical methods The statistical methods employed in this research study on “Serum Homocysteine Levels in Women with Unexplained Infertility at Rural Hospital Setup and Its Correlation with Ovulation” will be crucial in analyzing the data and drawing meaningful conclusions in R studio version 2023.03.0-daily+82.pro2 statistical software. The following statistical methods will be used: 1. Descriptive statistics : Descriptive statistics will be used to summarize and present the characteristics of the study population, including mean, standard deviation, median, and interquartile range for continuous variables, and frequencies and percentages for categorical variables. This will provide an overview of the participants’ demographic and clinical characteristics. 2. Comparison of serum homocysteine levels : To assess the association between serum homocysteine levels and unexplained infertility, a comparison will be made between women with unexplained infertility and those without infertility within the study population. Depending on the distribution of the data, either parametric (t-tests) or non-parametric (Mann-Whitney U tests) tests will be used for continuous variables. For categorical variables, chi-square or Fisher’s exact tests will be employed. 3. Correlation analysis : Correlation analysis will be performed to examine the relationship between serum homocysteine levels and ovulation parameters ( e.g., serum progesterone levels, menstrual cycle regularity). This will involve calculating correlation coefficients, such as Pearson correlation for continuous variables with a linear relationship, or Spearman’s rank correlation for non-linear associations. Ethical considerations The Institutional Ethics Committee of Datta Meghe Institute of Higher Education and Research (DU) has granted its approval to the study protocol (Reference number: DMIHER (DU)/IEC/2022/119. Date:21-07-2022). Prior to commencing the study, we will obtain written informed consent from all participants, providing them with a comprehensive explanation of the study’s objectives. Limitations The study’s limitations, encompassing generalizability concerns due to a single-center setting and sample size restrictions, alongside potential selection and information biases, underscore the importance of methodological refinement. The observational design’s inherent constraints on establishing causality and the potential influence of recall bias on qualitative data necessitate meticulous attention. The exclusion of male partners further prompts a comprehensive approach for a well-rounded understanding. Addressing these limitations, we have implemented strategic actions. Collaborative efforts with diverse rural healthcare centres enhance participant recruitment, augmenting the study’s external validity. Rigorous data collection protocols, executed by highly trained personnel utilizing standardized tools, mitigate biases and elevate data reliability. Employing advanced statistical methods, including multivariate regression analysis, counteracts confounding variables, facilitating nuanced insights from the observed data. To rectify potential recall bias, meticulous question crafting minimizes discrepancies, complemented by participant review through member checking, ensuring data fidelity. Confronting the exclusion of male partners, subsequent phases will incorporate their perspectives, enriching the comprehensive understanding of multifaceted infertility dynamics. By proactively embedding these measures, we anticipate heightened robustness, pertinence, and applicability of our study outcomes. These strategic undertakings not only elevate the caliber of our findings but also underscore the pragmatic implications for both clinical practice and future research inquiries. Dissemination After the completion of the study, we will publish in an indexed journal or conferences. Study status The study has not yet started. After publication of the protocol, we will start recruitment in the study. Discussion While the complete pathogenesis of unexplained infertility remains not fully comprehended, several studies 11 – 13 have indicated that hyperhomocysteinemia poses a risk factor for this condition. 14 Findings from a case-control study demonstrated that reduced Hcy levels in the embryo culture medium correlated with improved pregnancy chances and higher embryo grades. 15 Moreover, in polycystic ovary syndrome patients undergoing assisted reproductive technology (ART), follicular fluid homocysteine levels were found to be linked to clinical pregnancy, poor oocyte quality, and embryo quality. 15 , 16 Furthermore, Hcy levels were observed to have an inverse association with fertility outcomes, 16 and lower Hcy concentrations were detected in azoospermic seminal plasma compared to normozoospermic seminal plasma. 17 Despite these findings, the precise relationship between Hcy levels and unexplained infertility has not been clearly established as of yet. Several previous studies have indicated that an elevated Hcy concentration can have negative effects on oocyte numbers, oocyte maturity, fertilization, and embryo quality. 18 Additionally, an increased level of Hcy in the follicular fluid may cause follicular occlusion, resulting in reduced oocyte quantity and quality and influencing early embryo quality. 15 Elevated Hcy levels in the follicular fluid can also impact female reproductive functions, leading to the production of inflammatory cytokines, increased oxidative stress, and disrupted methylation reactions. All these alterations have significant associations with oocyte development, fertilization, embryo implantation, and the maintenance of pregnancy. 18 The study’s outcomes carry significant implications for both clinical practice and public health. Notably, the observed implications extend beyond the immediate findings, as they have the potential to impact the management and care of women with unexplained infertility. While our current study design is based on a single-center approach and involves a specific study population, these limitations are recognized as potential constraints on the broader generalizability of the findings. Therefore, future research endeavors involving larger and more diverse samples are warranted to corroborate and validate these results across varied settings. Such investigations will help to establish a more robust foundation upon which healthcare practitioners and policymakers can base their decisions, fostering improved outcomes and strategies for addressing unexplained infertility across different demographic and healthcare contexts. Data availability No data are associated with this article. References 1. Infertility: Accessed: August 1, 2023. Reference Source 2. Walker MH, Tobler KJ: Female Infertility. StatPearls. Treasure Island (FL); StatPearls Publishing: 2023. 3. Sharma A, Shrivastava D: Psychological Problems Related to Infertility. Cureus. 14 : e30320. PubMed Abstract | Publisher Full Text | Free Full Text 4. Ayad B, Omolaoye TS, Louw N, et al. : Oxidative Stress and Male Infertility: Evidence From a Research Perspective. Front. Reprod. Health. 2022; 4 : 822257. PubMed Abstract | Publisher Full Text | Free Full Text 5. Karunyam BV, Abdul Karim AK, Naina Mohamed I, et al. : Infertility and cortisol: a systematic review. Front. Endocrinol (Lausanne). 2023; 14 : 1147306. Publisher Full Text 6. Liu L, Lin Z, Lin P, et al. : Association between serum homocysteine level and unexplained infertility in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI): A retrospective, hospital-based, case-control study. J. Clin. Lab. Anal. 2020; 34 : e23167. PubMed Abstract | Publisher Full Text | Free Full Text 7. Suman A, Sinha DS, Singh DS: ASSOCIATION OF SERUM HOMOCYSTEINE LEVELS WITH UNEXPLAINED STILL BIRTHS. Stud. J. Health Res. Afr. 2023; 4 : 7–7. Publisher Full Text 8. Chari S, Gupta MM: Malondialdehyde and Homocysteine Levels in Patients with Unexplained Female Infertility. J. South Asian Fed. Obstet. Gynecol. 2014; 6 : 18–20. Publisher Full Text 9. Abbassi-Ghanavati M, Greer LG, Cunningham FG: Pregnancy and Laboratory Studies: A Reference Table for Clinicians. Obstet. Gynecol. 2009; 114 : 1326–1331. Publisher Full Text 10. Sultana MN, Rahman S, Ara R: Comparison of the Levels of Blood Homocysteine between Women with Unexplained Infertility and Normal Fertility. Mymensingh Med. J. 2022; 31 : 683–689. PubMed Abstract 11. Yücel B, Kelekci S, Demirel E: Decline in ovarian reserve may be an undiagnosed reason for unexplained infertility: a cohort study. Arch. Med. Sci. 2018; 14 : 527–531. PubMed Abstract | Publisher Full Text | Free Full Text 12. Bydlowski M: Facteurs psychologiques dans l’infertilité féminine. Gynecol. Obstet. Fertil. 2003; 31 : 246–251. PubMed Abstract | Publisher Full Text 13. Demir B, Guven S, Guvendag Guven ES, et al. : ORIGINAL ARTICLE: Serum IL-6 Level May Have Role in the Pathophysiology of Unexplained Infertility. Am. J. Reprod. Immunol. 2009; 62 : 261–267. PubMed Abstract | Publisher Full Text 14. Dubey P, Gupta N, Dwivedi S, et al. : Hyperhomocysteinemia: a risk factor in unexplained infertility. Int. J. Reprod. Contracept. Obstet. Gynecol. 2013; 2 : 165–171. Publisher Full Text 15. Berker B, Kaya C, Aytac R, et al. : Homocysteine concentrations in follicular fluid are associated with poor oocyte and embryo qualities in polycystic ovary syndrome patients undergoing assisted reproduction. Hum. Reprod. 2009; 24 : 2293–2302. Publisher Full Text 16. Ocal P, Ersoylu B, Cepni I, et al. : The association between homocysteine in the follicular fluid with embryo quality and pregnancy rate in assisted reproductive techniques. J. Assist. Reprod. Genet. 2012; 29 : 299–304. PubMed Abstract | Publisher Full Text | Free Full Text 17. Crha I, Kralikova M, Melounova J, et al. : Seminal plasma homocysteine, folate and cobalamin in men with obstructive and non-obstructive azoospermia. J. Assist. Reprod. Genet. 2010; 27 : 533–538. PubMed Abstract | Publisher Full Text | Free Full Text 18. Altmäe S, Stavreus-Evers A, Ruiz JR, et al. : Variations in folate pathway genes are associated with unexplained female infertility. Fertil. Steril. 2010; 94 : 130–137. PubMed Abstract | Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 23 Feb 2024 ADD YOUR COMMENT Comment Author details Author details 1 Department of Obstetrics and Gynaecology, Acharya Vinoba Bhave Rural Hospital, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education & Research, Wardha, Maharashtra, 442001, India Swasti Shukla Roles: Conceptualization, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Deepti Shrivastava Roles: Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 23 Feb 2024, 13:141 https://doi.org/10.12688/f1000research.140685.1 Copyright © 2024 Shukla S and Shrivastava D. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Shukla S and Shrivastava D. A cross sectional study on serum homocysteine levels in women with unexplained infertility at rural hospital setup and its correlation with ovulation [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :141 ( https://doi.org/10.12688/f1000research.140685.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 23 Feb 2024 Views 0 Cite How to cite this report: Abou Hashish EA. Reviewer Report For: A cross sectional study on serum homocysteine levels in women with unexplained infertility at rural hospital setup and its correlation with ovulation [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :141 ( https://doi.org/10.5256/f1000research.154069.r332073 ) The direct URL for this report is: https://f1000research.com/articles/13-141/v1#referee-response-332073 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 23 Aug 2025 Ebtsam Aly Abou Hashish , King Saud bin Abdul-Aziz University for Health Sciences, Jeddah, Saudi Arabia; Faculty f Nursing, Alexandria University, Alexandria, Alexandria Governorate, Egypt Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.154069.r332073 General Assessment The study addresses an important question in reproductive medicine: the role of serum homocysteine in unexplained infertility. The topic is relevant in both clinical and rural healthcare contexts. The manuscript is clear in its intent but requires ... Continue reading READ ALL General Assessment The study addresses an important question in reproductive medicine: the role of serum homocysteine in unexplained infertility. The topic is relevant in both clinical and rural healthcare contexts. The manuscript is clear in its intent but requires significant refinement in methodological details, consistency of design, and control of potential confounding variables to ensure scientific rigor and reproducibility. Title and Abstract The title reflects the main variables but is inconsistent with the methods section, which describes the study as both prospective and cross-sectional. The terminology should be harmonized. The abstract is concise but does not provide enough methodological detail (sampling strategy, control group definition, confounding adjustments). It also lacks clear specification of the study’s primary outcome. Recommendation: Revise to ensure consistency in study design (cross-sectional vs. prospective). Expand the abstract to include methodology, sample size justification, and primary/secondary outcomes. Introduction Provides a rationale linking homocysteine to infertility, but the evidence cited is conflicting (higher homocysteine in fertile women in some studies). Lacks a clear hypothesis statement that aligns with the cited evidence. Recommendation: Strengthen the introduction by clarifying the biological plausibility, resolving contradictions in cited evidence, and explicitly stating the study hypothesis and expected direction of effect. Methods Design: Labeled as cross-sectional in some parts and prospective in others. Must be unified. Sample: Inclusion criteria for infertile women are clearer than for fertile controls. Fertility status of controls needs rigorous definition (e.g., recent spontaneous conception, no ART). Specimen handling: The text describes plain tubes but also mentions plasma. This is inconsistent; plain tubes yield serum, not plasma. Confounding: Age, BMI, smoking, folate/B12 status, and medication use are not clearly recorded or planned for adjustment. Ovulation outcome: Defined by ultrasound, but no biochemical confirmation (mid-luteal progesterone) is pre-specified. Lab procedures: ELISA kit details (manufacturer, detection range, intra/inter-assay CV) are missing. Sample size: Calculation presented, but estimand (difference in means) and assumptions need clearer specification. Recommendation: Clearly define the study design. Standardize biological specimen handling. Strengthen definitions of fertile controls. Include a clear confounding control strategy. Add biochemical confirmation of ovulation. Provide full laboratory assay details. Clarify sample size assumptions and estimand. Results (Not yet available as the study has not started.) Recommendation: Plan to present descriptive statistics, group comparisons, and regression analyses adjusting for key covariates. Discussion Presently limited. Should anticipate and discuss possible confounders, biological plausibility, and implications for rural health services. Should address the conflicting evidence in prior studies and justify how this study adds value. Ethical Considerations Ethical approval has been obtained. Participant informed consent and anonymity are adequately addressed. Strengths Focus on unexplained infertility, a clinically significant problem. Integration of both hormonal and ultrasound measures of ovulation. Potential contribution to rural reproductive health knowledge. Major Revisions Required Align study design terminology throughout the paper. Standardize and clarify specimen type (serum vs plasma). Rigorously define control group fertility. Pre-specify confounders and plan for statistical adjustment. Add biochemical confirmation of ovulation. Provide detailed laboratory assay methods. Clarify sample size calculation assumptions. Strengthen introduction and discussion for coherence with evidence. Questionnaire Is the rationale for, and objectives of, the study clearly described? Partly The manuscript identifies the role of homocysteine in reproductive dysfunction and highlights the gap in evidence, particularly in rural populations. However, the objectives are not expressed as a clear, testable hypothesis, and the introduction contains conflicting evidence (e.g., higher homocysteine reported in fertile groups in some studies). The expected direction of association is not explicitly stated. Recommendation: Clarify the hypothesis, resolve contradictions in the literature cited, and explicitly define whether the study expects higher homocysteine in infertile women compared with fertile controls. Is the study design appropriate for the research question? Partly The cross-sectional design can detect associations between homocysteine levels and infertility status but cannot establish causality. There is inconsistency in the manuscript where some sections describe the study as “prospective observational.” This undermines clarity. Additionally, fertile controls are not rigorously defined, which may cause misclassification. Recommendation: Align study design terminology throughout (cross-sectional is most accurate). Define fertile controls precisely (e.g., spontaneous conception within last 2–3 years, parous within 5 years without ART). Consider addressing temporality limitations of cross-sectional design in the discussion. Are sufficient details of the methods provided to allow replication by others? No Key methodological details are missing or inconsistent: Blood specimen handling: the text refers to both serum and plasma without clarification. Laboratory assay details: manufacturer, lot, detection range, inter/intra-assay variability, calibration procedures, and blinding are not reported. Confounding control: demographic, metabolic, and lifestyle factors are not clearly measured or planned for adjustment. Ovulation assessment: relies on ultrasound but lacks biochemical confirmation (e.g., mid-luteal progesterone). Recommendation: Add full details on specimen type and handling, ELISA protocols, blinding, fasting state, and storage conditions. Pre-specify confounders and add biochemical confirmation of ovulation. Recommendation Major Revision The manuscript is promising but requires significant methodological and reporting refinements before it can be considered for indexing. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? No Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: nursing, management, leadership , education, health sciences, education, research I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Abou Hashish EA. Reviewer Report For: A cross sectional study on serum homocysteine levels in women with unexplained infertility at rural hospital setup and its correlation with ovulation [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :141 ( https://doi.org/10.5256/f1000research.154069.r332073 ) The direct URL for this report is: https://f1000research.com/articles/13-141/v1#referee-response-332073 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 23 Feb 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 1 23 Feb 24 read Ebtsam Aly Abou Hashish , King Saud bin Abdul-Aziz University for Health Sciences, Jeddah, Saudi Arabia; Alexandria University, Alexandria, Egypt Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Abou Hashish E. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 23 Aug 2025 | for Version 1 Ebtsam Aly Abou Hashish , King Saud bin Abdul-Aziz University for Health Sciences, Jeddah, Saudi Arabia; Faculty f Nursing, Alexandria University, Alexandria, Alexandria Governorate, Egypt 0 Views copyright © 2025 Abou Hashish E. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions General Assessment The study addresses an important question in reproductive medicine: the role of serum homocysteine in unexplained infertility. The topic is relevant in both clinical and rural healthcare contexts. The manuscript is clear in its intent but requires significant refinement in methodological details, consistency of design, and control of potential confounding variables to ensure scientific rigor and reproducibility. Title and Abstract The title reflects the main variables but is inconsistent with the methods section, which describes the study as both prospective and cross-sectional. The terminology should be harmonized. The abstract is concise but does not provide enough methodological detail (sampling strategy, control group definition, confounding adjustments). It also lacks clear specification of the study’s primary outcome. Recommendation: Revise to ensure consistency in study design (cross-sectional vs. prospective). Expand the abstract to include methodology, sample size justification, and primary/secondary outcomes. Introduction Provides a rationale linking homocysteine to infertility, but the evidence cited is conflicting (higher homocysteine in fertile women in some studies). Lacks a clear hypothesis statement that aligns with the cited evidence. Recommendation: Strengthen the introduction by clarifying the biological plausibility, resolving contradictions in cited evidence, and explicitly stating the study hypothesis and expected direction of effect. Methods Design: Labeled as cross-sectional in some parts and prospective in others. Must be unified. Sample: Inclusion criteria for infertile women are clearer than for fertile controls. Fertility status of controls needs rigorous definition (e.g., recent spontaneous conception, no ART). Specimen handling: The text describes plain tubes but also mentions plasma. This is inconsistent; plain tubes yield serum, not plasma. Confounding: Age, BMI, smoking, folate/B12 status, and medication use are not clearly recorded or planned for adjustment. Ovulation outcome: Defined by ultrasound, but no biochemical confirmation (mid-luteal progesterone) is pre-specified. Lab procedures: ELISA kit details (manufacturer, detection range, intra/inter-assay CV) are missing. Sample size: Calculation presented, but estimand (difference in means) and assumptions need clearer specification. Recommendation: Clearly define the study design. Standardize biological specimen handling. Strengthen definitions of fertile controls. Include a clear confounding control strategy. Add biochemical confirmation of ovulation. Provide full laboratory assay details. Clarify sample size assumptions and estimand. Results (Not yet available as the study has not started.) Recommendation: Plan to present descriptive statistics, group comparisons, and regression analyses adjusting for key covariates. Discussion Presently limited. Should anticipate and discuss possible confounders, biological plausibility, and implications for rural health services. Should address the conflicting evidence in prior studies and justify how this study adds value. Ethical Considerations Ethical approval has been obtained. Participant informed consent and anonymity are adequately addressed. Strengths Focus on unexplained infertility, a clinically significant problem. Integration of both hormonal and ultrasound measures of ovulation. Potential contribution to rural reproductive health knowledge. Major Revisions Required Align study design terminology throughout the paper. Standardize and clarify specimen type (serum vs plasma). Rigorously define control group fertility. Pre-specify confounders and plan for statistical adjustment. Add biochemical confirmation of ovulation. Provide detailed laboratory assay methods. Clarify sample size calculation assumptions. Strengthen introduction and discussion for coherence with evidence. Questionnaire Is the rationale for, and objectives of, the study clearly described? Partly The manuscript identifies the role of homocysteine in reproductive dysfunction and highlights the gap in evidence, particularly in rural populations. However, the objectives are not expressed as a clear, testable hypothesis, and the introduction contains conflicting evidence (e.g., higher homocysteine reported in fertile groups in some studies). The expected direction of association is not explicitly stated. Recommendation: Clarify the hypothesis, resolve contradictions in the literature cited, and explicitly define whether the study expects higher homocysteine in infertile women compared with fertile controls. Is the study design appropriate for the research question? Partly The cross-sectional design can detect associations between homocysteine levels and infertility status but cannot establish causality. There is inconsistency in the manuscript where some sections describe the study as “prospective observational.” This undermines clarity. Additionally, fertile controls are not rigorously defined, which may cause misclassification. Recommendation: Align study design terminology throughout (cross-sectional is most accurate). Define fertile controls precisely (e.g., spontaneous conception within last 2–3 years, parous within 5 years without ART). Consider addressing temporality limitations of cross-sectional design in the discussion. Are sufficient details of the methods provided to allow replication by others? No Key methodological details are missing or inconsistent: Blood specimen handling: the text refers to both serum and plasma without clarification. Laboratory assay details: manufacturer, lot, detection range, inter/intra-assay variability, calibration procedures, and blinding are not reported. Confounding control: demographic, metabolic, and lifestyle factors are not clearly measured or planned for adjustment. Ovulation assessment: relies on ultrasound but lacks biochemical confirmation (e.g., mid-luteal progesterone). Recommendation: Add full details on specimen type and handling, ELISA protocols, blinding, fasting state, and storage conditions. Pre-specify confounders and add biochemical confirmation of ovulation. Recommendation Major Revision The manuscript is promising but requires significant methodological and reporting refinements before it can be considered for indexing. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? No Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise nursing, management, leadership , education, health sciences, education, research I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Abou Hashish EA. Peer Review Report For: A cross sectional study on serum homocysteine levels in women with unexplained infertility at rural hospital setup and its correlation with ovulation [version 1; peer review: 1 not approved] . F1000Research 2024, 13 :141 ( https://doi.org/10.5256/f1000research.154069.r332073) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-141/v1#referee-response-332073 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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