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Melatonin levels and microRNA (miRNA) relative expression profile in the follicular ambient microenvironment in patients undergoing in vitro fertilization process

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Intrafollicular fluid (IFF) melatonin plays a decisive role in maintaining granulosa cells’ DNA integrity and protects them against apoptosis. It reduces oxidative stress and improves the oocyte quality with a higher fertilization rate.

Method

This prospective study investigated the antioxidant property of IFF melatonin and its impact on IVF outcome parameters. We also explored the relative expression of five microRNAs (miR-663b, miR-320a, miR-766-3p, miR-132-3p, miR-16-5p) and levels of cell-free DNA (cfDNA) by real-time PCR in unexplained infertile patients. We collected 425 follicular fluid (FF) samples containing mature oocytes from 295 patients undergoing IVF.

Results

Patients were subgrouped based on IFF melatonin concentration (group A ≤ 30 pg/mL, group B > 70 to ≤ 110 pg/mL, group C > 111 to ≤ 385 pg/mL). Our results showed that patients with ≤ 30 pg/mL IFF melatonin levels have significantly higher oxidative stress markers, cfDNA levels, and lower relative expression of miR-663b, miR-320a, miR-766-3p, miR-132-3p, and miR-16-5p compared to other subgroups (p < 0.001). Similarly, they have a low fertilization rate and a reduced number of high-quality day 3 embryos.

Conclusion

Findings suggest that the therapeutic use of melatonin produces a considerable rise in the number of mature oocytes retrieved, fertilization rate, and good-quality embryo selection. Furthermore, miRNA signature enhances the quality of embryo selection, thus, may allow us to classify them as non-invasive biomarkers to identify good-quality embryos.

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Data availability

The data set used and analyzed during the current study is available from the corresponding author on reasonable request.

Abbreviations

IVF:

in vitro fertilization

IFF:

intrafollicular fluid

AFC:

antral follicle count

AMH:

anti-Müllerian hormone

PCOS:

polycystic ovarian syndrome

cfDNA:

cell-free DNA

FF:

follicular fluid

PGD:

preimplantation genetic diagnosis

hESCs:

human endometrial stromal cells

TAC:

total antioxidant capacity

ROS:

reactive oxygen species

SOD:

superoxide dismutase

GSH:

glutathione

miRNA:

microRNA

ROC:

receiving operating characteristics

E2 :

17β-estradiol

BMI:

body mass index

FSH:

follicular stimulating hormone

LH:

luteinizing hormone

TSH:

thyroid-stimulating hormone

TVS:

transvaginal ultrasonography

COS:

controlled ovarian stimulation

ICSI:

intracytoplasmic sperm injection

TBARS:

thiobarbituric acid reactive substances

8-OHdG:

8-hydroxy-2′-deoxyguanosine

CI:

confidence interval

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Acknowledgments

We acknowledge the research initiative and gratefully thank Professor Dr. Rashid Latif Khan, Professor of Emeritus in Obstetrics and Gynecology, for manuscript editing. The study is conducted under the infertility research center of Hameed Latif Hospital.

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Authors and Affiliations

  1. Lahore Institute of Fertility and Endocrinology, Hameed Latif Hospital, 14-Abu Bakar Block, New Garden Town, Lahore, 54800, Pakistan

    Haroon Latif Khan, Shahzad Bhatti, Sana Abbas & Yousaf Latif Khan

  2. Department of Human Genetics and Molecular biology, University of Health Sciences, Lahore, 54600, Pakistan

    Shahzad Bhatti

  3. Department of Medical Education, Rashid Latif Medical College, Lahore, Pakistan

    Shahzad Bhatti

  4. Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, 54800, Pakistan

    Shahzad Bhatti

  5. Department of Histology and Embryology, Faculty of Medicine, Sivas-Cumhuriyet University, 58140, Sivas, Turkey

    Celal Kaloglu

  6. Department of Biochemistry, Kinnaird College, Lahore, Pakistan

    Syeda Qurat-ul-Ain Zahra

  7. Department of Gynecology and Obstetrics, Hameed Latif Hospital, 14 – Abu Bakar Block, New Garden Town, Lahore, 54800, Pakistan

    Yousaf Latif Khan

  8. Department of Cellular Pathology, Royal Free Hospital, London, NW3 2QG, UK

    Zahira Hassan

  9. Bayındır Hastanesi, Department of Obstetrics and Gynecology, Nispetiye Mah. Aydın sokak No:8, 34340, Beşiktaş, Istanbul, Turkey

    Nilgün Öztürk Turhan

  10. Department of Medical Biochemistry, Ege University School of Medicine, Bornova, Izmir, Turkey

    Hikmet Hakan Aydin

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  1. Haroon Latif Khan
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Contributions

HLK and YLK: reviewing and editing, software; SB: conceptualization, methodology, software, data curation, project administration, writing—original draft preparation, supervision, writing—reviewing and editing; SA: formal analysis, validation, methodology, investigation, writing—reviewing and editing; CK: writing—reviewing and editing; SQ: data curation, writing—original draft preparation; ZH: reviewing and editing, methodology, software; NZT: writing—reviewing and editing; HHY: software, validation, methodology.

Corresponding author

Correspondence to Shahzad Bhatti.

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The study was approved by our Institutional Ethical Committee (IEC). Informed consent was obtained from all subjects before the research and publishing of the results of the investigation.

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Supplementary information

ESM 1

(DOCX 26 kb).

Figure 1S

Relationship between cfDNA levels and melatonin concentration in individual FF samples. (PNG 194 kb).

Figure 2S

Pearson’s correlation between IFF melatonin concentration and different biomarkers of oxidative balance. (A) Total antioxidant capacity (TAC) (B) Reactive oxygen species (ROS) (C) Thiobarbituric acid reactive substances (TBARS) and (D) 8-hydroxy-2′-deoxyguanosine (8-OHdG) concentrations. (PNG 220 kb).

ESM 1

(PNG 190 kb).

ESM 2

(PNG 229 kb).

ESM 3

(PNG 204 kb).

Figure 3S

Predicted pathway analysis heat map for all miRNAs in detail. Red color indicates high expression and lower p values. Yellow color indicates intermediate expression. (PNG 974 kb).

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Khan, H.L., Bhatti, S., Abbas, S. et al. Melatonin levels and microRNA (miRNA) relative expression profile in the follicular ambient microenvironment in patients undergoing in vitro fertilization process. J Assist Reprod Genet 38, 443–459 (2021). https://doi.org/10.1007/s10815-020-02010-2

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