Melatonin improves fertilization rate in assisted reproduction: Systematic review and meta-analysis

Veiga, Eduardo Carvalho de Arruda; Samama, Marise; Ikeda, Fabio; Cavalcanti, Giovanna Santos; Sartor, Amanda; Parames, Suelen Fernanda; Baracat, Edmund C.; Ueno, Joji; Soares Junior, Jose Maria

doi:10.1016/j.clinsp.2024.100397

Eduardo Carvalho de Arruda Veiga ^**Corresponding author. E-mail address:eduardo.veiga@fm.usp.br (E.C.d.A. Veiga).

GERA Instituto de Ensino e Pesquisa em Medicina Reprodutiva de, São Paulo, SP, Brazil

Department of Obstetrics and Gynecology, Hospital das Clínicas, Faculdade de Medicina de Ribeirao Preto da Universidade de São Paulo (FMRP-USP), São Paulo, SP, Brazil

https://orcid.org/0000-0002-0167-861X

Marise Samama

GERA Instituto de Ensino e Pesquisa em Medicina Reprodutiva de, São Paulo, SP, Brazil

Department of Gynecology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, SP, Brazil

https://orcid.org/0000-0002-3732-1057

Fabio Ikeda

GERA Instituto de Ensino e Pesquisa em Medicina Reprodutiva de, São Paulo, SP, Brazil

Giovanna Santos Cavalcanti

Lim-58 - Laboratorio de Ginecologia Estrutural e Molecular da Disciplina de Ginecologia, Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil

Amanda Sartor

GERA Instituto de Ensino e Pesquisa em Medicina Reprodutiva de, São Paulo, SP, Brazil

Department of Gynecology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, SP, Brazil

Suelen Fernanda Parames

GERA Instituto de Ensino e Pesquisa em Medicina Reprodutiva de, São Paulo, SP, Brazil

https://orcid.org/0000-0002-6710-8716

Edmund C. Baracat

Lim-58 - Laboratorio de Ginecologia Estrutural e Molecular da Disciplina de Ginecologia, Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil

Joji Ueno

GERA Instituto de Ensino e Pesquisa em Medicina Reprodutiva de, São Paulo, SP, Brazil

Jose Maria Soares Junior

Lim-58 - Laboratorio de Ginecologia Estrutural e Molecular da Disciplina de Ginecologia, Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil

https://orcid.org/0000-0003-0774-9404

*Corresponding author. E-mail address:eduardo.veiga@fm.usp.br (E.C.d.A. Veiga).

Declaration of competing interest

The authors declare no conflicts of interest.

Authors	Years	Study design	Technique	Melatonin treatment	Justifications for inclusion criteria	Main outcomes
Tamura et al. [¹¹11 Maganhin CC, Fuchs LF, Simoes RS, Oliveira-Filho RM, de Jesus Simões M, Baracat EC, et al. Effects of melatonin on ovarian follicles. Eur J Obstet Gynecol Reprod Biol 2013;166(2):178–84.]	2008	Controlled Clinical Trial	IVF ET	3 mg/day	The study has results that melatonin improves among other aspects of ARTs and fertility rates	improves oocyte and embryo quality and better fertility taxes.
Unfer et al. [¹⁹19 Jing T, Shile S, Sun Y, Li H, Li WP, Cong Z, et al. Melatonin levels in follicular fluid as markers for IVF outcomes and predicting ovarian reserve. Reproduction 2017;153 (4):443–51.]	2011	Clinical Trial	IVF	3 mg/day	The study has results that melatonin improves oocyte quality	had improved on pregnancy rate
Batioglu et al. [¹⁸18(Professor of SR and P Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, et al. Writer on evidence-based medicine. In: Page MJ, ed. Cochrane Handbook For Systematic Reviews of Interventions; 2023. p. 694.]	2012	Randomized Controlled Trial	IVF ET	3 mg/day	The justification for the inclusion is the efficacy of melatonin administered in improving oocyte quality	improves oocyte and embryo quality
Fernando et al. [¹⁷17 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71.]	2014	Clinical Trial	IVF ICSI	4 mg/twice per day	Double-blind randomized study evaluating melatonin in infertility treatments	Melatonin in ART will be the first trial designed to determine a relationship of melatonin on clinical pregnancy rates.
Nishihara et al. [²⁰20 Fernando S, Osianlis T, Vollenhoven B, Wallace E, Rombauts L. A pilot double-blind randomised placebo-controlled dose-response trial assessing the effects of melatonin on infertility treatment (MIART): study protocol. BMJ Open 2014;4(8):e005986.]	2014	Clinical Trial	IVF	3 mg/day	The justification for the inclusion is the efficacy of melatonin administered in improving oocyte quality	improves oocyte and embryo quality
Jahromi et al. [²¹21 Batiioǧlu AS, Şahin U, Grlek B, Öztrk N, Ünsal E. The efficacy of melatonin administration on oocyte quality. Gynecol Endocrinol 2012;28(2):91–3.]	2017	Randomized Controlled Trial	IVF	3 mg/day	Double-blind randomized study evaluating melatonin in infertility treatments in women with low ovarian reserve	improves oocyte and embryo quality
Tong et al. [²²22 Espino J, Macedo M, Lozano G, Ortiz Á, Rodríguez C, Rodríguez AB, et al. Impact of melatonin supplementation in women with unexplained infertility undergoing fertility treatment. Antioxidants 2019;8(9):338.]	2017	Clinical Trial	IVF ICSI	Melatonin measument in folicular fluid with range was 2.3‒1000 pg/mL.	The justification for the inclusion is that melatonin levels can be markers and predictors of low ovarian reserve and better results in IVF	improves oocyte and embryo quality
Zheng et al. [²³23 Tong J, Sheng S, Sun Y, Li H, Li WP, Zhang C, et al. Melatonin levels in follicular fluid as markers for IVF outcomes and predicting ovarian reserve. Reproduction 2017;153 (4):443–51.]	2017	Clinical Trial	IVF	Melatonin measument in folicular fluid.	The work seals the concentrations of melatonin in the follicular fluids and their role in human reproduction	We have demonstrated that higher folicullar fluid melatonin concentrations were related to better ART outcomes
Ma et al. [²⁴24 Zheng M, Tong J, Li WP, Chen ZJ, Zhang C. Melatonin concentration in follicular fluid is correlated with antral follicle count (AFC) and in vitro fertilization (IVF) outcomes in women undergoing assisted reproductive technology (ART) procedures. Gynecol Endocrinol 2018;34(5):446–50.]	2018	Clinical Trial	IVF ICSI ET		This study was the only one that did not have the presence of melatonin, therefore it was important for the inclusion criteria in the present systematic review because it worked with studies of two fluids of two follicular follicles in women with ovarian hyperstimulation syndrome.	Follicle count measured on the day of hCG administration was the only predictive factor for the occurrence of OHSS
Espino et al. [²⁵25 Jahromi BN, Sadeghi S, Alipour S, Mohammad, Parsanezhad E, Alamdarloo SM. Effect of melatonin on the outcome of assisted reproductive technique cycles in women with diminished ovarian reserve: a double-blinded randomized clinical trial. Irian J Med Sci 2017;42(1):73–8.]	2019	Clinical Trial	IVF	3 mg/day or 6 mg/ day	The authors studied the use of melatonin in infertilities with no apparent or apparent cause in unexplained infertilities	improves oocyte and embryo quality
Fernando et al. [²⁶26 Unfer V, Raffone E, Rizzo P, Buffo S. Effect of a supplementation with myo-inositol plus melatonin on oocyte quality in women who failed to conceive in previous in vitro fertilization cycles for poor oocyte quality: a prospective, longitudinal, cohort study. Gynecol Endocrinol 2011;27(11):857–61.]	2019	Randomized Controlled Trial	IVF	2, 4 or 8 mg/twice a day	This work, despite having arguments that go against current literature, is important for studying melatonin in ovarian vascular indices	Melatonin and vascular indices cannot predict the number or quality of oocytes or embryos obtained in an IVF cycle.
Li et al. [²⁷27 Ma T, Niu Y, Wei B, Xu L, Zou L, Che X, et al. Moderate-to-severe ovarian hyperstimulation syndrome: a retrospective multivariate logistic regression analysis in Chinese patients. Adv Clin Exp Med 2020;29(1):85–90.]	2019	Case control Study	IVF ICSI ET	Melatonin measument in folicular fluid.	The authors studied in the same work the functions of melatonin in ovarian hyperstimulation syndrome	Role of melatonin as a predictor of ovarian hyperstimulation syndrome
Zheng et al. [²⁸28 Fernando S, Wallace EM, Rombauts L, White N, Hong J, Vollenhoven B, et al. The effect of melatonin on ultrasound markers of follicular development: a double-blind placebo-controlled randomised trial. Aust N Z J Obstet Gynaecol 2020;60(1):141–8.]	2019	Clinical Trial	IVF	Melatonin measument in folicular fluid	This work was important to be selected because it was the first to demonstrate that melatonin in the follicular fluids is significantly increased in women with OHSS	The authors studied in the same work the functions of melatonin in ovarian hyperstimulation syndrome
Espinola et al. [²⁹29 Li Y, Fang L, Yu Y, Shi H, Wang S, Guo Y, et al. Higher melatonin in the follicle fluid and MT2 expression in the granulosa cells contribute to the OHSS occurrence. Reproductive Biology and Endocrinology 2019;17(1):37.]	2020	Prospective Randomized and Controlled Pilot Study	IVF	1 mg/day	As justifications for the inclusion of this work, there is a randomized study that studied vitamin D, melatonin, or myo-inositol and folic acid in assisted reproduction	The main failure was that increased vitamin D levels were positively correlated with IVF implantation rates.
Wdowiak et al. [³⁰30 Bezerra Espinola MS, Bilotta G, Aragona C. Positive effect of a new supplementation of vitamin D3 with myo-inositol, folic acid and melatonin on IVF outcomes: a prospective randomized and controlled pilot study. Gynecol Endocrinol 2021;37 (3):251–4.]	2020	Prospective Randomized and Controlled Trial	IVF ICSI	1 mg/day	A study comparing other two substances together with melatonin in women with OHSS	A combination of myo-inositol, vitamin D and melatonin including better fertilization and pregnancy outcomes as well as reduced risk of OHSS
Li et al. [³¹31 Wdowiak A, Filip M. The effect of myo-inositol, vitamin D3 and melatonin on the oocyte quality and pregnancy in in vitro fertilization: a randomized prospective controlled trial. Eur Rev Med Pharmacol Sci 2020;24(16):8529–36.]	2021	Randomized Controlled Trial	IVF IVM	MT in fluid folicular in IVF and addition in vitro culture of 10^–5 mol/L melatonina in IVM.	It was a pilot study that compared IVF protocols with in vitro maturation and the presence of melatonin and its results in human reproduction.	Melatonin supplementation has efficacy in clinical results of assisted reproduction as higher rates of oocytes in IVF
Zheng et al. [³²32 Li X, Mu Y, Elshewy N, Ding D, Zou H, Chen B, et al. Comparison of IVF and IVM outcomes in the same patient treated with a modified IVM protocol along with an oocytes-maturing system containing melatonin: a pilot study. Life Sci 2021;264:118706.]	2022	Clinical Trial	–	Melatonin treatment in 10 μM cell culture	The authors studies the functions of melatonin in ovarian hyperstimulation syndrome	Melatonin attenuated reactive oxygen species during apoptosis

[1] *Corresponding author. E-mail address:eduardo.veiga@fm.usp.br (E.C.d.A. Veiga).

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Melatonin improves fertilization rate in assisted reproduction: Systematic review and meta-analysis

Abstract

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