Keywords
Protein malnutrition
Placenta
Ovary
Endocannabinoid system
How to Cite
Copyright © | All rights reserved.
The journal holds the exclusive copyright for the publication of this article under the terms of Brazilian law 9610/98.
Partial reproduction
The use of parts of the texts, figures and questionnaire of the article is free, being mandatory the citation of the authors and journal.
Total reproduction
It is expressly prohibited and must be authorized by the journal.
Abstract
Objective: To analyze the effects of gestational protein malnutrition on the ovary–placenta interface, focusing on oxidative and inflammatory mechanisms and endocannabinoid modulation. Literature review: Pregnancy involves complex morphofunctional adaptations of the female reproductive system, in which adequate protein intake is essential for ovarian steroidogenesis, placentation, angiogenesis, and redox homeostasis. Protein restriction impairs antioxidant enzyme activity, promotes reactive oxygen species accumulation, and activates inflammatory pathways such as NF-κB, leading to placental dysfunction, impaired maternal–fetal vascularization, and hormonal imbalance. The endocannabinoid system plays a central role in embryo implantation, immune tolerance, and placental development. Experimental studies indicate that cannabidiol exhibits antioxidant and anti-inflammatory properties and modulates signaling pathways including Nrf2, PI3K/Akt/mTOR, and CREB, suggesting a potential role in maintaining ovarian and placental homeostasis. Final considerations: Gestational protein malnutrition is a critical risk factor for ovary–placenta interface dysfunction. Although cannabidiol shows modulatory potential, its use during pregnancy remains controversial and requires further investigation to ensure maternal–fetal safety.
References
AFTAB N, et al. Development of tailored non psychoactive Cannabis sativa L. genotypes in half sib seed progeny segregation generation adhering to requirements through morpho-cannabinoid & terpene profile diversity. Food Research International, 2025; 117476.
ALLEN S, et al. Cannabidiol exposure during rat pregnancy leads to labyrinth-specific vascular defects in the placenta and reduced fetal growth. Cannabis and Cannabinoid Research, 2024; 3: 766-780.
ALVES P, et al. Cannabidiol disrupts apoptosis, autophagy and invasion processes of placental trophoblasts. Archives of toxicology, 2021; 10: 3393-3406.
AVNON T, et al. The impact of a vegan diet on pregnancy outcomes. Journal of Perinatology, 2021; 5: 1129-1133.
AYALEW H, et al. Ontogeny and function of the intestinal epithelial and innate immune cells during early development of chicks: to explore in ovo immunomodulatory nutrition. Poultry Science, 2025; 1: 104607.
BUSS C, et al. Fetal programming of brain development: intrauterine stress and susceptibility to psychopathology. Science signaling, 2012; 5: pt7-pt7.
CAIN JW, et al. SPARC expression in the mouse decidua, placenta, and fetus: correlations with SPP1 expression. Placenta, 2025.
CHEN X, et al. Proangiogenic Macrophage Development in Human Prenatal Stage: A Key Element in Maternal-Fetal Medicine Puzzle. Maternal-Fetal Medicine, 2024; 1: 5-8.
DE ASSIS LIMA IV, et al. Cannabidiol anticonvulsant effect is mediated by the PI3Kγ pathway. Neuropharmacology, 2020; 176: 108156.
DE MOURA TDB, et al. Preeclampsia and transport of ions and small molecules: A literature review. Placenta, 2024; 156: 77-91.
DEER E, et al. The role of immune cells and mediators in preeclampsia. Nature Reviews Nephrology, 2023; 4: 257-270.
DUHIG K, et al. Oxidative stress in pregnancy and reproduction. Obstetric medicine, 2016; 3: 113-116.
EJIKEME C, et al. Respiratory physiological changes in pregnancy. Respiratory Medicine, 2025; 246: 108245.
EL BAKALI I, et al. A Comparative Phytocannabinoid profiling of resin from five hemp (Cannabis sativa L.) cultivars from central-northern Morocco. Food Chemistry Advances, 2025; 101069.
EKINER SA, et al. The molecular activity of cannabidiol in the regulation of Nrf2 system interacting with NF-κB pathway under oxidative stress. Redox Biology, 2022; 57: 102489.
ETIENNE R, et al. Aspectos fisiopatológicos da inflamação e o planejamento de fármacos: uma visão geral atualizada. Rev. Virtual Quim, 2021; 1: 167-191.
GUO Y, et al. Maternal protein deficiency impairs peroxisome biogenesis and leads to oxidative stress and ferroptosis in liver of fetal growth restriction offspring. The Journal of nutritional biochemistry, 2023; 121: 109432.
GURM H, et al. Sinalização canabinoide na interação imuno-reprodutiva durante a gravidez humana. Biomedicines, 2021; 3: 267.
HALES CN, BARKER DJP. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. International journal of epidemiology, 2013; 5: 1215-1222.
HUPPERTZ B. Trophoblast invasion: remodelling of spiral arteries and beyond. In: Preeclampsia: basic, genomic, and clinical. Singapore: Springer Singapore, 2018; 47-62.
JOSOWITZ R, et al. The placenta in congenital heart disease: form, function and outcomes. NeoReviews, 2023; 9: e569-e582.
KEIMPEMA E, HARKANY T. Molecular and cellular principles of endocannabinoid signaling and their sensitivity to cannabis in the developing brain. In: Cannabis and the Developing Brain. Academic Press, 2022. p. 149-170.
KHINE PP, et al. MR of fallopian tubes: MR imaging clinics. Magnetic Resonance Imaging Clinics, 2023; 1: 29-41.
LIU l, et al. Decoding the molecular pathways governing trophoblast migration and placental development; a literature review. Frontiers in Endocrinology, 2024; 15: 1486608.
LU HC, MACKIE K. Review of the endocannabinoid system. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2021; 6: 607-615.
MARESCA S, et al. Effect of protein restriction of bovine dams during late gestation on offspring postnatal growth, glucose-insulin metabolism and IGF-1 concentration. Livestock Science, 2018; 212: 120-126.
MÜLLER O, KRAWINKEL M. Malnutrition and health in developing countries. Cmaj, 2005; 3: 279-286.
PAPAGEORGHIOU AT, et al. The INTERGROWTH-21st fetal growth standards: toward the global integration of pregnancy and pediatric care. American journal of obstetrics and gynecology, 2018; 2: S630-S640.
PAULESU L, et al. hCG and its disruption by environmental contaminants during human pregnancy. International journal of molecular sciences, 2018; 3: 914.
PENG J, et al. A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD). Basic & clinical pharmacology & toxicology, 2022; 4: 439-456.
PETE DD, NAROUZE SM. Endocannabinoids: Anandamide and 2-arachidonoylglycerol (2-AG). In: Cannabinoids and Pain. Cham: Springer International Publishing, 2021; 63-69.
REYNOLDS LP, et al. Developmental programming of fetal growth and development. Veterinary Clinics of North America: Food Animal Practice, 2019; 2: 229-247.
ROSARIO FJ, et al. Maternal protein restriction in the rat inhibits placental insulin, mTOR, and STAT3 signaling and down-regulates placental amino acid transporters. Endocrinology, 2011; 3: 1119-1129.
SILVA AJ, et al. Uso do canabidiol (Cannabis sativa L.) como possível forma de tratamento para doença trofoblástica gestacional associada a Mola Hidatiforme. Revista Eletrônica Acervo Saúde, 2024; 9: e17261.
SPICAROVA D, PALECEK J. Anandamide-mediated modulation of nociceptive transmission at the spinal cord level. Physiological Research, 2024; 1: S435.
STANZIANO A, et al. The use of real time strain endometrial elastosonography plus endometrial thickness and vascularization flow index to predict endometrial receptivity in IVF treatments: a pilot study. BMC Medical Imaging, 2023; 1: 130.
STEPHENS TV, et al. Healthy pregnant women in Canada are consuming more dietary protein at 16-and 36-week gestation than currently recommended by the Dietary Reference Intakes, primarily from dairy food sources. Nutrition research, 2014; 7: 569-576.
SURYAWANSHI H, et al. A single-cell survey of the human first-trimester placenta and decidua. Science advances, 2018; 10: eaau4788.
TOK A, et al. The effect of mode of delivery on oxidative stress and antioxidant parameters in the mother, neonate and maternal milk. BMC Pregnancy and Childbirth, 2025; 25: 726.
WILINSKA M, et al. Oxidative stress and total antioxidant status in term newborns and their mothers. Annals of Agricultural and Environmental Medicine, 2015; 22: 4.