Vol 7, No 1 (2019) ISSN 2167-8677 (online) DOI 10.5195/d3000.2019.84 http://dentistry3000.pitt.edu New articles in this journal are licensed under a Creative Commons Attribution 4.0 United States License. This journal is published by the University Library System, University of Pittsburgh as part of its D-Scribe Digital Publishing Program and is cosponored by the University of Pittsburgh Press. The effect of estrogen on craniofacial dimensions: a systematic review Marjorie Ayumi Omori1, Mirian Aiko Nakane Matsumoto1, Raquel Assed Bezerra Segato,1 Léa Assed Bezerra da Silva1, Paulo Nelson Filho1, Erika Calvano Kuchler1 1Department of Pediatric Dentistry, School of Dentistry of Ribeirão Preto (University of São Paulo), Ribeirão Preto/SP Brazil Abstract Sex hormones have an effect on bone metabolism. However, it remains unclear how estrogen hormone affects mandible and maxilla growth and development. The aim of this study was to perform a systematic review to evaluate if estrogen is associated with developmental alterations in the maxilla/mandible phenotype. Material and methods: A computer search of the literature was performed using: Pubmed Medline (1966 – August 2018), Google Scholar and manual searching. A combination of the terms ‘estrogens', ‘mandible’, ‘dental arch’, ‘maxilla’, ‘craniofacial’, ‘growth’ and ‘development’ was used. Studies that used animal models to evaluate the role of estrogen during growth and development on the dimensions of the maxilla and/or mandible were included. Results: 5 studies were selected to compose this systematic review. One study used zebrafish as a model. Two studies used female mice and 2 studies used female rats as a model. Two studies treated the animals with estrogen. Four studies demonstrated that estrogen has an effect on mandible dimension and 2 studies demonstrated that estrogen has an effect on maxilla. One study did find an association between estrogen deficiency and mandible/maxilla dimensions Conclusion: The current evidence suggested that both, increased and decreased levels of estrogen, have an effect on the maxilla and mandible dimensions. Citation: Omori M, et al. (2019) The effect of estrogen on craniofacial dimensions: a systematic review. Dentistry 3000. 1:a001 doi:10.5195/d3000.2019.84 Received: August 7, 2018 Accepted: September 18, 2018 Published: June 26, 2019 Copyright: ©2019 Omori M, et al. This is an open access article licensed under a Creative Commons Attribution Work 4.0 United States License. Email:erikacalvano@gmail.com Introduction The understanding of craniofacial growth has been investigated in orthodontic field (1-3). Studies have demonstrated that the properly growth and development of the maxilla and mandible requires the coordination of a variety of molecular mechanisms (4-6). In fact, bone growth and development is mediated by different factors, such as hormones and sex hormones. It is well known that sex hormones are important in the regulation of reproductive functions and play an important in bone growth and maintenance (7). Estrogen is a sex hormone, mainly produced by ovaries, which has a multifunctional role in growth, development, differentiation and function of various tissues. The role of estrogen in the bone development begins in the embrionary period (8) until the puberty (9). Different studies with animal models have suggested that estrogen has an important role on the maxillary arches (9-12). Therefore, the aim of this study is to perform a systematic review to evaluate the effect of estrogen and/or Estrogen receptors on the maxilla and mandible growth. Material and Methods Focused questions, protocol and Data search The present systematic review was conducted in order to answer two focused questions: I) Does estrogen levels affect maxilla and mandible growth? II) Does Estrogen receptors (ERs) affect maxilla and mandible growth? To conduct this review, the PRISMA STATEMENT (Figure 1) checklist was used. Initially a broad survey was conducted on computer of the literature by using the Pubmed Medline (1966- Aug 2018), Google Scholar (1960- Aug 2018) and manual search databases. Review process http://dentistry3000.pitt.edu/ http://www.library.pitt.edu/ http://www.pitt.edu/ http://www.library.pitt.edu/articles/digpubtype/index.html http://upress.pitt.edu/ http://creativecommons.org/licenses/by/4.0/ The effect of estrogen on craniofacial dimensions: a systematic review Vol 7 No 1 (2019) DOI 10.5195/d3000.2019.84 http://dentistry3000.pitt.edu The initial selection of the studies was done through the title and abstract. The full text analyses of the potentially relevant studies were made. Two examiners selected the studies. When there was some sort of disagreement, a third examiner was requested. Terms The search strategy was based on the following Medical Subject Heading terms (MeSH) or Text Word [tw] in different combination strategy. The following terms were used: “Estrogens” AND “Mandible OR maxilla OR dental arch OR craniofacial” AND “Growth OR development”. Data was extracted and pooled in a table, to facilitate the visualization of information. Inclusion and Exclusion Criteria Studies that used animal models to assess the effect of estrogen during maxilla and mandible growth and have maxilla and mandible dimensions as an outcome were included. There was no language or date restriction. In vitro studies, clinical studies, case reports, case series and review have been excluded, as well as patents and conferences were excluded. Data extraction Two authors extracted the relevant data from the included papers. From each included study, the description of the animal models used, experimental design, dimensions results and additional information were summarized in tables 1 and 2. Results The electronic search of PubMed and Google Scholar yielded 1.120 citations. A total of 31 titles and abstracts were screened from the selected databases. There were 15 in PubMed, and 16 in google scholar. The duplicates were considered only once, totalizing just 1 paper. Additionally, 1 more paper was selected by manual searching. Initially, the titles and abstracts not connected with the topic were excluded. Afterwards, the papers were selected according to the inclusion and exclusion criteria, then 13 papers were selected for full text analysis. After reading, 8 papers were excluded. Thus, 5 full texts were included for this systematic review. http://dentistry3000.pitt.edu/ The effect of estrogen on craniofacial dimensions: a systematic review Vol 7 No 1 (2019) DOI 10.5195/d3000.2019.84 http://dentistry3000.pitt.edu The summary of the characteristics of the 5 included papers is described in the table 1. The authors followed different protocols to evaluate the effect of estrogen levels or ERs in the maxilla and mandible growth. Only one study used zebrafish as animal model (13). The others 4 studies used mammals, 2 female rats (10, 11) and 2 female mice (9, 12). Two studies ovarectomized the experimental group in order to induce estrogen deficiency (9, 11). Others two studies treated with Estradiol (E2) to induce an increase of estrogen (10, 13), and only one study treated the animals with Estrogen Receptors (alfa and beta) antagonists (12). The author who treated the animals with E2 (10) found an increase in mandibular measurements: Condylion- Pogonion (Co-Pog) and Condylion- Gonion (Co-Go). Fujita et al. (9) induced estrogen deficiency and found some smaller linear distances in the maxilla: Mu- Pr (Mu: Point on intersection between maxillary bone and mesial surface of upper first molar; Pr: Most inferior and anterior point on alveolar process of premaxilla), A-Pr (A: Most anterior point on nasal bone; Pr: Most inferior and anterior point on alveolar process of premaxilla), Iu-Bu (Iu: Most prominent point between incisal edges of upper incisors; Bu: Point on premaxilla between jawbone and lingual surface of upper incisors). In the mandible, the distances Pg-Gn (Pg: Point on most inferior contour of lower border of mandible, adjacent to incisors; Gn: Point on most inferior contour of angular process of mandible), Ml-Bl (Ml: Point on intersection between the mandibular alveolar bone and mesial surface of first molar; Bl: Point on intersection between lingual surface of lower incisor and anteriormost part of lingual alveolar bone), Co-Co’ (Co: Most posterosuperior point of condylar process; Co’: Crossing point on Pg- Gn perpendicular to Pg-Gn from http://dentistry3000.pitt.edu/ The effect of estrogen on craniofacial dimensions: a systematic review Vol 7 No 1 (2019) DOI 10.5195/d3000.2019.84 http://dentistry3000.pitt.edu Co) and Il-Id (Il: Most prominent point between incisal edges of lower incisor; Id: Most inferior and anterior point on alveolar process of mandible) were significantly smaller. Besides, no significant differences in all angular measurements were found between the ovarectomized and sham-operated groups. The study that treated Zebrafish with different concentrations of E2 detect a deformation of the upper jaw plate, leading to a smaller maxilla and hypoplasia of the lower jaw, leading to a smaller mandible. Márquez Hernández et al. (12) evaluate the effect of ERβ antagonist in the mandible and found that condylar height and mandibular length were significantly smaller; the mandibular growth was significantly affected with the injection. Just one author (11) from this systematic review found no significant differences in its study. Discussion Previous studies have already demonstrated that sex hormones can stimulate osteoclast differentiation directly (14) or indirectly (15) and that estrogen has an effect on bone metabolism (16-18). In cases of low levels of estrogen, there is an increase of the osteoclast count and surface; whereas in cases of high levels of estrogen, the opposite occurs: bone formation, bone healing and regeneration (19, 20). This hormone express its skeletal effects by its binding to estrogen receptors (ERs) (21). In the present systematic review, we included studies that used mammals as well as zebrafish as animal models. These studies demonstrated the effect of estrogen on the maxilla (9, 12, 13) and mandible dimensions (9, 10, 12, 13). The zebrafish is an important animal model in health and genetic science nowadays due the fact that its genome has been fully sequenced and evidences revealed that 71.4% of human genes are related to zebrafish genes (22). Only one study observed that an increase of estrogen causes a deformation of the upper and lower jaw leading to a smaller maxilla and mandible, interestingly this study used Zebrafish as animal model (13). This fact could be explained by the physiological differences that exist between mammals and zebrafish. Otherwise, studies that used mice found that a reduction of the craniofacial dimensions occurs when estrogen decreases or when there is a binding in the specific estrogen receptors, blocked through ERs antagonists (9, 12). Following the same line, Singh & Gunberg (10) demonstrated an increase in the linear measurements of the mandible when rats receive estrogen daily. These results clearly suggested that estrogen play an important role in mammals maxilla and mandible development. Studies that use mammals as an animal model allow more reproducibility for human development understanding once over 90% of human and mouse genomes can be divided into parts with corresponding regions (23) and http://dentistry3000.pitt.edu/ The effect of estrogen on craniofacial dimensions: a systematic review Vol 7 No 1 (2019) DOI 10.5195/d3000.2019.84 http://dentistry3000.pitt.edu the comparative genomics allow a link between researches using animal model (preclinical researches) and humans (23-25). It is important to highlight that none of the studies evaluated the role of the estrogen during puberty period. In the orthodontic treatment it is crucial to predict the effective period of treatment to improve the skeletal discrepancy between maxillary and mandibular arches, so it is necessary a development of an indicator of bone maturity (for example a hormonal indicator), that would help to establish the beginning and end of growth (12). Therefore, more studies should focus in the understanding of the role of the estrogen and estrogen receptor during different periods of the craniofacial development. Briefly, these translational investigations are indispensable to clearly demonstrate the influence of sex hormones, specifically estrogen, on craniofacial bone growth. Conclusion The current evidence suggested that both, increased and decreased levels of estrogen have an effect on the maxilla and mandible dimensions. Acknowledgments Funding sources: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 2016/13982-4; 2015/ 06866-5. References 1. Choi SH, Fan D, Hwang MS, Lee HK, Hwang CJ. Effect of growth hormone treatment on craniofacial growth in children: Idiopathic short stature versus growth hormone deficiency. J Formos Med Assoc. 2016. 2. da Fontoura CS, Miller SF, Wehby GL, Amendt BA, Holton NE, Southard TE, et al. Candidate Gene Analyses of Skeletal Variation in Malocclusion. 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