Key Points
Question
Is exogenous estrogen associated with development of head and neck cancer (HNC) in female patients?
Findings
This cohort study including 849 936 female patients found that patients with oral contraceptive intake had a higher risk of an HNC diagnosis than 1:1 matched patients without oral contraceptive use. In contrast, patients with postmenopausal hormone replacement therapy had a lower risk of an HNC diagnosis than matched patients without hormone replacement therapy.
Meaning
These findings indicate that exogenous hormonal intake should be considered in the study of risk factors for HNC in female patients.
Abstract
Importance
Sex differences in head and neck cancer (HNC) incidence suggest a potential contribution of sex hormones.
Objective
To assess the role of exogenous estrogen exposure in the development of HNC in female patients.
Design, Settings, and Participants
This large multicenter cohort study using clinical records from the TriNetX real-world database included 20 years of data (through May 31, 2023) from 87 health care organizations. The TriNetX database was searched for medical records for female patients with and without exogenous estrogen exposure according to their chronological age. Cohort 1 included 731 366 female patients aged 18 to 45 years old with regular oral contraceptive (OC) intake and cohort 2 included 3 886 568 patients in the same age group who did not use OC. Cohort 3 comprised 135 875 female patients at least 50 years old receiving hormone replacement therapy (HRT), whereas cohort 4 included 5 875 270 patients at least 50 years old without HRT. Propensity score matching was performed for the confounders age, alcohol dependence, and nicotine dependence. Data analyses were performed in May 2023.
Main Outcome and Measures
Diagnosis of HNC (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision: C00-C14), and after propensity score matching (1:1 nearest-neighbor greedy matching), a risk analysis to investigate risk differences and risk ratios (RRs) with a 95% CI.
Results
Among the 718 101 female patients in each of cohorts 1 and 2 (mean [SD] age at diagnosis, 25.9 [6.7] years), those with OC intake had a higher risk of an HNC diagnosis (RR, 1.47; 95% CI, 1.21-1.78) than those without OC use. Among the 131 835 female patients in each of cohorts 3 and 4 (mean [SD] age, 67.9 [12.0] years), those with postmenopausal HRT intake had a lower risk of an HNC diagnosis (RR, 0.77; 95% CI, 0.64-0.92) than those without HRT use.
Conclusions and Relevance
The findings of this cohort study illustrate a positive association between OC and a negative association between HRT and the development of HNC in female patients. Given the limitations of the TriNetX database, future research should include detailed information on the intake of OC and HRT and reproductive health information (eg, age at menarche/menopause, number of pregnancies) to more accurately define the strength and direction of the possible association between exogeneous estrogen exposure and the development of HNC in female patients.
This large cohort study assesses the association of exogenous estrogen exposure through oral contraception and hormone replacement therapy and the development of head and neck cancer in female patients.
Introduction
Head and neck cancers (HNC) include malignant neoplasms of the oral cavity, the oropharynx, the hypopharynx, the larynx, and the salivary glands. The most common histological entity of HNC is squamous cell carcinoma.1 A multitude of these cancers are associated with risk behavior such as tobacco use and/or alcohol consumption, among others.2 Additionally, infection with human papillomavirus (HPV) is a well-known cause of oropharynx cancer.3,4 However, HNC also occur in patients who may not present with the predominant risk factors.5
The predominantly male incidence, which is evident for most HNC,6 might not be exclusively explained by differences in tobacco use, alcohol consumption, and HPV infection.7,8 Moreover, recent reports indicated an increasing number of HNC, ie, oral squamous cell carcinoma (OSCC), in younger female patients.9 Sex differences in HNC incidence and cancer mortality suggest a potential contribution of female sex hormones in the development of HNC.7,10
The role of sex hormones and their receptors in HNC has not yet been clarified. Studies have indicated a protective effect of female sex hormones in the development of HNC, but only limited data are available.11,12 A 2017 study by Hashim et al11 including 1572 female patients with HNC reported a risk reduction of HNC through exogenous and endogenous estrogen exposures. Exogenous estrogen intake in terms of hormone replacement therapy (HRT) during menopause as well as pregnancy and giving birth when younger than 35 years were associated with a lower risk of HNC. On the other hand, the results from Suba et al13 suggested an association between an increased oral cancer incidence in female patients and estrogen deficiency during the postmenopausal period of life.
To date, the role of estrogen in the pathogenesis of HNC in female patients remains unclear. This study aimed to investigate a potential association between exogenous estrogen exposure and the development of HNC in female patients based on clinical data analysis. To account for differences between age groups, this study included the analysis of female patients from 18 to 45 years of age, who did or did not use oral contraceptives (OC), and female patients at least 50 years old who did or did not receive HRT.
Methods
Data Collection and Study Population
The TriNetX network was accessed on May 31, 2023, and included all data from 87 health care organizations (HCOs) from the last 20 years prior to the access date. The database was searched for electronic medical records of female patients aged 18 to 45 years old with and without OC use and female patients at least 50 years old with and without HRT use (Figure 114).
Figure 1. Patient Selection Process.
Modified CONOSORT14 flow diagrams for cohorts 1 and 2 including female patients with or without use of oral contraceptives (A), and cohorts 3 and 4 including female patients with or without hormone replacement therapy (B).
Female patients aged 18 to 45 years with regular OC intake were incorporated in cohort 1 (n = 731 366) and those patients that did not use OC in cohort 2 (n = 3 886 568). Cohort 3 consisted of 135 875 female patients at least 50 years old receiving HRT, whereas cohort 4 included patients in the same age group without HRT (n = 5 875 270). Propensity score matching was applied to reduce confounding variables and allocate groups based on similar covariate distributions. A 1:1 matching was carried out for age, alcohol dependence (ICD-10 code, F10.2), and nicotine dependence or tobacco use (ICD-10 code, F17). After matching, cohorts 1 and 2 each comprised 718 101 patients, and cohorts 3 and 4 each comprised 131 835 patients.
The datasets used and analyzed in this retrospective study were retrieved from existing deidentified data of the TriNetX database,15 which is compliant with the Health Insurance Portability and Accountability Act; therefore, the study was exempt from review and informed consent was waived. We followed the Reporting of Studies Conducted Using Observational Routinely-Collected Data (RECORD) Statement.
Statistical Analysis
The time window for the outcomes was defined as 5 years and the outcome was the primary diagnosis of an HNC per codes C00 to C14 in the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Further analyses assessed the occurrence of the suboutcomes defined as the respective 15 anatomical subsites designated by the corresponding ICD-10 codes C00 to C14. Patients were categorized according to age group and use of OC or HRT, and outcomes were calculated by comparing cohorts 1 and 2, as well as cohorts 3 and 4, respectively. Patients with a preexisting diagnosis of HNC prior to the index event (defined as documentation of OC/HRT user status at an HCO included in the TriNetX database) were excluded from the analyses. Propensity score matching was conducted. Patients were matched using propensity scores obtained from logistic regression analysis adjusted for age, alcohol dependence, and nicotine dependence in a 1:1 manner by employing greedy nearest neighbor algorithms and a caliper width of 0.1 pooled SDs, and the order of rows was randomized. To assess the efficacy of matching, a standardized mean difference of below 0.1 was considered negative for residual imbalance. The risk analysis conducted consisted of risk differences and risk ratios (RRs) estimates along with their 95% CIs to compare outcomes between the 2 groups, and P values were provided. Data analyses were performed in May 2023.
Results
Assessment, Allocation, and Matching
After matching, cohorts 1 and 2 each comprised 718 101 patients (mean [SD] age at tumor diagnosis, 25.9 [6.7] years); and cohorts 3 and 4 each comprised 131 835 patients (mean [SD] age at tumor diagnosis, 67.9 [12.0] years). Table 1 presents the patient characteristics of the 4 cohorts before and after matching.
Table 1. Patient Characteristics Before and After Propensity Score Matchinga.
| Characteristic | Before matching, No. (%)b | After matching, No. (%)b | ||||
|---|---|---|---|---|---|---|
| OC | Cohort 1 | Cohort 2 | SMD | Cohort 1 | Cohort 2 | SMD |
| Patients, No. | 731 366 | 3 886 568 | NA | 718 101 | 718 101 | NA |
| Age at tumor diagnosis, mean (SD), y | 25.9 (6.7) | 26.4 (8.6) | 0.430 | 25.9 (6.7) | 25.9 (6.7) | <0.001 |
| Nicotine dependence | 59 266 (8.1) | 117 626 (3.0) | 0.212 | 57 720 (8.0) | 57 720 (8.0) | <0.001 |
| Alcohol dependence | 10 187 (1.4) | 9205 (0.2) | 0.068 | 7655 (1.1) | 7655 (1.1) | <0.001 |
| HRT | Cohort 3 | Cohort 4 | SMD | Cohort 3 | Cohort 4 | SMD |
| Patients, No. | 135 875 | 5 875 270 | NA | 131 835 | 131 835 | NA |
| Age at tumor diagnosis, mean (SD), y | 67.9 (12) | 64.3 (13.7) | 0.276 | 67.9 (12.0) | 67.9 (12.0) | <0.001 |
| Nicotine dependence | 23 489 (17.3) | 239 669 (4.1) | 0.426 | 23 489 (17.8) | 23 489 (17.8) | <0.001 |
| Alcohol dependence | 4106 (3.0) | 24 616 (0.4) | 0.200 | 4106 (3.1) | 4106 (3.1) | <0.001 |
Abbreviations: HRT, hormone replacement therapy; NA, not applicable; OC, oral contraceptive; SMD, standardized mean difference.
Cohorts 1 and 2 comprised female patients (age 18-45 years) who either used OC (cohort 1) or did not use OC (cohort 2). Cohorts 3 and 4 comprised female patients (age ≥50 years) who either received HRT (cohort 3) or did not receive HRT (cohort 4).
Percentages refer to each of the respective cohorts.
Risk Analyses for OC
Statistical analysis was performed to compare outcomes regarding the diagnosis of an HNC and the respective HNC sublocalizations. The baseline occurrence of HNC in the cohort of female patients who did not use OC (cohort 2) was 0.000245 and the occurrence of HNC in female patients who did use OC (cohort 1) was 0.000359, for an absolute risk increase of 0.000114 and a relative risk increase of 1.47 (95% CI, 1.21-1.78) (Table 2). Subsequently, the results were further analyzed with regard to tumor localizations according to ICD-10 codes C00 to C14, as defined per suboutcomes (Figure 2A). The risk of gum cancer (ICD-10: C03) was more than 2-fold higher in cohort 1 with female patients using OC as compared with cohort 2 (RR, 2.09; 95% CI, 1.02-4.29). The analysis of suboutcomes revealed that the risk of tumors of the palate, the oropharynx, and the hypopharynx (ICD-10: C05, C10, C13) was lowest among female patients with regular OC intake compared with those without OC.
Table 2. Risk Difference and Risk Ratios for Head and Neck Cancer (ICD-10 Codes, C00-C14) in Female Patients (Age 18-45 Years) After Propensity Score Matching.
| Cohort statisticsa | Patients, No. | Patients with outcome, No. | Risk |
|---|---|---|---|
| Cohort 1 (with OC) | 717 792 | 258 | 0.000359 |
| Cohort 2 (without OC) | 717 914 | 176 | 0.000245 |
| Risk analysis | Z value | P value | |
| Risk difference (95% CI) | 0.000114 (0.000-0.000) | 3.94 | <.001 |
| Risk ratio (95% CI) | 1.47 (1.21-1.78) | NA | NA |
Abbreviations: ICD-10, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; NA, not applicable; OC, oral contraceptive.
Some patients in cohort 1 (309 patients) and cohort 2 (187 patients) were excluded from the results because the outcome had occurred before the time period.
Figure 2. Risk Ratios for the Diagnosis of Head and Neck Cancer Among Study Patients.
Risk ratios for the diagnosis of a head and neck cancer (ICD-10 codes C00-14) and the respective sublocalizations in female patients 18 to 45 years old using oral contraceptives (A) and female participants at least 50 years old using hormone replacement therapy (B). ICD-10 indicates the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision.
Risk Analyses for HRT
The risk analyses were conducted in cohorts 3 and 4 in female patients receiving HRT to compare outcomes for the diagnosis of HNC and the defined suboutcomes according to ICD-10 codes. The baseline occurrence of HNC in the cohort of female patients without HRT (cohort 4) was 0.00203 and the occurrence of HNC in the cohort of female patients who did use HRT (cohort 3) was 0.00156, for an absolute risk decrease of 0.000466 and a relative risk decrease of 0.77 (95% CI, 0.64-0.92) (Table 3). Further analyses assessed the risk of developing HNC at different localizations according to ICD-10 codes C00 to C14 (Figure 2B). In contrast with the overall trend for a reduced risk of HNC in females who used HRT, there was an increased risk in females in cohort 3 who used HRT (RR, 2.00; 95% CI, 1.17-3.42) regarding the diagnosis of gum cancer (ICD-10: C03) compared with cohort 4.
Table 3. Risk Difference and Risk Ratios for Head and Neck Cancer (ICD-10 Codes, C00-C14) in Female Patients (Age ≥50 Years) After Propensity Score Matching.
| Cohort statisticsa | Patients, No. | Patients with outcome, No. | Risk |
|---|---|---|---|
| Cohort 3 (with HRT) | 130 713 | 204 | 0.00156 |
| Cohort 4 (without HRT) | 131 267 | 266 | 0.00203 |
| Risk analysis | Z value | P value | |
| Risk difference (95% CI) | −0.000466 (−0.001 to −0.000) | −2.817 | .005 |
| Risk ratio (95% CI) | 0.77 (0.64 to 0.92) | NA | NA |
Abbreviations: HRT, hormone replacement therapy; ICD-10, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; NA, not applicable.
Some patients in cohort 3 (1122 patients) and cohort 4 (568 patients) were excluded from results because the outcome had occurred before the time period.
Discussion
This clinical (real-world) data study assessed the role of exogenous estrogen in the development of HNC in female patients undergoing OC or HRT, by chronological age. This study illustrates a possible association between the regular use of exogenous estrogen drugs and the development of HNC in a large cohort of female patients. In the younger cohort of female patients, those with regular OC intake were at a moderately increased risk of HNC compared with age-matched patients without OC intake. In female patients at least 50 years old, the use of HRT was associated with a moderately reduced risk of the development of HNC. It should be noted that the baseline risk for the development of HNC in both the younger and the older cohorts was exceedingly small, and the absolute risk difference must be considered when interpreting the risk ratios presented in this study. In fact, if the use of OC in younger females were causally associated with the development of HNC, nearly 8800 female patients (number needed to harm = 1/0.000114) would have to take OC to see 1 additional HNC case compared with females who did not use OC. For females at least 50 years old, nearly 2150 (number needed to treat = 1/0.000466) would have to take HRT to prevent 1 additional cancer case compared with females not receiving HRT.
During pregnancy, there are high concentrations of estrogen and progesterone in the blood. Clinical findings in pregnant women indicate a high susceptibility of the oral mucosa, and pregnancy is often associated with the occurrence of oral lesions and acute inflammation of the gingiva, such as epulis gravidarum and gingivitis, among others.16 Levels of endogenous 17β-estradiol and progesterone are also altered by menopause and the use of OC.16,17 Moreover, oral health is influenced by hormonal influences throughout the menstrual cycle.18 It has not been determined what role hormones and their receptors play in the development of HNC. A review published in 2022 by Qin et al19 described the interaction of estrogen receptors and androgen receptors in HNC. Whereas estrogen receptors beta (ERβ; but not estrogen receptor α [ERα]) are expressed in healthy oral mucosa,20 the expression of estrogen receptors is altered in OSCC, oropharyngeal squamous cell carcinoma, and precancerous oral lesions.21,22,23,24 A prognostic role of the expression of ERα in oropharyngeal squamous cell carcinoma21,22 and OSCC23 has been suggested. Differences in hormone receptor expression and hormone responsiveness may account for differences in the development of HNC at different sublocalizations, as suggested for other malignant neoplasms that are not primarily known as hormone-sensitive cancers.25 Observations made in this study regarding the risk of HNC development at different sublocalizations must be interpreted carefully, and the possible trend towards an association between HRT use and the development of gum cancers may be false-positive.
The influence of hormones on cancers has been subject to previous discussion.26 The use of oral contraceptives during the reproductive years and menopausal HRT often comprises the combined intake of progesterone and estrogen. Ethinylestradiol, a derivative of 17β-estradiol, usually constitutes the estrogen part of these drugs. Previous studies have demonstrated an association between the use of OC and a reduced risk of endometrial cancer, ovarian cancer, or colon cancer, among others.27,28 Studies portended an elevated risk of breast cancer associated with the use of OC or HRT.29,30 Current literature is inconsistent regarding the effect of OC intake on the development of cervical cancer, which is also associated with HPV status as a subset of HNC.31,32
A protective effect of female endogenous and exogenous sex hormones in the development of HNC has been hypothesized.11,12 Hashim et al11 previously suggested the protective role of sex hormones in the development of HNC in female participants. Their study, which included 1572 female patients with HNC and 4343 female controls, found that endogenous hormones and exogenous hormone use were associated with a reduced risk of HNC. There was a negative correlation between HNC and HRT as well as pregnancy and giving birth before age 35 years. The risk of HNC was increased in female participants in whom the menopause was evident in whom menopause was evident at younger than 52 years. Female patients who had given birth at least once had a lower risk of HNC. Furthermore, this study demonstrated an inverse association of the longer use and earlier start of HRT with HNC. These results were corroborated by Langevin et al12 in a case-control study of 149 female patients with HNC that found a protective effect of hormone intake in postmenopausal females (odds ratio, 0.47). A retrospective analysis of menopausal females in Korea (n = 1 180 630) determined a significantly higher risk of oral cavity cancer in participants who underwent menopausal hormone therapy with oral estrogen or tibolone.33
Future population-based studies should investigate these factors to ascertain the association between hormone therapy and the development of HNC. Depending on the strength of evidence, these findings may be included in future recommendations regarding the use of exogenous estrogen. The use of exogenous hormones may alter endogenous hormone levels.17,34 Exogenous hormones possibly affecting actual hormonal exposure, which may play a role in cancer development and disease progression, has been suggested in the discussion of OC as a risk factor for breast cancer.35 When interpreting data, additional factors such as sociocultural aspects should be taken into consideration alongside female biological characteristics for patients who identify as women. The use of HRT may reflect a high level of health awareness and health-seeking behavior. This may produce a possible bias in the assessment of HNC risk.
These study findings suggest a multidirectional association of sex hormones with HNC development. The promising use of antiestrogen therapies has been demonstrated for other cancer types (eg, non−small cell lung cancers), with estrogens playing an important role in disease progression.36 These therapies could also be considered for treatment of HNC.
Limitations
Literature on female patients with HNC is limited due to the small number of affected patients. Due to the nature of this study based on a large clinical database, there is no detailed information available on the intake of OC and HRT with regard to product, dose, or duration of intake. Additional information on reproductive data or hormones, such as the age of menarche or menopause, pregnancies or births, genetic factors, HPV status, receipt of HPV vaccine, and reliability of HRT or OC, was not compiled. In addition, the outcome of an HNC diagnosis was based on ICD-10 codes, and information on the pathohistologic entity or tumor stage was not available from the TriNetX database. Other risk factors for HNC and respective sublocalizations, ie, poor oral hygiene, and more detail on alcohol or nicotine dependence, such as pack-years or frequency and dose of alcohol use, were not available from the TriNetX database. Tumor characteristics and important risk factors should be considered in future studies.
Conclusions
The findings of this large cohort study demonstrate an association between the use of OC and HRT and the development of HNC in female patients. Given the limitations of real-world (ie, clinical) data retrieved from the TriNetX database, future research should include detailed information on the intake of OC and HRT and reproductive health information to more accurately determine the association. Exogenous hormonal intake should be considered in the investigation of risk factors for HNC development in female individuals.
Data Sharing Statement
References
- 1.Mody MD, Rocco JW, Yom SS, Haddad RI, Saba NF. Head and neck cancer. Lancet. 2021;398(10318):2289-2299. doi: 10.1016/S0140-6736(21)01550-6 [DOI] [PubMed] [Google Scholar]
- 2.Aupérin A. Epidemiology of head and neck cancers: an update. Curr Opin Oncol. 2020;32(3):178-186. doi: 10.1097/CCO.0000000000000629 [DOI] [PubMed] [Google Scholar]
- 3.D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944-1956. doi: 10.1056/NEJMoa065497 [DOI] [PubMed] [Google Scholar]
- 4.Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-475. doi: 10.1158/1055-9965.EPI-04-0551 [DOI] [PubMed] [Google Scholar]
- 5.Nokovitch L, Maquet C, Crampon F, et al. Oral cavity squamous cell carcinoma risk factors: state of the art. J Clin Med. 2023;12(9):3264. doi: 10.3390/jcm12093264 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660 [DOI] [PubMed] [Google Scholar]
- 7.Haupt S, Caramia F, Klein SL, Rubin JB, Haupt Y. Sex disparities matter in cancer development and therapy. Nat Rev Cancer. 2021;21(6):393-407. doi: 10.1038/s41568-021-00348-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Park JO, Nam IC, Kim CS, et al. Sex differences in the prevalence of head and neck cancers: a 10-year follow-up study of 10 million healthy people. Cancers (Basel). 2022;14(10):2521. doi: 10.3390/cancers14102521 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Satgunaseelan L, Allanson BM, Asher R, et al. The incidence of squamous cell carcinoma of the oral tongue is rising in young non-smoking women: an international multi-institutional analysis. Oral Oncol. 2020;110:104875. doi: 10.1016/j.oraloncology.2020.104875 [DOI] [PubMed] [Google Scholar]
- 10.Clocchiatti A, Cora E, Zhang Y, Dotto GP. Sexual dimorphism in cancer. Nat Rev Cancer. 2016;16(5):330-339. doi: 10.1038/nrc.2016.30 [DOI] [PubMed] [Google Scholar]
- 11.Hashim D, Sartori S, La Vecchia C, et al. Hormone factors play a favorable role in female head and neck cancer risk. Cancer Med. 2017;6(8):1998-2007. doi: 10.1002/cam4.1136 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Langevin SM, Grandis JR, Taioli E. Female hormonal and reproductive factors and head and neck squamous cell carcinoma risk. Cancer Lett. 2011;310(2):216-221. doi: 10.1016/j.canlet.2011.07.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Suba Z. Gender-related hormonal risk factors for oral cancer. Pathol Oncol Res. 2007;13(3):195-202. doi: 10.1007/BF02893499 [DOI] [PubMed] [Google Scholar]
- 14.Schulz KF, Altman DG, Moher D; CONSORT Group . CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010;63(8):834-840. doi: 10.1016/j.jclinepi.2010.02.005 [DOI] [PubMed] [Google Scholar]
- 15.TriNetX LLC . TriNetX database. Accessed February 23, 2024. https://trinetx.com/real-world-resources/publications/trinetx-publication-guidelines/
- 16.Markou E, Eleana B, Lazaros T, Antonios K. The influence of sex steroid hormones on gingiva of women. Open Dent J. 2009;3:114-119. doi: 10.2174/1874210600903010114 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Seeland U, Demuth I, Regitz-Zagrosek V, Steinhagen-Thiessen E, König M. Sex differences in arterial wave reflection and the role of exogenous and endogenous sex hormones: results of the Berlin Aging Study II. J Hypertens. 2020;38(6):1040-1046. doi: 10.1097/HJH.0000000000002386 [DOI] [PubMed] [Google Scholar]
- 18.Balan U, Gonsalves N, Jose M, Girish KL. Symptomatic changes of oral mucosa during normal hormonal turnover in healthy young menstruating women. J Contemp Dent Pract. 2012;13(2):178-181. doi: 10.5005/jp-journals-10024-1117 [DOI] [PubMed] [Google Scholar]
- 19.Qin C, Lu Y, Zhang H, et al. Biological roles and clinical significance of estrogen and androgen receptors in head and neck cancers. J Cancer. 2022;13(7):2189-2199. doi: 10.7150/jca.66707 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Välimaa H, Savolainen S, Soukka T, et al. Estrogen receptor-beta is the predominant estrogen receptor subtype in human oral epithelium and salivary glands. J Endocrinol. 2004;180(1):55-62. doi: 10.1677/joe.0.1800055 [DOI] [PubMed] [Google Scholar]
- 21.Kwon S, Ahn SH, Jeong WJ, et al. Estrogen receptor α as a predictive biomarker for survival in human papillomavirus-positive oropharyngeal squamous cell carcinoma. J Transl Med. 2020;18(1):240. doi: 10.1186/s12967-020-02396-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Koenigs MB, Lefranc-Torres A, Bonilla-Velez J, et al. Association of estrogen receptor alpha expression with survival in oropharyngeal cancer following chemoradiation therapy. J Natl Cancer Inst. 2019;111(9):933-942. doi: 10.1093/jnci/djy224 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Doll C, Bestendonk C, Kreutzer K, et al. Prognostic significance of estrogen receptor alpha in oral squamous cell carcinoma. Cancers (Basel). 2021;13(22):5763. doi: 10.3390/cancers13225763 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Grimm M, Biegner T, Teriete P, et al. Estrogen and progesterone hormone receptor expression in oral cavity cancer. Med Oral Patol Oral Cir Bucal. 2016;21(5):e554-e558. doi: 10.4317/medoral.21182 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Thomas C, Gustafsson JA. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer. 2011;11(8):597-608. doi: 10.1038/nrc3093 [DOI] [PubMed] [Google Scholar]
- 26.Orzołek I, Sobieraj J, Domagała-Kulawik J. Estrogens, Cancer and Immunity. Cancers (Basel). 2022;14(9):2265. doi: 10.3390/cancers14092265 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Shulman LP. The state of hormonal contraception today: benefits and risks of hormonal contraceptives: combined estrogen and progestin contraceptives. Am J Obstet Gynecol. 2011;205(4)(suppl):S9-S13. doi: 10.1016/j.ajog.2011.06.057 [DOI] [PubMed] [Google Scholar]
- 28.Cooper DB, Patel P, Mahdy H. Oral Contraceptive Pills. StatPearls; 2023. [PubMed] [Google Scholar]
- 29.Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol. 2005;96(2):95-108. doi: 10.1016/j.jsbmb.2005.02.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc. 2006;81(10):1290-1302. doi: 10.4065/81.10.1290 [DOI] [PubMed] [Google Scholar]
- 31.Anastasiou E, McCarthy KJ, Gollub EL, Ralph L, van de Wijgert JHHM, Jones HE. The relationship between hormonal contraception and cervical dysplasia/cancer controlling for human papillomavirus infection: A systematic review. Contraception. 2022;107:1-9. doi: 10.1016/j.contraception.2021.10.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Asthana S, Busa V, Labani S. Oral contraceptives use and risk of cervical cancer: a systematic review & meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2020;247:163-175. doi: 10.1016/j.ejogrb.2020.02.014 [DOI] [PubMed] [Google Scholar]
- 33.Yuk JS, Kim BY. Relationship between menopausal hormone therapy and oral cancer: a cohort study based on the health insurance database in South Korea. J Clin Med. 2022;11(19):5848. doi: 10.3390/jcm11195848 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Edlefsen KL, Jackson RD, Prentice RL, et al. The effects of postmenopausal hormone therapy on serum estrogen, progesterone, and sex hormone-binding globulin levels in healthy postmenopausal women. Menopause. 2010;17(3):622-629. doi: 10.1097/gme.0b013e3181cb49e9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Lovett JL, Chima MA, Wexler JK, et al. Oral contraceptives cause evolutionarily novel increases in hormone exposure: a risk factor for breast cancer. Evol Med Public Health. 2017;2017(1):97-108. doi: 10.1093/emph/eox009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Maitra R, Malik P, Mukherjee TK. Targeting estrogens and various estrogen-related receptors against non-small cell lung cancers: a perspective. Cancers (Basel). 2022;14(1):80. doi: 10.3390/cancers14010080 [DOI] [PMC free article] [PubMed] [Google Scholar]
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