Role of Sex Hormones in OSCC and Periodontitis: History
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Contributor:
Federica Di Spirito
,
Alessandra Amato
,
Antonio Romano
,
Gianna Dipalma
,
Edit Xhajanka
,
Adone Baroni
,
Rosario Serpico
,
Francesco Inchingolo
,
Maria Contaldo

Sex hormones may also influence gingival microcirculation, thus impacting the spatial progression of periodontitis. The specific role of sex hormones in the onset and prognostic features of oral cancer must also be considered. 

  • gender
  • sex
  • oral cancer
  • periodontitis
  • oral microbiota

1. Oral Cancer

Except for rare non-epithelial tumors [1][2][3], oral squamous cell carcinoma (OSCC) is the central and most common oral malignancy. OSCC is a malignant neoplasia of epithelial origin, of the head and neck district, at the seventh place for worldwide prevalence among cancers [4]. OSCC may arise from potentially malignant oral diseases (OPMDs), which are precursor lesions and conditions with an increased risk of malignancy [5]. Furthermore, OSCC recognizes a series of risk factors—mainly alcohol and/or tobacco consumption [6], betel quid chewing [7], chronic traumatism [8], micronutrient deficiencies [9], and infections [10][11][12][13]—which contribute both to keratinocyte derailment toward cancerogenesis and sustain the related chronic inflammation, posing the ideal environment for tumor growth [14][15][16].
In 2020, the lip and oral cavity cancer incidence counted 264,000 new cases in males (70% of total cases) and 113,000 in females, with a male/female ratio equal to 2.3:1; a prevalence in 5 years of over 656,000 and 303,000 and mortality for over 125,000 and 53,000, respectively. Among them, the cases attributable to alcohol were 67,000 for males and 8200 for women [17].
In 2011, Kruse et al. [18] retrospectively reported clinical and demographic differences between 278 patients (159 males and 119 females) with OSCC followed up meanly for 36 months. While the overall median age was similar in both sexes (61 years for males, 65 years for females), their results revealed a slightly higher proportion of females (54%) over men (46%) in the OSCC patients older than 70 years. Smoking was reported in 76% of males and 51% of females; alcohol in 80% and 48%, respectively; conversely, neither alcohol nor tobacco consumption was reported in 14% of males and 39% of females, who were predominantly affected by maxillary OSCC. Furthermore, clinical stage and metastases still seem sex-independent prognostic factors. However, the literature usually did not often correlate the classical prognostic indicators and main outcome with sex [19], merely considering their distribution by sex but not focusing on the differential predictive meaning they could have in different sexes from a statistical point of view [20][21][22].
More recently, Park et al. [23] compared the prevalence by biological sex of head and neck (HN) cancers in 10 million healthy Korean during a 10-year follow-up. In that period, almost 11,000 subjects developed HN cancers, whose 1698 were oral cancers (84% in males and 16% in females). Additionally, in this case, the gap between males/females decreased over 70 years of age. Among men and women who developed oral cancers, the percentages of never smokers were 31% of males and 95% of females; similarly, non-alcohol consumers were 32% of males and 75% of females; both differences were statistically significant. The authors also discussed the higher prevalence of HN cancers in males, also regardless of smoking and drinking, and addressed this evidence to the role of sex hormones, mainly androgens, as associated with higher risks and poor outcomes in men, contrary to estrogen’s protective effects in females [24][25]. Conversely, further gender-specific differences in OSCC survival could also be related to protective gene polymorphisms for males but not for females, which are significantly associated with smoking, as Nagam et al. reported [26].
Furthermore, biological sex differences in the humoral and cell-mediated immune responses also seem to participate in the differences among biological sex on the onset of oral and HN cancers [27], while the detection of HPV, human papillomavirus, was not always investigated, despite its crucial role in a subset of HN cancers, mainly, but not exclusively, of the pharyngeal region [10]. Hence, a more complex interplay among sexual hormones, sex chromosomes, as well as the immune system and metabolism could differentially contribute to establishing sex-specific tumor microenvironments determining the cancer development in biological males and females [28][29].

2. Periodontitis

Periodontitis is a microbially associated periodontal disease characterized by peculiar chronic host-mediated inflammation, resulting in progressive loss of periodontal attachment, alveolar bone resorption, and teeth loss [30].
In detail, as recently defined by Hajishengallis, “Periodontitis is an exemplar of a microbe-driven chronic inflammatory disease that persists in susceptible individuals, in part due to reciprocally reinforced interactions between the dysbiotic microbiome and the host inflammatory response” [31]. Indeed, periodontitis can manifest in predisposed subjects when specific bacteria trigger local inflammation, which becomes chronic and is responsible for progressive periodontal damage. The bacteria associated with periodontitis are well recognized and Socransky et al. grouped and classified them into color-labeled groups according to their periodontopathogen role [32]. According to this classification, each specific bacterium contributes at different stages and with different weights. First, the early colonizers (green complex) adhere to the dental pellicle. Then, the bridge species (yellow and orange complexes) create favorable local conditions for the co-aggregation between different species. Later, in a mature subgingival dental plaque, the most strongly periodontopathogen species (red complex) are the final and directly responsible for the destruction of the periodontium and the triggering of the inflammatory hyper-reactivity of the susceptible host [32][33].
Incidentally, periodontitis determines consequences not only on periodontal health but also extra-orally, mainly by spilling and dissemination to distant organs of bacteria and bacterial toxins from the gingival pockets via ingestion and bloodstream. These events alter gut permeability and perpetuate chronic extra-oral inflammation, which is responsible for systemic effects [34]. The most robust evidence on the role of periodontitis in aggravating or worsening extra-oral morbidities confirms its association with cardiovascular, metabolic, autoimmune, and neurodegenerative diseases, but also with the cancers and health of pregnant women and their infants [35][36].
Periodontitis is the sixth most prevalent condition worldwide in the adulthood and elderly, and its global prevalence is estimated to be between 20 and 50% [37], affecting over 700 million people [38], greater in men, who also show the worst severe degrees than women [39][40]. In detail, while the male-to-female prevalence rate is 1.3 for mild forms of periodontitis, it doubled for severe and aggressive ones, so 28% and 71% more adult males than females suffer mild and severe forms, respectively [41].
Nevertheless, a recent study from Freitag-Wolf et al. [42] reported an earlier onset of periodontitis in young women than in men. The authors addressed this evidence to what they called “genotype-by-sex (GX S) interactions”, which, according to natural genetic variation, could affect the different heritability of periodontitis among sexes; hence they suggested that genes from maternal inheritance could contribute to intersex phenotypic variation in early onset periodontitis. However, that observation was done in a sample of almost 900 subjects from the European region, and it must be considered that the genetic variability among different geographic areas could lead to contrasting results as for other diseases worldwide.

3. The Role of Sex Hormones

The specific role of sex hormones in the onset and prognostic features of oral cancer must also be considered, both in association and without tobacco and alcohol as risk factors [43]. Two pieces of evidence exist on the role of estrogen associated with OSCC.
On one side, higher estrogen levels—as in women, women under hormone replacement therapy, pregnant, or given birth before 35 years of age—would play a protective role in cancer development, reinforced by the fact that early menopause onset and estrogen lower levels parallel increase the risk of HN cancers [44]. On the other side, some authors convey that estrogen can increase the risk and worsen the prognosis of OSCC [45][46].
Estrogen receptors (ER) are expressed on oral cancer cells and macrophages associated with the proinflammatory tumoral microenvironment, where estrogen may act with opposite results. Indeed, while estrogen–ER interactions on macrophages lead toward a decrease of proinflammatory cytokine release, with protective effects against oral cancer progression [47], they can also positively promote oral cancer cell migration and proliferation [43]. In detail, Colella et al. [48] reported higher expression of ER (ER-a, and ER-b) and lower androgen receptors (AR) in cancer tissue than in healthy tissue close to cancer. Data have been further detailed in a systematic review by Saranya et al. [49], which confirmed that ER presence on tumoral cells influences the OSCC progression [50]. OSCC with positive ER-α expression was mainly associated with HPV-positive tumors [51] and lesser expressed in men than females [52], while, conversely, 40% of OSCC expressed ER-b and only 26% expressed AR, significantly higher in men [53]. Furthermore, ER-α was majorly present in advanced stages with frequent bone invasion and was associated with significantly lower overall and relapse-free survivals than ER-α negative OSCC [52].
For a clearer understanding of the issue, it must be considered that a peculiar clinical variable of OSCC, early OSCC, affects mainly non-smoker/drinking young women under the age of 45 [54][55]. In this cluster, estrogen could play a crucial role in cancerogenesis more than the extrinsic risk factors, such as alcohol and smoking, probably due to the polymorphism of estrogen and its receptors [56].
Sex hormones may also influence gingival microcirculation, thus impacting the spatial progression of periodontitis. Compared with women, men significantly experience higher vasodilatation in case of inflammation or during wound healing, as well as during active phases of periodontitis [57]. Recently, Vag et al. reported significantly higher gingival blood flow and endothelial reactivity of males, both in healthy and periodontal diseases, and higher nitric oxide—with vasodilating effects—release during periodontitis, thus suggesting an increased destructive inflammatory reaction in males with periodontitis [57][58].
Furthermore, peculiar sex-prevalent comorbidities may also influence and be influenced by periodontitis. Osteoporosis exemplifies this bidirectional relationship and the clinical differences between women and men. Osteoporosis is a systemic disease of the skeletal system, characterized by low mineral density and the deterioration of the micro-architecture of the bone tissue, with a consequent increase in bone fragility mainly linked to aging and sexual hormones [59]. As with any bone in the body, it can also affect the alveolar bone, thus accelerating periodontal destruction during co-occurring periodontitis [60]. Despite osteoporosis doubling the risk of periodontitis in both sexes, around the world, osteoporosis is more prevalent in women (mainly of postmenopausal age) than men [60][61]. This epidemiological prevalence in women could explain the strong association between osteoporosis and periodontitis in women.

This entry is adapted from the peer-reviewed paper 10.3390/app12189135

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