Periodontitis is a common inflammatory disease characterized by progressive destruction of the periodontal ligament and alveolar bone (1). Globally, the total prevalence of periodontitis has increased by 99.0% (2), and the age-standardized prevalence of severe periodontitis increased by 8.44% from 1990 to 2019 (3). The etiology of periodontitis is multifactorial and various risk factors have been identified, including old age, smoking, and diabetes. Mental disorders, drug abuse, poor dental care, and unhealthy dietary and lifestyle habits are also associated with periodontitis (4). Dynamic interactions between specific bacterial pathogens and the host inflammatory and immune responses are involved in the pathogenesis of periodontitis (5). Clinically, the principle of treating periodontitis is primarily to block the inflammatory process by controlling infection (6). Home care, and scaling and root planing (SRP) are the primary nonsurgical strategies, and regular long-term supportive therapy is crucial for good outcomes (7). If not treated appropriately and/or, in a timely manner, periodontitis may ultimately lead to tooth loss, thus greatly reducing quality of life (7, 8).

Because the periodontium is a target tissue for sex hormones, hormone-related events in females, such as pregnancy and menopause, are also important factors involved in the occurrence and progression of periodontitis (9–11). Perimenopause represents a transitional period of fluctuation(s) in sex hormone levels, indicating the initiation of reproductive senescence (12). Obvious physiological, emotional, and psychological changes occur in women during the perimenopausal period, along with a series of other problematic symptoms (13, 14). Notably, periodontal diseases, including periodontitis, tend to occur during the perimenopausal period because changes in sex hormone levels significantly influence the inflammatory response, bone resorption, and bone mineral density (15, 16). Gil-Montoya et al. reported that moderate or severe periodontitis presents in 52.6% of perimenopausal women, and that low bone mineral density in females > 58 years of age is positively associated with the onset of periodontitis (10). Chandra et al. reported that the perimenopausal-postmenopausal transition leads to an increasing oxidative stress in periodontal tissues and gingival crevicular fluid (GCF) (17). Manual intervention during perimenopause, therefore, is necessary to reduce the risk for periodontitis.

Estrogen and progesterone (PG) are the two most important sex hormones in females. During the normal menstrual cycle, PG physiologically antagonizes the effects of estrogen (18, 19). However, the production of PG is limited due to the absence of corpus luteum in the perimenopausal period (20). Without sufficient PG, estrogen may stimulate endometrial proliferation, leading to endometrial hyperplasia and carcinoma (21). Thus, PG is commonly administered to protect the endometrium in perimenopausal women. Interestingly, evidence has supported multiple roles for PG in the periodontal environment. PG can promote bone formation, exhibiting potential for the prevention and treatment of menopause-related osteoporosis (22). However, PG enhances chronic reactions by acting as an immunosuppressant in gingival tissues, resulting in exaggerated inflammation (23–25). Nevertheless, the specific role of PG in periodontitis among perimenopausal women has rarely been reported.

In the present study, perimenopausal women with periodontitis who were treated with SRP and/or PG (6 months) were enrolled. Differential responses of periodontitis to PG were evaluated in patients who did or did not undergone SRP. The study aimed to reveal the differential effects of routine PG intervention on the progression of periodontitis among perimenopausal women, in the presence or absence of SRP.

PG is a physiological partner of estrogen and is widely administered for a series of indications in females, such as assisted reproductive technology, anovulatory menstrual cycle, contraception during lactation, and postmenopausal endometrial hyperplasia (28). PG is commonly used to antagonize the adverse effects of estrogen (18, 19, 21). In this study, responses of the periodontal environment to PG were evaluated in perimenopausal women with periodontitis. Results demonstrated that a 6-month intervention with PG significantly increased PPD, SBI, and BOP. These results indicate an adverse role of PG in the periodontal environment, which is similar to previous findings in pregnant women. For example, Taani et al. found higher gingival index and PPD in pregnant women with high PG level than in non-pregnant women (29). Raga et al. revealed that decreasing PG after delivery is associated with a reduction in BOP, PPD, and CAL in pregnant women without periodontal treatment (30). Gil et al. reported decreased PG, BOP, and PPD levels in pregnant women after childbirth (31). Potential mechanisms underlying the adverse effects of PG on the periodontium are twofold. First, PG induces the hyperproliferation of periodontal ligament cells, contributing to gingival hyperplasia (32, 33). Second, PG exacerbates inflammation initiated by dental plaque (23). In addition, we found that CAL tended to decrease with PG by the intervention, although the difference was not significant. This phenomenon may be explained by the fact that PG inhibits alveolar bone loss in patients with periodontitis. PG is a “link” between the ovaries and bone in women. More specifically, PG level is positively associated with bone formation and negatively associated with bone resorption in perimenopausal women (34). Therefore, the protective effects of PG on the alveolar bone may offset its adverse effects on the periodontium. In addition, results of this study revealed that the effects of PG on the above periodontal parameters disappeared 6 months after withdrawal of PG. This phenomenon indicates the effects of PG on periodontitis are instantaneous.

SRP is a common nonsurgical strategy to clean subgingival biofilms and is indisputably effective for the treatment of periodontitis (35, 36). In this study, SRP significantly decreased PPD, CAL, SBI, and BOP, demonstrating its efficacy in improving periodontitis in perimenopausal women. Interestingly, we found that CAL and SBI were slightly decreased, and BOP was significantly decreased after 6 months of PG treatment in patients who underwent SRP. These results indicate that PG plays an anti-inflammatory role in the periodontal environment after SRP. These findings are consistent with those of previous studies investigating many other disorders. For example, PG inhibits inflammation, neovascularization, and neurogenesis during endometriosis (37). PG inhibits airway inflammation by synergistically interacting with glucocorticoids (38). PG suppresses inflammation and apoptosis to protect the brain from hypoxic-ischemic damage (39). Notably, the anti-inflammatory effect of PG in the presence of SRP was contrary to its pro-inflammatory effect in the absence of SRP. This difference may be attributed to the status of dental plaque. Dental plaque is a diverse microbial community present on the tooth surface, and its accumulation is a leading risk factor for the onset of periodontitis (40). Wu et al. reported that PG exacerbates periodontal inflammation initiated by dental plaque (23). Therefore, when dental plaque is cleared by SRP, PG may inhibit inflammation. In addition, after SRP treatment, we found a slight elevation in PPD in patients treated with PG, although the difference was not significant. This result is similar to findings in patients who did not undergo SRP and indicates that the promoting effect of PG on gingival hyperplasia persists after SRP.

In the mouth, various immune regulators are involved in the defense response against pathogenic bacteria, including pro-inflammatory cytokines, matrix metalloproteinases, and reactive oxygen species, all of which contribute to periodontal damage (41). IL-6 and TNF-α are common inflammatory cytokines that are elevated in patients with periodontitis (42). Our previous study found that 3 months of PG treatment elevates GCF levels of IL-6 and TNF-α in women with periodontitis (43). Accordingly, this study also revealed that IL-6 and TNF-α levels were increased by 6 months of treatment with PG in patients who did not undergo SRP. As the mainstay of periodontal therapy, SRP is associated with reduced GCF levels of inflammatory cytokines (44). In this study, SRP significantly decreased the GCF levels of IL-6 and TNF-α, which supports the anti-inflammatory effect of SRP in periodontitis. Of note, a significant decrease in IL-6 level and a slight decrease in TNF-α level were induced by PG in patients who underwent SRP. These results indicate that PG exerts an anti-inflammatory effect in the presence of SRP, which is different from its pro-inflammatory effect in the absence of SRP. These findings also support changes in SBI and BOP in patients with periodontitis, demonstrating that PG plays a “double-edged” role in periodontal inflammation by regulating inflammatory cytokines. In addition, CRP is an acute-phase protein produced in response to infection or damage and an inflammatory marker (45). Elevated CRP level is closely associated with the onset of periodontitis (46). Evidence has demonstrated that SRP is effective in reducing CRP level (47), which is consistent with results obtained in this study. In addition, Gil et al. reported that CRP level increases during pregnancy with high PG level, which is positively correlated with BOP (31). Consistent with BOP, CRP level also significantly increased 6 months after PG in patients who did not undergo SRP. In contrast, CRP was slightly decreased by PG in patients who underwent SRP. Therefore, CRP also exhibits different responses to PG in perimenopausal women with periodontitis in the presence or absence of SRP.

SRP relieved periodontitis in perimenopausal women. Intervention with PG instantaneously enhanced periodontal inflammation in the absence of SRP but inhibited it in the presence of SRP. Active SRP is recommended for perimenopausal women with periodontitis, and PG can further enhance the inhibitory effect of SRP on inflammation. However, this study is limited by an insufficient sample size. As such, the mechanisms of action of PG in periodontitis related to dental plaque need to be further explored.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Ethics Committee of Shengli Oilfield Central Hospital (Q/ZXYY-ZY-YWBLL-201819). The patients/participants provided their written informed consent to participate in this study.

Conception and design: SY, YM, FN, and JQ; Data collection: SY, YM, LC, FN, and JQ; Data analysis and interpretation: SY, YM, and JL; Drafting the manuscript: SY and YM; Revising the manuscript critically for important intellectual content: FN and JQ; Funding acquisition: YM; All authors contributed to the article and approved the submitted version.