Introduction

In the past decade, the focus on women’s health has undergone drastic reformation. Though women and men share comparable health challenges, the metamorphoses are such that the health of women deserves attention. Among the biological systems, endocrines have influenced the overall health, especially with reference to hormones that play an integral molecular role in creating balance between the host and the external environment. Their influence not only reflects on the general body but also displays concerns in the oral cavity. This literature review is structured around the effect of sex hormone fluctuations and its impact on the periodontium, along with therapeutic information concerning different conditions seen during the lifetime of a woman.

Methods

In the current literature review, scientific articles were searched in Google Scholar, Scopus, and PubMed electronic databases until October 2020. The following search terms and their combinations were used: “female sex hormones”, “periodontal health”, “periodontal disease”, “menstrual cycle”, “pregnancy”, “oral contraceptives”, “adverse pregnancy outcomes”, “polycystic ovarian syndrome”, “menopause”, “hormone replacement therapy”, “periodontal management”.

Current State of Knowledge

Female Sex Hormones: Metabolism, Function, Receptors

The anterior pituitary gland, at the time of puberty, begins secreting gonadotropins: follicle-stimulating hormones and the luteinizing hormone, which act on the ovaries to begin cyclical production and secretion of the two main female sex hormones: estrogen and progesterone [1].

The main functions of estrogen are in the development and maintenance of the primary and secondary sex characteristics, uterine growth, and increased bone mineral density, etc. Among the naturally occurring estrogens, the most potent is Estradiol. Its actions are conveyed through certain receptors within the target cell, which have been identified as ERα and ERβ [2].

The other vital female hormone is progesterone. They belong to a group of steroid hormones called progestins. The natural progestins are derived from a 21-carbon saturated steroid hydrocarbon known as pregnane, and like estrogen, they mediate their actions through certain progesterone receptors. Two isoforms of these receptors have been identified in most rodents and humans: PR-A and PR-B [3].

Sex steroid hormone receptors are not ubiquitous but are found at high concentrations in hormone-sensitive tissues, termed target tissues. Cytoplasmic and nuclear receptors that bind specific hormones lead to the preferential accumulation and their retention within these tissues. One of the target tissues is the periodontium with specific estrogen and progesterone receptors present in human gingiva [4, 5].

There is sufficient evidence showing female sex hormones and their metabolic products within the gingival tissues and their ability to produce or modify the gingival response to dental plaque [6, 7, 8•]. Certain enzymatic mechanisms involved in the metabolism of sex hormones have been identified within the gingiva, and the presence of an inflammatory component significantly affects its metabolism. The conversion of estrone to estradiol is three times higher in inflamed tissues, and the metabolism of progesterone is more efficient in a chronically inflamed gingiva. The duration of inflammation also determines the rate of metabolism. Chronic inflammation is shown to have a higher degree of conversion of estrone to estradiol when compared to that of an acutely inflamed tissue due to increase in the number of fibroblasts which are known to contribute greatly to the enzymatic conversion [8•].

Effects of Female Sex Hormones on the Periodontal Tissues

  1. 1.

    Estrogen:

    Estrogen is known to decrease keratinization, increase epithelial glycogen, and alter the polymerization of the ground substance which results in decrease of the effectiveness of the epithelial barrier. Similarly, fibroblast cell proliferation and protein production are also affected.

    Lindhe and Brånemark studied the effect of estrogen on hamster models. The authors observed increased proliferation of blood vessels which provoked disturbances in the plasma-endothelial wall by inducing adhesion between granulocytes, platelets, and endothelium [9, 10].

    Likewise, it influences the immune complex by reducing T-cell–mediated inflammation, inhibiting polymorphonuclear leukocyte chemotaxis, IL6 suppression and has a bimodal action on prostaglandin E2 synthesis.

  2. 2.

    Progesterone

Similar to estrogen, this hormone has the ability to influence the periodontium alone or in combination. They increase vascular permeability, lower the synthesis of glycosaminoglycans, alter the rate and pattern of collagen production and in high concentrations, and downregulate IL6 production. Along with estrogen, it has shown to increase the rate of folate metabolism in the oral mucosa thereby affecting tissue repair and also enhancing the production of prostaglandin E2 [11,12,13].

Hormonal Effects on the Periodontium in Different Age Groups

  1. 1.

    Adolescence

Puberty

Puberty is the period of maturation into adulthood and is associated with changes in the physical appearance and behavior with a major increase in the secretions of the sex steroid hormones. In relation to the periodontium, several changes occur during puberty with an increased prevalence of gingivitis followed by remission. Puberty gingivitis is clinically characterized by exuberant inflammation and gingival overgrowth which may be associated with gingival bleeding. Interestingly, gingival inflammation may not be consistent with the plaque levels, rather may be closely related to the fluctuations in the hormonal levels [14, 15].

However, this concept was contradicted as per the study that showed the influence of oral hygiene on the gingival condition of pubertal children was more beneficial than the rising level of steroid hormones [16]. The microbial changes seen during this age are the result of the responses of the gingival tissue to the sex hormones that alter its microenvironment along with the ability of certain species of bacteria to capitalize on the higher concentration of the hormones present as described in Table 1 [17, 18•, 19].

Table 1 Studies describing the microbiological changes seen during puberty
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The Menstrual Cycle

The menstrual or reproductive cycle is characterized by the onset of increased production and secretion of estrogen and progesterone in a cyclic pattern coincident with the onset of puberty. Significant gingival inflammatory changes have been documented and are aggravated by an imbalance in the sex hormones. Mühlemann presented a “gingivitis intermenstrualis” which was characterized by bright red hemorrhagic lesions of the interdental papilla developed prior to the menstrual period [20]. Gingival changes including variations in the gingival crevicular fluid (GCF) flow during menstruation are mostly attributed to those with pre-existing gingivitis compared to that of a healthy gingiva [21, 22]. Additionally, inflammatory cytokines like interleukin 1β (IL1β) levels were also reported to have significant changes, i.e., steady increase in the GCF from the day of menstruation to the peak progesterone day. This may be explained by the contribution of progesterone to stimulate the inflammatory cells to express more IL1β [23•]. Other inflammatory cytokines like IL6 and tumor necrosis factor alpha may also contribute to the inflammatory changes seen in the gingiva during the menstrual cycle.

  1. 2.

    Womanhood

Pregnancy

Estrogen and progesterone are the predominant pregnancy hormones. During this fascinating phase, the periodontium may cater to pathological conditions like gingivitis, pregnancy granuloma, periodontitis, and dental caries. Pregnancy gingivitis is prevalent in approximately 35% to 100% woman which may be non-specific, vascularizing, and proliferative inflammation with increased cell infiltration that begins to appear in the 2nd month of pregnancy and continues till the 8th month with maximum effect seen between the 1st and 2nd trimester [24, 25]. Another common oral finding is tooth mobility including alterations in probing depth which seemed to increase as a result of edema or the hyperplastic changes of the gingiva [26]. Furthermore, microbial alterations have been noticed in both supra- and subgingival environment which has been described in Table 2 [27, 28•, 29]. Reports have also stated some important immune-modulators like T-lymphocytes are also affected during pregnancy [28•, 29, 30]. Accumulation of active hormone within the gingival tissue and its increased levels are immunosuppressive, preventing acute inflammatory reaction to plaque. Thus, a chronic type of inflammatory reaction occurs, resulting in an exaggerated appearance of gingival inflammation. The combined effects of the immunosuppressive actions of progesterone, its increased levels in the gingiva, and the microbial action contribute to the periodontal disease state during pregnancy. An inflammatory gingival lesion, “pyogenic granuloma” synonym “pregnancy tumor,” and/or “epulis gravidarum” may appear during the 1st or 2nd trimester. It is clinically and histologically similar to any pyogenic granuloma, but the initiation of this proliferative lesion is due to a combination of factors such as plaque, altered hormonal balance or trauma. The cause could be attributed to the general effects of progesterone and estrogen on the immune system, gingival vasculature, and ability of progesterone to inhibit collagenase. The lesion either regresses or develops into a residual fibrous mass postpartum. But some of them may be painful, continue to bleed or suppurate, and might interfere with mastication. The following case describes a gingival lesion developed during the 2nd trimester of pregnancy.

Table 2 Studies describing the microbiological changes seen during pregnancy
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Case Report

A 31-year-old female patient, reported to the Department of Periodontology with a chief complaint of a swelling in the maxillary anterior region, which interfered with mastication, speech, and esthetics. The swelling gradually increased in size over the period of 4 months and was associated with bleeding on brushing. Intra-oral examination revealed an ovoid sessile gingival overgrowth measuring 11 × 8 mm, which extended onto the buccal gingiva in relation to left lateral incisor and canine. The surface appeared red, smooth with no ulcerations. Oral hygiene was graded as fair (Fig. 1).

Fig. 1
figure 1

Reddish ovoid overgrowth in relation to left lateral incisor and canine region

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Non-surgical periodontal therapy was initiated to eliminate the inflammatory component. Following parturition, the lesion persisted; therefore, complete excision was carried out under local anesthesia. The histopathologic examination revealed, “Pyogenic granuloma”. Hematoxylin and eosin–stained section showed para-keratinized stratified squamous epithelium with endothelial lined vascular spaces seen within the epithelium. Connective tissue showed bundles of collagen fibers, numerous endothelial lined vascular spaces, proliferating endothelial cells, infiltrate of chronic inflammatory cells, and few areas of dystrophic calcification (Fig. 2). Post-operative visit 1 month after the excision showed good wound healing and improvement in function and esthetics (Fig. 3).

Fig. 2
figure 2

H&E-stained specimen revealed para-keratinized epithelium with inflammatory cell infiltrate in the connective tissue suggestive of pyogenic granuloma

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Fig. 3
figure 3

Post-operative view 1 month after excision

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Adverse Pregnancy Outcomes

Adverse pregnancy outcomes are those complications that occur rather than normal live birth, namely preterm birth, stillbirth, low birth weight, and preeclampsia. In pregnancy, immune response plays a vital role in maintaining a healthy equilibrium between mother and fetus. There is a shift in the specific immune response towards a Th2 type as well as activation of the inflammatory cascade during normal pregnancy. An exacerbation of this inflammatory response may lead to adverse outcomes. A correlation between periodontitis and the birth of preterm low-birth-weight (PLBW) infants has been identified where patients with clinical evidence of periodontitis were 7.5 times more likely to have PLBW infants than the control [31]. The proposed theory stated that periodontal infections serve as reservoirs for gram-negative anaerobic organisms and inflammatory mediators which might pose a threat to the fetal-placental unit through hematogenous transmission. Women with PLBW demonstrate worse periodontal parameters and significantly higher GCF levels of IL6, PGE2 and tumor necrosis factor alpha compared to women with full-term birth infants [32]. Periodontitis may also contribute to overall increase of contractions, in turn resulting in pre-term labor onset. However, a recent systematic review and meta-analysis failed to confirm if periodontal disease was an independent risk factor for these adverse pregnancy outcomes [33•]. The evidence that does state the correlation between periodontal disease and adverse pregnancy outcomes justifies the need for non-surgical periodontal therapy in pregnant women to prevent such complications. Contradictorily, a study reported that even though nonsurgical periodontal therapy during pregnancy improved periodontal clinical parameters and decreased periodontal inflammatory biomarker levels, it did not influence inflammatory biomarker level from cord blood nor consistently reduced preterm birth or low birth weight occurrence [34•]. Another common adverse pregnancy outcome that has been associated with periodontal disease is preeclampsia which clinically manifests as hypertension and proteinuria and is usually seen during the 2nd trimester. Since periodontal disease is a multi-factorial condition with low-grade chronic inflammation, it can be hypothesized that patients with periodontal disease have an increased risk of developing preeclampsia. Severe preeclamptic women were 3.78 times more likely to present periodontal diseases, and the elevated levels of pro-inflammatory cytokines like PGE2, tumor necrosis factor alpha, and IL1β in the GCF and serum were consistent with the worsening preeclamptic state [35•].

Acute phase proteins like C-reactive proteins which are seen to increase in chronic periodontitis have shown to manifest preeclamptic complications in pregnant women. Even though periodontal therapy during pregnancy generally demonstrates a positive impact on periodontal disease, its impact on various pregnancy outcomes is conflicting. Thus, there is a need to evaluate novel strategies of preventive and therapeutic approaches at early stages of pregnancy to prevent adverse outcomes.

Oral Contraceptives

Oral contraceptives are among the most widely used classes of drugs in the world today. In the early sixties, the concentrations of estrogen in the oral contraceptives were high resulting in multiple systemic side effects like cardiovascular disorders and malignancy. Therefore, currently, the concentrations of the hormone have been greatly reduced and consist of low doses of estrogens (0.05 mg/day) and/or progestins (1.5 mg/day); {1 mg norethisterone acetate + 0.05 mg ethinylestradiol/mestranol}. The effects of estrogen and progesterone on the periodontium are enhanced during oral contraceptive therapy. Early studies on the effect of oral contraceptives on the periodontium have shown increased gingival exudate, hyperplastic gingivitis, and marked gingival inflammation [36, 37]. The changes on the gingival tissues not only were dependent on the dosage but also the duration of use and are cumulative with time [38]. Oral contraceptives also tend to influence the subgingival microflora and certain Candida species which were able to survive the conditions created by the sex hormones even after 3 years of consumption of the drugs [39]. The gingiva was not the only structure to be affected by these drugs but also the underlying alveolar bone. Along with the gingiva being affected, a stimulatory effect on bone metabolism was identified with decreasing serum levels of bone biomarkers like alkaline phosphatase and higher mean bone mineral density especially with long-term use of oral contraceptives [40, 41]. Thus, suggesting women on long-term oral contraceptives tend to have a lower risk of osteoporosis.

The presence of inflammatory changes in gingival tissues due to oral contraceptives noted in early studies is in contrast to current findings of a lack of gingival inflammation in women using present-day oral contraceptive formulations [42•, 43]. However, gingival tissues may have an exaggerated response to local irritants.

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common specific metabolic syndrome affecting 6.5–8% of women of reproductive age according to the National Institutes of Health criteria; women with PCOS have increased prevalence of insulin resistance, central obesity, dyslipidemia, and cardiovascular risk factors. Periodontal disease has also been associated with these systemic conditions. High levels of oxidative stress and inflammatory cytokines like IL6 and C-reactive protein have been identified in both PCOS and periodontal disease, and this might be suggestive of a common pathophysiological mechanism for both these conditions. PCOS and gingival inflammation appear to act in a synergistic manner by increasing the expression of proinflammatory cytokines IL6, IL17, and tumor necrosis factor alpha, and PCOS may have an impact on gingival inflammation and vice versa [44]. But periodontal breakdown and inflammation may be dependent on systemic inflammation [45]. PCOS may affect the composition of the oral microflora and modify the systemic antibody responses and thus potentiating the interaction between the oral microorganisms and gingival inflammation [46]. Considering oxidative stress conditions, both chronic periodontitis and PCOS result in an increase in serum levels of oxidative products and reduced antioxidant status suggesting a link between the two [47•]. A positive correlation between PCOS and periodontal disease has been established and that females with PCOS are at a higher risk of developing periodontitis.

  1. 3.

    Geriatrics

Menopause and its Effects

Menopause is the natural cessation of a woman’s menstrual cycle usually seen between the ages of 45–55 years of age and marks the end of fertility. Due to the declining ovarian function, the changes seen in the oral cavity during menopause is in contrast to the one seen during pregnancy. Oral disturbances are not a common feature of menopause, but few women do suffer from certain conditions like menopausal gingivostomatitis. It is characterized by dry and shiny oral mucosa and gingiva which may appear abnormally pale or bright red with a tendency to bleed easily [48]. More commonly reported gingival changes seen in women of this age are desquamative in nature and are characterized by a smooth and polished gingival surface, mottled appearance. But it is difficult to link sex hormones to its pathogenesis because of its multifactorial etiologies.

Osteoporosis and Menopause

The most common finding seen during the menopausal phase is the increased tendency towards the development of osteoporosis. Reduced levels of estrogen affects the overall collagen metabolism and bone maintenance. Thirty-three percent of the women over the age of 60 years have postmenopausal osteoporosis which includes reduced bone mass, density, and strength and are at a high risk of fractures. Cross-sectional studies have demonstrated decreased bone mass, density, and mineral content in post-menopausal women with the mandible being more affected than maxilla and show proportionality with age [49, 50]. Post-menopausal women are at a higher risk of developing osteoporosis and therefore may also be susceptible to periodontal disease, but the correlation between the two is controversial. Evidence have shown a positive correlation between osteoporosis and periodontal disease in the form of clinical attachment loss, alveolar crest height loss, and tooth loss [51, 52]. Studies linking osteoporosis and periodontal disease are described in Table 3 [53,54,55, 56•, 57]. Despite many studies that display positive correlation between the two conditions, there are a few which states otherwise, especially in terms of bone mineral density and clinical attachment levels [56•, 58]. The possible mechanisms linking osteoporosis and periodontal disease have been discussed. The reduced systemic bone mineral density due to decreased estrogen levels may be associated with the low bone mineral density in the alveolar bones leading to accelerated bone loss following an insult by the periodontopathogenic microorganisms. The second hypothesis is the systemic release of pro-inflammatory cytokines like IL1 and IL6 in response to the skeletal bone loss which may modify the local tissue response to periodontal pathogen [59•]. Although there are a number of studies associating postmenopausal osteoporosis with periodontal disease, the exact cause-effect relationship is yet to be determined [53,54,55, 56•, 57, 58, 59•, 60].

Table 3 Studies correlating osteoporosis with periodontal disease in postmenopausal women
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Periodontal Management of the Female Patient

During Puberty

As mentioned previously, sex hormones tend to alter the periodontium during puberty with an exaggerated inflammatory response seen at sites with increased plaque or calculus deposits. Patient or parent education on the periodontal changes during puberty is an important aspect in its management. Preventive care, motivation, and rigorous oral hygiene maintenance form the basis of management of oral changes. Professional periodontal debridement along with frequent oral hygiene reinforcement could be done for managing mild cases of puberty gingivitis. Severe cases are dealt with antimicrobial mouthrinse or local delivery of antiseptic based on the microbial culture analysis [61•]. Depending on the risk of periodontal disease progression, recalls for maintenance should be more frequent. In subjects with hyperplastic gingiva, the inflammatory component can be removed by scaling and root planing, but the fibrotic tissue requires a surgical procedure, i.e. gingivectomy, which can be achieved using scalpel or lasers.

During Menstrual Cycle

The fluctuating levels of sex hormones during the menstrual cycle induce some changes in the periodontal tissues especially those with pre-existing gingivitis. Conventional non-surgical periodontal therapy is usually the mode of treatment for menstrual gingivitis along with reinforced training of oral hygiene measures. For patients with severe periodontal inflammation and tenderness, the frequency of periodontal recall should be 3–4 months [61•]. Some women also experience premenstrual syndrome which consists of various physical and emotional symptoms that may contribute to an exaggerated response to pain. Hence, the clinician may schedule the appointments for periodontal procedures, post menstrual cycle. Other conditions seen during this phase are recurrent aphthous ulcers, increased gag reflex, and other gastrointestinal symptoms. Most of the symptoms are self-limiting and resolves once the cycle begins.

During Pregnancy

The periodontal management for pregnant women should be multidisciplinary. Thorough medical history which includes previous pregnancy complications should be taken and proper diagnosis and treatment planning should be discussed with the patient’s obstetrician. The main goals of treatment in a pregnant patient are to establish and maintain an optimal oral environment. Patient education about the increased tendency of gingival inflammation should be explained. Appropriate oral hygiene instructions should be reinforced, maintained, and monitored throughout pregnancy. In the 1st trimester, the focus is on full clinical periodontal examination and to understand the susceptibility to periodontal disease. Only emergency dental procedures are recommended during this phase, and all elective procedures are avoided as far as possible. Therapy in the 2nd trimester is aimed at controlling active disease and eliminating potential problems. Periodontal debridement should be performed at this stage including severe cases of pregnancy granuloma which is treated by surgical excision extending down to the periosteum to prevent recurrence. This has been described in the above case report. Other treatment modalities like use of diode laser, flash lamp pulsed dye laser, cryosurgery, intralesional injection of ethanol or corticosteroids, and sodium tetradecyl sulfate sclerotherapy have also been proposed [62•, 63]. Routine dental procedures can be done during the early phase of the 3rd trimester, but the most challenging and extensive surgical procedures should be done after delivery. A periodontal maintenance visit should be performed during the early- to mid-3rd trimester due to increased gingival inflammation at that time. The clinician should be aware of the risk category for each drug before prescribing it to a pregnant patient. Thorough knowledge of the medical history, the phase of pregnancy, and the pharmacological agents aids in formulating a treatment plan for managing periodontal diseases during pregnancy.

During Menopause

In contrast to pregnancy, the oral changes seen in menopause are relatively low. But one of the more common diseases seen at this age is osteoporosis. It may be a contributing factor in aggravating pre-existing periodontitis. Periodic review and update of medical history and oral status are essential for such patients. The gold standard for the prevention of severe osteoporosis in osteopenic postmenopausal women is hormone replacement therapy (HRT). The hormone replacements available now contain micronized 17β-estradiol including the standard conjugated equine estrogens and synthetic ethinylestrogens. The progestins that may be used in combination include the older nor-testosterone derivatives like nor-ethisterone acetate, progesterone derivatives like medroxyprogesterone acetate or the newer ones like levonorgestrel and micronized progesterone [64]. The use of HRT has been studied widely and is not only known to reduce the risk of osteoporosis and myocardial infarction and even delay the onset of Alzheimer’s disease, but it also affects the periodontium. Postmenopausal women not taking HRT are 2.1 times more likely to have periodontitis than premenopausal women [65]. Women with early menopause are more likely to develop osteoporosis due to a longer period of estrogen deficiency, and HRT could be more beneficial to such women. Adverse effects have been reported with HRT use such as thromboembolism, coronary artery disease, and breast and endometrial cancer and are highly related to the drugs, dosage, route of administration, and the duration and frequency of use. Therefore, HRT is customized to each individual after analysing the risks and benefits. A newer alternative to HRT called phytoestrogens, a group of plant-based aromatic sterol, has been introduced. They are classified into four main classes: isoflavones, lignans, coumestans, and stilbenes out of which the isoflavones and lignans are the most common. Phytoestrogens have shown lower incidences of menopausal symptoms and osteoporosis in women. They have also shown to affect the periodontal tissues through their antioxidant and estrogenic actions especially on the alveolar bone [66, 67]. Although phytoestrogens may affect the periodontal tissues, more long-term studies are required to analyze its benefits. Other drugs used to treat post-menopausal osteoporosis are bisphosphonates. They inhibit bone resorption by inducing osteoclast apoptosis and cell death and inhibit calcification and hydroxyapatite breakdown. Their ability to inhibit proinflammatory cytokines and modify bone turnover has made them a successful adjunct to mechanical debridement in the management of periodontal disease [68]. In postmenopausal women, bisphosphonates have shown positive results in the improvement of soft and hard tissue periodontal parameters independent of oral hygiene. They can also be considered prior to placing dental implants because they positively affect the quality and quantity of the cortical bone [69]. One of the major side effects involved in the long-term use of bisphosphonates is the risk of developing osteoradionecrosis of the jaw. But long-term clinical trials are necessary to assess its possible occurrence from adjunctive bisphosphonate therapy in periodontal disease. Osteoporosis in post-menopausal women is also associated with decreased calcium absorption and increased excretion and thereby increases the daily calcium requirement. To reduce the progression as well as the risk of future osteoporosis, vitamin D and calcium intake is an important factor. The recommendations for calcium are 1000 mg for premenopausal women and 1500 mg for post-menopausal women. For vitamin D, the doses recommended are 400 IU/day for premenopausal women and 800 IU/day for postmenopausal women. When vitamin D and calcium supplements were added as an adjunct to non-surgical periodontal therapy, women had 44% lesser prevalence of severe periodontitis [70•]. Therefore, calcium and Vitamin D supplements can be considered in managing periodontal disease in post-menopausal women especially in those with a risk of osteoporosis.

Conclusion

The complexities of the female patient are unique to each phase of her life. Female sex hormones play a crucial role, and their cyclic nature is often reflected on the periodontal structures. Substantial evidence collected in this narrative review reflects on the actions of female sex hormones on the periodontium. Although every patient differs, the dental professional should have sound knowledge and understanding of the mechanisms involved that link periodontal disease and female hormone fluctuations. These alterations in the levels of the hormones usually aggravate a pre-existing gingival or periodontal condition. Thus, it becomes important to educate patients about these changes and reinforce proper oral hygiene and maintenance. The management of female patients during various stages of life varies from individual to individual. Patient education, prevention, and oral hygiene care and maintenance form the basis of treating female patients.