Journal of the International Clinical Dental Research Organization

REVIEW ARTICLE
Year
: 2018  |  Volume : 10  |  Issue : 1  |  Page : 3--11

Ascendancy of sex hormones on periodontium during reproductive life cycle of women


Ashutosh Nirola, Priyanka Batra, Jaspreet Kaur 
 Department of Periodontology and Oral Implantology, Luxmi Bai Institute of Dental Sciences and Hospital, Patiala, Punjab, India

Correspondence Address:
Dr. Ashutosh Nirola
Department of Periodontology and Oral Implantology, Luxmi Bai Institute of Dental Sciences and Hospital, Patiala - 147 001, Punjab
India

Abstract

Throughout the reproductive life cycle of women, fluctuating levels of sex hormones during puberty, menses, pregnancy, and menopause have direct and indirect effects on oral health and they also influence their susceptibility to periodontal disease. These physiological conditions are associated with an exaggerated inflammatory response without accompanying an increased plaque level. Changes in hormone levels also lead to alteration in the subgingival microflora, epithelial keratinization, decreased salivary flow, altered gingival crevicular fluid, effects on specific cells of periodontium and local immune system, burning sensation, halitosis, interproximal alveolar bone loss, and to a lesser extent, clinical attachment loss. The presence of maternal periodontitis has been associated with adverse pregnancy outcomes, such as preterm birth, preeclampsia, gestational diabetes, delivery of a small-for-gestational age infant, and fetal loss. The strength of these associations ranges from a 2–7-fold increase in risk. The increased risks suggested that periodontitis might be an independent risk factor for adverse pregnancy outcomes. Thus, the female body has a series of reaction to the hormonal changes seen within. Improper oral hygiene and hormonal imbalance seen during different life cycles of female patients exaggerate the oral tissue response to the plaque and other local factors, thus worsening the condition. Prevention is better than cure; hence, necessary precautions need to be taken at the earliest once the condition of the patient is known.



How to cite this article:
Nirola A, Batra P, Kaur J. Ascendancy of sex hormones on periodontium during reproductive life cycle of women.J Int Clin Dent Res Organ 2018;10:3-11


How to cite this URL:
Nirola A, Batra P, Kaur J. Ascendancy of sex hormones on periodontium during reproductive life cycle of women. J Int Clin Dent Res Organ [serial online] 2018 [cited 2018 Dec 17 ];10:3-11
Available from: http://www.jicdro.org/text.asp?2018/10/1/3/236094


Full Text



 Introduction



The homeostasis of the periodontium involves complex multifactorial relationships, in which the endocrine system plays an important role.[1] Fluctuating levels of sex hormones during puberty, menses, pregnancy, and menopause have direct and indirect effects on oral health and they also influence their susceptibility to periodontal disease.[2] Steroid sex hormones (androgens, estrogens, and progesterone) show effects on cellular growth, proliferation, and differentiation in target tissues including keratinocytes and fibroblasts in the gingiva.[1]

The present study discusses the effect of hormones on oral tissue in health and disease in women during puberty, menstruation, pregnancy, and menopause.

 Sex Steroid Hormone Physiology



Androgens

In women, the major plasma androgen is androstenedione (androst-4-ene-3,17-dione), which can be secreted into the bloodstream or converted into either testosterone or estradiol by the ovary [Figure 1].[3],[4]{Figure 1}

Estrogens

Estradiol is the most potent estrogen and is secreted by the ovary, testis, placenta, as well as peripheral tissues. Estrone is also secreted by the ovary; however, the principal source in both women and men is through extragonadal conversion of androstenedione in peripheral tissues [Figure 1]. In premenopausal women, the most abundant physiological estrogen is estradiol, and in men and postmenopausal women, the most abundant estrogen in the plasma is estrone.[3],[4]

Progestins

The natural progestins, or steroids that have progestational activity, are derived from a 21-carbon saturated steroid hydrocarbon known as pregnane. Corticosteroids are also derived from pregnane but differ from progestins because they contain an α-ketol group at C-17 and a ketone or hydroxy group at C-11 [Figure 1]. The principal progestational hormone secreted into the bloodstream is progesterone (pregn-4-ene-3,20-dione), which is synthesized and secreted by the corpus luteum, placenta, and adrenal cortex. The biological activities of progestins are principally observed during the luteal phase of the menstrual cycle and pregnancy.[3],[4]

 Mechanism of Action of Sex Steroid Hormones



When the steroid hormone is bound to the receptor, it transforms the receptor to an active configuration, and the activated receptor–steroid hormone complex binds with high affinity to specific nuclear sites (e.g., discrete DNA sequences, nuclear matrix, nonhistone proteins, and nuclear membrane). The activation step of this process may occur in the cytoplasm or the nucleus. Once the receptor–hormone complex is bound to nuclear regulatory elements, gene activation and transcription of messenger RNA occurs. Following the nuclear interaction, the receptor–hormone complex disassociates, leaving an unoccupied receptor and the steroid hormone [Figure 2].[4]{Figure 2}

 Effect of Sex Hormones on Periodontium



Sex steroid hormones exert considerable influence, both directly and indirectly, on cellular differentiation, proliferation, and growth in target tissues. In the oral cavity, androgens, estrogens, and progestins are known to affect several cell types. Sex steroid hormone research has focused primarily on two cell groups, the keratinocyte and the fibroblast. There are two theories for the actions of the hormones on these cells:

Change of the effectiveness of the epithelial barrier to bacterial insultEffect on collagen maintenance and repair.[5]

 Effects of Androgens (Testosterone) on Periodontal Tissues



Testosterone receptors are found in the periodontal tissues, and the number of receptors on fibroblasts tends to increase in inflamed or overgrown gingiva, where testosterone has an effect on periodontal tissues by increasing matrix synthesis. It has inhibitory effects on the cyclooxygenase pathway of arachidonic acid metabolism in the gingiva by inhibiting prostaglandin secretion. The various effects of androgen on periodontal tissue are as follows:

Inhibits prostaglandin secretionEnhances osteoblast proliferation and differentiationReduces interleukin-6 production during inflammationEnhances matrix synthesis by periodontal ligament (PDL) fibroblasts and osteoblasts.

 Effects of Estrogen on the Periodontal Tissues



Estrogen has significant biological actions on the oral cavity [Figure 3]. Receptors for estrogen have been demonstrated in the gingiva, periosteal fibroblasts, scattered fibroblasts of the lamina propria, and also PDL fibroblasts and osteoblasts. The effects of estrogen on the periodontium are as follows:{Figure 3}

Decreases keratinization while increasing epithelial glycogen that results in the diminution in the effectiveness of the epithelial barrierIncreases cellular (erythrocytes, granulocytes, platelets, and mast cells) proliferation in blood vesselsStimulates polymorphonuclear leukocyte (PMNL) phagocytosisInhibits PMNL chemotaxisSuppresses leukocyte production from the bone marrowInhibits proinflammatory cytokines released by human marrow cellsReduces T-cell-mediated inflammationStimulates the proliferation of the gingival fibroblastsStimulates the synthesis and maturation of gingival connective tissuesIncreases the amount of gingival inflammation with no increase of plaque.[1]

 Effects of Progesterone on the Periodontal Tissues



Progesterone is secreted by the corpus luteum, placenta, and adrenal cortex and is active in bone metabolism and has significant effect in the coupling of bone resorption and bone formation by engaging osteoblast receptors directly. The effects of progesterone on periodontal tissues are as follows [Figure 3]:

Increases vascular dilatation, thus increasing permeabilityIncreases the production of prostaglandinsIncreases PMNLs and prostaglandin E2 in the gingival crevicular fluid (GCF)Reduces glucocorticoid anti-inflammatory effectInhibits collagen and noncollagen synthesis in PDL fibroblastInhibits proliferation of human gingival fibroblast proliferationAlters rate and pattern of collagen production in gingiva, resulting in reduced repair and maintenance potentialIncreases the metabolic breakdown of folate which is necessary for tissue maintenance and repair.[1]

 Influence on Periodontium During Puberty



A peak prevalence of gingivitis has been determined at 12 years, 10 months in females and 13 years, 7 months in males, which is consistent with the onset of puberty. There is a higher incidence of black-pigmented Bacteroides and higher populations of other Gram-negative rods in the subgingival microflora compared with healthy sulci in puberty. The alteration in the subgingival microflora includes the presence of Prevotella intermedia, which can substitute estrogen and progesterone for Vitamin K, an essential bacterial growth factor, spirochetes, Capnocytophaga sp., Actinomyces sp., and Eikenella corrodens. Capnocytophaga species have been associated with a tendency toward increased bleeding.[5]

The characteristics of puberty-associated gingivitis include:

Plaque present at gingival marginPronounced inflammatory response of gingivaMust be circumpubertal as designated by Tanner Stage 2[6] or greater (girls, estradiol ≥26 pmol/L; boys, testosterone ≥8.7 nmol/L)Change in gingival colorChange in gingival contour with possible modification of gingival sizeIncreased gingival exudatesBleeding upon provocationAbsence of attachment lossAbsence of bone lossReversible following puberty.[7]

 Influence on Periodontium During Menstruation



Muhlemann was the first to report on gingival changes during the menstrual cycle, and coined the term “gingivitis intermenstrualis” to describe a condition of bright red, hemorrhagic lesions in the interdental papilla.[8]

During the menstrual cycle, progesterone peaks at approximately 10 days (increases from the 2nd week) and drops before menstruation. Progesterone has been associated with increased permeability of the microvasculature, alters the rate and pattern of collagen production in the gingiva, increases folate metabolism, stimulates the production of prostaglandins, and enhances the chemotaxis of PMNLs.[1]

The characteristics of menstrual cycle-associated gingivitis are as follows:

Plaque present at gingival marginModest inflammatory response of gingiva before ovulationMust be at ovulatory surge when luteinizing hormone levels are >25 mLU/mL and/or estradiol levels are >200 pg/mLIncrease in gingival exudates by at least 20% during ovulationAbsence of attachment lossAbsence of bone lossReversible following ovulation.[6]

Other complaints seen during menstruation are as follows:

Burning sensation in the oral cavityProlonged hemorrhage following oral surgerySwollen salivary glandsActivation of herpes labialis and oral aphthous ulcersInfections with Candida albicansEstrogen levels have been implicated in menstrual cycle-associated mood changes which have in turn been linked with increased susceptibility to major depression.[8]

 Influence on Periodontium During Pregnancy



During pregnancy, both progesterone and estrogen are elevated due to continuous production of these hormones by the corpus luteum. By the end of the third trimester, progesterone and estrogen reach peak plasma levels of 100 and 6 ng/mL, respectively, which represent 10 and 30 times the levels observed during the menstrual cycle.[9]

The relationship between pregnancy and periodontal inflammation is known since long. In 1788, Vermeeren discussed “tooth pains” in pregnancy. In 1818, Picarin described gingival hyperplasia in pregnancy. In 1877, Pinard recorded the first case of “pregnancy gingivitis.”[10]

Susceptibility to infections (e.g., periodontal infection) increases during early gestation due to alterations in the immune system and can be explained by the hormonal changes observed during pregnancy, suppression on T-cell activity, decreased neutrophil chemotaxis and phagocytosis, altered lymphocyte response and depressed antibody production, chronic maternal stress, and even nutritional deficiency associated with increased nutritional demand by both the mother and the fetus.[9]

The clinical and microbial changes in the periodontal tissues during pregnancy are as follows:

Increased gingival probing depthsIncreased gingival inflammationIncreased GCF flowIncreased bleeding upon probingIncreased tooth mobilityIncreased incidence of pyogenic granulomasIncreased number of periodontopathogens, especially P. gingivalis and P. intermedia.[6]

The characteristics of pregnancy-associated gingivitis are as follows:

Plaque present at gingival marginPronounced inflammatory response of gingivalOnset in pregnant women (second and third trimester)Change in gingival colorChange in gingival contourIncrease in gingival exudatesBleeding upon provocationAbsence of attachment lossAbsence of bone lossReversible at parturition.[6]

The characteristics of pregnancy-associated pyogenic granuloma/pregnancy tumor/granuloma gravidarum/epulis gravidarum are as follows:

Plaque present at gingival marginPronounced inflammatory response of gingivalCan occur anytime during pregnancyMore common in maxillaMore common interproximallySessile or pedunculated protuberant massNot a neoplasm, has histologic appearance of a pyogenic granulomaRegresses following parturition.[6]

Periodontal infection is one of many infections that have been associated with adverse pregnancy outcomes. Recent research suggests that the presence of maternal periodontitis has been associated with adverse pregnancy outcomes, such as preterm birth, preeclampsia, gestational diabetes, delivery of a small-for-gestational-age infant, and fetal loss. The strength of these associations ranges from a 2–7-fold increase in risk. The increased risks suggest that periodontitis may be an independent risk factor for adverse pregnancy outcomes.[11]

 Influence on Periodontium During Menopause



In the menopause stage, the estrogen levels decline rapidly and lead to systemic bone loss. Estrogen deficiency leads to upregulation of immune cells (macrophages and monocytes) and osteoclasts, which are responsible for a greater production of bone-resorbing cytokines. Lipopolysaccharide-released by-products related to periodontal tissues and bacterial plaque biofilm stimulate the production of inflammatory cytokines, which further activates the osteoclasts that resorb the bone [12] [Figure 4].{Figure 4}

Oral manifestations at menopause

Oral discomfort

PainBurning sensationModification of the gustatory sensations (salty, hot, and sour)Xerostomia

Modifications of the oral mucous membrane

Gingival atrophyMenopause gingivostomatitis

Other symptoms

Lichen planusNeurological disordersEating disorders

Osteoporosis

Accelerated bone atrophySevere osteoporosis-rapid loss of teeth and atrophy of the residual edentulous ridgeMay affect the severity of the preexisting periodontopathy.[13]

Management

Throughout a woman's life cycle, hormonal influences affect therapeutic decision-making in periodontics. Historically, therapies have been gender biased. However, the advents of new research have provided keener appreciation of the unique systemic influences on oral, periodontal, and implant tissues. Oral health-care professionals have greater awareness of, and better capabilities for dealing with, hormonal influences associated with the reproductive process. Periodontal and oral tissue responses may be altered, creating diagnostic and therapeutic dilemmas. Therefore, it is imperative that the clinician recognize, customize, and appropriately alter periodontal therapy according to the individual woman's needs based on the stage of her life cycle [Table 1] and [Table 2].[14],[15]{Table 1}{Table 2}

Management during menopause

If the patient is susceptible to osteoporosis, the dentist should consult the patient's physician as to the risks versus benefits of hormone replacement therapy (HRT)/estrogen replacement therapy and calcium/Vitamin D supplementation for the individual patient.

The National Institutes of Health (1994 Conference on Optimal Calcium Intake) recommends as follows:[14]

Premenopausal women (25–50 years old), 1000 mg/dayPostmenopausal women (estrogen therapy), 1000 mg/dayPostmenopausal women (no estrogen therapy), 1500 mg/dayWomen >65 years old, 1500 mg/day.

Sodium fluoride, bisphosphonates (e.g., alendronate), selective estrogen receptor modulators, and parathyroid hormone may be other therapies for the osteoporotic patient.

 Bisphosphonates



The bisphosphonates are bone-seeking agents that inhibit bone resorption by disrupting osteoclast activity [Table 3].{Table 3}

Bisphosphonates affect both bone resorption and deposition by various mechanisms:

They bind to hydroxyapatite, thus preventing its dissolutionThey inhibit osteoclast activation, thus reducing the rate of bone resorptionThey increase osteoblast differentiation, thus aiding in bone formationTheir anticollagenase activity prevents degradation of the organic components of bone.[16]

 Effects of Bisphosphonates



At molecular level, bisphosphonates inhibit mevalonate pathway and posttranslational prenylation of guanosine triphosphate-binding proteins. This causes changes at cellular level which include:

Decrease osteoclastic activity as shown by the lack of ruffled border on osteoclast present in Howship's lacunaeDecrease depth of resorption siteDecrease release of cytokinesIncrease osteoblast differentiation and number.[16]

 Effects of Oral Contraceptives on the Periodontium



The use of hormonal contraceptives by women has been considered to influence gingival and periodontal disease progression. The two possible factors influencing the effects of oral contraceptives (OCPs) on periodontal condition include hormonal dosage and the total duration of intake. A continued exposure of OCPs used for a longer period results in a higher risk to periodontal disease development and progression because of increased production of proinflammatory cytokines and prostaglandins resulting from elevated levels of these hormones.[17]

Gingival tissues may have an exaggerated response to local irritants. OCPs can aggravate patients' inflammatory condition, causing erythema and an increased propensity to gingival bleeding. Inflammation may vary from mild edema, erythema to severe inflammation with hemorrhagic or hyperplastic gingival tissues. There is evidence that the presence of metabolic products of the sex hormones in gingiva is an essential factor in the pathogenesis of chronic gingivitis.[17]

 Gingival Hyperplasia



OCPs have been reported to induce gingival enlargement. The incidence of gingival overgrowth by OCPs is common and resolves when the drug is withdrawn. Maintenance of adequate plaque control is essential for gingival health during the intake of OCPs.[17]

 Other Effects of the Oral Contraceptives



Pigmentation of the oral mucosa

Pigmentation of the oral mucosa can be caused by the use of OCPs, and withdrawal of the drug does not produce complete regression. Estrogens are well known to induce high levels of cortisol-binding globulin which leads to a decrease in plasma-free cortisol. This produces a hypersecretion of adrenocorticotropic hormone and melanocyte-stimulating hormone. The latter may cause increased pigmentation of the oral mucosa.[17]

Alveolar osteitis

OCP is the only medication associated with developing alveolar osteitis following extraction of impacted lower third molars. Estrogen plays a significant role in the fibrinolytic process. It is believed to indirectly activate the fibrinolytic system, contributing to the premature destruction of the clot and the development of dry socket.[17]

Saliva

Several changes have been observed in the composition and flow of saliva in women taking contraceptive medications. There is a decrease in concentrations of protein, sialic acid, hydrogen ions, and total electrolytes. Studies have shown both an increase and a decrease in salivary flow. A study has also shown that salivary buffer effect of OCP users is significantly higher than nonusers.[17]

 Bioidentical Hormone Replacement Therapy



Bioidentical hormone replacement therapy (BHRT) usually involves the use of steroid hormones including estrone sulfate, estropipate, 17β-estradiol, estriol, progesterone, testosterone, and dehydroepiandrosterone. Bioidentical hormones are derived from plant sources and are termed bioidentical because it is claimed that they are structurally identical to endogenous hormones, not just human hormone receptor binders. BHRT is sometimes referred to as natural HRT by its proponents.[18]

 Effect of Phytoestrogens on Osteoporosis



Phytoestrogens are plant compounds that are structurally and functionally similar to β-estradiol and bind to estradiol receptors. Whereas their affinity for binding is only 1/500–1/1000 of that of estradiol, they compete with estradiol for receptor sites. As a result, phytoestrogens are thought to act as both agonists and antagonists.[19] Phytoestrogens are divided into various classes that include [Table 4]:{Table 4}

IsoflavonesLignansCoumestansResorcylic Acid LactonesMycotoxins.

Soy isoflavones may be useful in preventing and treating postmenopausal osteoporosis due to their similarity in structure to estradiol. They may thus act as potential replacements for estrogen deficiency.[20]

 Summary and Conclusion



Periodontitis is one of the most ubiquitous diseases and is, by definition, an inflammatory disease of specific bacterial origin that affects the supporting structures of the teeth. Scientific evidence has emerged in the field of periodontology linking periodontitis to an individual's overall health.

Medical history and dialogs should include thoughtful investigation of the individual patient's needs. Hormonal fluctuations differ from patient to patient. The dental professional should explore hormonal stability and medications associated with hormone regulation. Patients should be educated regarding the profound effects that sex hormones may play on periodontal and oral tissues as well as the need for proper oral self-care and frequent professional intervention.

Female patients may present with periodontal and systemic considerations that alter conventional periodontal therapy. Hence, clinicians need to take initiative and become familiar with all these systemic relationships and to initiate treatment coordination with the patient's physician.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Güncü GN, Tözüm TF, Caǧlayan F. Effects of endogenous sex hormones on the periodontium – Review of literature. Aust Dent J 2005;50:138-45.
2Deepa MS. Women, hormones and oral health. IJWDC 2013;1:15-20.
3Mariotti A. Sex steroid hormones and cell dynamics in the periodontium. Crit Rev Oral Biol Med 1994;5:27-53.
4Mariotti A, Mawhinney M. Endocrinology of sex steroid hormones and cell dynamics in the periodontium. Periodontol 2000 2013;61:69-88.
5Markou E, Eleana B, Lazaros T, Antonios K. The influence of sex steroid hormones on gingiva of women. Open Dent J 2009;3:114-9.
6Kumar PS. Sex and the subgingival microbiome: Do female sex steroids affect periodontal bacteria? Periodontol 2000 2013;61:103-24.
7Marcuschamer E, Hawley CE, Speckman I, Romero RM, Molina JN. A lifetime of normal hormonal events and their impact on periodontal health. Perinatol Reprod Hum 2009;23:53-64.
8Balan 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;13:178-81.
9Apoorva SM, Suchetha A. Effect of sex hormones on the periodontium. Indian J Dent Sci 2010;2:36-40.
10Shah M, Gohil M, Dave D. Effect of sex hormones on female periodontium. Guident 2011;4:86-9.
11Jared H, Boggess KA. Periodontal diseases and adverse pregnancy outcomes: A review of the evidence and implications for clinical practice. J Dent Hyg 2008;82:1-20.
12Grover CM, More VP, Singh N, Grover S. Crosstalk between hormones and oral health in the mid-life of women: A comprehensive review. J Int Soc Prev Community Dent 2014;4:S5-S10.
13Georgescu A, Dumitriu HT. Histopathology of marginal superficial periodontium at menopause. IJMD 2012;2:63-7.
14Otomo-Corgel J. Periodontal Therapy in a Female Patient. Textbook of Clinical Periodontology by Carranza. 10th ed. Saunders: 2006. p. 636-49.
15Otomo-Corgel J. Dental management of the female patient. Periodontol 2000 2013;61:219-31.
16Shah DV, Dave D, Deshpande N, Dave R, Sharma D. Bisphosphonates in periodontal therapy. Indian J Res 2013;2:293-5.
17Reddy P, Jamadar S, Chaitanya Babu N. Effects of oral contraceptives on the oral cavity. Indian J Dent Adv 2013;5:1274-6.
18Conaway E. Bioidentical hormones: An evidence-based review for primary care providers. J Am Osteopath Assoc 2011;111:153-64.
19Umland EM, Cauffield JS, Kirk JK, Thomason TE. Phytoestrogens as therapeutic alternatives to traditional hormone replacement in postmenopausal women. Pharmacotherapy 2000;20:981-90.
20Miadoková E. Isoflavonoids – An overview of their biological activities and potential health benefits. Interdiscip Toxicol 2009;2:211-8.