There are five key life stages in the female life cycle: puberty, menstruation, contraceptive use, pregnancy and menopause. Each of these phases involve fluctuating levels of sex hormones that have direct and indirect effects on oral health and may also influence susceptibility to periodontal disease. These changes in oral health are associated with more frequent and exaggerated inflammatory response to oral bacteria without an accompanying increase in plaque levels, that may initiate gingival and periodontal lesions 1. Some of these changes are bleeding on probing or with tooth brushing, inflamed gingivae, hyperplastic gingivae, pyrogenic granuloma, tooth mobility and bone loss 2.

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In addition, it has now been established that cardio-vascular disease (CVD)3 diabetes 4 and adverse pregnancy outcomes 5 are all potential sequelae of poor oral health. It is imperative, therefore, that the dental team understand the effect of hormone status on the oral health of our female patients and recognise our role in the promotion of oral systemic health and the impact this has on the health of women.

This article aims to provide an overview of the female hormones and how hormone status can impact on the oral health of our female patients through the menopause and beyond.

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Menopause

Menopause usually begins at approximately 47-51 years of age 6, unless accelerated by hysterectomy or ovariectomy. Menopause is a point in time 12 months after a woman's last period. The years leading up to that point, when women may have changes in their monthly cycles, hot flashes, or other symptoms, are called the menopausal transition or perimenopause 7. The word “menopause” derives from the Greek “men” (month or monthly cycle) and “pausis” (end, stop), i.e., “the cessation of monthly cycle.” The World Health Organization (WHO) describes it as the permanent cessation of menstruation as a result of the loss of ovarian follicular function 8.

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Several factors including genetic and environmental factors can influence when menopause begins. These include smoking more than 10 cigarettes a day and having a history of heart disease. For example, women who had a history of heart disease reached menopause 1.4 years earlier than those without such a history (median age of 50.0 years vs. 51.4), and women who smoked 10-19 cigarettes a day reached menopause sooner than those who had never smoked (50.2 years vs. 51.4 years) 9.

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 At this stage there is a dramatic decrease of oestrogen and progesterone production. Whereas the pre-menopausal woman has cycling plasma levels of oestradiol and progesterone of 50 – 500 pg/ml and 0.5- 20 ng/ml respectively 10, the post-menopausal woman has non cycling, circulating levels of 5 – 25pg/ml and 0.5ng/ml respectively. This represents a dramatic decrease of oestrogen and progesterone production and a 10-fold drop in circulating levels of female hormones.

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Steroid Hormones

Steroid hormones are all derivatives of cholesterol and they can be divided into three principal sets: corticosteroid hormones (glucocorticoids, and mineralocorticoids), calcium regulating steroid hormones   (vitamin D and its metabolites) and gonadal or sex steroid hormones (oestrogens, androgens, and progesterone). They are not bound but synthesized and immediately released. All steroid hormones are lipid soluble making them freely permeable to lipid membranes. They are not stored in cells and have a half-life of about 20 minutes 11.

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Oestrogen

Oestrogen refers to a class of hormones, which include oestradiol, oestriol and oestrone. Oestradiol (E 2) is the most common type of oestrogen in females during their reproductive years. Whereas levels of oestriol(E3) rise during pregnancy and peak just before birth, oestrone(E1) is the only type of oestrogen present in the body after menopause. It is a weaker form of oestrogen and is also synthesised from adipose tissue and adrenal glands 12.  The primary functions of oestrogen are highlighted in Table 1 and include the regulation of fluid and electrolyte balance and the maintenance of bone density.

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Table 1

Functions of Oestrogens

• Promote development and maintenance of female reproductive structures.

• Promote development of secondary sex characteristics.

• Help control fluid and electrolyte balance.

• Increase protein metabolism.

• Promote growth in synergy with Human Growth Hormone.

• Maintains bone density.

 

Functions of Progesterone.

• Precursor to other sex hormones.

• Maintains secretory endometrium.

• Natural diuretic.

• Works in synergy with thyroid hormone.

• Normalises blood clotting.

• Stimulates osteoblast-mediated bone formation.

• Helps regulate blood sugar balance.

 

Functions of Testosterone in females

• Combined with oestrogen:

• growth, maintenance, and repair of female reproductive tissues.

• Bone mass

• Human behaviours :

• Reduces anxiety, antidepressant

• Promotes improved mood and mental health in both men and women

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Oestrogen also has known effects on the cardiovascular system: increased HDL cholesterol (the good kind), decreased LDL cholesterol (the bad kind) and oestrogens also relaxes, smooths, and dilates blood vessels so blood flow increases. Oestrogens also have antioxidant properties which are due to their ability to bind to oestrogen receptors and to up-regulate the expression of antioxidant enzymes via intracellular signalling pathways. Antioxidants quench free radicals, naturally occurring particles in the blood that can damage the arteries and tissues 13,14 .

 

Progesterone

Progesterone is the precursor to all other sex hormones (oestrogens, progesterone, and testosterone) and the adrenal hormone corticosterone. It works in synergy with the thyroid hormone and helps regulate blood sugar balance and stimulate osteoblast mediated bone formation. Table 1 In fact sex steroid hormones directly and indirectly exert influences on cellular proliferation, differentiation, and growth in target tissues 15.

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Testosterone

Although primarily thought of as an androgen (male hormone), testosterone is also produced in relatively small quantities by the ovaries and is released into the bloodstream by the ovaries and adrenal glands. Combined with oestrogen, testosterone helps with the growth, maintenance, and repair of a woman's reproductive tissues, bone mass and human behaviours 16.

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Androgens may also play a role in the maintenance of bone mass. In association with oestrogen, testosterone inhibits bone resorption, inhibits osteoclastic function, and inhibits pro-inflammatory prostaglandin synthesis. Testosterone stimulates bone cell proliferation and differentiation and has a positive effect on bone metabolism 17, 18 . Androgen receptors are found in both human gingival and periodontal ligament fibroblasts 19,20.

 

Hormone Receptors and Target Tissues

Targets for sex hormones were primarily thought to be the reproductive organs, the vascular system, central nervous system, gastrointestinal tract, immune system, skin, kidney, and lung. Bone is also recognised as a target tissue for oestrogen and progesterone in bone density.

In periodontal tissues hormone receptors have been found for oestrogens, androgens, and progesterone. Oestrogen receptors are also found on periosteal fibroblasts, fibroblasts of the lamina propria, and periodontal ligament fibroblasts and osteoblasts 21.

The proposed mechanism of how sex hormones affect the periodontal tissues is thought to be initiated by a sex steroid induced increase in specific microbiota. Immune endocrine interactions exaggerate periodontal responses in specific populations of fibroblasts and epithelial cells which are modulated by sex steroid hormones. This results in an increased release of pro-inflammatory cytokines, leading to the changes manifest in periodontal tissues 22,23 .

 

The presence of hormone receptors in periodontal tissue mean that hormone fluctuations and endocrine disturbances affect the periodontal tissues directly by modifying the tissue response to local factors and producing anatomic and immune changes in the gingiva that compromise the periodontium. A better understanding of the periodontal changes to varying hormonal levels throughout life can help the dental team in the diagnosis and treatment of oral conditions that are associated with the menopause.

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Part Two will examine the oral manifestation of hormone deficiency throughout the menopause and beyond.

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References

1. Hugoson A, Hoch C, Rylander H; Prevalence and distribution of gingival periodontitis in children and adolescents. 1981 Swed Dent J 5:(3)91-103.

 

2.Halling A, Bengtsson C: The number of children, use of oral contraception and menopausal status in the relationship to the number of remaining teeth and periodontal bone height. Comm Dent health 1989 6:39-45.

3.Tonetti M S, Van Dyke T E, Working group 1 of the joint EFP/AAP workshop. Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Clin Periodontol 2013; 40: S24–29.

 

4. Chapple I L, Genco R, Working group 2 of joint EFP/AAP workshop. Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Clin Periodontol 2013; 40: S106–112.

 

5. Sans M, Kornman K, Working group 3 of joint EFP/AAP workshop. Periodontitis and adverse pregnancy outcomes: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Clin Periodontol 2013; 40: S164–169.

 

6. Santoro, Nanette. “Perimenopause: From Research to Practice.” Journal of women's health (2002) vol. 25,4 (2016): 332-9.

 

7. Soules MR, Sherman S, Parrott E, Rebar R, Santoro N, Utian W, Woods N. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Climacteric. 2001 Dec;4(4):267-72.

 

8. WHO Scientific Group on Research on the Menopause & World Health Organization. (‎1981)‎. Research on the menopause : report of a WHO scientific group [‎meeting held in Geneva from 8 to 12 December 1980]‎. World Health Organization. https://apps.who.int/iris/handle/10665/41526 accessed 24/03/22

 

9. Gold EB et al., Factors associated with age at natural menopause in a multiethnic sample of midlife women, American Journal of Epidemiology, 2001, 153(9):865-874.

 

10. Mishell DR: menopause: physiology and pharmacology. Chicago Book Medical Pubs Inc. pp75 1987.

 

11.Holst JP, Soldin OP, Guo T, Soldin SJ. Steroid hormones: relevance and measurement in the clinical laboratory. Clin Lab Med. 2004 Mar;24(1):105-18.

 

12.Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. 2013 Mar;19(3):197-209.

 

13. Mendelsohn ME. Protective effects of estrogen on the cardiovascular system. Am J Cardiol. 2002 Jun 20;89(12A):12E-17E

 

14. Consuelo Borrás, Juan Gambini, Raúl López-Grueso, Federico V. Pallardó, Jose Viña: Direct antioxidant and protective effect of estradiol on isolated mitochondria. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease,2010, 1802;(1):205-211

 

15. Jafri Z et al: Influence of female sex hormones on periodontium: A case series. J Nat Sci Biol Med. 2015;6(Suppl 1):S146-S149.

 

16. Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol 2001; 22(3):185–212

 

17. Kasperk CH et al: Gonadal and adrenal androgens are potent regulators of human bone cell metabolism in vitro. J Bone Miner Res 1997;12:464-471.

 

18. Karsenty, G.The mutual dependence between bone and gonads, Journal of Endocrinology, 2012; 213(2), 107-114.

 

19. Gornstein RA et al: Androgens modulate interleukin-6 production by gingival fibroblasts in vitro. J Periodontol 1999;70:604-609.

 

20. Parkar M et al: IL-6 expression by oral fibroblasts is regulated by androgen. Cytokine 1998;10:613-619

 

21. Mariotti A. Sex steroid hormones and cell dynamics in the periodontium.Crit Rev Oral Biol Med. 1994;5(1):27-53.

 

22. Cornejo Ulloa P, Krom BP, van der Veen MH. Sex Steroid Hormones as a Balancing Factor in Oral Host Microbiome Interactions. Front Cell Infect Microbiol. 2021 Sep 29;11:714229.

 

23. Mariotti, A. and Mawhinney, M. Endocrinology of sex steroid hormones and cell dynamics in the periodontium. Periodontology 2000; 2013: 61: 69-88.