endocrinology of sex hormones and cell dynamics in periodontium

1. ENDOCRINOLOGY OF SEX
HORMONES
AND CELL DYNAMICS IN
PERIODONTIUM
PRESENTED BY:
SONAL GOYAL
II YEAR MDS
DEPARTMENT OF PERIODONTOLOGY

2. CONTENTS
• Introduction
• Sex steroid hormones
• Mechanism of action
• Periodontium as a target tissue
• Etiologies of periodontal endocrinopathies
 Microbial organisms
 Periodontal vasculature
 Immune system
 Cells of periodontium
• Periodontal teleology
• Conclusion
• Reference

3. INTRODUCTION
• Hormones are specific regulatory molecules that have potent effects on
the major determinants of the development and the integrity of the
skeleton and oral cavity including periodontal tissues.
• Gingival inflammation has been extensively reported in association
with elevated female hormonal surges, and the biological mechanisms
underlying this florid inflammatory condition have been examined for
over a century.
Kumar PS. Sex and the subgingival microbiome: do female sex steroids affect periodontal
bacteria? Periodontol 2000 2013;61:103-124.

4. • Pregnancy, puberty, menstruation and menopause are four
physiological conditions that offer a means to examine the changes
that occur in the oral microbial community during fluctuations in
endogenous hormonal levels.
• Oral contraceptive use and hormone replacement therapy have been
used to examine the effect of exogenous hormonal fluctuations on oral
microbial profiles.

5. • It is intriguing that the sex steroid hormones are so similar in chemical
composition yet produce such dramatically different effects.
• The apparently superficial differences in the molecular structure of
steroid hormones alter the molecules shape and qualitatively change its
biological activity.
Mariotti A, Mawhinney M. Endocrinology of sex steroid hormones and cell dynamics in the
periodontium. Periodontol 2000 2013;61:69-88.

6. SEX STEROID HORMONES
• Androgens
Androgens are derived from a 19-carbon tetracyclic hydrocarbon
nucleus (androstane).
One of the most potent androgenic
hormones.
Testosterone is synthesized by the
testicular Leydig cells, the thecal cells
of the ovary and the adrenal cortex.

7. • There are two types of androgens:
1. Gonadal androgen, dihydrotesterone (DHT), and
2. Adrenal androgen, dehydroepiandrosterone.
• The former is the most active form.
• The adrenal androgen, androstenedione, is converted to
testosterone and to estrogens in the circulation, and represents an
important source of estrogens in men and postmenopausal
women.

8. • In men, testosterone is the principal plasma androgen.
• Enzymatically reduced within target tissue cells to
dihydrotestosterone.
• Relative to testosterone, dihydrotestosterone exhibits a preferential
affinity for the intracellular androgen receptor - active intracellular
androgen.

9. Testosterone (but not dihydrotestosterone)
aromatizes to estradiol by a number of
extragonadal tissues (e.g. primarily adipose
tissue and skeletal muscle), which is a common
route of estrogen production in men.
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.

10. Effects of androgens on the periodontal
tissues
• Inhibit prostaglandin secretion
• Enhance osteoblast proliferation and
differentiation
• Reduce IL-6 production during
inflammation
• Enhance matrix synthesis by periodontal
ligament fibroblasts and osteoblasts

11. Estrogens
They are characterized by an aromatic A ring, a hydroxyl group at C-3
and either hydroxyl groups (C-16 and C-17) or a ketone group (C-17)
on the D ring.
They are secreted by the ovary, testis
and placenta, as well as by peripheral tissues.

12. Three forms of estrogen are present, namely

13. Functions of Estrogen:
The main function of the estrogen is to cause cellular proliferation
and growth of the tissues of the sexual organs and of other tissues
related to reproduction.

14. • Decreases keratinization while increasing epithelial glycogen that
results in the diminution in the effectiveness of the epitelial barrier.
• Increases cellular proliferation in blood vessels
• Stimulates PMNL phagocytosis
• Inhibits PMNL chemotaxis
• Suppress leukocyte production from the bone marrow
• Inhibits proinflammatory cytokines released by human marrow cells
• Reduces T-cell mediated inflammation
• Stimulates the proliferation of the gingival fibroblast
• Stimulates the synthesis and maturation of gingival connective tissues
• Increases the amount of gingival inflammation with no increase of
plaque

15. Transport of Estrogen in the Plasma:
• Estrogen is transported with the plasma protein, albumin. A small
quantity of estrogen is also transported by globulin. The binding of
these hormones with the plasma protein is so loose, that the hormones
can be released in the tissues easily.
• Normal value - 24- 149pg/ml

16. Fate of Estrogen:
• Estrogen is degraded mainly in the liver. Here, it is conjugated
with glucoronides and sulfates. The conjugated products are
excreted in the bile and urine
• Liver also converts the potent active beta estradiol into the almost
inactive estrogen, the estirol.

17. • Progestins
 They are derived from a 21-carbon saturated steroid hydrocarbon known as
pregnane.
 They are synthesized and secreted by the corpus luteum and placenta.

18. Progesterone:
Progesterone is secreted in significant amount during the latter
half of each ovarian cycle. It is synthesized from acetate or
cholesterol in the ovaries along with estrogen.
Normal value – 150ng/dl

19. Source of Secretion:
• In a normal non-pregnant female, progesterone is secreted in
significant amount only during the latter half of each ovarian cycle, i.e.
during follicular phase, only minute quantities of progesterone is
secreted by the ovaries.
• But, during pregnancy, large amount of progesterone is secreted by
corpus leutum in the first trimester and then by the placenta from
second trimester onwards.
• Small amount of progesterone is secreted from adrenal cortex also.

20. Synthesis of Progesterone:
Progesterone is synthesized from acetate or cholesterol in the ovaries
along with estrogen.
Transport of Progesterone in Blood:
Like estrogen, progesterone is also transported in the blood by the
plasma proteins-albumin and globulin.

21. Fate of Progesterone:
Within a few minutes after secretion, almost all the progesterone is
degraded into other steroids, which do not have progesterone
effect. The main end product of progesterone degradation is
pregnanediol. 10% of this end product is excreted in the urine.
Regulation of Secretion of Progesterone:
Luteinizing hormone from anterior pituitary activates the corpus
leutum to secrete progesterone. Secretion of luteinizing hormone is
influenced by the gonadotropic releasing hormone secreted in
hypothalamus.

22. FUNCTIONS OF PROGESTERONE:
Progesterone is concerned mostly with the final preparation of
the uterus for pregnancy and the breasts for location.

23. • Increases vascular
dilatation, thus
increases
permeability
• Increases the
production of
prostaglandins
• Increases PMNL
and prostaglandin
E2 in the gingival
crevicular fluid
(GCF)
• Reduces
glucocorticoid anti-
inflammatory effect
• Inhibits collagen
and noncollagen
synthesis in PDL
fibroblast
• Inhibits
proliferation of
human gingival
fibroblast
proliferation
• Alters rate and
pattern of collagen
production in
gingiva resulting in
reduced repair and
maintenance
potential
• Increases the
metabolic
breakdown of
folate which is
necessary for tissue
maintenance and
repair
Effects of progesterone on the periodontal tissues

24. MECHANISM OF ACTION
• Many actions of estradiol, progesterone, and testosterone are
mediated by the classical or genomic mechanism of action that
involves specific intracellular receptors, ER, PR, and AR,
respectively,
• These receptors are members of the nuclear receptor superfamily
of ligand-dependent transcription factors.

25. • PR isoforms-
Encoded by the same gene
Regulated by distinct
promoters.
These isoforms are pr-b of
114 kda and an n-terminal
truncated form, pr-a of 94
kda.
• Two subtypes of ER-
 ER-𝛼 of 66 kda and ER-𝛽 of 55
kda,
 Transcribed from different
genes
• Two isoforms of AR-
 Encoded by a single gene, AR-
A and AR-B.

28. PERIODONTIUM AS A TARGET TISSUE
• Evidence implicating the gingiva as a target tissue for sex steroid
hormones was based on clinical manifestations of morphological
and inflammatory responses during periods of hormone fluctuation.

29. EFFECTS OF SEX STEROID HORMONES ON
BACTERIAL INFECTIONS

30. PUBERTY
• The dramatic rise in steroid hormone levels during puberty in both
sexes is believed to have a transient effect on the inflammatory
status of the gingiva.
An increase in gingival inflammation in circumpubertal age
individuals of both sexes.
An abrupt and transitory increase in the incidence of gingivitis
without a change in plaque levels.

31. • Severe gingival inflammation is noted at interproximal
sites at puberty.

32.  The mean age at which girls and boys
reached their maximum gingivitis
experience was 12 years and 10 months
and 13 years and 7 months,
respectively.
 Male and female children to puberty
has demonstrated that elevated
testosterone in boys and elevated
estradiol and progesterone in girls were
positively correlated with increases in
gingival inflammation.
 In a 4-year longitudinal study of 22
boys and 20 girls, a clinically and
statistically significant increase in
gingival inflammation was correlated
with testicular growth in boys and with
breast development in girls
Sutcliffe P et al, 1972
Nakagawa S et al, 1994
Mombelli et al, 1989

33. • Subgingival microbiota changes-
Prevotella intermedia
Spirochetes
Capnocytophaga (increased bleeding tendencies)
Actinomyeces species
Eikenella corrodens

34. • Management:
Patient/ parents education
Adequate maintenance of oral hygiene
Mild to moderate cases- scaling and root planing
Severe- scaling and polishing, use of antimicrobial agent for
subgingival irrigation, use of mouth rinses.
Mouth breathing- application of lubricants over the inflamed
tissue before going to the sleep

35. MENSTRUAL CYCLE
• Menstrual cycle consists of ovarian and uterine cycles controlled
by hormones such as estrogen, progestrone, LH, FSH.
• In general, the periodontium does not exhibit clinically obvious
changes during the menstrual cycle.

36. • Two different clinical findings have been reported to occur in the
oral cavity.
1. The inflammatory changes that develop in gingival tissues of
periovulatory women. Ulcerations of the oral mucosa, vesicular
lesions and bleeding have been described during ovulation or
several days before menstruation.
2. The more common inflammatory changes that develop in the
gingiva is the increase in the amount of gingival exudate (an
indicator of gingival inflammation) during ovulation.

37. • The other significant observation that has been described during
the luteal phase of menstrual cycle is the appearance of aphthous
ulcers.

38. • Muhlemann (123),
• Clinically and histologically, described a case of gingivitis
intermenstrualis where bright-red, hemorrhagic lesions of the
interdental papilla developed prior to the menses.

39. • Effects on periodontium:
Increased permeability of microvasculature
Increased production of prostaglandin
Due to these changes- significant inflammatory changes occur in
gingiva.
Inflammatory changes occur in interproximal sites, greater in
molars.
Increase in GCF in proliferative phase, associated with increased
levels of estrogen and progestrone.

40. • Management:
Moderate to severe cases:
1. Scaling and root planing
2. Maintenance of good oral hygiene by patients
 Patients with excessive menstrual flow- surgical procedures are
scheduled after cyclic menstruation is over
 Anaemic patients- referral to physician

41. • In summary, during the menstrual cycle, there is a small increase
in gingival inflammation that has been noticed in clinical research
studies.
• This subclinical inflammation is, to all intents and purposes,
asymptomatic.
• In regard to aphthous ulcers, there are no consistent data to
suggest that their occurrence is influenced by hormonal changes
during the menstrual cycle.

42. ORAL CONTRACEPTIVES
• Oral contraceptive agents are one of the most widely
utilized classes of drugs.
•Low doses of estrogens (≤ 50 µg ⁄ day) and ⁄ or
progestins (≤ 1.5 mg ⁄ day)
•Early formulations of oral contraceptives contained
higher concentrations of sex steroid hormones.
Effects- gingival enlargement, excessive inflammation
and, controversially, attachment loss.

43. • Increased inflammation and hemorrhagic gingival sites are
observed at maxillary area.

44. • Oral contraceptives should not be viewed as a risk factor for
gingival or periodontal disease.

45. PREGNANCY
• Pregnant women near or at term produce large quantities of sex
steroid hormones (20 mg of estradiol, 80 mg of estriol and 300 mg
of progesterone) on a daily basis.
• This prominent increase in plasma hormone levels over several
months has a dramatic effect on the periodontium.

47. • Mild gingival inflammation at
the marginal gingiva during
pregnancy.
•Pregnancy tumors

48. The severity of
gingival
inflammation is
independent of
the amount of
plaque and
does not result
in attachment
loss.
Gingival
probing
depths are
larger
Bleeding on
probing or
during
toothbrushing
increases
The amount
of gingival
crevicular
fluids get
elevated.
Localized
gingival
enlargements

49. ADULT MEN
• The effects of androgens on periodontal tissues in adult men have
not been thoroughly catalogued.
• Men with low plasma androgen levels have generally not
demonstrated a greater loss of periodontal attachment over
controls.
• High plasma androgen levels, as a result of exogenous hormone
administration, in healthy adult men, stimulates the growth of
gingival tissues.

50. MENOPAUSE, ANDROPAUSE
• Ovarian function declines and there is a significant reduction in
the production and secretion of sex steroid hormones.
• In men, an age related decline in circulating plasma testosterone
levels, which may lead to physiologic changes, has been termed
andropause.

53. • There are no endogenous hormone induced increases in gingival
inflammation or size.
• The gingival epithelium becomes thin, atropic and prone to
inflammatory changes.
• May exhibit oral discomfort that is characterized by a burning
sensation or desquamations of gingival epithelium.
• In postmenopausal women, positive correlations between
estrogens and bone density have been demonstrated.

54. • Androgen deprivation is associated with appendicular bone loss
and the elderly men have increased amounts of destructive
periodontal disease and tooth loss as they age;
• However, the causal relationship between declining plasma
androgen levels and periodontal diseases has not been
demonstrated.

55. Hormone Fibroblasts
Androgens (testosterone &
hydrotestosterone)
Decrease proliferation
Decrease IL-6 production
Progestrone Decrease proliferation
Decrease protein synthesis
Decrease cytokine
production
Estradiol Increase proliferation
Increase cytokine
production
• Sex steroid hormones and the cells of periodontium

56. ETIOLOGIES OF PERIODONTAL
ENDOCRINOPATHIES
• The response of the periodontium in disease is probably not a
single mechanism but, rather, is multifactorial in nature.
• To date, the most prominent explanations for the significance of
hormone action in the periodontium have dealt with the effect of
hormones on microbial organisms, the vasculature, the immune
system and specific cells in the periodontium.

57. MICROBIAL ORGANISMS
• Gingivitis is considered to be primarily a microbial disease that
can be modulated by different systemic and environmental
factors.
• Exacerbations in gingival inflammation observed during
increases in plasma sex steroid hormones could be caused by
hormone-induced alterations in the microbial flora of the
gingival sulcus.

58. PERIODONTAL VASCULATURE
• As with all inflammatory reactions, the increase in blood vessel
permeability occurs in gingivitis.
• In women, estrogen is the principal sex steroid hormone
responsible for alterations in blood vessels.

59. • The endothelial cells synthesize estrogens
• The blood vessel function is modulated by both estrogen
receptor-α and estrogen receptor-β.

60. • Inhibiting the movement of calcium ions
through the voltage sensitive calcium
channels of uterine arteries after metabolic
conversion to catechol estrogens,
• Influencing the release or disposition of
sympathetic transmitter, or affecting alpha-
adrenoceptor number or affinity,
• It may increase capillary permeability by
stimulating the release of various mediators
(e.g. Adenosine, bradykinin, vasoactive
intestinal polypeptide, neurotensin, substance
P, various prostaglandins, AMP, ADP, ATP,
camp, guanosine, thymidine, histamine,
cytidine, uridine, acetylcholine, isoproterenol
and glycosaminoglycans),
• Activation o the estrogen receptor-a was
responsible for nitric oxide-induced
vasodilation, re-endothelialization and
angiogenesis.
Putative
mechanisms
by which
estrogens
may control
blood vessel
tone include

61. • In contrast to the principal effects
induced by estrogen on blood
vessels, progesterone may have
little or no direct effect on the
vasculature.
• Antagonizes the actions of
estrogen, presumably by
reducing estrogen receptor
numbers.
• Progestins have been shown to
have an inhibitory effect on
angiogenesis.
•In men, testosterone, which
can be metabolized to estradiol,
will cause a sharp, transient
dilation of arterioles and
venules in sex accessory
organs.

62. • In pregnant women, the amount of gingival crevicular fluid is
elevated by as much as 54% when compared with gingival
crevicular fluid levels from postpartum women.
• Progesterone is primarily responsible for a reduction in
corpuscular flow rate, increased vascular permeability and
vascular proliferation.
• Low concentrations of estradiol (1.5 gM) have been shown to
reduce polymorphonuclear leukocyte chemotaxis by as much as
26.8%
Although estrogens are primarily responsible for vascular
changes reported in reproductive target tissues, such as the
uterus, several periodontal studies have suggested that
increased vascular permeability in the gingiva was essentially
the result of progesterone.

63. IMMUNE SYSTEM
• Straub proposed that the effects of sex steroid hormones on the
immune system are dependent on:
1. The immune stimulus and the antigen-specific immune response;
2. The target cells involved;
3. The microenvironment of the tissue;
4. Hormone concentration;
5. The variability of receptor isoforms;
6. The intracellular metabolism of hormones to either biologically
active or inactive forms.

64. The concentrations of a
number of immune-
sensitive cells, including
CD1 cells (i.E. Primarily
langerhans cells) and CD3
cells (i.E. The majority of
mature T lymphocytes) in
the oral gingival
epithelium, as well as CD4
cells (i.E. Helper T cells)
in the oral and sulcular
gingival epithelium, were
elevated during pregnancy.
For androgens,
immunologic functions
related to adaptive
immunity and innate
inflammatory
responsiveness have
been hypothesized to
affect the progression
of periodontal disease
in men
Immunological
reactions in the
pathogenesis of
periodontal
diseases

65. CELLS OF THE PERIODONTIUM
• In the periodontium, estrogens, androgens and the progestins are
known to affect mainly, keratinocytes and fibroblasts.
• Estrogens increased epithelial keratinization and stimulated
proliferation.

66. Trott (1957) noticed a reduction in keratinization of
marginal gingival epithelium in postmenopausal women
when plasma estrogen levels were declining.
Litwack et al. (1970) found the length of rete pegs, the
number of basal epithelial cells per area of basement
membrane and thymidine labeling of epithelial cells in oral
mucosa to be significantly increased after administration of
estrogen to castrated adult female squirrel monkeys.
In humans, simians and rodents, androgens were perceived
to stimulate an increase in epithelial cell number.

67. In a study by Klinger et al, 1981, using
progestins, daily administration of
norethisterone acetate to nine healthy
women, between days 3 and 27 of the
menstrual cycle, resulted in
• A significant reduction in the keratinization
index and the karyopyknotic index from gingival
smears .
• The reduction in gingival proliferation was not
caused by the direct effects of the progestin but
rather by a reduction of plasma estradiol induced
by daily administration of progesterone.

69. • The extracellular matrix of the periodontium is an intricate
mosaic of cells (e.g. fibroblasts, mesenchymal cells, mast cells
and endothelial cells) interspersed among a diverse number of
macromolecules
• The actions of sex steroid hormones on the extracellular matrix
are a prime example of the dynamic response of cells in gingival
connective tissue during hormone fluctuations.
Extracellular matrix

70. Testosterone was found to have
an effect on extracellular matrix
components.
Kofoed (1971) demonstrated that
gingival hyaluronic acid, but not
heparan sulfate, chondroitin-4-
sulfate, chondroitin-6-sulfate or
dermatan sulfate, was androgen
sensitive.

71. • Testosterone receptors are found in the periodontal tissues
• The number of receptors on fibroblasts tends to increase in
inflamed or overgrown gingivae
• Where testosterone has an effect on periodontal tissues by
increasing matrix synthesis.

72. These results demonstrate the important influence of specific types of
extracellular matricies on protein production by gingival fibroblast cells
stimulated with estrogens.
Whereas noncollagen protein production on plastic and collagen I matrices was
reduced.
Specifically, stimulation of human gingival fibroblasts derived from
noninflamed explants significantly depressed collagen production on plastic and
collagen IV matrices,
Has shown that both hormone and extracellular matrix affect protein production.
Estrogen-induced effects on extracelluar matrix proteins at a cellular level
(Mariotti, 2005)

73. Gingival fibroblasts
are affected by all
three sex steroid
hormones.
Estrogen
stimulates alkaline
phosphatase
activity and
mineralizes
nodule formation
by periodontal
ligament
fibroblasts in cell
culture.
The difference between the
estrogen-induced secretory
activity of gingival and
periodontal ligament fibroblasts
is a result of the unique biology
of the cell type as well as the
concentration of estrogen used
to stimulate these activities in
periodontal ligament fibroblasts
(e.G. 20 ng of estradiol ⁄ ml of
culture media) vs. Gingival
fibroblasts (e.G. 0.30 ng of
estradiol⁄ ml of culture media)
in cell culture.
Fibroblasts

74. Significantly reduce the proliferative rate of fibroblasts
derived from phenytoin enlargement.
Dihydrotestosterone stimulated the proliferation of
fibroblasts derived from either normal human gingiva or
hereditary gingival enlargements.
Androgens (e.g. testosterone or dihydrotestosterone) inhibit
the production of interleukin-6
Human gingival fibroblasts metabolizes testosterone to 5a
dihydrotestosterone, 4-androstenedione and 5a-
androstanediols in cell culture, a characteristic shared by
classic androgen-dependent tissues.
Currently, it is unclear whether the increase in androgen
metabolism by fibroblasts derived from these drug-
influenced gingival enlargements is caused by the inflamed
nature of the donor tissue or the drug involved in increasing
tissue size.
Testosterone

75. Inhibition of
fibroblast
proliferation.
Significantly
reduced the
proliferative
rate of
fibroblasts
derived from
either
phenytoin-
enlarged
human
gingiva
20 µg ⁄ ml of
progesterone
inhibited
DNA
synthesis and
that
40 µg ⁄ ml of
progesterone
reduced
protein
synthesis by
as much as
50%
A dose-
dependent
decrease in
the
production of
interleukin- 6
by gingival
fibroblasts in
culture.
Progesterone

76. Stimulatory
effect on
gingival
fibroblast.
Estradiol
induced
proliferation
of fibroblasts
derived from
either feline
or human
drug enlarged
gingiva.
physiologic
concentration
s of estradiol
in healthy
gingiva of
post-
menopausal
women
increased cell
proliferation
in vitro.
the
proliferation
of gingival
fibroblasts
derived from
the
noninflamed
papilla of
healthy
premenopausa
l women was
increased by
up to 310%
by 1 ɳM
estradiol.
a dose-
dependent
increase in
interleukin-6,
interleukin-8
and vascular
endothelial
growth factor
In periodontal
ligament
acells,
estrogens
causes a
down-
regulation of
lipopolysacch
aride-induced
cytokines
while
enhancing the
production of
osteoprotegrin
however,
estrogen does
not affect the
cell number in
culture.
Estrogen

78. • Although sex hormones have been linked to periodontal
pathology, it would be counterintuitive to believe that these potent
hormones are purely detrimental to the periodontium.
• In consideration of the idea that sex steroid hormones help to
sustain the normal viability of the periodontium, a teleological
argument has been constructed, focusing on the importance of
inflammatory processes for the preservation of the periodontium.
PERIODONTAL TELEOLOGY

79. On injury, blood vessels dilate and become more permeable,
resulting in increased blood flow and leakage of plasma and
cells into the extracellular matrix.
The cells and platelets carry out their functions with the
support of the three major plasma protein systems (the
complement system, the clotting system and the kinin system).
Inflammation destroys and removes noxious agents, confines
the injurious agents for efficacious removal, limits systemic
effects of cellular agents, enhances the immune response and
promotes wound healing.
Therefore, the biologic significance of inflammation is
primarily associated with the defense of the body from injury
and infection.

80. • In the periodontium, the effects of sex steroid hormones are
manifested in the
1. Endothelium,
2. Gingival epithelium
3. Connective tissue cells found in the gingiva, periodontal ligament,
bone and cementum
4. Cells from the immune system.

81. Puberty Pregnancy
Acute inflammatory process.
SSH
Destroys, dilutes or walls off the invading organisms.
Protect both the local (i.e. periodontal attachment) and
systemic (i.e. toxic sepsis) environments
Chronic inflammatory response
Detrimental effects of SSH

82. CONCLUSION
• Sexual hormones play an important role in influencing
periodontal disease progression and wound healing.
• These effects are different depending on the gender as well as the
lifetime period analyzed.
• In addition, the influence of sex hormones can be minimized with
good plaque control as well as with hormone replacement
therapies; however, the true mechanism of how these interactions
actually occur remains to be determined.

83. • The actions of androgens, estrogens, and progesterone in tissues
of the periodontium remain an enigma in many ways;
nonetheless, future investigations into the actions of sex steroid
hormones will provide an extraordinary understanding of
periodontal endocrinology.

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