Skin, the carotid artery and Skin, the carotid artery and intervertebral discs: intervertebral discs:

making the connectionmaking the connection

Mark P. Brincat

Estrogentherapy

Decreased skin thickness

(reversed)

Cerebral changes (Alzheimer’s decreased)

CVS effects (including carotids)

Genital organs(improved)

Bone loss (stopped and

reversed)

Connective tissue: different Connective tissue: different effectseffects

Cartilage

Extracellular matrixExtracellular matrix

• Glycoaminoglycans (GAGs)

• Proteins– Collagen– Elastin

Skin collagen changes with ageSkin collagen changes with age

120

115

110

105

100

20 30 40 50 60

Age (years)

Castelo-Branco C, et al. Maturitas 1992;15:113–19

150

200

250

0 5 10 15

Treated (59)

Untreated (148)

Years since menopause

Brincat M, et al. Br J Obstet Gynaecol 1985;92:256–9

Th

igh

co

llag

en c

on

ten

t (m

g/m

m2)

Thigh collagen with the number Thigh collagen with the number of years since the menopauseof years since the menopause

0 2 4 6 8 10 12

Months of treatment

Ski

n t

hic

knes

s (m

m)

*

***

***

* p < 0.05***p < 0.001

n = 40

Brincat M, et al. Obstet Gynecol 1987;70:840–5

Skin thickness in women onSkin thickness in women on100 mg estradiol implants100 mg estradiol implants

1.05

1.00

0.95

0.90

0.85

HRTNo HRT

Pierard-Franchimont C, et al. 1999

Scatterplot of tensile strength of Scatterplot of tensile strength of skin in menopausal womenskin in menopausal women

MD (mm)

Bio

log

ical

ela

stic

ity

(%)

90

80

70

60

50

40

30

20

10

01 2 3 4 5 6 7 8

Effects of menopause on the skinEffects of menopause on the skin

• Hot flushes, altered hot/cold sensation

• Dizzy spells, falling, fractures

• Skin collagen changes– Tensile properties of the skin– Wound healing

• Atrophic changes– Dry vulva, dry eyes– Hair– Incontinence– Dyspareunia– Psychosexual role of the skin, effect on relationships– Transdermal role

Brincat MP. HRT and the Skin, 2001

The collagen familyThe collagen family

Collagen class Types Tissue distribution

Fibril-forming I Most connective tissuesII Cartilage and vitreous humorIII Extensible connective tissues, skinV LungXI Tissues containing collagen I

Tissues containing collagen II

Fibril-associated IX Tissues containing collagen IIXII Tissues containing collagen IXIV Tissues containing collagen IXVI Many tissues

Network-forming IV Basal laminae

Anchoring filaments VII Attachments of basal laminae to underlying tissues

Brincat MP. HRT and the Skin, 2001

Carotid artery wall thicknessCarotid artery wall thickness

• The vessel wall is made up of three main layers which are affected by estrogen replacement– The intima– The media– The adventitia

• The effects of estrogens are:– Intima thickness – Externa thickness – Media thickness

24

25

26

27

28

29

30

31

32

33

34

Controls vs oral HRT p < 0.05Controls vs implants p < 0.005Oral HRT vs implants p = N.S.

Car

oti

d a

rter

y w

all

(med

ia)

thic

kne

ss (

mm

)

**

*

***

Controls Oral HRT Implants

n = 51 n = 46 n = 32

Muscat Baron Y. Maturitas 1997;27:47–53

Effect of HRT on carotid artery Effect of HRT on carotid artery wall wall

in postmenopausal women in postmenopausal women (media) (mean ± SE)(media) (mean ± SE)

0.85

0.90

0.95

1.00

1.05

1.10

1.15

1.20

1.25

1.30

Controls vs. oral HRT p < 0.05Controls vs. implants p < 0.05Oral HRT vs. implants p = NS

Car

oti

d a

rter

y w

all

thic

knes

s (

inti

ma

/med

ia)

(mm

)

**

Controlsn = 51

Oral HRTn = 46

Implantsn = 32

**

Muscat Baron Y. Maturitas 1997;27:47–53

Effect of HRT on carotid artery wall Effect of HRT on carotid artery wall thickness in postmenopausal womenthickness in postmenopausal women

(intima/media) (mean ± SE)(intima/media) (mean ± SE)

Normal intervertebral discNormal intervertebral disc

Collagen types II and IX– inner lamellae

Collagen type I outer lamellae

Collagen type II, IX, X

Collagentypes II and IV

Aged intervertebral discAged intervertebral disc

Collagen types I, III, VI

Early lesionscollagens II & IX Advanced lesions

collagens III & VI

Significant decreases in glycoaminoglycans and

elastin

Functions of intervertebral discs Functions of intervertebral discs

• Intervertebral discs are responsible for 20% of the spinal column height

• Allow flexion and extension of the spine

• Also act as ‘shock absorbers’ of the spinal column

• This may have an impact on osteoporotic compression fracture

1

1.2

1.4

1.6

1.8

2

2.2

2.4

2.6

2.8

3

Calcium Biphos Menop Menstr HRT

(cm

)

****

** HRT/MENS vs MENO, CAL p < 0.05

D1 – D3 total length

Muscat Baron Y, Brincat MP, et al. Hum Reprod 2005;20:3566–70

Total intervertebral disc height in Total intervertebral disc height in different groups of women different groups of women

**

** p < 0.01

Effect of HRT on disc thickness in Effect of HRT on disc thickness in postmenopausal women taking postmenopausal women taking

corticosteroidscorticosteroids

0.4

0.45

0.5

0.55

0.6

0.65

0.7

0.75

0.8

1 2 3 4 5 6 7

Years since menopause

(cm

) HRT

Untreated

Bone density, skin and disc thickness Bone density, skin and disc thickness in postmenopausal women on HRTin postmenopausal women on HRT

0.4

0.5

0.6

0.7

0.8

0.9

1

1 2 3 4 5 6 7

Years

Disc thickness

Skin

Bone density

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

2.2

(cm

)Intervertebral disc space in normal Intervertebral disc space in normal women plotted as a function of agewomen plotted as a function of age

((n n = 464)= 464)

**

** ** ****

*p < 0.05 vs. younger age groups** p < 0.05 vs. younger age groups by Fisher test

Gambacciani M, et al. Climacteric 2007;10:298–305

20–25 26–30 31–35 36–40 40–45 46–50 51–55 56–60 61–65 65–70 71–75 >75

Age (years)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Years since menopause

(cm

)

*p < 0.05 vs. other groups† p < 0.05 vs. preceding groups§ p < 0.05 vs. preceding groups by Fisher test

Gambacciani M, et al. Climacteric 2007;10:298–305

Intervertebral disc space in normal Intervertebral disc space in normal postmenopausal women (postmenopausal women (n n = 312) plotted as = 312) plotted as

a function of years since menopausea function of years since menopause

† †

* §

1.84

1.65

1.38

0

0.5

1

1.5

2

2.5

(cm

)

Premenopause

Perimenopause

Postmenopause

***

Intervertebral disc space inIntervertebral disc space in 3 groups of age- 3 groups of age- matched (47 years; matched (47 years; n n = 39 in each group) pre-, = 39 in each group) pre-,

peri- and postmenopausal women peri- and postmenopausal women

p < 0.001 by ANOVAp < 0.002 vs. premenopausal group** p < 0.0001 vs. premenopausal and perimenopausal groups by Fisher test

Gambacciani M, et al. Climacteric 2007;10:298–305

Scattergram of bone density index of Scattergram of bone density index of femoral neck in menopausal women femoral neck in menopausal women

and skin biological elasticityand skin biological elasticity

Pierard-Franchimont C, et al. 2001

Bone mass density index

Bio

log

ical

ela

stic

ity

(%)

90

80

70

60

50

40

30

20

10

00 0.2 0.4 0.6 0.8 1

War

d's

tri

ang

le d

ensi

ty (

g/c

m2)

Skin thickness (mm)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3

Fractures, n = 129

Controls, n = 411

Sensitivity % Accuracy %Skin thickness 91.7 39.2Ward’s triangle 100.0 50.9Box Ward’s triangle 91.7 59.1 Brincat MP, Galea R, 2001

Scattergram of Ward's triangle Scattergram of Ward's triangle bone density vs. skin thicknessbone density vs. skin thickness

ConclusionConclusion

• Menopause has been shown to directly or indirectly increase symptoms and signs of aging in the skin

• Hormone replacement therapy (HRT) has a positive effect on skin connective tissue parameters, both directly and indirectly

• This is in keeping with the general improvement demonstrated in several connective tissue sites such as blood vessels, bone and cartilage as a result of HRT in postmenopausal women