1

2

Testosterone -deficient

Testosterone -

sufficient

Poor beard & moustache

Small wrinkles

Hypotonic

face muscles

Small wrinkles

Dry eyes

Pale face

Dry, thin hair

The importance of Testosterone

3

Low

Testosterone -deficient

Testosterone –

excessive

4

TESTOSTERONE ENANTHATE 100 mg injections in

aging men & effects on serum lipoproteins

Figure : effects of 3 month of 100 mg testosterone enanthate injections (1

x/week) or placebo injections in 13 healthy men aged 57-76 years old

(Tenover JS, J Clin Endocrinol Metab, 1992, 75: 1092-1098)

0

50

100

150

200baselineTotal

chole-

sterol

(mg/dl)

placebo

testo

0

40

80

120

LDL

cholesterol

199 203

177 128 132

113

placebo

testo

(mg/dl)

5

Testosterone

=> Serum

Total cholesterol

6

TESTOSTERONE ENANTHATE 100 mg injections

in aging men & effects on serum lipoproteins

Figure: effects of 3 month of 100 mg testosterone

enanthate injections (1 x/week) or placebo

injections in 13 healthy men aged 57-76 years old

(Tenover JS, J Clin Endocrinol Metab, 1992, 75: 1092-1098)

0

15

30

45

baselineHDL

(mg/dl)

placebotesto

0

25

50

75

100

125

Triglycerids

(mg/dl)49

4644 112

123

105

placebo

testo

7

Total Cholesterol

American Heart association

8

Serum cholesterol

1 mmol/l = 39 mg/dl (38,647 mg/dl)

3 mmol/l= 115 mg/dl

5 mmol/l = 193 mg/dl

8 mmol/l = 308 mg/dl

9

Men with serum cholesterol => life expectancy

0

3

6

9

+ 3,8 yrs

Men with low serum cholesterol

(less than 200 mg/dl)

Increase

in life span

n = 92.488 men

(18-39 yrs)

+ 8,7 yrs

Figure: Data from 3 studies:

Chicago Heart Association project (n= 11,017 men (18-39 yrs) followed in 1967-1973;

Peoples Gas Company Study (n= 1266 men (25-39 yrs) followed in 1959-1963;

Multiple risk Factor Intervention Trial (n= 62,205 men (35-39 yrs) evaluated in 1973-1975.

A constant, progressive, solid & independent exists between serum cholesterol & long

term risk of coronary disease & cardiovascular mortality versus men with low cholesterol.

Stamler J, Daviglius ML, Garside DB, et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of

younger men to long-term coronary, cardiovascular, & all-cause mortality & longevity. JAMA 2000; 284: 311-318

10

Testosterone

=> Serum

HDL cholesterol

11

HDL Cholesterol

American Heart association

12

Men with serum HDL cholesterol

=> all-cause mortality

0

0,5

1

All-cause

Mortality

(Relative

risk)

Serum HDL Cholesterol

p < 0.05

Figure: A high HDL cholesterol is a sign. protector against all-cause

mortality, & near sign. protector against cardiovasc. dis. mortality.

Okamura T, ….,Ueshima H;The inverse relationship between serum high-density lipoprotein cholesterol level and all-

cause mortality in a 9.6-year follow-up study in the Japanese general population. Atherosclerosis. 2006

Jan;184(1):143-50 JShiga Un.apan

n = 7175 Japanese residents ; 9.6 yrs of foloow-up

(1.04 (40

mg/dl)-1.55

mmol/L

(59.61),

p < 0.05

0.63

(0.41-

0.94)

0.73

(0.41-

0.94)

Men

-27 % -37 %

very high HDL-C category (>

or = 1.82 mmol/L = 70 mg/dl),

1

Women

13

14

LDL Cholesterol

with age

HDL Cholesterol

with age

in men

Atherogenic ratio

LDL/HDL Cholesterol

with age

Men

Women

LDL

HDL

LDL/HDL

15

0

10

20

30

40

50

"good" HDL cholesterol "bad" VLDL cholesterolBlood cholesterol levels (mg/dl)

men with

low testosterone

Figure : The blood HDL cholesterol level increases and the level of the VLDL cholesterol declines proportionately to the increase of testosterone in the blood.

247 men of middle age participated in this study. The extreme values of blood levels of testosterone were for the three groups respectively 780-5330, 6.420-7.610 and 9.370-16.500 pg/ml.

(Gutai J et al, AM J Cardiol, 1981, 48 : 897-902)

men with

average testosterone

men with

high testosterone

TESTOSTERONE &

BLOOD CHOLESTEROL

VLDL

HDL

16

the higher the plasma testosterone :

- the higher the HDL cholesterol (+ 12 % for the highest quartile) (in 391 men aged 30-79 years)( 1,2,3)

- the the VLDL cholesterol (1, 3)

- the the triglycerids (3)

the higher the plasma DHT :

the higher the HDL cholesterol (4) (in coronary heart disease patients)(1) Khaw KIT et al, Arterioscler Thromb, 1991, 11(3): 489-94 for study in 391 men aged 30-79 yrs

(2) Freedman DS et al, Arterioscler Thrombos, 1991, 11(2): 307-15 for study in 4.062 men

(3)Gutai I et al, Am J Cardiology, 1981, 48: 897-902 (4) Hämäläinen E et al, Atheroscdlerosis, 1987, 67: 155-62

Plasma Testosterone => Serum Lipids

17

Oral testosterone undecanoate (Andriol®) in men with

coronary heart disease :

- E2/testo : testo, E2 =

- sign. total cholesterol, TG, HDL =

- apolipoproteins A & B =

(Wu S et al, Chim Med Sci J, 1992, 7(3): 137-41)

Injectable testosterone esters (Sustanon®)

(Wu S et al, Chin Med Sci J, 1993, 8(4): 207-9)

in coronary heart patients (60-75 years) :

- thromboxane A-2 => constrictory peptide

- prostaglandins 2 =>dilatatory peptide

peptides that have dilatatory & constrictory effects on the coronary arteries

Testosterone therapy =< Cardiovascular blood parameters

18

0

0,2

0,4

0,6

0,8

1

1,2

1,4

HDL - CHOLESTEROL

& TESTOSTERONE THERAPY

HDL

choles-

terol

nmol/l

Figure : Effect of various androgen medications during 12 weeks each on HDL-cholesterol in 18 young health men. No effect on total cholesterol, total triglycerides or insulin levels from these preparations.

(Friedl KE et al, 1990)

1.2

0.77 0.89

1.2

synthetic testosterone derivatives

‘the HDL cholesterol is not modified if an aromatizable androgen is administered”

methyltestosterone

- 36 %

testolactone

- 25 % testosterone enanthate

no change

19

Testosterone

=>

Serum

Triglycerides

20

Serum Testo => correlated negatively w/ Serum Triglycerides & Lipoprotein a

0

50

100

150Serum

levels

(% versus

healthy

controls)

Men + low testosterone (< 270 ng/ml)

Figure: Low plasma T level may be arisk factor for coronary heart

disease, which may relate to the changes of plasma lipoproteins.

Zhao S, Li X, Wang Z. Plasma levels of lipids, lipoproteins and apolipoproteins affected by endogenous testosterone.

Hunan Yi Ke Da Xue Xue Bao. 1998;23(3):299-301 Hunan Medical University, Changsha

n = 201subjects, among them 102 patients + coronary heart disease & 99 healthy subjects

+34 %

- 14 %

100 %

Lipoprotein aTriglyce-

rides

25 vs

17 g/L1.47 vs

1.10

mmol/

L

HDL-

cholesterol

p < 0.05 for all

HDL 3-

chole-

sterol

Men + normal

testosterone

> 270 ng/ml

1.31 vs

1.44

mmol/L

0.88 vs

1.02

mmol/L

+ 47 %

-11 %

21

Triglycerides

American Heart association

22

Men with serum triglycerides

=> risk of ischemic heart disease

0

1

2

3Ischemic

heart

disease

(Relative

risk)

Serum Triglycerides

p = 0.5

Figure: Men belonging to the highest tertile of serum triglycerides

have an increased risk of developping ischemic heart disease (8 yrs of follow-up, initially aged: 53 - 74 yrs, 229 on 2906 developped the disease).

Jeppesen J, et al. Triglyceride concentration and ischemic heart disease: an eight-year

follow-up in the Copenhagen Male Study. Circulation 1998; 97 (11): 1029-36

n = 2906

white men

Lowest

tertile

p < 0.001

2.2

(1.4 - 3.4)

1.5

(1.0-2.3)

Middle

tertile

+ 50 %

+ 120 %

Highest

tertile

1

23

Testosterone =>

Lipoprotein a

24

Lipoprotein aSerum lipoproteine a

=> should be

< 24 mg/dl (Cheng 2001)

or < 30 mgdl (Koda 1999)

Cheng SW, Ting AC. Lipoprotein (a) level and mortality in patients with critical lower limb ischaemia.

Eur J Vasc Endovasc Surg. 2001 Aug;22(2):124-9. Department of Surgery, The University of Hong Kong Medical Centre, Hong Kong, China.

Koda Y, Nishi S, Suzuki M, Hirasawa Y. Lipoprotein(a) is a predictor for cardiovascular mortality of

hemodialysis patients. Kidney Int Suppl. 1999 Jul;71:S251-3. Kidney Center of Shinraku-en Hospital,

Niigata University, School of Medicine, Japan. WG8Y-KUD@asahi-net.or.jp

25

Men, not women, with lipoprotein a

=> mortality

0

1

2

Relative Risk

(adjsuted for age, sex,; other risk

factors such as total & HDL cholest.,

iglycerides; carotid-wall thickness;

smokin or little effect)g status; tdiabetes

or not,& systolic & diastolic ypertension

had no or little effect)

Serum Lipoprotein a in men

p < 0.05

Figure: Similar analyses for women,which also included adjustment

for estrogen use or nonuse, revealed no suchrelation.

Ariyo AA, Thach C, Tracy R; Cardiovascular Health Study Investigators. Lp(a) lipoprotein, vascular disease, and

mortality in the elderly. N Engl J Med. 2003 Nov 27;349(22):2108-15. Dallas, TX 75212, USA

n =5888 community-dwelling older

adults (65 years of age or older) in

the United States,2375 women and

1597 men

Lowest

quintile

p < 0.05

2.54

(1.59-

4.08)

1.76

(1.31-

2.36)

+ 76 %

2.5 x

1

Highest qukntiles

All-cause

Mortality

Vasc. events

Mortality

3.00

(1.59-

5.65)

Stroke

Risk

p < 0.05

3 x

26

• What is Lp-a? = a lipoprotein particle found in the bloodstream. The structure of the Lp-a particle is very similar to an LDL particle linked to a plasminogen molecule. Plasminogen is involved in dissolving blood clots. The function of Lp(a) is unknown.

• How is Lp-a related to atherosclerosis?

• Lp-a is a marker for the development of atherosclerotic vascular disease. Individuals with elevated Lp-a are definitely at an elevated risk of developing atherosclerosis. Whether Lp-a is directly involved in the atherogenic process has not been determined. The concentration of Lp-a is race specific.

• How is Lp-a treated ? Treatments of Lp-a are very few. Nicotinic acid (vit. B3) has been shown to lower concentration of Lp-a to a small degree as well as estrogen supplementation.

Lipoprotein a - Lp(a) – part 1

Preventive Cardiology website- Victoria

27

Serum Testo => correlated negatively w/ Serum Triglycerides & Lipoprotein a

0

50

100

150Serum

levels

(% versus

healthy

controls)

Men + low testosterone (< 270 ng/ml)

Figure: Low plasma T level may be arisk factor for coronary heart

disease, which may relate to the changes of plasma lipoproteins.

Zhao S, Li X, Wang Z. Plasma levels of lipids, lipoproteins and apolipoproteins affected by endogenous testosterone.

Hunan Yi Ke Da Xue Xue Bao. 1998;23(3):299-301 Hunan Medical University, Changsha

n = 201subjects, among them 102 patients + coronary heart disease & 99 healthy subjects

+34 %

- 14 %

100 %

Lipoprotein aTriglyce-

rides

25 vs

17 g/L1.47 vs

1.10

mmol/

L

HDL-

cholesterol

p < 0.05 for all

HDL 3-

chole-

sterol

Men + normal

testosterone

> 270 ng/ml

1.31 vs

1.44

mmol/L

0.88 vs

1.02

mmol/L

+ 47 %

-11 %

28

Serum testo => neg assoc. w/ Lp-a

Serum testosterone: Lipoprotein a

Patients-Controls Reference

an inverse correlation between T & Lp(a) (r=-0.24, P=0.04).

108 postmenop. women (age 62+/-7 yrs)

Kaczmarek A, Int J Cardiol. 2003 Jan;87(1):53-7

a negative assoc. between serum Total testo & serum TG level & Lp-a (r=-0.163,P<0.05)

201 subjects, among them 102patients with CHD and 99 healthy subjects

Int J Cardiol. 1998 Jan 31;63(2):161-4

No difference in homocysteine

47 p. (5 men; 38 yrs) + SH & 50 controls (4 men; 34 yrs )

Aldasouqi S, Endocr Pract. 2004 Sep-Oct;10(5):399-403, Saudi Arabia

S. higher homocysteine => T4 => reduced hom.

33 women + SH, 25 control women

Sengul E, Endocr Res. 2004 Aug;30(3):351-9 Kocaeli Un., Izmit, Turkey.

29

Chemical castration => reduced or

increases Lp-a!Serum testosterone Patients-Controls Reference

GnRH analog triptorelin => sign. increased serum Lp-a from 278 to 377U/l (P=0.004)

10 healthy men + serum testo reversibly suppressed

for 5 weeks

Kaczmarek A, Int J Cardiol. 2003 Jan;87(1):53-7

Suppression of testosterone => sign. increased serum Lp-afrom 5.5 to 8.5 mg/dL

12 healthy young men + during 3 weeks daily s.c. inj. of Cetrorelix, a GnRH antagonist

von Eckardstein A, J Clin Endocrinol Metab. 1997 Oct;82(10):3367-72

GnRH analog buserelin

=> reduced serum Lp-a

by - 48%

elderly males +

prostate cancer

Arrer E, J Clin Endocrinol Metab. 1996 Jul;81(7):2508-11. Austrai

Finasteride => increases Lp-a, but reduces DHT

13 men + benign prostate hyperplasia

+ finasteride;

15 controls

Denti L, Atherosclerosis. 2000 Sep;152(1):159-66.

30

Serum testo => no assoc. w/ Lp-aSerum testosterone: Lipoprotein a

Patients-Controls Reference

No correlation w/ Lp-a, nor CRP 715 healthy middle-aged men

Van Pottelbergh I, Atherosclerosis. 2003;166(1):95-102

No changes in Lp-a in the study population as a whole, but a 17.6% (p < 0.05) reduction in the subjects + high pre-treatmentLp(a) (> 20 mg/dL).

62 healthy obese patients (21 men aged 32 +/- 9.6years and 41 women aged 37 +/- 14.6 years

Nutr Metab Cardiovasc Dis. 2001 Jun;11(3):153-7

Lp(a) concentrations were not

related to all hormonal & clinical

parameters ; Lp(a), did not

change sign. after treatment

22 + idiopathic

hypogonadotropic

hypogonadism & 9 +

Klinefelter's syndrome

Ozata M, J Clin

Endocrinol Metab.

1996 Sep;81(9):3372-8

no assoc. between sex hormones

& Lp(a) levels, incl. Testo &

DHEAs

33 women + SH, 25 control women

Haffner SM,

Arterioscler Thromb.

1994 Jan;14(1):19-24

Lipoprotein(a) levels increased by similar amounts in both(testosterone treated, 3 mg/dL; placebo treated, 4 mg/dL; P = 1.0).

108 healthy men > 65 years +serum testons >1 SD below the mean for young men

Snyder PJ, Am J Med. 2001 Sep;111(4):255-60.

31

Testo => reduces Lipoprotein a

0

50

100

150Serum

Lipoprotein

a

(% versus

healthy

controls)

Normal men

Figure: testosterone reduces Lp(a) in men primarily by anandrogenic

effect and not by its conversion to estradiol.Publication

Study 2: Zmunda JM, Thompson PD, Dickenson R, Bausserman LL. Testosterone decreases lipoprotein(a) in men. Am J

Cardiol. 1996 Jun 1;77(14):1244-7.

187 vs

140 mg/L

- 28 %

100 %

Study 1 (n = 33 )

Prior

treatment

- 25 %

Testo enanthate

(IM 200 mg/wk

after 16 weeks)Testo

Study 1: Anderson RA, Wallace EM, Wu FC. Effect of testosterone enanthate on serum lipoproteins in man. Contraception.

Testo +

testoslactone

(aromatase

inhibitor)

Study 2

- 37%

32

Testo therapy => no effect on Lp-atestosterone => lipoprotein

A

N = participants Reference

Short 16 wks transd.

testo => no change of

Lp-a, nor CRP

Postmenop .women

+transd.estrogen for at least 8

weeks + 2 mg.d of transd.

testo

Davies SR,

Menopause.

2006;13(1):37-45

Australia

Non sign. reduction of

Lp-a with testosterone.

50 women + surgical

menopause + oral 2 mg of E2

valerate + 40 mg of Testo

undecanoate or placebo for

24 wks

Floter A,

Maturitas. 2004

20;47(2):123-9

Sweden

Lo dose testo => no

differences in Lp-a

22 women + severe PMS

(39.6 yrs) + subcut. T

implants (100 mg/6 months)

for at least 2 yrs

Buckler HM, Clin

Endocrinol (Oxf).

1998

Aug;49(2):173-8

Testo => no effect on

Serum Lp(a)

22 + idiopathic

hypogonadotropic

hypogonadism & 9 +

Klinefelter's syndrome

Ozata M, J Clin

Endocrinol Metab.

1996

Sep;81(9):3372-8

33

The End