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Safety Issues in Chronic Androgen Therapy in Post-menopausal Women: What we know, what we don’t know PowerPoint PPT Presentation


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Safety Issues in Chronic Androgen Therapy in Post-menopausal Women: What we know, what we don’t know . Adrian S. Dobs, M.D., M.H.S. Professor of Medicine The Johns Hopkins University School of Medicine Baltimore, MD. Effects of Testosterone and Its Metabolites in Women.

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Safety Issues in Chronic Androgen Therapy in Post-menopausal Women: What we know, what we don’t know

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Safety issues in chronic androgen therapy in post menopausal women what we know what we don t know l.jpg

Safety Issues in Chronic Androgen Therapy in Post-menopausal Women: What we know, what we don’t know

Adrian S. Dobs, M.D., M.H.S.

Professor of Medicine

The Johns Hopkins University School of Medicine

Baltimore, MD


Effects of testosterone and its metabolites in women l.jpg

Effects of Testosterone and Its Metabolites in Women


Outline of safety concerns of testosterone administration to women l.jpg

Outline of Safety Concerns of Testosterone Administration to Women

  • Androgenic effects

  • Cardiovascular

    • Lipids

    • Vascular

    • Glucose tolerance

    • Hematopoietic

  • Endometrial and breast effects

  • Recommendations


Effect of testosterone on acne hirsutism and virilization l.jpg

Effect of Testosterone on Acne, Hirsutism and Virilization

  • Clinical presentation: Acne, hirsutism, clitoromegaly, temporal balding, voice deepening

  • All commonly associated with high doses of testosterone

  • Rare in low dose androgen replacement

  • Mild acne and hirsutism reported in cases of methyl testosterone

  • Dose and duration dependent and mostly reversible

Hickok, Obstet Gynecol 1993;82:919-24,

Lobo, Fertil Steril 2004;79:1341-1352


Hirsutism scores in women on estrogens and androgens l.jpg

90

80

70

60

50

40

Worse

30

Same

20

Better

10

0

Estrogen +

CEE 0.625

Estrogen +

CEE 1.25

Androgen

Androgen- Hi

- Low

Hirsutism Scores in Women on Estrogens and Androgens

% of Women

Barrett-Connor, J Reprod Med 1999


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Outline of Safety Concerns of Testosterone Administration to Women

  • Androgenic effects

  • Cardiovascular

    • Lipids

    • Vascular

    • Glucose tolerance

    • Hematopoietic

  • Endometrial and breast effects

  • Recommendations


Odds ratio of cardiovascular events by quartile of endogenous hormone levels l.jpg

2

1.8

1.6

1.4

Testosterone

1.2

T - adjusted for risks

1

0.8

FAI - p=0.02

0.6

FAI - adjusted for risks

0.4

0.2

0

1st Qtr

2nd Qtr

3rd Qtr

4th Qtr

Odds Ratio of Cardiovascular Events by Quartile of Endogenous Hormone Levels

n=200

Women’s Health Study

Rexrode, Circulation 2003;108:1688-93


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Effects of Exogenous Testosterone on Serum Lipids

  • Clinical: Oral androgens – significant reduction in HDL, neutral to LDL, lowers TG

  • Physiology: Changes in hepatic lipase

  • Data from women:

    • Effect mainly dependent on route of administration and type

    • Aromatizable androgens are generally neutral


Change in lipids in women randomized to estrogen vs with estrogen and methyltestosterone l.jpg

15

10

5

0

-5

Estrogen

-10

-15

Estrogen + 2.5 methyl

T

-20

-25

-30

-35

HDL

LDL

TG

% Change in Lipids in Women Randomized to Estrogen vs. with Estrogen and Methyltestosterone

*

*

Dobs, JCEM, 2002


Lipid parameters did not change with transdermal t administration l.jpg

Placebo

Baseline

150 mg

300 mg

250

200

150

100

Lipid Level (mg/dL)

50

0

Total

HDL

LDL

Triglycerides

Lipid Parameters Did Not Change with Transdermal T Administration

Cholesterol

Shifren, et al. JCEM


Effect of testosterone on vasculature l.jpg

Effect of Testosterone on Vasculature

  • Clinical: Endothelial dysfunction is an early marker of disease

  • Epidemiology: Decrease in Flow-Mediated Vasodilation after menopause

  • Measurement: Endothelial-independent dilation (glyceryl trinitrate induced) measured at the brachial artery


Effect of t on the vasculature reactivity in women l.jpg

18

16

14

12

10

0

8

6 wks

6

4

2

0

FMD - Test

FMD- Control

GTN- Test

Effect of T on the Vasculature Reactivity in Women

p<0.05

p<0.05

Worbys, JCEM 2001;86;158-61


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Plasma Viscosity

  • Clinical: Increased plasma viscosity is an established risk factor for CV disease and predicts CAD

  • Physiology: Affected by fibrinogen and triglycerides

  • Women: Small study of methyl T – viscosity decreased

Neumann, Br Heart J 1991;66:425-430.

Sweetman Eur Heart J 1996;17:1814-20.

Ernst, Fibrinogen BMJ 1991;303:596-7.


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Coagulation and Blood

  • Clinical: Hypercoagulation and polycythemia are CV risk factors

  • Physiology: Androgens stimulate hematopoiesis

    • Erythropoiten, Erythroid Colony Units

  • Men: Erythrocytosis can be observed in men with excess testosterone administration (injectable)

  • Women: No effect on clotting factors in 22 young women using implants

  • No reports of polycythemia in women

Buckler. Clin Endocrinol 1998;49:173-8.

Shahidi, NEJM 1973;289:72-80.

Barrett-Connor J Reprod Med 1999;44:1012-20.

20, 25


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Glucose Metabolism

  • Clinical: Hyperglycemia and hyperinsulinism are clear risk factor of CV risk

  • Women: No evidence of changes in fasting glucose or insulin sensitivity

  • Caveat: Unclear relationship to Polycystic Ovarian Disease

Shifren, NEJM 2000;343:682-826. Lovejoy, JCEM 1996;81:3298-0330


Carbohydrate metabolism did not change with transdermal t administration l.jpg

Placebo

120

Baseline

150 mg

300 mg

100

80

60

Mean Concentration (SEM)

40

20

0

Fasting Glucose

Insulin

(mg/dL)

(U/L)

Carbohydrate Metabolism Did Not Change with Transdermal T Administration

Sifren et al. NEJM 2000;343:682-688


Endogenous testosterone and cardiovascular risk in women l.jpg

Endogenous Testosterone and Cardiovascular Risk in Women

  • Polycystic Ovarian Syndrome/Metabolic syndrome – obesity, hyperinsulinism, hyperandrogenism, hyperlipidemia

  • Mechanism – Hyperinsulinism stimulates testosterone production from the ovary and decreases SHBG from the liver

  • Question – Is there an effect of testosterone per se on CV risk or via its metabolism to estradiol?


Outline of safety concerns of testosterone administration to women18 l.jpg

Outline of Safety Concerns of Testosterone Administration to Women

  • Androgenic effects

  • Cardiovascular

    • Lipids

    • Vascular

    • Glucose tolerance

    • Hematopoietic

  • Endometrial and breast effects

  • Recommendations


Odds ratios for endometrial cancer by quartiles of steroid hormone in post menopausal women l.jpg

6

5

4

Estradiol (p=0.0001)

3

Testosterone (p=0.02,

adjusted p=0.06)

2

1

0

1st Qtr

2nd Qtr

3rd Qtr

4th Qtr

Odds Ratios for Endometrial Cancer by Quartiles of Steroid Hormone in Post-Menopausal Women

Lukanova, Int J Cancer 2004;108:425-432


Endometrial hyperplasia and cancer l.jpg

Endometrial Hyperplasia and Cancer

  • Reports of hyperplasia and cancer with high doses of T (transsexuals)

  • No cancers reported with low doses

  • Endometrial hyperplasia in 1/107 given methyl T as well as 1/111 of estrogen only

  • 6% incidence of cystic endometrial hyperplasia

  • Stable vaginal cytology

Futter JCEM 1986;62:16-21, Hickok Obstet Gynecol 1993;82:919-24,

Lobo Fertil Steril 2003;79:1341-52, Sarrel J Reprod 199843;847-56


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Breast Cancer Risk

  • Epidemiology: May be a relationship between high endogenous T and breast cancer

    • Hyperandrogenism associated with metastasis

  • Physiology: Androgen receptors found in 50-90% of breast tumors and may stimulate breast epithelium via aromatization

  • Women: No reports of breast cancer with exogenous T treatment

Ballerini Breast Cancer Res Treat 1993;26:1-6. Secreto, Eur J Cancer 1994;30A:1629. Endogenous Hormones and Breast Cancer Group, J National Cancer Institute 2003


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Other Possible Effects of Testosterone in Women

  • Liver Function

    • Men: High dose of alkylated androgens have been associated with hepatotoxicity and hepatic adenomas

    • Women: No evidence of abnormal LFT with lower doses either pellets or transdermal

  • Fluid retention

    • Minimal

Basaria JCEM 2001;86:5108-17. Barrett-Connor J Reprod Med 1999;44:1012-20;

Shifren NEJM 2000;343:682-88


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Anger and Hostility

  • Clinical presentation: Difficult to measure

  • Physiology: Androgen and estrogen receptors in the brain

  • Men: Some questionable data on testosterone and violent behavior in men

  • Women: Increase in hostility scores in women given high doses

  • No evidence in lower doses

Bagatell, JCEM 1994;79:561-567,

Sherwin, Psychoneuroneuroendorinology 1985:10:325-335


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Outline of Safety Concerns of Testosterone Administration to Women

  • Androgenic effects

  • Cardiovascular

    • Lipids

    • Vascular

    • Glucose tolerance

    • Hematopoietic

  • Endometrial and breast effects

  • Recommendations


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Contraindications of T Treatment

  • Absolute

    • Pregnancy, lactation

    • Endometrial cancer of unexplained vaginal bleeding

    • Breast cancer

  • Relative

    • Moderate-severe acne or hirsutism

    • Androgenic alopecia

    • Severe insulin resistance

    • Anger management disorders

Basaria and Dobs, Mayo Clin Proc 2004 Apr;79(4 Suppl):S25-32


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Monitoring of Women on Testosterone Treatment

  • Acne and hirsutism – at each visit

  • Virilization - at each visit

  • Anger and hostility – at each visit

  • Breast exams and serial mammograms – annually

  • Ensure regular OB/GYN exams

    • Discontinue if vaginal bleeding

  • Hematocrits – after 3 mos. and then annually

  • Serum lipids – as indicated

  • Serum total testosterone – 6 weeks and every 6 mos.???


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Remaining Questions About the Safety of Testosterone Therapy

  • Long-term effects on androgenic signs and symptoms

  • Conceptual difficulties with endogenous T vs. exogenous treatment and CV risk

  • Testosterone alone vs. in combination with estrogens and progestins

  • Risk on breast and uterine tissue


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