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A Primer on Anabolic Steroid Use in HIV Infection. Antonio E. Urbina, M.D. Medical Director of HIV/AIDS Education and Training St. Vincent Catholic Medical Center-Manhattan A Local Performance Site of the New York/New Jersey AETC. Anabolic Steroids. Definitions Commonly Used Agents

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A primer on anabolic steroid use in hiv infection l.jpg

A Primer on Anabolic Steroid Use in HIV Infection

Antonio E. Urbina, M.D.

Medical Director of HIV/AIDS Education and Training

St. Vincent Catholic Medical Center-Manhattan

A Local Performance Site of the New York/New Jersey AETC


Anabolic steroids l.jpg
Anabolic Steroids

  • Definitions

  • Commonly Used Agents

  • Indications/Diagnosis

    • Hypogonadism

    • HIV Wasting

  • Adverse Effects

  • Studies

  • Management


Definitions l.jpg
Definitions

  • Androgens: all male sex hormones, usually testosterone, but also testosterone derivatives

  • Androgenic: refers to masculinizing properties such as libido, aggression, acne, hair growth and loss

  • Anabolic: refers to assimilation of nitrogen into tissue (muscle growth)

  • Cannot completely separate one from the other


Testosterone derivatives l.jpg
Testosterone & Derivatives

17b-Esterification

& 17a-Alkylation

OH

19-Nor

A-Ring

Modifications

O

5a-Reduction


Target organs and physiological effects of testosterone and metabolites l.jpg
Target Organs and Physiological Effectsof Testosterone and Metabolites

  • CNS ( libido, well-being, aggression, spatial cognition)

  • Hypothalamus/ Pituitary ( GnRH, LH, FSH;  GH)

  • Larynx (lowers voice)

  • Breast (E2 size)

  • Liver ( SHBG, HDL)

  • Kidney ( erythropoietin)

  • Genitals ( development, spermatogenesis, erections)

  • Prostate ( size, secretions)

  • Skin ( facial/ body hair, sebum production)

  • Bone ( BMD)

  • Muscle ( lean mass, strength)

  • Adipose Tissue ( lipo-lysis,  abdominal fat)

  • Blood ( hematocrit)

  • Immune system ( auto-antibody production)


Androgenic vs anabolic l.jpg

Androgenic

Testosterone (IM)

Androgel (transdermal)

Androderm (transdermal)

Anabolic

Deca-Durabolin (IM)

Oxandrin (oral)

Anadrol (oral)

Androgenic vs Anabolic


Slide9 l.jpg

Production and Regulationof Testosterone

Hypothalamus

GnRH

Free T

2%

Albumin-

bound T

38%

Pituitary

FSH

Testosterone

LH

Testis

SHBG-bound T

60%

Testosterone

T = testosterone

Only 2% is free testosterone

and 98% is bound

Sperm

Adapted from Bagatell CJ, Bremner WJ. N Engl J Med. 1996;334:707-715.

Adapted from Braunstein GD. In: Basic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403-433.


Laboratory diagnosis and workup of primary vs secondary hypogonadism l.jpg
Laboratory Diagnosis and Workup of Primary vs. Secondary Hypogonadism

  • Hypogonadism in adult male - presence of signs or symptoms of hypogonadism with confirmation by laboratory testing

  • Laboratory Testing:

  • AM total testosterone x 2

    • Normally diurnal rhythm with highest levels in AM

  • Free testosterone (2%) - (sometimes even if total normal)

  • Bioavailable testosterone - free (2%) plus loosely bound to albumin (38%) - (total 40%)

    • 60% tightly bound to SHBG


Diagnosis and workup of primary vs secondary hypogonadism cont l.jpg
Diagnosis and Workup of Primary vs. Secondary Hypogonadism (Cont.)

  • LH and FSH - (if low T is established or as initial workup); Repeat with 2 samples taken 20-30 min. apart and pooled

    • FSH and LH secreted in short pulses

  • Prolactin ; Estradiol (if gynecomastia or testicular or adrenal tumor suspected)

  • Definitive diagnosis of T deficiency on the basis of laboratory tests for the aging male has not been established

    • <200 ng/dL clearcut

    • total T may not be an accurate measurement if there is increased or decreased SHBG

    • deficiency considered at 200-350 ng/dL (depending on assay) or if the T or bioavailable T (or free T) is in the lower range of normal


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Diagnosis and Workup of Primary vs. Secondary Hypogonadism (Cont.)

  • If studies indicate clear primary hypogonadism

    • Low T with reciprocal elevated FSH and LH

    • Then pituitary workup not indicated

  • If studies indicate secondary hypogonadism or combined:

    • Low T with low FSL/LH or

    • Low T with normal or high-normal FSH/LH - not appropriately elevated

  • Then MRI of pituitary indicated

    • MRI of pituitary always indicated if elevated prolactin

    • Other pituitary testing may be necessary

  • Stimulation tests generally of limited clinical value to distinguish 1º from 2º or pituitary from hypothalamic defect

AACE Guidelines, Endocrine Practice:8,439,2002


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Medications (common) contribute to hypogonadism (Cont.)

  • Glucocoticoids - testicular and pituitary/hypothalamic

  • ketoconazole - inhibitor of gonadal and adrenal steroidogenesis

  • spironolactone - aldosterone antagonist; and blocks androgen at receptor,inhibits androgen biosynthesis, interferes with binding T to SHBG

  • cimetidine - weak antiandrogen

  • finasteride (propecia) - inhibitor of typeII 5alpha reductase, antiandrogen

  • flutamide and other antiandrogens

  • megastrol acatate (megace) - decreased androgen production and androgen mediated action


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Testosterone Deficiency (Cont.)with Aging

  • Decline in Testosterone with age

    • Decrease in testosterone production

    • Decrease in testosterone clearance

    • Increase in SHBG

      • may be due to higher serum estradiol levels from increased adipose tissue

    • Therefore, bioavailable T decreases more than total T

    • Circadian rhythm (higher T values in AM) lost with aging

Tenover,L.J. End.Metab.Clinics NA:27,969,1998


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Prevalence and Diagnosis of (Cont.)Hypogonadism In HIV

  • Approximately 30% of HIV+ men and 50% of men with AIDS are hypogonadal

    • Correlated with stage of disease, lymphocyte depletion, weight loss, reduced muscle mass, and decreased functional status

    • Free testosterone is the preferred measurement

    • Sex hormone binding globulin (SHBG) increases in men with HIV-infection

Dobs AS. Baillière’s Clin Endocrinol Metab. 1998;12:379-390.Grinspoon S, et al. J Clin Endocrinol Metab. 2000;85:60-65.Wiley S, et al. AIDS. 2003; 17(2): 183-8. Habasque C, et al. Mol Hum Reprod 2002 8(5): 419-25.


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Effects of Testosterone in (Cont.)Hypogonadal Men With AIDS Wasting

Study design

  • 6-month, randomized, placebo-controlled trial

  • 51 men with hypogonadism and AIDS wasting

  • Randomly assigned to receive testosterone enanthate 300 mg or placebo IM every 3 weeks

Grinspoon S, et al. Ann Intern Med. 1998;129:18-26.


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Testosterone (Cont.)

3.5

3

2.5

2

1.5

Changes, kg

1

0.5

0

-0.5

-1

-1.5

Fat-Free Mass

Lean Body

Muscle Mass

(n=21)

Mass (n=22)

(n=21)

No Testosterone

3.5

3

2.5

2

1.5

1

Changes, kg

0.5

0

-0.5

-1

-1.5

Fat-Free Mass

Lean Body

Muscle Mass

(n=19)

Mass (n=19)

(n=18)

Effects of Testosterone in Hypogonadal Men With AIDS Wasting

Grinspoon S, et al. Ann Intern Med. 1998;129:18-26.


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IM Testosterone Therapy and Resistance Exercise in Hypogonadal HIV+ Men

Study design

  • A 16-week, placebo-controlled, double-blind, randomized trial

  • 61 HIV+ men, aged 18 to 50 years old

  • Randomized to 1 of 4 groups

    • Placebo, no exercise (n=14)

    • Testosterone enanthate 100 mg/wk, no exercise (n=17)

    • Placebo and exercise (n=15)

    • Testosterone and exercise (n=15)

Bhasin S, et al. JAMA. 2000;283:763-770.


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IM Testosterone Therapy and Resistance Exercise in Hypogonadal HIV+ Men

Study results

  •  weight in testosterone alone or exercise alone

  •  maximum voluntary muscle strength in all 4 treatment groups

  • Greater  in thigh muscle volume in T alone or PRE alone

  •  lean body mass with testosterone or T + PRE

  •  hemoglobin in testosterone recipients

Bhasin S, et al. JAMA. 2000;283:763-770.


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IM Testosterone and/or Exercise in Hypogonadal HIV+ MenEugonadal Men With AIDS Wasting

Study design

  • 12-week randomized, controlled trial

  • 54 eugonadal men with AIDS wasting

  • Randomized to testosterone enanthate 200 mg/wk or placebo and progressive resistance training (3x/wk) or no exercise

Grinspoon S, et al. Ann Intern Med. 2000;133:348-355.


Im testosterone and or exercise in eugonadal men with aids wasting22 l.jpg

1400 Hypogonadal HIV+ Men

Intervention

Placebo

1200

1000

P=.045

800

P=.002

P=.001

P=.004

Change in Muscle Mass, mm2

600

400

200

0

Arm

Leg

Arm

Leg

Progressive Exercise(3 times/wk)

IM Testosterone (200 mg/wk)

IM Testosterone and/or Exercise in Eugonadal Men With AIDS Wasting

Grinspoon S, et al. Ann Intern Med. 2000;133:348-355.


Background l.jpg
Background Hypogonadal HIV+ Men

  • Despite HAART, HIV-wasting is still very common, affecting up to 30% of patients in the US and Europe (Wanke et al. 2000, Balslef et al. 1997)

  • Death due to wasting in patients with AIDS is related to the magnitude of tissue depletion, independent of the underlying cause (Kotler DP et al. Am J Clin Nutr. 1989)


Aids wasting syndrome aws l.jpg
AIDS-Wasting Syndrome (AWS) Hypogonadal HIV+ Men

  • 10% involuntary weight loss in last 12 months

  • 7.5% involuntary weight loss in last 6 months

  • 5% loss of BCM in last 6 months

  • Men: BCM <35% B.W. and BMI <27 kg/m2Women: BCM <23% B.W. and BMI <27 kg/m2

Polsky, Kotler and Steinhart.


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Major Causes of AWS Hypogonadal HIV+ Men

  • Reduced food intake

  • Malabsorption/diarrhea

  • Infections

  • HIV-enteropathy

  • Altered metabolism

  • Medications


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Treatment Strategies of AWS Hypogonadal HIV+ Men

  • Appetite stimulants (megestrol acetate, dronabinol)

  • Nutritional supplements (beta-hydroxy-beta-methyl-butyrate, glutamine, arginine, vitamins, micronutrients, protein)

  • Cytokine inhibitors (thalidomide, pentoxifyllin)

  • Anabolic proteins (human growth hormone, Insulin-like growth factor)

  • Anabolic steroids

  • Physical exercise


Oxymetholone as therapy to maintain body composition in hiv positive subjects urbina a 2003 l.jpg
Oxymetholone as Therapy to Maintain Body Composition in HIV-Positive Subjects(Urbina,A. 2003)

  • Open label, single center, Phase III study involving pts who have received at least 4 months of prior anabolic (nandrolone or oxandrolone) for a past or current dx of wasting

  • Pts were then switched to oxymetholone 50 mg QD and followed for 6 months

  • Efficacy and safety evaluations performed at 4 week interval from baseline through week 12, then q6 weeks until week 24


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Oxymetholone as Therapy to Maintain HIV-Positive Subjects(Urbina, A 2003)

  • Study Objectives

    • Maintenance (no change) or improvement (increase) in BCM as measured by BIA

    • Evaluate the effects on HIV replication as measured by change in CD4 and viral load from baseline

    • Evaluate clinical laboratory (hematology, lipids, LFTs, testosterone, PSA) and vital sign measurements


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Oxymetholone as Therapy to Maintain HIV-Positive Subjects(Urbina, A 2003)

  • 16 HIV+ men were successfully switched to oxymetholone

  • BCM was maintained over the 24 week period with a mean increase of 2.2 lbs (p=.091)

  • Increase in FFM for all weeks with significant increase at 24 weeks (3.1 lbs, p=0.027)


Oxymetholone to maintain urbina a 2003 l.jpg
Oxymetholone to Maintain HIV-Positive Subjects(Urbina, A 2003)

  • Lipids decreased over time (especially HDL and LDL)

  • Overall, no clinically significant effect on LFTs

  • CD4 values increased over time (mean of 21 cell increase)

  • Testosterone levels increased by week 18 and 24


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Oxymetholone to maintain HIV-Positive Subjects(Urbina, A 2003)


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Effects of Testosterone on Bone Density in Eugonadal Men With AIDS Wasting

  • Bone Density increased significantly in response to testosterone (P=.02)

Fairfield WP, et al. J Clin Endocrinol Metab. 2001;86:2020-2026.


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Anabolic Drugs: With AIDS Wastinga Comparison of Clinical Studies


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Depression Indices in Hypogonadal HIV-Infected Men With AIDS Wasting

Study design

  • 6-month, randomized, placebo-controlled trial

  • 51 men with hypogonadism and AIDS wasting

  • Randomly assigned to receive testosterone enanthate 300 mg or placebo IM every 3 weeks

  • 10 age and weight matched men with AIDS wasting who were not hypogonadal were recruited as a control group for baseline comparison only and did not receive testosterone

Grinspoon S. et al. J Clin Endocrinol Metab. 2000;85:60-65.


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Depression Indices in Hypogonadal HIV-Infected Men With AIDS Wasting

  • Beck Depression Inventory

    • Administered to all patients (hypogondal and eugonadal) at baseline and again after 6 months to the hypogonadal patients in the randomized study

    • Normal range <10

Grinspoon S. et al. J Clin Endocrinol Metab. 2000;85:60-65.


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Depression Indices in Hypogonadal HIV-Infected Men With AIDS Wasting

*P=.02

N=51

15.5 +1

N=10

10.6 +1.4

Grinspoon S. et al. J Clin Endocrinol Metab. 2000;85:60-65.


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Depression Indices in Hypogonadal HIV-Infected Men With AIDS Wasting

n.s.

P< 0.001

Grinspoon S. et al. J Clin Endocrinol Metab. 2000;85:60-65.


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ADVERSE EFFECTS With AIDS Wasting

  • Acne

  • Hair loss

  • Increased libido (supraphysiologic)

  • Insomnia

  • Testicular atrophy

  • Agressiveness (supraphysiologic)

  • Hypertension


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ADVERSE EFFECTS With AIDS Wasting

  • Gynecomastia

  • Virilization

  • Polycythemia

  • Increase in transaminases

    • Hepatis peliosis

    • Inceased risk with co-infected

  • Hyperlipidemia (↓HDL)

  • Prostatic enlargement


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Algorithim for Use of Anabolics With AIDS Wasting

  • Select appropriate patient

    • Wasting, post-inpatient, after tx of OI

    • Hypogonadol vs eugonadol

      • Free or bioavilable

  • Prior to initiation

    • Check LFTs, CBC, PSA and DRE


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Algorithim for Use of Anabolic Steroids With AIDS Wasting

  • Treatment for short duration

    • 3-6 months

  • Monitoring of lab values

    • Testosterone

    • LFT’s

    • CBC

    • Lipid panel

    • PSA


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Monitoring PSA during Androgen Therapy With AIDS Wasting

  • Elevated serum PSA levels before or during therapy must be investigated.

  • Measure PSA at baseline, 6 months, then annually

  • Interval increase of PSA of > 0.75 ng/ml (even if still in “normal” range) requires investigation


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