Transcript A Primer on Anabolic Steroid Use in HIV Infection

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
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Definitions
Commonly Used Agents
Indications/Diagnosis
Hypogonadism
 HIV Wasting
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Adverse Effects
Studies
Management
Definitions
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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
17b-Esterification
& 17a-Alkylation
19-Nor
A-Ring
Modifications
O
5a-Reduction
OH
Target Organs and Physiological Effects
of Testosterone and Metabolites
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CNS ( libido, well-being,
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aggression, spatial cognition)
Hypothalamus/ Pituitary
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( GnRH, LH, FSH;  GH) 
Larynx (lowers voice)
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Breast (E2  size)
Liver ( SHBG, HDL)
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Kidney ( erythropoietin)
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Genitals ( development,
spermatogenesis, erections)
Prostate ( size, secretions)
Skin ( facial/ body hair,
sebum production)
Bone ( BMD)
Muscle ( lean mass,
strength)
Adipose Tissue ( lipolysis,  abdominal fat)
Blood ( hematocrit)
Immune system ( autoantibody production)
Androgenic vs Anabolic
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Androgenic
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Testosterone (IM)
Androgel (transdermal)
Androderm (transdermal)
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Anabolic
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Deca-Durabolin (IM)
Oxandrin (oral)
Anadrol (oral)
Mean Steady-State Testosterone Concentrations in
Patients Receiving AndroGel®
Day 90
Data on file. Unimed Pharmaceuticals, Inc.
Hypothalamus
GnRH
Production and Regulation
of Testosterone
Albuminbound T
38%
Pituitary
Testosterone
Free T
2%
LH FSH
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
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Hypogonadism in adult male - presence of signs or
symptoms of hypogonadism with confirmation by laboratory
testing
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Laboratory Testing:
AM total testosterone x 2
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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.)
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LH and FSH - (if low T is established or as initial workup);
Repeat with 2 samples taken 20-30 min. apart and pooled
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FSH and LH secreted in short pulses
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Prolactin ; Estradiol (if gynecomastia or testicular or adrenal
tumor suspected)
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Definitive diagnosis of T deficiency on the basis of
laboratory tests for the aging male has not been established
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<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
Diagnosis and Workup of Primary vs.
Secondary Hypogonadism (Cont.)
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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
Medications (common) contribute to
hypogonadism
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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
Testosterone Deficiency
with Aging
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Decline in Testosterone with age
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Decrease in testosterone production
Decrease in testosterone clearance
Increase in SHBG
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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
Prevalence and Diagnosis of
Hypogonadism In HIV
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Approximately 30% of HIV+ men and 50% of men
with AIDS are hypogonadal
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Correlated with stage of disease, lymphocyte
depletion, weight loss, reduced muscle mass, and
decreased functional status
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Free testosterone is the preferred measurement
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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.
Effects of Testosterone in
Hypogonadal Men With AIDS Wasting
Study design
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6-month, randomized, placebo-controlled trial
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51 men with hypogonadism and AIDS wasting
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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.
Effects of Testosterone in
Hypogonadal Men With AIDS Wasting
Changes, kg
Testosterone
3.5
3
2.5
2
1.5
1
0.5
0
-0.5
-1
-1.5
Fat-Free Mass
(n=21)
Muscle Mass
(n=21)
No Testosterone
3.5
3
Changes, kg
Lean Body
Mass (n=22)
2.5
2
1.5
1
0.5
0
-0.5
-1
-1.5
Fat-Free Mass
(n=19)
Lean Body
Mass (n=19)
Muscle Mass
(n=18)
Grinspoon S, et al. Ann Intern Med. 1998;129:18-26.
IM Testosterone Therapy and Resistance
Exercise in Hypogonadal HIV+ Men
Study design
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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.
IM Testosterone Therapy and Resistance
Exercise in Hypogonadal HIV+ Men
Study results
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 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.
IM Testosterone and/or Exercise in
Eugonadal Men With AIDS Wasting
Study design
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12-week randomized, controlled trial
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54 eugonadal men with AIDS wasting
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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.
Change in Muscle Mass, mm2
IM Testosterone and/or Exercise in
Eugonadal Men With AIDS Wasting
1400
Intervention
Placebo
1200
1000
P=.045
800
600
P=.002
P=.001
P=.004
400
200
0
Arm
Leg
Progressive Exercise
(3 times/wk)
Arm
Leg
IM Testosterone
(200 mg/wk)
Grinspoon S, et al. Ann Intern Med. 2000;133:348-355.
Background
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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)
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10% involuntary weight loss in last 12 months
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7.5% involuntary weight loss in last 6 months
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5% loss of BCM in last 6 months
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Men: BCM <35% B.W. and BMI <27 kg/m2
Women: BCM <23% B.W. and BMI <27 kg/m2
Polsky, Kotler and Steinhart.
Major Causes of AWS
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Reduced food intake
Malabsorption/diarrhea
Infections
HIV-enteropathy
Altered metabolism
Medications
Treatment Strategies of AWS
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Appetite stimulants (megestrol acetate, dronabinol)
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Nutritional supplements (beta-hydroxy-beta-methylbutyrate, glutamine, arginine, vitamins, micronutrients,
protein)
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Cytokine inhibitors (thalidomide, pentoxifyllin)
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Anabolic proteins (human growth hormone, Insulinlike growth factor)
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Anabolic steroids
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Physical exercise
Oxymetholone as Therapy to Maintain Body
Composition in HIV-Positive Subjects
(Urbina,A. 2003)
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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
Oxymetholone as Therapy to
Maintain
(Urbina, A 2003)
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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
(Urbina, A 2003)
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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)
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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
Oxymetholone to maintain
(Urbina, A 2003)
Measure
Result
BMI
Increased 0.8±0.2 (p=0.006)
FFM (lbs)
Increased 3.8±1.5 (p=0.027)
Waist circumference (cm) Decreased 0.4±0.9
(p=0.647)
Triceps skinfold measure Decreased 0.1±0.1
(cm)
(p=0.424)
Mid-arm muscle (cm2)
Increased 4.9±2.0 (p=.037)
Effects of Testosterone on Bone Density
in Eugonadal Men With AIDS Wasting
Change Lumbar Spine Regional BMD, %
5
4
3
2
1
0
-1
-2
-3
Testosterone
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No
Testosterone
Bone Density increased significantly in response to
testosterone (P=.02)
Fairfield WP, et al. J Clin Endocrinol Metab. 2001;86:2020-2026.
Anabolic Drugs:
a Comparison of Clinical Studies
Drug
(No of subjects)
Oxymetholone
(n=30)
Hengge 1996
Duration
(weeks)
12
Control Arm
Nandrolone
Decanoate
(n=17)
Gold 1996
16
No
open-label
study
Nandrolone
Decanoate
(n=10)
Strawford 1999
12
Yes
No
open-label
study
Oxandrolone
(n=10)
Romeyn 2000
12
No
pilot-study
Oxandrolone
(n=21)
Berger 1996
16
Yes
Inclusion
Criteria
Loss of B.W.
>10% last 4
mths.
Mean Gain of
Weight
5.7 kg
(Oxymetholone)
4.4 kg (Oxy +
Ketotifen)
Body
Composition
No
Comments
Loss of B.W. 5- 62 kg
15 %
2.3 kg
Yes
Good
tolerance
Loss of B.W.
>5% reduced
testosterone
levels
No data
4.9  1.2 kg
Yes
No data
2.7 kg
Oxandrolone,
3.9 kg + PRE
No
No data
1.7 kg
No
Loss of B.W.
>5%
reduction of
muscle mass
Loss of B.W.
>10%
Baseline
Body Weight
56.5 kg
(Oxymetholone)
56 kg (Oxy +
Ketotifen)
Significant
increase of
BMI in both
groups
No increased
strength
Depression Indices in
Hypogonadal HIV-Infected Men
Study design
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6-month, randomized, placebo-controlled trial
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51 men with hypogonadism and AIDS wasting
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Randomly assigned to receive testosterone enanthate 300 mg or
placebo IM every 3 weeks
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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.
Depression Indices in
Hypogonadal HIV-Infected Men
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Beck Depression Inventory
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Administered to all patients (hypogondal and eugonadal) at
baseline and again after 6 months to the hypogonadal
patients in the randomized study
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Normal range <10
Grinspoon S. et al. J Clin Endocrinol Metab. 2000;85:60-65.
Depression Indices in
Hypogonadal HIV-Infected Men
*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.
Depression Indices in
Hypogonadal HIV-Infected Men
P< 0.001
n.s.
Grinspoon S. et al. J Clin Endocrinol Metab. 2000;85:60-65.
ADVERSE EFFECTS
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Acne
Hair loss
Increased libido (supraphysiologic)
Insomnia
Testicular atrophy
Agressiveness (supraphysiologic)
Hypertension
ADVERSE EFFECTS
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Gynecomastia
Virilization
Polycythemia
Increase in transaminases
Hepatis peliosis
 Inceased risk with co-infected
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Hyperlipidemia (↓HDL)
Prostatic enlargement
Algorithim for Use of Anabolics
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Select appropriate patient
Wasting, post-inpatient, after tx of OI
 Hypogonadol vs eugonadol
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Free or bioavilable
Prior to initiation
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Check LFTs, CBC, PSA and DRE
Algorithim for Use of Anabolic Steroids
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Treatment for short duration
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3-6 months
Monitoring of lab values
Testosterone
 LFT’s
 CBC
 Lipid panel
 PSA
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Monitoring PSA during Androgen
Therapy
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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