A Primer on Anabolic Steroid Use in HIV Infection

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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

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Anabolic Steroids

• Definitions
• Commonly Used Agents
• Indications/Diagnosis
• Hypogonadism
• HIV Wasting
• Adverse Effects
• Studies
• Management

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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

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Testosterone Derivatives
17b-Esterification 17a-Alkylation
OH
19-Nor
A-Ring Modifications
O
5a-Reduction
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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)

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Androgenic vs Anabolic

• Androgenic
• Testosterone (IM)
• Androgel (transdermal)
• Androderm (transdermal)

• Anabolic
• Deca-Durabolin (IM)
• Oxandrin (oral)
• Anadrol (oral)

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Production and Regulationof Testosterone
Hypothalamus
GnRH
Free T 2
Albumin- bound T 38
Pituitary
FSH
LH
Testosterone
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. 1996334707-715.
Adapted from Braunstein GD. In Basic Clinical
Endocrinology. 5th ed. Stamford, Conn Appleton
Lange 1997403-433.
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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

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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
• lt200 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 Practice8,439,2002
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Medications (common) contribute to hypogonadism

• 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 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 NA27,969,1998
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Prevalence and Diagnosis ofHypogonadism 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. Baillières Clin Endocrinol Metab.
199812379-390.Grinspoon S, et al. J Clin
Endocrinol Metab. 20008560-65.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 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.
199812918-26.
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Effects of Testosterone in Hypogonadal Men With
AIDS Wasting
Grinspoon S, et al. Ann Intern Med.
199812918-26.
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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 (n14)
• Testosterone enanthate 100 mg/wk, no exercise
  (n17)
• Placebo and exercise (n15)
• Testosterone and exercise (n15)

Bhasin S, et al. JAMA. 2000283763-770.
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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. 2000283763-770.
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IM Testosterone and/or Exercise in Eugonadal 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.
2000133348-355.
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IM Testosterone and/or Exercise in Eugonadal Men
With AIDS Wasting
Grinspoon S, et al. Ann Intern Med.
2000133348-355.
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Background

• 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)

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AIDS-Wasting Syndrome (AWS)

• 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 lt35 B.W. and BMI lt27 kg/m2Women BCM
  lt23 B.W. and BMI lt27 kg/m2

Polsky, Kotler and Steinhart.
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Major Causes of AWS

• Reduced food intake
• Malabsorption/diarrhea
• Infections
• HIV-enteropathy
• Altered metabolism
• Medications

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Treatment Strategies of AWS

• 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

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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(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(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, p0.027)

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Oxymetholone to Maintain(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(Urbina, A 2003)
Measure Result
BMI Increased 0.80.2 (p0.006)
FFM (lbs) Increased 3.81.5 (p0.027)
Waist circumference (cm) Decreased 0.40.9 (p0.647)
Triceps skinfold measure (cm) Decreased 0.10.1 (p0.424)
Mid-arm muscle (cm2) Increased 4.92.0 (p.037)
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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.
2001862020-2026.
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Anabolic Drugs a Comparison of Clinical Studies
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Depression Indices in Hypogonadal HIV-Infected Men

• 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.
20008560-65.
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Depression Indices in Hypogonadal HIV-Infected Men

• 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 lt10

Grinspoon S. et al. J Clin Endocrinol Metab.
20008560-65.
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Depression Indices in Hypogonadal HIV-Infected Men
P.02
N51 15.5 1
N10 10.6 1.4
Grinspoon S. et al. J Clin Endocrinol Metab.
20008560-65.
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Depression Indices in Hypogonadal HIV-Infected Men
n.s.
Plt 0.001
Grinspoon S. et al. J Clin Endocrinol Metab.
20008560-65.
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ADVERSE EFFECTS

• Acne
• Hair loss
• Increased libido (supraphysiologic)
• Insomnia
• Testicular atrophy
• Agressiveness (supraphysiologic)
• Hypertension

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ADVERSE EFFECTS

• 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

• 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

• Treatment for short duration
• 3-6 months
• Monitoring of lab values
• Testosterone
• LFTs
• 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 gt 0.75 ng/ml (even if
  still in normal range) requires investigation