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 • Indications/Diagnosis • Hypogonadism • HIV Wasting • Adverse Effects • Studies • Management
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 17b-Esterification & 17a-Alkylation OH 19-Nor A-Ring Modifications O 5a-Reduction
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 Testosterone (IM) Androgel (transdermal) Androderm (transdermal) Anabolic Deca-Durabolin (IM) Oxandrin (oral) Anadrol (oral) Androgenic vs Anabolic
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 • 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.) • 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
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
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
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 NA:27,969,1998
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. 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 • 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.
Testosterone 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.
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.
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.
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. 2000;133:348-355.
1400 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 • 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) • 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.
Major Causes of AWS • Reduced food intake • Malabsorption/diarrhea • Infections • HIV-enteropathy • Altered metabolism • Medications
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
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
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
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, p=0.027)
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
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.
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. 2000;85:60-65.
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 <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 n.s. P< 0.001 Grinspoon S. et al. J Clin Endocrinol Metab. 2000;85:60-65.
ADVERSE EFFECTS • Acne • Hair loss • Increased libido (supraphysiologic) • Insomnia • Testicular atrophy • Agressiveness (supraphysiologic) • Hypertension
ADVERSE EFFECTS • Gynecomastia • Virilization • Polycythemia • Increase in transaminases • Hepatis peliosis • Inceased risk with co-infected • Hyperlipidemia (↓HDL) • Prostatic enlargement
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
Algorithim for Use of Anabolic Steroids • Treatment for short duration • 3-6 months • Monitoring of lab values • Testosterone • LFT’s • CBC • Lipid panel • PSA
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