Testosterone / Anabolic steroid misuse

Anabolic–androgenic steroids (AAS) are synthetic analogues of testosterone. Therapeutically they are prescribed for confirmed androgen-deficiency states (e.g. primary or secondary hypogonadism, selected catabolic disorders). Outside these indications they are commonly misused—often in “cycles” or “stacks”—to accelerate gains in muscle mass, reduce recovery times, and enhance physical appearance or sporting performance.

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Formulations & Illicit Sources

Legal preparations	Common strengths	Comments
Injectables – testosterone esters, nandrolone decanoate, boldenone undecylenate	50–300 mg/mL	Slow-release depot; favoured for longer “bulking” cycles
Orals – 17-α-alkylated agents (oxandrolone, oxymetholone, methandienone, stanozolol)	2.5–50 mg tablets/capsules	Higher hepatotoxic risk
Transdermals – gels, creams, patches	20–50 mg daily dose	Therapeutic use only
Veterinary products / counterfeits – “Stanabolic”, “Testo L.A.”, “Equipoise”	Variable, often unlabelled	Frequently under- or over-dosed; risk of contaminants

Gym, internet or “underground lab” AAS frequently contain substituted compounds, incorrect strengths, or veterinary-grade hormones. Needle sharing adds blood-borne virus risk.

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Classification of Widely Misused AAS

1. 17-α-Alkylated (mainly oral)

• Oxandrolone (Anavar)
• Oxymetholone (Anadrol)
• Methandienone (Dianabol)
• Fluoxymesterone
• Stanozolol (Winstrol)
• Testosterone undecanoate (Restandol)*

*Note: testosterone undecanoate is absorbed via lymphatics; it behaves more like an oral pro-drug of injectable T.

2. 17-β-Esterified (injectable depot)

• Testosterone cypionate / enanthate / propionate / phenylpropionate
• Boldenone undecylenate (Equipoise)
• Nandrolone decanoate (Deca-Durabolin) / phenpropionate
• Dromostanolone propionate (Masteron)

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Mechanism of action

1. Routes of Administration

• Intramuscular (IM) injection
  • Common vehicle: vegetable oils (e.g. arachis oil).
  • Excipients added: benzyl alcohol (BA) and benzoyl benzoate (BB) for bacteriostatic properties and solubility.
  • Forms oil depot in muscle tissue; AAS slowly diffuse out.
• Oral ingestion
  • Rapid GI absorption; peak serum concentration ~1–2 hrs (e.g. methyltestosterone).
  • Extensive first-pass metabolism reduces bioavailability unless structurally modified.

2. Depot Kinetics (IM Injections)

• Release rate determined by ester group attached at carbon 17 of steroid nucleus.
• Esterification at 17β-OH increases lipophilicity → slows release:
  • Testosterone (no ester): ~10 min half-life.
  • Testosterone propionate (3C ester): ~1 day.
  • Testosterone enanthate (7C ester): ~4.2 days.
• Cleavage by esterases in systemic circulation releases the active compound.

3. Oral Bioavailability and Modifications

• Non-modified testosterone: <4% bioavailability due to liver metabolism.
• Strategies to improve oral bioavailability:
  • Esterification (e.g. undecanoate): increases lymphatic absorption, but still low (~6.8%).
  • SEDDS formulations (e.g. JATENZO®): further enhance absorption; require twice-daily dosing.
  • 17α-methylation: significantly increases bioavailability, but causes hepatotoxicity.

4. Circulatory Transport

• AAS circulate bound to:
  • Sex hormone-binding globulin (SHBG) – high affinity, low capacity.
  • Albumin – low affinity, high capacity.
  • Corticosteroid-binding globulin (CBG) and orosomucoid (less significant).
• At supraphysiological doses:
  • SHBG becomes saturated.
  • Albumin-bound and unbound fractions increase.
  • SHBG has low affinity for many AAS (e.g. nandrolone, stanozolol).
• Unbound testosterone (~1–4%) is believed to reflect true androgenic activity more accurately than total testosterone.

5. Tissue Distribution and Cellular Mechanisms

• AAS diffuse into target tissues from blood (via extravascular compartment).
• Cross cell membrane by passive diffusion.

Inside the cell:

• AAS may:
  • Bind to androgen receptor (AR).
  • Undergo biotransformation:
    1. Into a more potent androgen (e.g. DHT via 5α-reductase).
    2. Into inactive metabolites (via phase I & II liver metabolism).
    3. Into estrogens (via aromatase).

6. Metabolism

• Bioactivation:
  • Testosterone → DHT in androgen-sensitive tissues (e.g. prostate, skin).
  • DHT not significant in skeletal muscle; inactivated by 3α-HSD.
  • Conversion follows Michaelis-Menten kinetics (Km ≈ 3.35 nM).
• Bioinactivation:
  • Occurs in liver, kidney, and target tissues.
  • Phase I: reductions (C3, C5) and oxidations (C17).
  • Phase II: glucuronidation and some sulfation.
• Estrogenic conversion:
  • AAS like testosterone → estradiol via aromatase.
  • Contributes to gynecomastia and HPGA suppression.

7. Mechanism of Action via Androgen Receptor

• Unbound AR resides in cytoplasm with chaperone proteins.
• Ligand binding → conformational change → nuclear translocation.
• Forms AR homodimer → binds to androgen response elements (AREs) in DNA.
• Regulates gene transcription of androgen-responsive genes.
• Also exerts nongenomic effects (e.g. via GPRC6A receptor) – mechanisms unclear.

8. Clinical Effects

• Primary effect: increased muscle mass and strength.
• Supported by:
  • Bhasin et al. (1996): dose-dependent muscle gain with 600 mg testosterone enanthate/week.
  • Additional RCTs confirm anabolic efficacy, especially with resistance training.
• AAS effects vary by compound, dose, receptor affinity, and conversion/metabolism profile.

Pharmacokinetic Comparison of AAS

Steroid Compound	Route	Formulation / Modification	Bioavailability	Onset	Half-Life / Duration	Metabolism
Testosterone	IM Injection	Unmodified	—	Fast	~10 min	Rapid hepatic metabolism
Testosterone Propionate	IM Injection	3C ester	—	Moderate	~1 day	Ester hydrolysis → testosterone → liver
Testosterone Enanthate	IM Injection	7C ester	—	Slow	~4.5 days	Same as above
Testosterone Undecanoate	Oral / IM	11C ester; SEDDS oral form (JATENZO®)	Oral: ~6.8% (variable)	Oral: ~2–4 hrs	Oral: Short; IM: weeks	Lymphatic absorption bypasses first-pass
Methyltestosterone	Oral	17α-methylation	Moderate (~10–40%)	1–2 hours	Short (hours)	Resistant to hepatic metabolism
Oxymetholone (Anadrol)	Oral	17α-methylated AAS	Moderate–high	1–2 hours	8–10 hours	Phase I and II hepatic metabolism
Oxandrolone (Anavar)	Oral	17α-methylated DHT derivative	High	1–2 hours	9–10 hours	Minimal aromatization, hepatically cleared
Stanozolol (Winstrol)	Oral / IM	17α-methylated; synthetic	Oral: moderate–high	1–2 hours	Oral: ~9 hours; IM: ~1–2 days	Extensive hepatic metabolism
Nandrolone Decanoate	IM Injection	10C ester	—	Slow	~6–12 days	Converted to nandrolone → hepatic metabolism
Methandienone (Dianabol)	Oral	17α-methylated	High	~1–2 hours	3–6 hours	Rapid hepatic metabolism
Fluoxymesterone	Oral	17α-methylated, non-aromatizable	Moderate	Fast	~9 hours	Hepatic metabolism (Phase I/II)

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Administration

Typical Misuse Regimens (illustrative)

Compound	Route	Common “cycle” dose*	Duration
Testosterone cypionate	IM	250–750 mg weekly	8–16 weeks
Testosterone undecanoate (Nebido)	IM	750 mg wk 0, 4 then q10 wk	Often “cruise” phase
Nandrolone decanoate	IM	200–400 mg weekly	8–12 weeks
Stanozolol	Oral	20–50 mg daily	4–8 weeks
Dromostanolone	IM	200–400 mg weekly	6–10 weeks

* Doses far exceed therapeutic ranges (e.g. TRT 75–125 mg T/week).

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Claimed Benefits

• ↑ Skeletal muscle mass & strength (especially Type II fibres)
• ↓ Recovery time & muscle soreness
• ↓ Fat mass / “cutting” effect (variable, often confounded by diet & stimulants)
• Psychological drive / confidence during training

Evidence for sustained performance gain is limited and offset by significant morbidity.

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Adverse Effects

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🫀 Cardiovascular System

1. Hypertension

• Mechanism: RAAS activation, ↑ thromboxane A2, endothelin-1, norepinephrine.
• HAARLEM: +7 mmHg SBP, +3 mmHg DBP.
• Prevalence: 41% hypertensive during AAS cycle.
• Reversible: Yes, typically resolves post-cycle.

2. Erythrocytosis (Polycythemia)

• Mechanism: ↑ erythropoietin, ↓ hepcidin, ↑ gut iron absorption.
• HAARLEM: 3% ↑ hematocrit; 33% exceeded normal limits.
• Complications: ↑ blood viscosity → VTE, arterial thrombosis.
• Reversible: Yes (returns to baseline ~3 months post-cycle).

3. Dyslipidemia

• HDL: ↓ 0.4 mmol/L in HAARLEM; more with oral 17α-AAS.
• LDL: ↑ with oral AAS; +0.45 mmol/L in HAARLEM.
• Lp(a): ↓ up to 50%; unclear benefit.
• Mechanism: ↑ hepatic lipase; unclear for LDL/Lp(a).
• Reversible: Yes, but atherogenic changes may accumulate.

4. Cardiomyopathy & Subclinical Myocardial Dysfunction

• LV dysfunction: ↓ LVEF (up to 11%); ↓ E’ and strain.
• Structural changes: ↑ LV mass, wall thickness, LA volume.
• Reversible: Partially reversible in short-term; chronic damage possible.
• Baggish et al.: >50% had LVEF <52%; reversibility seen post-cycle.
• HAARLEM: All echo abnormalities normalized by 8 months.

5. Atrial Fibrillation

• Increased prevalence: Danish registry study (x3 risk).
• Mechanism: Possibly from atrial stretch, LV stiffness.

🧠 Neuropsychiatric & Sexual Health

6. Erectile Dysfunction (ED)

• Causes:
  • Post-cycle hypogonadism (low T).
  • Psychogenic (performance anxiety, relational conflict).
  • Estrogenic imbalance (low estradiol).
• HAARLEM:
  • 8% baseline, 12% during cycle, 14% 3 months post-cycle, 1% at 1 year.
• Management: PDE5 inhibitors, psychological support.

🧬 Endocrine & Reproductive System (Men)

7. Testosterone Deficiency / Hypogonadism

• Mechanism: HPGA suppression (↓ GnRH, LH, FSH).
• Symptoms: Fatigue, ↓ libido, ED, mood change.
• HAARLEM: 90% recover by 3 months, 100% by 1 year (if normal pre-cycle).
• Reversible: Usually, but may be prolonged or permanent in some.

8. Infertility

• Mechanism: ↓ intratesticular testosterone → impaired spermatogenesis.
• HAARLEM:
  • Sperm concentration ↓ from 46.8 to 11.7 million/mL.
  • 68% met criteria for oligo-/azoospermia.
• Recovery:
  • Mean sperm recovery: 10.4–14.1 months.
  • Prolonged suppression seen in chronic users.
• Reversible: Often yes, but delayed.

🧖 Dermatological

9. Acne Vulgaris

• Mechanism: ↑ sebum via androgen receptor activation in sebaceous glands.
• HAARLEM: 10% → 52% self-reported; 13% → 29% clinician observed.
• Management: Topical agents, isotretinoin (self-used).

10. Male-Pattern Hair Loss

• Mechanism: Androgenic stimulation of scalp follicles → miniaturization.
• HAARLEM: Self-reported alopecia ↑ from 2% → 12%.
• Ancillary use: Finasteride, minoxidil (questionable efficacy in high AAS doses).
• Reversibility: Often irreversible.

🧫 Hepatic

11. Hepatotoxicity

• Common with: Oral 17α-alkylated AAS.
• Lab changes: ↑ AST, ALT, GGT, LDH.
• Rare complications: Jaundice, peliosis hepatis, hepatic adenoma/carcinoma.
• HAARLEM: No clinical liver damage observed, but GGT elevations noted.
• Confounder: Resistance training can also ↑ AST/ALT.

🧪 Renal

12. Nephrotoxicity

• HAARLEM: Creatinine ↑ from 93.1 → 97.8 μmol/L; 16% developed albuminuria.
• Interpretation challenges: High muscle mass, creatine supplements → ↑ creatinine.
• FSGS: Case series suggest link to chronic AAS + high lean mass.
• Reversible: Often yes; FSGS may cause chronic damage.
• Better GFR marker: Cystatin C.

🧖‍♂️ Breast / Hormonal Axis

13. Gynecomastia

• Mechanism: ↑ estradiol via aromatization of testosterone.
• HAARLEM: 7% → 19% prevalence (mostly Simon grade 1).
• Misconceptions: Prolactin & progestin roles are not evidence-based.
• Management:
  • SERM (tamoxifen): partial or complete regression.
  • Aromatase inhibitors: limited efficacy.
  • Surgery in persistent/fibrotic cases.

👩 Female-Specific Effects

14. Virilisation

• Dysphonia:
  • Early, sometimes irreversible.
  • ↓ pitch, creakiness, loss of range.
• Hirsutism:
  • Onset ~4–6 months; dosage threshold ~6.25–12.5 mg/week.
  • Reversible post-cessation.
• Clitoromegaly:
  • Dose-dependent; ↑ size by 3–4.6 cm in transmasc studies.
  • Not seen at <25 mg/week in postmenopausal women.

15. Menstrual Irregularity & Infertility

• Mechanism: HPGA suppression → ↓ LH/FSH → anovulation.
• Reversible: Often yes, but depends on dose/duration.

Dependence & Withdrawal

Up to one-third of AAS users develop a DSM-5 “other substance use disorder”. Withdrawal may present with lethargy, major depression, hypogonadal symptoms and is managed with organised tapering, endocrine review, and CBT.

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Legal & Public-Health Context (Australia)

• Scheduling: Most AAS are Schedule 4 (Prescription-Only); some compounded testosterone preparations may be Schedule 8 in certain jurisdictions.
• Criminal offences: Importation without permit, possession or supply without prescription prosecuted under the Customs Act 1901, Therapeutic Goods Act 1989, and state poisons regulations (e.g. Drugs Misuse Act 1986 (Qld) s 9D).
• Sport: Prohibited under the WADA Code; positive tests → bans.
• Harm-reduction: Needle & Syringe Program access, BBV screening (HIV, HBV, HCV).

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Clinical Approach for General Practice & Addiction Medicine

1. Screen & Ask – Targeted history in patients with disproportionate muscularity, acne, mood change, fertility issues.
2. Examination – BP, gynaecomastia, testicular volume, acne, tendon integrity.
3. Investigations
   • FBC (polycythaemia), LFTs, lipids, fasting glucose, eGFR
   • Endocrine profile: total testosterone, LH/FSH, oestradiol, SHBG, prolactin
   • Viruses: HIV, HBV, HCV serology
4. Counselling – Non-judgemental education re: adverse effects, legal risks; provide written resources (e.g. NSW Health AAS Harm Reduction leaflet).
5. Referral – Endocrinology (HPG-axis recovery), Sports & Exercise physician, Addiction medicine or Clinical Psychology for dependence.
6. Monitoring – 3- to 6-monthly CV risk profile, liver enzymes, BP, mood.

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Advise to patients

• Can I take other Medications to stop Side Effects?
  • Not really, as these drugs ( HCG, Diuretics) have potential side effects as well. Further more when used together they may be more dangerous.
• But They Work!
  • This is controversial. Scientific evidence shows that they enhance physical performance, if you continue to train, diet and are motivated to continue to muscle build. Remember you cannot give more than what you have!  Also you may become psychologically dependent on them. A feeling of Euphoria exists as well as improvement of self-esteem. You may also have mood swings; “ roid – rages” may occur or you may even become paranoid or depressed.
• What about if I only use small amounts?
  • There is “no safe dose” of anabolic steroids. Remember the higher the dose does not mean, bigger muscles.
• What about the doctor prescribing it?
  • This is also illegal. Your doctor can’t prescribe them unless they are used for medical reason.
  • Bodybuilding, or improvement of sporting performance is not medical reasons for using anabolic Steroids. 
• IF I am using them, what can I do to decrease side effects?
  • Use low doses
  • Never share needles
  • Avoid diuretics with anabolic steroids
  • If side effects develop, don’t use other drugs to treat them
  • Tell your doctor that you are using them
  •  Make sure you know exactly what you are taking

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Mechanism of AAS-Induced Hypogonadism (AAIH)

Anabolic-androgenic steroid (AAS)-induced hypogonadism is a functional suppression of the hypothalamic–pituitary–gonadal axis (HPGA) caused by exogenous androgen administration. It may be transient, prolonged, or permanent, depending on individual susceptibility, AAS regimen, and duration of use.

🔬 Normal HPGA Physiology

Hypothalamus

• Releases GnRH (gonadotropin-releasing hormone) in a pulsatile fashion.

Pituitary

• GnRH stimulates anterior pituitary to release:
  • LH → stimulates Leydig cells to produce testosterone.
  • FSH → stimulates Sertoli cells to support spermatogenesis.

Negative Feedback

• Testosterone and estradiol (via aromatization):
  • Exert negative feedback on both the hypothalamus and pituitary to suppress GnRH, LH, and FSH.
  • Estradiol is ~200× more potent than testosterone at suppressing gonadotropins.

🔬Effect of AAS Use on the HPGA

1. Exogenous AAS = Supraphysiological Androgen Levels

• Suppress endogenous GnRH, LH, and FSH via negative feedback.
• Suppression can occur even with moderate doses (e.g. 200–600 mg/week testosterone enanthate).

2. Consequences of LH and FSH Suppression

• ↓ LH → ↓ Leydig cell stimulation → ↓ intrinsic testosterone production.
• ↓ FSH → ↓ Sertoli cell activity → arrested spermatogenesis.
• Intratesticular testosterone (ITT) drops → <10% of normal → infertility.

3. Post-Cycle Hypogonadism

• After stopping AAS:
  • Exogenous androgen levels fall.
  • HPGA remains suppressed.
  • May take weeks–months for GnRH pulsatility and pituitary sensitivity to resume.
• Persistent suppression in some users due to:
  • Long-acting esterified AAS still in circulation.
  • SHBG suppression (↑ testosterone clearance).
  • Hypothalamic-pituitary “reset delay”.
  • Pre-existing subclinical hypogonadism unmasked.

🔬 Evidence of Suppression and Recovery

• HAARLEM study:
  • LH/FSH: undetectable during cycle.
  • T levels: 90% returned to baseline by 3 months, 100% by 12 months if normal pre-cycle.
  • 37% had low baseline testosterone, mostly prior AAS users → suggests incomplete HPGA recovery.

Clinical Features of AAIH

Symptom	Pathophysiology
Low libido	↓ Testosterone
Erectile dysfunction	↓ T, ↓ E2
Fatigue	Androgen deficiency
Depression, mood changes	Central effects of T
Infertility	↓ ITT, ↓ spermatogenesis
Testicular atrophy	Shrinkage of seminiferous tubules

Diagnosis

Labs:

• Low serum testosterone
• Low or inappropriately normal LH and FSH → secondary hypogonadism.
• Elevated LH/FSH (rare) → primary hypogonadism.

Additional tests:

• SHBG, prolactin, estradiol.
• Semen analysis if fertility is a concern.

💊 Management

Watchful Waiting

• In recent AAS cessation:
  • Monitor over 3–6 months.
  • Supportive care (psychosexual counselling, lifestyle modification).

Pharmacologic (off-label, limited evidence)

Agent	Mechanism	Use
SERM (clomiphene, tamoxifen)	Blocks estrogen feedback → ↑ LH/FSH → ↑ endogenous T	Often used in post-cycle therapy (PCT)
Aromatase Inhibitors (AI)	↓ E2 → less negative feedback	Limited standalone efficacy
hCG	Mimics LH → stimulates Leydig cells directly	May worsen suppression of FSH → infertility
Testosterone replacement	Direct T replacement	Avoid unless HPGA fails to recover; will suppress axis further

📌 Key Points

• AAIH is a predictable and common consequence of AAS use.
• It may be transient or persistent, and may impair fertility and sexual function.
• Post-cycle therapy (PCT) is widely practiced by users but lacks robust evidence.
• Persistent hypogonadism beyond 6 months warrants endocrinology referral.
• Avoid testosterone therapy unless HPGA recovery is clearly not occurring.