Can lisdexamfetamine (Vyvanse) cause hypogonadism in patients, particularly those with a history of endocrine disorders or risk factors for hypogonadism?

Lisdexamfetamine and Hypogonadism: No Direct Causal Link Established

Lisdexamfetamine (Vyvanse) is not recognized as a cause of hypogonadism in current clinical guidelines, and there is no established mechanism by which therapeutic doses would induce hypogonadotropic or hypergonadotropic hypogonadism in humans. The 2025 European Association of Urology guidelines on male hypogonadism do not list amphetamines or lisdexamfetamine among the drug-induced causes of hypogonadism 1.

Evidence from Drug Pharmacology Studies

The most relevant human data comes from a controlled pharmacology study showing that lisdexamfetamine (100 mg, equivalent to 40 mg d-amphetamine) does not alter plasma testosterone levels compared to placebo 2. This study demonstrated that while lisdexamfetamine stimulates the hypothalamic-pituitary-adrenal (HPA) axis—increasing cortisol, ACTH, and adrenal androgens (DHEA, DHEA-S, androstenedione)—it specifically does not affect testosterone or mineralocorticoid production 2. The lack of testosterone suppression indicates that therapeutic lisdexamfetamine does not disrupt the hypothalamic-pituitary-gonadal (HPG) axis in the manner required to cause hypogonadism 2.

Animal Toxicology Data: Limited Clinical Relevance

One animal study found that chronic high-dose lisdexamfetamine exposure during the juvenile-to-peripubertal period (PND 23-53) in rats caused reduced sperm count, increased immobile sperm, and testicular morphometric changes in adulthood 3. However, this study has critical limitations for human extrapolation:

• The exposure occurred during critical developmental windows (juvenile/peripubertal periods) that do not reflect typical adult ADHD treatment 3
• The doses used (5.2-12.1 mg/kg/day) caused significant systemic toxicity, including reduced body weight gain, altered blood counts, and organ weight changes, indicating supratherapeutic exposure 3
• Fertility was not compromised despite the sperm abnormalities, and sexual behavior remained normal 3
• No measurement of testosterone or gonadotropin levels was reported, so whether true hypogonadism occurred is unknown 3

Clinical Context: Recognized Drug-Induced Causes

The EAU guidelines clearly delineate medications that cause hypogonadism through specific mechanisms 1:

• Androgen receptor blockade: Cyproterone acetate, spironolactone, flutamide, bicalutamide 1
• 5α-reductase inhibition: Finasteride, dutasteride 1
• Estrogen receptor modulation: Clomiphene, tamoxifen, raloxifene 1
• Aromatase inhibition: Letrozole, anastrozole, exemestane 1
• SHBG elevation: Anticonvulsants, estrogens, thyroid hormone 1

Lisdexamfetamine operates through dopamine and norepinephrine release and does not interact with these pathways 2.

Differential Diagnosis: Metabolic and Lifestyle Factors

If a patient on lisdexamfetamine presents with symptoms of hypogonadism, consider alternative explanations:

• Obesity-associated secondary hypogonadism: Increased aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback, suppressing LH secretion 4, 5
• Metabolic syndrome/Type 2 diabetes: These conditions are independently associated with hypogonadism and are more prevalent in ADHD populations 4, 5
• Medication-induced appetite suppression: Lisdexamfetamine reduces food intake, which could lead to weight loss and nutritional deficiencies that secondarily affect testosterone 3
• Sleep disorders: Untreated sleep apnea or disrupted sleep patterns can suppress testosterone production 4

Diagnostic Approach if Hypogonadism is Suspected

If a patient on lisdexamfetamine develops symptoms of hypogonadism (diminished libido, erectile dysfunction, reduced spontaneous erections), follow standard diagnostic protocols 1, 4:

1. Confirm biochemical hypogonadism: Measure morning total testosterone (8-10 AM) on two separate occasions; levels <300 ng/dL indicate hypogonadism 1, 4
2. Measure free testosterone by equilibrium dialysis if total testosterone is borderline or if obesity/diabetes is present, as SHBG alterations can mask true hypogonadism 4, 6
3. Distinguish primary from secondary hypogonadism: Measure LH and FSH; low/low-normal gonadotropins with low testosterone indicate secondary (hypothalamic-pituitary) hypogonadism 1, 4
4. Investigate reversible causes: Check prolactin, thyroid function, iron saturation, assess for sleep disorders, metabolic syndrome, and review all medications 4

Do not attribute hypogonadism to lisdexamfetamine without excluding these more common etiologies 1, 5.

Management Considerations

If hypogonadism is confirmed in a patient taking lisdexamfetamine:

• Address lifestyle factors first: Weight loss through calorie restriction and regular exercise can improve testosterone levels in obesity-associated secondary hypogonadism 4, 5
• Optimize metabolic control: Intensify diabetes management if present, as improved glycemic control may restore testosterone levels 4
• Consider testosterone replacement therapy if biochemical hypogonadism persists after addressing reversible causes, with realistic expectations of small improvements in sexual function (SMD 0.35) but minimal effects on energy, mood, or cognition 4
• Do not discontinue lisdexamfetamine based on unfounded concerns about hypogonadism, as untreated ADHD has its own adverse metabolic and quality-of-life consequences 1

Critical Pitfall to Avoid

Do not diagnose hypogonadism based on symptoms alone (fatigue, low energy, reduced motivation) in patients taking stimulants, as these symptoms overlap with inadequately treated ADHD, depression, or sleep disorders 1, 4. Biochemical confirmation with morning testosterone measurements is mandatory before attributing symptoms to hypogonadism 1, 4.