What medications are associated with secondary hypogonadism?

Medications Associated with Secondary Hypogonadism

Multiple medications can cause secondary hypogonadism by disrupting the hypothalamic-pituitary-gonadal axis, with opioids being among the most significant contributors due to their dose-dependent suppression of gonadotropin-releasing hormone. 1

Drug Categories That Cause Secondary Hypogonadism

Hormonal Agents

• Estrogens - Suppress hypothalamic GnRH secretion 1
• Testosterone/androgenic anabolic steroids - Cause negative feedback on the HPG axis 1, 2
• Progestogens (including cyproterone acetate) - Suppress gonadotropin secretion 1
• GnRH agonists and antagonists - Directly suppress the HPG axis 1

Opioids and Pain Medications

• Opioids (including prescription pain medications and illicit opioids) - Cause dose-dependent suppression of GnRH 1, 3, 4
  • Higher morphine equivalent daily doses significantly increase the odds of developing hypogonadism (odds ratio 1.44 per 100-unit increase) 3
  • Affects both short-term and long-term users, including patients on methadone and buprenorphine for opioid use disorder 5

Glucocorticoids

• Corticosteroids (prednisone, dexamethasone, etc.) - Suppress the HPG axis 1, 2
  • High-dose corticosteroids used for conditions like chronic graft-versus-host disease can affect sexual function 1

Drugs That Induce Hyperprolactinemia

• Antipsychotics (especially typical antipsychotics)
• Some antidepressants
• Metoclopramide
• Domperidone
• Methyldopa
• Reserpine
• Verapamil 1

Other Medications

• Spironolactone - Acts as an androgen receptor antagonist 1
• Ketoconazole - Inhibits steroidogenesis
• Clomiphene citrate - Paradoxically can cause hypogonadism when used incorrectly 2

Clinical Presentation and Diagnosis

Common Symptoms

• Sexual symptoms: Reduced libido, erectile dysfunction, decreased spontaneous/morning erections 1
• Physical symptoms: Decreased energy, decreased physical strength/activity, fatigue 1
• Psychological symptoms: Low mood, decreased motivation, concentration difficulties 1

Diagnostic Approach

1. Laboratory confirmation: Morning total testosterone levels <300 ng/dL on at least two separate occasions 2
2. Additional testing: LH and FSH levels to distinguish between primary and secondary hypogonadism 2, 6
   • In secondary hypogonadism: Low testosterone with low or normal LH/FSH
   • In primary hypogonadism: Low testosterone with elevated LH/FSH

Management Strategies

For Drug-Induced Secondary Hypogonadism

1. Discontinuation or dose reduction of the offending medication when possible 4
2. Medication substitution: Consider alternative medications with less impact on the HPG axis
3. Opioid rotation: If opioid therapy must continue, consider switching to a different opioid with potentially less impact on the endocrine system 4

Hormone Replacement Options

1. Testosterone replacement therapy if fertility is not a concern 2
2. Gonadotropin therapy (hCG alone or with FSH) for men who wish to preserve fertility 2
3. Selective estrogen receptor modulators or aromatase inhibitors as alternative treatments for men interested in fertility 2

Monitoring and Follow-up

• Testosterone levels should be measured after starting treatment and every 6-12 months while on therapy 2
• Monitor for improvement in symptoms after 3 months of treatment 2
• Screen for complications of hypogonadism (osteoporosis, anemia, metabolic syndrome) 1, 4

Prevention

• Regular screening for symptoms of hypogonadism in patients on high-risk medications 4
• Consider prophylactic measures in patients requiring long-term therapy with medications known to cause hypogonadism
• Address modifiable risk factors such as obesity and metabolic syndrome 1, 2

Remember that early recognition and management of medication-induced secondary hypogonadism can prevent negative physical and psychological sequelae, preserve normal bone mass, and restore fertility in affected patients 6.