What is the diagnosis and treatment for a male with hyperprolactinemia and hypogonadism?

High Prolactin and Low Testosterone in Males: Secondary Hypogonadism Due to Hyperprolactinemia

A male presenting with elevated prolactin and low testosterone has secondary (hypogonadotropic) hypogonadism caused by hyperprolactinemia, which requires immediate evaluation for a pituitary adenoma (prolactinoma) and treatment with dopamine agonist therapy, specifically cabergoline. 1

Diagnosis and Pathophysiology

Secondary hypogonadism results from impairment of the hypothalamic-pituitary-gonadal (HPG) axis, where elevated prolactin suppresses gonadotropin-releasing hormone (GnRH) pulsatile secretion, leading to decreased LH and FSH, which in turn causes low testosterone production. 1, 2

Diagnostic Workup

Confirm the hormonal pattern:

• Low testosterone (typically <300 ng/dL on two morning measurements between 8-10 AM) 1, 3
• Low or low-normal LH and FSH levels 1, 3
• Elevated serum prolactin (confirm with repeat measurement to exclude spurious elevation) 3, 4

Rule out laboratory artifacts:

• Exclude the "hook effect" (falsely low prolactin in very large tumors—request serial dilutions if suspected) 5
• Exclude macroprolactin (biologically inactive prolactin variant requiring chromatography) 6, 5

Identify the etiology of hyperprolactinemia:

• Pituitary MRI is mandatory for persistently elevated prolactin levels to evaluate for prolactinoma (micro- or macroadenoma) 1
• Men with testosterone <150 ng/dL and low/normal LH should undergo pituitary MRI regardless of prolactin levels, as non-secreting adenomas may also be present 3
• Review medications that can cause hyperprolactinemia (antipsychotics, opiates, progestogens) 1
• Measure serum iron saturation to exclude hemochromatosis 1

Clinical Presentation

Men with hyperprolactinemia typically present with:

• Hypogonadal symptoms: decreased libido, erectile dysfunction, reduced ejaculate volume, infertility, oligospermia 7, 6, 2
• Mass effect symptoms (more common in men due to larger tumors at presentation): visual field defects, headaches, hypopituitarism 7, 5
• Gynecomastia and galactorrhea (less common than in women) 8
• Long-standing cases may have osteoporosis, anemia, and metabolic syndrome 7

Men more frequently present with macroadenomas (>1 cm) compared to women, who typically have microadenomas, because symptoms are often subtle and diagnosis is delayed. 7, 5

Treatment Approach

First-Line: Dopamine Agonist Therapy

Cabergoline is the preferred dopamine agonist for treating prolactinomas and hyperprolactinemia-induced hypogonadism in men. 4, 7, 5

Cabergoline achieves:

• Prolactin normalization in approximately 80% of men 7
• Tumor shrinkage and improved visual fields in most patients 7
• Recovery of hypogonadism, improved libido, erectile function, and fertility 7, 2
• Rapid improvement in seminal fluid abnormalities 2

Dosing and monitoring:

• Use the lowest effective dose 4
• Periodically reassess the need for continuing therapy 4
• Following treatment initiation, conduct clinical and diagnostic monitoring (chest x-ray, CT scan, cardiac echocardiogram) to assess for cardiac valvulopathy risk 4
• Echocardiographic monitoring every 6-12 months or as clinically indicated for signs of valvular disease (edema, new cardiac murmur, dyspnea, congestive heart failure) 4
• Discontinue cabergoline if echocardiogram reveals new valvular regurgitation, restriction, or valve leaflet thickening 4

Important cabergoline warnings:

• Postmarketing cases of cardiac valvulopathy have been reported, particularly with high doses (>2 mg/day) for Parkinson's disease, but also at lower doses for hyperprolactinemia 4
• Monitor for extracardiac fibrotic reactions (pleural, pericardial, retroperitoneal fibrosis) 4
• Contraindicated in patients with history of cardiac or extracardiac fibrotic disorders 4

Alternative Approaches

For patients requiring testosterone replacement:

• Testosterone replacement therapy should NOT be used as monotherapy in men interested in fertility, as it suppresses spermatogenesis 1, 9
• If testosterone replacement is needed after cabergoline treatment, transdermal preparations (gel, patch) are generally preferred for stable daily levels 1
• Monitor testosterone levels 2-3 months after initiation and every 6-12 months once stable 1

For fertility restoration in hypogonadotropic hypogonadism:

• If the HPG axis integrity is preserved, gonadotropin therapy (hCG with or without FSH) can be used to restore spermatogenesis 1, 8
• Bromocriptine with human menopausal gonadotropin and hCG has shown benefit in treating hypogonadotropic hypogonadism with hyperprolactinemia 8

Resistant or Invasive Prolactinomas

Multi-modal approach for cabergoline-resistant cases:

• Surgery and occasionally radiotherapy combined with high-dose cabergoline 7
• Experimental treatments including temozolomide or pasireotide may improve clinical response in resistant prolactinomas 7, 5

Long-Term Management

Treatment withdrawal considerations:

• A substantial proportion of patients with micro- or macroprolactinoma achieve sustained normalization of prolactin levels and tumor disappearance after long-term cabergoline treatment 2
• Treatment withdrawal should be attempted in patients achieving prolactin normalization and tumor mass disappearance to assess for potential cure 2
• One-third of patients may achieve definitive cure, permitting treatment discontinuation 5

Common Pitfalls to Avoid

• Do not prescribe testosterone monotherapy in men with hyperprolactinemia interested in fertility—it will worsen spermatogenesis 1
• Do not delay pituitary imaging when hyperprolactinemia is confirmed—prolactinomas can cause serious complications including visual loss 1
• Do not assume all elevated prolactin is pathologic—check for macroprolactin and medication-induced causes first 6, 5
• Do not forget cardiovascular monitoring with cabergoline—baseline and periodic echocardiograms are essential 4
• Do not overlook the need for repeat prolactin measurement—ensure elevation is persistent before proceeding with extensive workup 3, 4