Should a selective estrogen receptor modulator be used to treat low testosterone in men with autosomal dominant polycystic kidney disease?

SERM Therapy for ADPKD-Related Low Testosterone in Men

Selective estrogen receptor modulators (SERMs) should not be used to treat low testosterone in men with ADPKD, as there is no evidence supporting their efficacy for testosterone replacement, and they carry significant risks including venous thromboembolism while lacking the established benefits of standard testosterone therapy.

Why SERMs Are Not Appropriate

SERMs are not testosterone replacement agents and do not function as androgens in men. While SERMs like clomiphene can stimulate endogenous testosterone production in some contexts, they:

• Lack evidence for efficacy in ADPKD patients: No studies have evaluated SERMs specifically for hypogonadism in men with ADPKD 1, 2, 3
• Carry thromboembolic risks: VTE remains a concern across most SERMs, which is particularly problematic in men with chronic kidney disease 2, 4
• Have tissue-specific effects designed for other indications: SERMs are developed primarily for breast cancer treatment and osteoporosis prevention in postmenopausal women, not male hypogonadism 3, 4

Standard Testosterone Therapy Considerations

If testosterone replacement is indicated for documented hypogonadism in men with ADPKD, standard testosterone therapy (transdermal or intramuscular) should be considered:

• Modest benefits documented: Testosterone therapy provides small improvements in sexual functioning and quality of life in men with low testosterone levels 5
• Limited effect on other symptoms: Little to no benefit for physical functioning, depressive symptoms, energy, or cognition 5
• Safety concerns remain: Long-term cardiovascular and prostate safety data are insufficient, particularly in men with comorbidities 5

ADPKD-Specific Hormonal Considerations

The relationship between sex hormones and ADPKD progression is complex:

• Male gender accelerates disease: Men with ADPKD experience faster kidney disease progression compared to women, and orchiectomy in animal models attenuates disease progression 6
• Estrogen may be protective: Female gender appears protective in ADPKD, with slower renal disease progression attributed to hormonal dynamics 6, 7
• Testosterone may worsen outcomes: Animal studies suggest intact androgen status promotes ADPKD progression through upregulation of endothelin-1 and changes in vascular mediators 6

This creates a therapeutic dilemma: Standard testosterone replacement could theoretically accelerate ADPKD progression, though human data are lacking 6, 7.

Clinical Approach for Men with ADPKD and Low Testosterone

Step 1: Confirm True Hypogonadism

• Obtain two fasting morning total testosterone levels
• Exclude reversible causes (obesity, medications, acute illness)
• Document symptoms clearly attributable to hypogonadism 5

Step 2: Risk-Benefit Discussion

• Acknowledge that testosterone therapy may provide modest symptomatic benefit 5
• Discuss theoretical risk of accelerating ADPKD progression based on animal data 6
• Consider disease stage using Mayo Imaging Classification 8
• Patients with rapid progression (MIC 1C-1E) may face higher theoretical risk 8

Step 3: Prioritize ADPKD-Specific Therapies

• Optimize blood pressure control (target <120/80 mmHg, or <110/75 mmHg for high-risk patients) 5, 8
• Consider tolvaptan for patients with MIC 1C-1E or eGFR decline >3 mL/min/1.73 m²/year 5, 8
• Ensure adequate hydration (>2.5 L daily) and sodium restriction (<2000 mg/day) 8

Step 4: If Testosterone Therapy Pursued

• Use transdermal formulations (may allow easier discontinuation if concerns arise) 5
• Start with lowest effective dose
• Monitor kidney function closely (eGFR every 3-6 months)
• Reassess symptoms and testosterone levels at 6 months 5
• Discontinue if no clear symptomatic benefit or if kidney function deteriorates 5

Key Pitfalls to Avoid

• Do not use SERMs as testosterone replacement: They are not indicated for this purpose and lack supporting evidence 1, 2, 3
• Do not ignore ADPKD progression risk: The theoretical concern about testosterone accelerating disease is based on solid preclinical data 6
• Do not use oral testosterone undecanoate: FDA specifically contraindicates it for age-related hypogonadism without structural causes 5
• Do not treat without documented low testosterone: Approximately 20% of men starting testosterone therapy have normal levels 5