How can low testosterone levels be treated to improve infertility?

Treatment of Low Testosterone in Infertile Men

Never prescribe testosterone monotherapy to any man interested in current or future fertility, as it suppresses spermatogenesis and can cause azoospermia. 1

Critical First Step: Determine the Etiology

The treatment approach depends entirely on whether the patient has hypogonadotropic hypogonadism (HH) versus normal/elevated gonadotropins with low testosterone. 1

For Hypogonadotropic Hypogonadism (Low LH/FSH)

Refer to endocrinology or male reproductive specialist immediately. 1 These patients have deficient LH and FSH secretion, resulting in inadequate testicular testosterone production and impaired spermatogenesis. 1

Treatment protocol for HH:

• Start with hCG injections (500-1,000 USP units three times weekly) to stimulate testosterone production 1, 2
• Monitor serum testosterone response 1
• After testosterone normalizes, add FSH or FSH analogues to optimize sperm production 1
• Alternative: Pulsatile GnRH therapy can also restore both testosterone and spermatogenesis 1, 3

This approach successfully initiates spermatogenesis and achieves pregnancies in many men with idiopathic HH. 1

For Normal/Elevated Gonadotropins with Low Testosterone

Use aromatase inhibitors (AIs), human chorionic gonadotropin (hCG), or selective estrogen receptor modulators (SERMs)—alone or in combination—to increase endogenous testosterone while preserving spermatogenesis. 1 These agents work through different mechanisms to boost the body's own testosterone production without suppressing the hypothalamic-pituitary-gonadal axis. 1

Important caveat: This is a conditional recommendation with Grade C evidence—the data supporting these medications is limited. 1

Specific Medication Considerations

SERMs (Clomiphene, Tamoxifen)

• Not FDA-approved for male infertility 1
• Start clomiphene at 50 mg daily for 5 days; may increase to 100 mg daily if no ovulation occurs (extrapolated from female dosing) 4
• Benefits are small and outweighed by assisted reproductive technology (ART) in idiopathic infertility 1
• For men with normal testosterone but idiopathic infertility, SERMs have limited benefits relative to IVF/ICSI 1

hCG Monotherapy or Combination

• Can be used at 500 USP units three times weekly 2, 5
• Low-dose hCG (500 IU every other day) combined with testosterone replacement preserves spermatogenesis in men who require testosterone therapy 6
• In one study, no patient became azoospermic on combined testosterone + hCG, and 9 of 26 men achieved pregnancy 6

FSH Analogues

• May consider for idiopathic infertility to improve sperm concentration, pregnancy rate, and live birth rate 1
• Not FDA-approved for this indication in men 1
• Requires 3+ months of treatment with only small incremental pregnancy rate improvements 1
• Cost-to-benefit ratio is questionable 1

What NOT to Do

Avoid supplements (antioxidants, vitamins): Benefits are of questionable clinical utility with inadequate data to recommend specific agents. 1 They are likely not harmful but of questionable value. 1

When Medical Therapy Has Limited Role

For non-obstructive azoospermia (NOA): Inform patients that data supporting SERMs, AIs, and gonadotropins prior to surgical sperm retrieval is limited (Grade C evidence). 1

For severe oligospermia: When total motile sperm count is <5 million after processing, intrauterine insemination (IUI) success rates are poor—proceed directly to IVF with intracytoplasmic sperm injection (ICSI). 1

Additional Workup Required

• Check prolactin if low/low-normal LH with decreased libido, impotence, or testosterone deficiency 1
• MRI indicated for persistently elevated prolactin without exogenous cause 1
• Treat hyperprolactinemia based on etiology 1

Bottom Line Algorithm

1. Measure morning testosterone twice (diagnosis requires <300 ng/dL on two occasions PLUS symptoms) 7
2. Check LH and FSH to determine etiology 1
3. If HH (low LH/FSH): Start hCG, then add FSH after testosterone normalizes 1
4. If normal/elevated gonadotropins: Use AIs, hCG, or SERMs to raise endogenous testosterone 1
5. Never use testosterone monotherapy in men desiring fertility 1
6. If medical therapy fails or time is limited: Proceed to ART (IVF/ICSI), which has higher success rates than medical management for most cases 1