Does low testosterone affect fertility?

Does Low Testosterone Affect Fertility?

Yes, low testosterone can significantly impair fertility, but the relationship is complex and depends critically on whether the low testosterone is caused by exogenous testosterone therapy versus endogenous hypogonadism. The most important clinical distinction is that exogenous testosterone therapy causes infertility through suppression of spermatogenesis, while naturally occurring low testosterone may or may not affect sperm production depending on the underlying cause. 1

The Critical Distinction: Exogenous vs. Endogenous Low Testosterone

Exogenous Testosterone (The Primary Fertility Threat)

Exogenous testosterone therapy should never be prescribed to men interested in current or future fertility—this is a clinical principle representing the highest level of directive guidance. 1, 2

• Exogenous testosterone provides negative feedback to the hypothalamus and pituitary gland, inhibiting gonadotropin (LH and FSH) secretion, which directly suppresses spermatogenesis and can cause complete azoospermia (zero sperm count). 1, 2, 3
• The FDA drug label explicitly warns that spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis, and reduced fertility, testicular atrophy, subfertility, and infertility have been reported. 3
• The impact on fertility may be irreversible in some cases. 3

Recovery After Stopping Testosterone Therapy

• Although most azoospermic men recover sperm production after cessation of testosterone therapy, the time course is prolonged—taking months or rarely years. 1, 2
• Therefore, testosterone therapy should be avoided in men pursuing family building in the near future. 1, 2
• Men considering distant future fertility may be offered testosterone therapy only after comprehensive counseling about the prolonged recovery period and potential for permanent infertility. 1, 2

Naturally Occurring Low Testosterone and Fertility

Hypogonadotropic Hypogonadism (Low Testosterone with Low LH/FSH)

• Men with hypogonadotropic hypogonadism have deficient LH and FSH secretion, which disrupts Leydig cell testosterone production and impairs spermatogenesis. 1
• These men should be evaluated to determine the underlying etiology and treated based on diagnosis, not with testosterone replacement. 1
• First-line treatment is human chorionic gonadotropin (hCG) at 500-2500 IU, 2-3 times weekly, followed by FSH injections when indicated after testosterone normalizes on hCG. 1
• The degree of response correlates with testicular size prior to treatment. 1

Low Testosterone with Normal Gonadotropins

• In men with total sperm counts greater than 5 million undergoing IVF, low total testosterone (<264 ng/dL) was not significantly associated with worse semen volume, sperm count, progressive motility, or morphology compared to men with normal testosterone. 4
• However, more patients in the low testosterone group had subnormal semen parameters, though the difference was not statistically significant. 4
• Multivariable regression analysis revealed that low testosterone and free testosterone levels had no significant effect on semen parameters in this population. 4

Surprising Finding: Some Men on Testosterone Maintain Fertility

• In a study of men with acquired hypogonadotropic hypogonadism being treated with testosterone, more than half had persistent spermatogenesis, with over one-third having sperm concentrations ≥15 million/mL. 5
• This may relate to residual gonadotropin levels being present, albeit low. 5
• However, this finding should not change clinical practice—men interested in fertility should still not receive testosterone therapy. 1, 2

Treatment Approach for Men with Low Testosterone Seeking Fertility

Pharmacologic Options That Preserve Fertility

Clinicians may use aromatase inhibitors (AIs), human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), or combinations thereof for infertile men with low serum testosterone. 1

• These medications increase endogenous testosterone production without suppressing spermatogenesis. 2, 6
• For men with idiopathic infertility, FSH analogue treatment may be considered to improve sperm concentration, pregnancy rate, and live birth rate. 1
• In patients with non-obstructive azoospermia, limited data support pharmacologic manipulation with SERMs, AIs, and gonadotropins prior to surgical intervention. 1

Novel Therapy: Natesto Intranasal Testosterone

• Natesto intranasal testosterone gel has been shown to increase serum testosterone levels while maintaining semen parameters due to its short-acting properties having lesser effect on the HPG axis. 6
• This represents a potential option for men requiring testosterone therapy while maintaining fertility, though this is not yet standard guideline-based practice. 6

Clinical Pitfalls to Avoid

• Never prescribe testosterone monotherapy to men interested in fertility—this is the single most important clinical principle. 1, 2
• Don't assume rapid recovery of fertility after stopping testosterone—counsel patients that fertility may not return for many months or even years. 1, 2
• Don't assume men on testosterone therapy are sterile—semen analysis should be routinely performed so they can be appropriately counseled regarding potential fertility. 5
• Consider sperm banking if a patient on testosterone may want future fertility. 2
• Recognize the severity of testosterone's effects—it can cause complete azoospermia, not just reduced counts. 1, 2, 3
• Don't reassure patients that supplements (antioxidants, vitamins) will improve fertility—existing data show questionable clinical utility. 1

Association with General Health

• Men with low sperm counts have a 12-fold increased risk of hypogonadism and higher prevalence of metabolic syndrome, elevated BMI, waist circumference, systolic pressure, LDL cholesterol, triglycerides, and HOMA index. 7
• Men with hypogonadism have lower bone mineral density with 51% prevalence of osteoporosis/osteopenia. 7
• Fertility evaluation provides a unique opportunity for comprehensive male health assessment and disease prevention. 7