What are the treatment options for high Sex Hormone-Binding Globulin (SHBG) and low semen volume?

Management of High SHBG and Low Semen Volume

The primary approach is to identify and treat the underlying cause rather than the symptoms themselves, with specific interventions directed at reversible etiologies such as ejaculatory duct obstruction, hypogonadotropic hypogonadism, or drug-induced causes. 1, 2

Understanding the Clinical Context

High SHBG reduces bioavailable testosterone by increasing protein binding, potentially contributing to functional hypogonadism even when total testosterone appears normal. 1 Common causes of elevated SHBG include:

• Medications: Anticonvulsants, estrogens, thyroid hormone 1
• Medical conditions: Hyperthyroidism, hepatic disease, HIV/AIDS 1
• Lifestyle factors: Aging, smoking 1

Low semen volume (<1.4 mL) suggests either obstruction of the ejaculatory system or inadequate secretory function of the prostate and seminal vesicles. 2, 3

Initial Diagnostic Algorithm

Physical Examination Priorities

• Palpate for bilateral vas deferens to rule out congenital bilateral absence of vas deferens (CBAVD), which can be diagnosed by examination alone 2
• Assess testicular size and consistency: Normal-sized testes suggest obstruction; atrophic testes indicate spermatogenic failure 2, 4
• Check for palpable varicoceles, as only clinical (palpable) varicoceles warrant treatment 2
• Digital rectal examination to evaluate prostate size and consistency 2

Critical Laboratory Tests

• Measure semen pH: Acidic semen (pH <7.0) with low volume strongly suggests ejaculatory duct obstruction or CBAVD 2
• Serum testosterone and FSH: Low testosterone with low/normal FSH indicates hypogonadotropic hypogonadism; elevated FSH (>7.6 IU/L) suggests primary testicular failure 2, 4
• SHBG levels to calculate free testosterone, as high SHBG may mask functional hypogonadism despite normal total testosterone 1
• Post-ejaculatory urinalysis when volume <1 mL (except in bilateral vasal agenesis or hypogonadism) to diagnose retrograde ejaculation 2

Imaging When Specifically Indicated

Do not perform TRUS or pelvic MRI as part of initial evaluation. 2 Reserve these studies only for suspected ejaculatory duct obstruction when ALL of the following are present:

• Acidic semen
• Volume <1.4 mL
• Azoospermia or severe oligospermia with very low motility
• Normal serum testosterone
• Palpable vas deferens 2

Treatment Based on Specific Etiology

For Ejaculatory Duct Obstruction (EDO)

Transurethral resection of ejaculatory ducts (TURED) is the definitive treatment when TRUS or MRI confirms dilated seminal vesicles and ejaculatory ducts. 1, 2 This may restore natural fertility. 1

Alternatively, surgical sperm extraction (TESE, TESA) with ICSI can be considered. 1

For Congenital Bilateral Absence of Vas Deferens (CBAVD)

• No medical or surgical treatment restores ejaculatory volume 2
• Proceed directly to sperm retrieval (TESE/MESA) with ICSI for fertility 2
• CFTR gene testing for the female partner is mandatory before assisted reproduction 2

For Hypogonadotropic Hypogonadism with High SHBG

When low bioavailable testosterone is confirmed (due to high SHBG binding):

• Treat underlying causes first: Address hyperthyroidism, hepatic disease, or discontinue SHBG-elevating medications if possible 1
• For fertility preservation: Use human chorionic gonadotropin (hCG), selective estrogen receptor modulators (SERMs), or aromatase inhibitors (AIs) rather than testosterone monotherapy 1
• Never prescribe testosterone monotherapy to men interested in current or future fertility, as it suppresses spermatogenesis 1

For Clinical Varicocele

• Varicocelectomy is indicated for palpable varicoceles with abnormal semen parameters 2
• This may improve semen parameters and restore sperm in ejaculate for men with azoospermia, particularly those with hypospermatogenesis 2
• Do not treat subclinical (non-palpable) varicoceles, as this does not improve outcomes 1, 2

For Drug-Induced High SHBG

Review and discontinue causative medications when possible:

• Anticonvulsants
• Estrogens
• Thyroid hormone (if excessive) 1

Consider alternative agents that decrease SHBG, such as growth hormone, glucocorticoids (though these have other fertility implications), or addressing insulin resistance if present. 1

Genetic Testing Before Proceeding with Assisted Reproduction

• Karyotype testing is mandatory for azoospermia or severe oligospermia (<5 million/mL) 2, 4
• Y-chromosome microdeletion analysis is required for azoospermia or sperm concentration <1 million/mL 2, 4
• Genetic counseling should precede ICSI, as genetic abnormalities may be transmitted to offspring 2

Critical Pitfalls to Avoid

• Do not routinely order TRUS or pelvic MRI as part of initial evaluation—reserve for clear clinical suspicion of EDO based on the specific criteria above 2
• Do not use ultrasound to hunt for subclinical varicoceles—only palpable varicoceles benefit from treatment 2
• Do not delay genetic testing—results impact counseling and treatment decisions before assisted reproduction 2
• Do not assume normal total testosterone excludes hypogonadism when SHBG is elevated—calculate free testosterone 1
• Avoid testosterone replacement therapy in men desiring fertility, as it suppresses spermatogenesis 4

When Conservative Measures Fail

If no reversible cause is identified or treatment fails to restore adequate semen parameters, assisted reproductive technology (ART) with ICSI remains an effective option, as ICSI overcomes most sperm quality issues when viable sperm are present. 1