How do sex hormone-binding globulin (SHBG) levels affect testosterone levels in patients with suspected hypogonadism or those undergoing testosterone replacement therapy?

How SHBG Levels Affect Testosterone

SHBG binds testosterone and renders it biologically inactive—only free (unbound) testosterone can enter tissues and exert physiological effects, meaning elevated SHBG reduces bioavailable testosterone even when total testosterone appears normal, while low SHBG increases free testosterone availability. 1, 2

The Binding Mechanism

• Approximately 40% of circulating testosterone is bound to SHBG, 2% remains free (bioactive), and the remainder is loosely bound to albumin and other proteins 3
• Higher SHBG levels result in less free testosterone available for tissues, including brain centers regulating libido, muscle, and other androgen-responsive organs 2
• Conversely, lower SHBG concentrations allow more testosterone to remain in the free, biologically active form 1

Clinical Implications for Diagnosis

Total testosterone alone is insufficient for diagnosing hypogonadism when SHBG is abnormal—measuring free testosterone is essential to avoid missing approximately half of diagnoses when SHBG is elevated. 2, 4

When SHBG is Elevated:

• Men with obesity and low total testosterone due solely to low SHBG typically have normal free testosterone levels and are not truly hypogonadal 1
• However, elevated SHBG can cause functional hypogonadism with symptomatic androgen deficiency (low libido, erectile dysfunction) despite normal or even high total testosterone 2, 4
• In men presenting with erectile dysfunction, the frequency of normal total testosterone with low free testosterone is 17.2% overall, rising to 26.3% in men over 60 years 4
• The free testosterone index (total testosterone/SHBG ratio) is more predictive of hypogonadal symptoms than total testosterone alone, with a ratio <0.3 indicating functional hypogonadism 2

When SHBG is Low:

• Obesity-related decreases in testosterone are frequently attributable to low SHBG concentrations 1
• A subset of obese men will have frankly low free testosterone levels due to increased aromatization of testosterone to estradiol in adipose tissue, causing estradiol-mediated negative feedback that suppresses pituitary luteinizing hormone secretion 1
• Symptomatic androgen deficiency develops only when both total and free testosterone decline—low total testosterone with normal free testosterone (due to low SHBG) does not produce hypogonadal symptoms 5

Diagnostic Algorithm

When evaluating suspected hypogonadism, measure morning (8-10 AM) total testosterone, free testosterone by equilibrium dialysis, and SHBG levels, repeating if abnormal to confirm the pattern. 1, 2

• In obese patients specifically, measurement of morning serum free testosterone is essential when total testosterone is low 1
• Single measurements can be misleading and require confirmation 2
• If testosterone levels are subnormal on repeat testing, measure serum LH and FSH to distinguish primary from secondary hypogonadism 1

Common Causes of Altered SHBG

Elevated SHBG:

• Hyperthyroidism, liver disease, aging, oral estrogens, anticonvulsants, and low insulin states increase SHBG production 2
• Aging is the main driver, with elevated SHBG prevalence increasing steeply after the sixth decade 4

Decreased SHBG:

• Obesity, insulin resistance, metabolic syndrome, and hypothyroidism lower SHBG levels 1, 6

Treatment Considerations

Address reversible causes of abnormal SHBG first (treating hyperthyroidism, discontinuing SHBG-elevating medications, optimizing metabolic health) before considering testosterone replacement therapy. 2

• Testosterone replacement should be considered only when morning free testosterone by equilibrium dialysis is frankly low on at least 2 separate assessments 1
• Transdermal testosterone preparations are preferred due to stable day-to-day levels 1
• A critical pitfall: Oral anabolic steroids like oxandrolone can paradoxically lower SHBG through first-pass hepatic metabolism, allowing exogenously supplied testosterone to be excreted and causing erectile dysfunction despite testosterone replacement 7
• When testosterone replacement is initiated, SHBG falls in testosterone-treated patients but may rise or remain unchanged with hCG treatment 8
• Monitor free testosterone levels 2-3 months after initiating therapy to ensure adequate replacement 2

Objective Markers of Testosterone Bioactivity

• Higher SHBG, independently of total testosterone, is associated with lower PSA and hematocrit—objective surrogate markers demonstrating reduced testosterone bioactivity 6
• Higher SHBG is also associated with more severe hypogonadal symptoms, independently of total testosterone levels 6
• This confirms that hypogonadism due to lower biological activity of testosterone (from elevated SHBG) exists as a distinct entity beyond hypogonadism from impaired testosterone production 6