Why do sex hormone binding globulin (SHBG) levels increase with age?

Why Sex Hormone-Binding Globulin Increases with Age

SHBG increases with age primarily due to declining growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels, which normally suppress SHBG production. 1, 2

Primary Mechanism: The GH/IGF-I Decline

The age-related rise in SHBG is fundamentally linked to the somatopause—the progressive decline in GH and IGF-I that occurs with aging:

• GH and IGF-I normally suppress SHBG production, and as these hormones decline with age, SHBG levels rise correspondingly 2
• Men with isolated GH deficiency demonstrate elevated SHBG levels that normalize when GH replacement therapy is initiated, directly proving this relationship 2, 3
• In elderly men, SHBG remains elevated despite high insulin levels (which would normally suppress SHBG), indicating that low GH/IGF-I levels override insulin's suppressive effect 2

Age-Related Changes in SHBG Levels

The magnitude and pattern of SHBG increase varies by age group:

• SHBG concentrations are significantly higher in men ≥55 years (mean 36.6 nmol/L) compared to men ≤54 years (mean 27.7 nmol/L), with 9% of older men having SHBG >60 nmol/L versus only 2.2% of younger men 4
• The age-related increase in SHBG shows a nearly 20-fold variation between individuals (range 6-109 nmol/L), indicating substantial interindividual variability 4
• SHBG decreases with age during childhood but reverses direction in adulthood, reaching a nadir before beginning its characteristic age-related rise 3

Clinical Consequences of Elevated SHBG

The rise in SHBG with aging has important physiological implications:

• Higher SHBG binds more testosterone, but the pituitary compensates by increasing LH secretion to maintain relatively stable total testosterone levels until approximately age 55 1, 2
• Despite compensatory mechanisms, free and bioavailable testosterone decline with age because the increase in total testosterone production cannot fully offset the binding effect of elevated SHBG 1, 2
• The pituitary primarily senses free testosterone rather than total testosterone, so elevated SHBG triggers increased gonadotropin secretion as a compensatory response 1

Additional Contributing Factors

While GH/IGF-I decline is the primary driver, other age-related changes contribute:

• Declining albumin concentrations with age may be a minor codeterminant of testosterone levels, as albumin also binds testosterone (though with much lower affinity than SHBG) 2
• Age-related increases in body mass index (BMI) occur commonly, though BMI itself is inversely correlated with SHBG—meaning the age effect on SHBG persists even after controlling for BMI 2
• Data not corrected for BMI may overestimate the age-associated decrease in testosterone levels 2

Critical Clinical Pitfall

The most important caveat is that SHBG levels vary widely even within age groups (nearly 20-fold range), so age alone cannot predict an individual's SHBG level 4. This means:

• Routine SHBG measurement is essential when evaluating testosterone status in aging men, rather than assuming SHBG based on age 4
• Relying solely on total testosterone without measuring SHBG can miss functional hypogonadism caused by elevated SHBG 1, 5
• Free testosterone or calculated free testosterone index (total testosterone/SHBG ratio <0.3) provides more accurate assessment of androgen status 1, 5