Does a low Sex Hormone-Binding Globulin (SHBG) level contribute to low total testosterone levels?

Relationship Between Low SHBG and Low Total Testosterone

Yes, low Sex Hormone-Binding Globulin (SHBG) levels directly contribute to low total testosterone measurements, though free testosterone levels may remain normal in these cases. 1, 2

Mechanism and Clinical Significance

• Low SHBG reduces total testosterone measurements because less testosterone is bound in circulation, while free testosterone (the biologically active form) may remain within normal range 1
• In obesity-related hypogonadism, low SHBG is a primary mechanism for decreased total testosterone, with many of these men having normal free testosterone levels 1
• SHBG acts as a regulator of testicular negative feedback, influencing gonadotropin synthesis and secretion, which explains in part why low SHBG is associated with low total testosterone 3

Factors That Lower SHBG

• Obesity (particularly central/abdominal obesity) is strongly associated with decreased SHBG levels 2, 4
• Insulin resistance and metabolic syndrome are associated with lower SHBG levels 2, 4
• High-dose glucocorticoids and exogenous testosterone administration can suppress SHBG production 2
• Other conditions associated with low SHBG include Cushing's syndrome, acromegaly, and polycystic ovary syndrome 2

Clinical Evaluation Approach

• When evaluating low total testosterone, measurement of morning serum free testosterone is essential, especially in men with obesity 1
• The diagnosis of testosterone deficiency requires both low testosterone measurements and the presence of symptoms/signs 1
• Total testosterone should be measured on two separate occasions in the early morning (between 8-10 AM) 1
• A threshold of total testosterone below 300 ng/dL is considered a reasonable cut-off for diagnosing low testosterone 1
• Measuring both SHBG and calculating free testosterone index (total testosterone/SHBG ratio) provides better assessment than total testosterone alone in cases of suspected abnormal SHBG levels 2

Clinical Implications

• Men with low total testosterone due solely to low SHBG generally do not require testosterone replacement therapy if free testosterone levels are normal 1, 2
• However, a subset of men with obesity will have both low total and free testosterone levels, requiring further evaluation 1
• When free testosterone is low despite normal total testosterone, this may be due to increased aromatization of testosterone to estradiol in adipose tissue 1
• Low SHBG and clinical androgen deficiency are associated with increased risk of developing metabolic syndrome, particularly in non-obese men 4

Diagnostic Algorithm

1. Measure morning total testosterone (two measurements on separate days) 1
2. If total testosterone is low (<300 ng/dL), measure SHBG and free testosterone 1, 2
3. Measure LH and FSH to determine primary vs. secondary hypogonadism 1
4. If SHBG is low but free testosterone is normal, the low total testosterone is likely due to the SHBG abnormality 1, 2
5. If both total and free testosterone are low, further evaluation is needed, including serum prolactin measurement in cases of low/normal LH 1

Treatment Considerations

• Treatment with testosterone replacement should be considered only when free testosterone is frankly low on at least two separate assessments 1
• Weight loss can increase both SHBG and total testosterone levels in men with obesity 1
• Addressing underlying causes of low SHBG (such as obesity, insulin resistance) should be the first approach before considering testosterone replacement 2