What is the most effective treatment to reduce sex hormone binding globulin (SHBG) in the serum?

From the Guidelines

Testosterone replacement therapy is the most effective treatment to reduce sex hormone binding globulin (SHBG) in the serum, particularly in men with low testosterone levels. According to the study published in Gastroenterology in 2017 1, testosterone replacement has been associated with favorable results, including improvements in metabolic and body composition parameters. For men, testosterone enanthate or cypionate injections at 100-200mg every 1-2 weeks, or daily application of testosterone gel (50-100mg) can effectively lower SHBG levels.

Key Considerations

• The mechanism behind testosterone replacement therapy involves creating a hormonal environment that naturally leads to decreased SHBG synthesis.
• Maintaining a healthy body weight is also important, as obesity is associated with higher SHBG levels 1.
• Regular resistance training 3-4 times weekly can help reduce SHBG levels by increasing insulin sensitivity and promoting hormonal balance.
• Certain medications like danazol can directly lower SHBG but have significant side effects and are rarely used for this purpose alone.

Treatment Approaches

• Transdermal testosterone preparations (gel, patch) have been favored due to the relative stability of testosterone levels from day-to-day, and the ability to avoid the discomfort of intramuscular injections 1.
• Testosterone injections offer the benefit of avoiding daily administration and can be advantageous in patients with reduced personal disease-management skills or resources.
• The method of testosterone replacement should be individualized for each patient, and patients should be monitored to determine that normal serum testosterone concentrations are being achieved 1.

Monitoring and Safety

• Testosterone levels should be tested 2 to 3 months after treatment initiation, and/or after any dose change 1.
• Once stable levels are confirmed on a given dose, monitoring every 6 to 12 months is typically sufficient.
• Data regarding the safety of testosterone therapy have been conflicting, and there is some evidence suggesting that testosterone injections are associated with a greater risk of cardiovascular events, hospitalizations, and deaths compared with gels 1.

From the Research

Reduction of Sex Hormone Binding Globulin (SHBG) in Serum

To reduce SHBG in the serum, several treatments have been studied, including:

• Androgen replacement therapy: Studies have shown that androgen administration can decrease SHBG levels in both normal men and patients with hypogonadism 2.
• Anabolic steroids: The anabolic steroid stanozolol has been found to decrease SHBG levels in control subjects, and this response can be used as a test of androgen sensitivity 3.
• Growth factors: Certain growth factors, such as insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), and transforming growth factor alpha (TGF-alpha), have been shown to decrease SHBG production in vitro 4.
• Nonsteroidal ligands: Compounds such as (-)3,4-divanillyltetrahydrofuran (DVT) and 3-(1H-imidazol-1-ylmethyl)-2phenyl-1H-indole (IPI) can bind to SHBG and increase the activity of testosterone by competitively displacing it from SHBG 5.

Mechanisms of SHBG Reduction

The mechanisms by which these treatments reduce SHBG levels are not fully understood, but may involve:

• Direct inhibition of SHBG production: Growth factors and anabolic steroids may directly inhibit the production of SHBG in the liver 4, 3.
• Competitive displacement of testosterone: Nonsteroidal ligands may competitively displace testosterone from SHBG, increasing the bioavailability of testosterone and reducing SHBG levels 5.
• Androgen-induced decline in SHBG: Androgen replacement therapy may induce a decline in SHBG levels by increasing the production of androgens, which can suppress SHBG production 2.