How much can thyroid hormone therapy increase Sex Hormone-Binding Globulin (SHBG) levels?

Thyroid Hormone Therapy Can Significantly Increase SHBG Levels by 80-120%

Thyroid hormone therapy typically increases Sex Hormone-Binding Globulin (SHBG) levels by 80-120% from baseline values, with the effect being dose-dependent and more pronounced in patients transitioning from hypothyroidism to euthyroidism. 1, 2

Mechanism and Magnitude of SHBG Increase

Thyroid hormones increase SHBG production through indirect mechanisms:

• Thyroid hormones increase hepatic SHBG production by upregulating hepatocyte nuclear factor-4alpha (HNF-4α) 3
• This effect occurs gradually over several days of thyroid hormone exposure
• The magnitude of increase depends on:
  • Baseline thyroid status (hypothyroid vs. euthyroid)
  • Dose of thyroid hormone
  • Duration of treatment
  • Gender of the patient

Clinical Evidence of SHBG Changes

Research demonstrates consistent patterns in SHBG response to thyroid hormones:

• In hypothyroid patients receiving levothyroxine therapy, SHBG levels increase significantly (p<0.01) as thyroid function normalizes 1
• SHBG increases in a dose-dependent manner with both T4 and T3 administration 2
• The increase in SHBG correlates positively with serum thyroid hormone levels 1, 2
• Women typically show greater SHBG increases than men at equivalent doses 2, 4

Monitoring SHBG in Clinical Practice

SHBG can serve as a useful biomarker of thyroid hormone action:

• SHBG levels can be used to monitor thyroid hormone action at the liver level 1
• Circulating SHBG levels have been suggested as a surrogate for target engagement in patients receiving thyroid receptor β-selective agonists like resmetirom 5
• In patients treated with resmetirom for metabolic dysfunction-associated steatotic liver disease (MASLD), a 120% increase in SHBG was associated with positive treatment response 5

Clinical Implications

The significant increase in SHBG has several important clinical implications:

• Increased SHBG leads to decreased free testosterone in both men and women 2, 4
• Men may experience symptoms of hypogonadism despite normal total testosterone levels 5
• Regular monitoring of SHBG, free testosterone, and total testosterone is recommended in male patients with symptoms of hypogonadism on thyroid hormone therapy 5
• The effect on SHBG precedes the expected elevation of plasma testosterone in males 2

Timing and Duration of Effect

The SHBG response to thyroid hormones follows a predictable timeline:

• Changes begin within days of starting thyroid hormone therapy
• Maximum effect typically requires at least 3-4 weeks of continuous therapy 2
• SHBG levels normalize when thyroid function returns to euthyroid state 1
• The effect is reversible upon discontinuation of thyroid hormone therapy

Practical Considerations

When interpreting laboratory values in patients on thyroid hormone therapy:

• SHBG increases may affect the interpretation of total testosterone levels
• Consider measuring free testosterone in addition to total testosterone
• For patients on thyroid hormone therapy for >1 year, laboratory values should generally be interpreted based on their affirmed gender 5
• The effect on SHBG is opposite to that on corticosteroid-binding globulin (CBG), which decreases with thyroid hormone therapy 1

The substantial increase in SHBG with thyroid hormone therapy (80-120%) represents an important consideration when evaluating hormonal status, particularly in patients with concurrent gonadal or metabolic disorders.