What if serum sex hormone-binding globulin (SHBG) levels have been elevated for a few weeks?

Management of Elevated Serum Sex Hormone-Binding Globulin (SHBG) Levels

Elevated SHBG levels for a few weeks may indicate thyroid hormone receptor engagement in patients taking resmetirom for metabolic dysfunction-associated steatotic liver disease (MASLD) and should be monitored but do not typically require intervention unless accompanied by symptoms of thyroid, gonadal, or bone disease.

Causes of Elevated SHBG

Elevated SHBG levels can occur due to several factors:

1. Medication-induced elevation:

   • Resmetirom therapy: SHBG elevation is an expected effect and reflects target engagement of the thyroid hormone receptor-β 1
   • Estrogen therapy

2. Pathological causes:

   • Hyperthyroidism: SHBG is significantly elevated in overt hyperthyroidism (Graves' disease, toxic nodular goiter) 2
   • Liver cirrhosis (in men) 3
   • Androgen insensitivity 3
   • Hypogonadism 3

Clinical Significance and Monitoring

For Patients on Resmetirom:

• Expected effect: Elevated SHBG is a marker of target engagement for resmetirom and is expected during treatment 1

• Monitoring recommendations:

  • Monitor for thyroid function abnormalities
  • Watch for potential long-term effects on gonadal or bone health 1
  • A >120% increase in SHBG is associated with positive treatment response in MAESTRO-NASH trial 1

• Clinical implications:

  • Despite SHBG elevation, free testosterone levels typically remain unchanged 1
  • No significant changes in bone mineral density have been reported 1
  • Current safety data do not suggest cause for concern 1

For Patients Not on Resmetirom:

• Thyroid function assessment: Elevated SHBG for a few weeks may indicate hyperthyroidism 2

  • Measure TSH and free T4 to determine thyroid status 4
  • In hyperthyroidism, SHBG levels can be 2-3 times higher than normal 2

• Other evaluations to consider:

  • Liver function tests (elevated SHBG can occur in hepatic cirrhosis) 3
  • Sex hormone levels (testosterone, estradiol) to assess impact on bioavailable hormone levels 3

Management Approach

1. If patient is on resmetirom:

   • Continue monitoring thyroid function tests
   • No specific intervention needed unless symptoms develop
   • SHBG elevation confirms target engagement 1

2. If patient is not on resmetirom:

   • Evaluate for hyperthyroidism:
     • Check TSH, free T4, and T3 levels
     • Physical examination for signs of thyroid disease
   • Assess liver function:
     • Liver enzymes, albumin, bilirubin
   • Consider sex hormone evaluation:
     • Total and free testosterone in men
     • Estradiol levels in women

3. Follow-up recommendations:

   • Recheck SHBG levels in 4-6 weeks if persistently elevated without explanation
   • Monitor for clinical symptoms related to altered hormone levels

Clinical Pearls and Pitfalls

• Pearl: SHBG levels barely influence levels of non-SHBG-bound testosterone in healthy men, contrary to common belief 5

• Pitfall: Elevated SHBG alone does not necessarily indicate pathology, especially in patients taking medications known to affect SHBG levels

• Pearl: SHBG can serve as an in vitro test for end-organ sensitivity to thyroid hormones 6

• Pitfall: In patients with generalized resistance to thyroid hormone, SHBG levels remain normal despite elevated thyroid hormone levels 2

• Important consideration: Elevated SHBG in women can be associated with multicystic/multifollicular ovaries that may normalize after treatment of underlying thyroid disease 7