In a patient with adrenal insufficiency receiving hydrocortisone replacement who has an isolated elevation of reverse triiodothyronine, does high reverse triiodothyronine increase sex hormone‑binding globulin?

Reverse T3 Does Not Increase SHBG

No, elevated reverse T3 (rT3) does not increase sex hormone-binding globulin (SHBG). In fact, the relationship is inverse: adrenal insufficiency causes elevated T3 and rT3 while glucocorticoid replacement decreases these levels, but neither rT3 nor T3 directly regulate SHBG production.

The Relationship Between Adrenal Function and Thyroid Hormones

In patients with adrenal insufficiency, withdrawal of glucocorticoid replacement leads to increased T3 and decreased reverse T3, while glucocorticoid administration causes the opposite effect. 1

• When glucocorticoid substitution is withdrawn in adrenal insufficiency patients, serum T3 increases from 110 to 133 ng/dL and reverse T3 decreases from 23 to 18 ng/dL 1
• Subsequent dexamethasone administration (0.5 mg four times daily) causes T3 to fall from 129 to 88 ng/dL and reverse T3 to rise from 17 to 37 ng/dL 1
• Secondary adrenal insufficiency specifically is associated with elevated T3 levels and decreased reverse T3, likely due to increased peripheral conversion of T4 to T3 2

This means your patient's isolated elevation of reverse T3 while on hydrocortisone replacement is unusual and warrants investigation of the adequacy of glucocorticoid dosing or other factors affecting thyroid hormone metabolism.

SHBG Regulation: What Actually Matters

SHBG is primarily regulated by estrogen, thyroid hormones (T4 and T3), insulin, and growth hormone—not by reverse T3. 3, 4

• Pregnancy and estrogen administration increase SHBG concentrations by augmenting thyroxine-binding globulin synthesis 3
• Growth hormone administration decreases SHBG concentrations: continuous low-dose GH infusion (0.02 U/kg/day) reduced SHBG levels in middle-aged men, with testosterone decreasing in parallel 4
• The ratio between SHBG and testosterone remained unchanged during GH treatment, indicating parallel regulation 4

In the context of adrenal insufficiency on hydrocortisone replacement, SHBG levels are not directly affected by reverse T3 elevations. If SHBG is abnormal in your patient, look for other causes such as thyroid dysfunction (T4/T3 excess or deficiency), insulin resistance, or growth hormone abnormalities.

Clinical Implications for Your Patient

The isolated elevation of reverse T3 in a patient with adrenal insufficiency receiving hydrocortisone is paradoxical and suggests either over-replacement with glucocorticoids or a separate thyroid disorder. 1, 2

• Glucocorticoid excess (whether endogenous or from over-replacement) increases reverse T3 and decreases T3 1
• Your patient's clinical presentation should be carefully assessed for signs of glucocorticoid over-replacement: weight gain, insomnia, peripheral edema, or hypertension 5
• Consider checking free T4, TSH, and total T3 to evaluate for primary thyroid dysfunction independent of the adrenal insufficiency 6

If SHBG is abnormal in this patient, investigate thyroid function comprehensively (not just reverse T3), insulin sensitivity, and other hormonal axes—but do not attribute SHBG changes to the elevated reverse T3 itself.

Key Pitfalls to Avoid

• Do not assume reverse T3 elevation is benign in adrenal insufficiency—it may indicate glucocorticoid over-replacement requiring dose adjustment 1, 7
• Do not confuse the effects of glucocorticoids on thyroid hormone metabolism with direct effects of reverse T3 on SHBG—these are separate pathways 1, 3, 4
• When treating concurrent hypothyroidism and adrenal insufficiency, always start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 6