The Hypothalamic-Pituitary-Thyroid Axis in Cushing Syndrome Before and After Curative Surgery

J Clin Endocrinol Metab. 2021 Mar 8;106(3):e1316-e1331. doi: 10.1210/clinem/dgaa858.


Background: We do not fully understand how hypercortisolism causes central hypothyroidism or what factors influence recovery of the hypothalamic-pituitary-thyroid axis. We evaluated thyroid function during and after cure of Cushing syndrome (CS).

Methods: We performed a retrospective cohort study of adult patients with CS seen from 2005 to 2018 (cohort 1, c1, n = 68) or 1985 to 1994 (cohort 2, c2, n = 55) at a clinical research center. Urine (UFC) and diurnal serum cortisol (F: ~8 am and ~midnight [pm]), morning 3,5,3'-triiodothyronine (T3), free thyroxine (FT4), and thyrotropin (TSH) (c1) or hourly TSH from 1500 to 1900 h (day) and 2400 to 04000 h (night) (c2), were measured before and after curative surgery.

Results: While hypercortisolemic, 53% of c1 had central hypothyroidism (low/low normal FT4 + unelevated TSH). Of those followed long term, 31% and 44% had initially subnormal FT4 and T3, respectively, which normalized 6 to 12 months after cure. Hypogonadism was more frequent in hypothyroid (69%) compared to euthyroid (13%) patients. Duration of symptoms, morning and midnight F, adrenocorticotropin, and UFC were inversely related to TSH, FT4, and/or T3 levels (r = -0.24 to -0.52, P < .001 to 0.02). In c2, the nocturnal surge of TSH (mIU/L) was subnormal before (day 1.00 ± 0.04 vs night 1.08 ± 0.05, P = .3) and normal at a mean of 8 months after cure (day 1.30 ± 0.14 vs night 2.17 ± 0.27, P = .01). UFC greater than or equal to 1000 μg/day was an independent adverse prognostic marker of time to thyroid hormone recovery.

Conclusions: Abnormal thyroid function, likely mediated by subnormal nocturnal TSH, is prevalent in Cushing syndrome and is reversible after cure.

Keywords: Cushing syndrome; central hypothyroidism; cortisol; hypothalamic-pituitary-thyroid axis; hypothyroidism.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Cohort Studies
  • Combined Modality Therapy
  • Cushing Syndrome / drug therapy
  • Cushing Syndrome / physiopathology*
  • Cushing Syndrome / surgery*
  • Female
  • Humans
  • Hydrocortisone / therapeutic use
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Male
  • Middle Aged
  • Postoperative Period
  • Preoperative Period
  • Remission Induction
  • Retrospective Studies
  • Thyroid Function Tests
  • Thyroid Gland / physiopathology*
  • United States
  • Young Adult


  • Hydrocortisone