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Preop TT3 Predicts HPA Axis Recovery After Cushing Surgery

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The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.

Key Takeaways

  • The hypothalamic-pituitary-adrenal (HPA) axis recovered in nearly three quarters of patients with Cushing disease (CD) within 2 years after successful trans-sphenoidal surgery (TSS), with a median recovery time of 12 months.

  • Preoperative total triiodothyronine (TT3) level appears to be an independent predictor of central adrenal insufficiency (CAI) in CD patients with biochemical remission post surgery.

Why This Matters

  • Transient CAI typically occurs after successful TSS, requiring physiologic hydrocortisone replacement until HPA recovery.

  • Inadequate replacement may result in glucocorticoid withdrawal symptoms, including adrenal crisis, while overreplacement could lead to glucocorticoid side effects.

  • Findings have been inconsistent regarding recovery time in CD patients and factors predicting HPA axis recovery.

  • The new findings could help clinicians predict HPA axis-function recovery time and adjust cortisone replacement treatment in postoperative CD patients.


Study Design

  • The retrospective study included 140 patients with biochemical remission following CD surgery at a single institution from 2014–2020.


Key Results

  • The HPA axis in 103 patients (73.6%) recovered during 2 years' postsurgical follow-up. In 57 patients (55% of this subgroup), it recovered within 12 months.

  • Patients were considered to have recovered if they achieved central adrenal sufficiency (CAS). These patients were significantly younger and had significantly lower midnight levels of adrenocorticotrophic hormone at baseline than those with persistent CAI.

  • The researchers found no significant differences in gender, disease duration, maximal tumor diameter, or history of surgery between the two groups at the time of their diagnosis with CD.

  • Both TT3 and free triiodothyronine levels were significantly lower in patients with persistent CAI vs CAS.

  • There were no significant differences between the two groups in other laboratory parameters, surgical approach, or extended compared with nonextended resection, but more patients in the persistent CAI group underwent partial hypophysectomy.

  • In a multiple logistic regression analysis, TT3 levels at diagnosis independently and significantly predicted HPA recovery at 2-year follow-up post surgery after adjustment for gender, age, duration at diagnosis, maximum tumor diameter, history of surgery, surgical approach (endoscopic or microscopic transsphenoidal surgery), adenomectomy range, and the minimal serum cortisol level within the first 7 postoperative days.

  • Among the 37 patients with persistent CAI at 2 years, 23 (62%) had multiple pituitary axis dysfunctions, including hypothyroidism (19 patients), hypogonadism (19), and central diabetes insipidus (5).


  • This retrospective study could not prove the causality of TT3 level for influencing recovery of the HPA axis. However, the number of enrolled patients was relatively large, and follow-up was regular ― factors that make the conclusion credible and representative, the authors said.


  • The study received no commercial funding.

  • The authors had no disclosures.

This is a summary of a preprint research study, "The Recovery Time of Hypothalamic-Pituitary-Adrenal Axis After Curative Surgery in Cushing’s Disease and Its Predictor," by researchers at Huashan Hospital Fudan University, Shanghai, China, published on Research Square and provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.


Patients with Cushing’s disease (CD) experienced transient central adrenal insufficiency (CAI) after successful surgery. However, the reported recovery time of hypothalamic-pituitary-adrenal (HPA) axis varied and the risk factors which could affect recovery time of HPA axis had not been extensively studied. This study aimed to analyze the duration of CAI and explore the risk factors affecting HPA axis recovery in post-operative CD patients with biochemical remission.

Design and methods

Medical records of diagnosis with CD in Huashan Hospital were reviewed between 2014 and 2020. 140 patients with biochemical remission and regular follow-up after surgery were enrolled in this retrospective cohort study according to the criteria. Demographic details, clinical and biochemical information at baseline and each follow-up (within 2 years) were collected and analyzed.


Overall, 103 patients (73.6%) recovered from transient CAI within 2 years follow-up and the median recovery time was 12 months [95% confidence intervals (CI): 10–14]. The age and midnight ACTH at baseline were significantly lower, while the TT3 and FT3 levels were significantly higher in patients with recovered HPA compared to patients with CAI at 2-year follow-up(p < 0.05). In persistent CAI group, more patients underwent partial hypophysectomy. TT3 at diagnosis was an independent predictor of the recovery of HPA axis, even after adjusting for gender, age, duration, surgical history, maximum tumor diameter, surgical strategy, and postoperative nadir serum cortisol level (p = 0.04, OR: 6.03, 95% CI: 1.085, 22.508). Among patients with unrecovered HPA axis at 2-year follow-up, 23 CAI patients (62%) were accompanied by multiple pituitary axis dysfunction besides HPA axis, including hypothyroidism, hypogonadism, or central diabetes insipidus.


HPA axis recovered in 73.6% of CD patients within 2 years after successful surgery, and the median recovery time was 12 months. TT3 level at diagnosis was an independent predictor of postoperative recovery of HPA axis in CD patients. Moreover, patients coexisted with other hypopituitarism at 2-year follow-up had a high probability of unrecovered HPA axis.

total triiodothyronine

Cushing’s disease

central adrenal insufficiency


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