Skip to main content

Advertisement

SpringerLink
Log in

The recovery time of hypothalamic-pituitary-adrenal axis after curative surgery in Cushing’s disease and its related factor

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

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 related 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 factors affecting HPA axis recovery in post-operative CD patients with biochemical remission.

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.

Results

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 was younger and midnight ACTH at baseline was significantly lower, while the TT3 and FT3 levels were significantly higher in patients with recovered HPA compared to patients with persistent CAI at 2-year follow-up (p < 0.05). In persistent CAI group, more patients underwent partial hypophysectomy. TT3 at diagnosis was an independent related factor 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.

Conclusion

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 related factor 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The data are available on request from the authors.

Abbreviations

ACTH:

adrenocorticotrophic hormone

TT3:

total triiodothyronine

FT3:

free triiodothyronine

UFC:

urinary free cortisol

PRL:

prolactin

FSH:

follicle-stimulating hormone

LH:

luteinizing hormone

TT4:

total thyroxine

FT4:

free thyroxine

TSH:

thyroid-stimulating hormone

IGF-1:

insulin-like growth factor 1

HbA1c:

hemoglobin A1c

TC:

total cholesterol

TG:

triglyceride

SBP:

systolic blood pressure

DBP:

diastolic blood pressure

IPSS:

Inferior Petrosal Sinus Sampling

References

  1. B.M. Biller, A.B. Grossman, P.M. Stewart et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 93, 2454–2462 (2008). https://doi.org/10.1210/jc.2007-2734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. L.K. Nieman, B.M. Biller, J.W. Findling et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008). https://doi.org/10.1210/jc.2008-0125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. L.K. Nieman, B.M. Biller, J.W. Findling et al. Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin. Endocrinol Metab. 100, 2807–2831 (2015). https://doi.org/10.1210/jc.2015-1818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. R.M. Paragliola, G. Papi, A. Pontecorvi, et al. (2017) Treatment with synthetic glucocorticoids and the hypothalamus-pituitary-adrenal axis. Int J. Mol. Sci. 18, https://doi.org/10.3390/ijms18102201.

  5. C.M. Berr, G. Di Dalmazi, A. Osswald et al. Time to recovery of adrenal function after curative surgery for Cushing’s syndrome depends on etiology. J. Clin. Endocrinol. Metab. 100, 1300–1308 (2015). https://doi.org/10.1210/jc.2014-3632

    Article  CAS  PubMed  Google Scholar 

  6. M.I. Khan, M.A. Habra, I.E. McCutcheon et al. Random postoperative day-3 cortisol concentration as a predictor of hypothalamic-pituitary-adrenal axis integrity after transsphenoidal surgery. Endocrine Pract. 17, 717–726 (2011). https://doi.org/10.4158/ep11013.Or

    Article  Google Scholar 

  7. A.L. Serban, E. Sala, G. Carosi et al. Recovery of adrenal function after pituitary surgery in patients with cushing disease: persistent remission or recurrence? Neuroendocrinology 108, 211–218 (2019). https://doi.org/10.1159/000496846

    Article  CAS  PubMed  Google Scholar 

  8. M. Fleseriu, R. Auchus, I. Bancos et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 9, 847–875 (2021). https://doi.org/10.1016/s2213-8587(21)00235-7

    Article  PubMed  PubMed Central  Google Scholar 

  9. C. Dai, M. Feng, B. Sun et al. Surgical outcome of transsphenoidal surgery in Cushing’s disease: a case series of 1106 patients from a single center over 30 years. Endocrine 75, 219–227 (2022). https://doi.org/10.1007/s12020-021-02848-1

    Article  CAS  PubMed  Google Scholar 

  10. E. Valassi, B.M. Biller, B. Swearingen et al. Delayed remission after transsphenoidal surgery in patients with Cushing’s disease. J Clin. Endocrinol Metab. 95, 601–610 (2010). https://doi.org/10.1210/jc.2009-1672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. X. He, J. Findling, R.J.P. Auchus, (2022) Glucocorticoid withdrawal syndrome following treatment of endogenous Cushing Syndrome. https://doi.org/10.1007/s11102-022-01218-y.

  12. E.V. Varlamov, G. Vila, M. Fleseriu, Perioperative management of a patient with cushing disease. J. Endocrine Soc. 6, bvac010 (2022). https://doi.org/10.1210/jendso/bvac010

    Article  Google Scholar 

  13. Q. Cui, D. Liu, B. Xiang et al. Morning serum cortisol as a predictor for the HPA axis recovery in cushing’s disease. Int. J. Endocrinol. 2021, 4586229 (2021). https://doi.org/10.1155/2021/4586229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. M. Fleseriu, I.A. Hashim, N. Karavitaki et al. Hormonal replacement in hypopituitarism in adults: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 101, 3888–3921 (2016). https://doi.org/10.1210/jc.2016-2118

    Article  CAS  PubMed  Google Scholar 

  15. C.P.A.S. Council, Consensus of Chinese experts on diagnosis and treatment of Cushing’s disease. Natl. Med. J. China 96, 835–840 (2015)

    Google Scholar 

  16. C. Tatsi, M. Neely, C. Flippo et al. Recovery of hypothalamic-pituitary-adrenal axis in paediatric Cushing disease. Clin. Endocrinol. 94, 40–47 (2021). https://doi.org/10.1111/cen.14300

    Article  CAS  Google Scholar 

  17. M. Lodish, S.V. Dunn, N. Sinaii et al. Recovery of the hypothalamic-pituitary-adrenal axis in children and adolescents after surgical cure of Cushing’s disease. J. Clin. Endocrinol. Metab. 97, 1483–1491 (2012). https://doi.org/10.1210/jc.2011-2325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. M. Klose, K. Jørgensen, L. Kristensen, Characteristics of recovery of adrenocortical function after treatment for Cushing’s syndrome due to pituitary or adrenal adenomas. Clin. Endocrinol. 61, 394–399 (2004). https://doi.org/10.1111/j.1365-2265.2004.02111.x

    Article  CAS  Google Scholar 

  19. R.N. Re, I.A. Kourides, E.C. Ridgway et al. The effect of glucocorticoid administration on human pituitary secretion of thyrotropin and prolactin. J. Clin. Endocrinol. Metab. 43, 338–346 (1976). https://doi.org/10.1210/jcem-43-2-338

    Article  CAS  PubMed  Google Scholar 

  20. T.J. Visser, S.W. Lamberts, Regulation of TSH secretion and thyroid function in Cushing’s disease. Acta endocrinologica 96, 480–483 (1981). https://doi.org/10.1530/acta.0.0960480

    Article  CAS  PubMed  Google Scholar 

  21. R.M. Paragliola, A. Corsello, G. Papi, et al. (2021) Cushing’s syndrome effects on the thyroid. Int. J. Mol. Sci. 22, https://doi.org/10.3390/ijms22063131.

  22. S. Shekhar, R. McGlotten, S. Auh et al. The hypothalamic-pituitary-thyroid axis in cushing syndrome before and after curative surgery. J. Clin. Endocrinol. Metab. 106, e1316–e1331 (2021). https://doi.org/10.1210/clinem/dgaa858

    Article  PubMed  Google Scholar 

  23. B. Xiang, R. Tao, X. Liu et al. A study of thyroid functions in patients with Cushing’s syndrome: a single-center experience. Endocrine Connections 8, 1176–1185 (2019). https://doi.org/10.1530/ec-19-0309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. H. Zheng, Q. Wang, Q. Cui et al. The hypothalamic-pituitary-gonad axis in male Cushing’s disease before and after curative surgery. Endocrine 77, 357–362 (2022). https://doi.org/10.1007/s12020-022-03083-y

    Article  CAS  PubMed  Google Scholar 

  25. S. Sciacchitano, C. Capalbo, C. Napoli et al. Nonthyroidal illness syndrome: to treat or not to treat? have we answered the question? a review of metanalyses. Front. Endocrinol. 13, 850328 (2022). https://doi.org/10.3389/fendo.2022.850328

    Article  Google Scholar 

Download references

Acknowledgements

We are indebted to the patients who participated in this study and all the doctors contributing to the diagnosis and treatment of these patients. This work was supported by grants from Multidisciplinary Diagnosis and Treatment (MDT) demonstration project in research hospitals (Shanghai Medical College, Fudan University, NO: DGF501053-2/014).

Author contributions

Q.C. analyzed the data and wrote the manuscript. Q.C., X.L., Q.S., W.S. and H.Z. collected the data. Z.M., M.S., X.S., Y.W. and Y.Z. performed transsphenoidal surgeries. Y.L. and Z.Z. revised the study and manuscript. S.Z. and M.H. recruited patients. H.Y. and S.Z. conducted the study design and quality control. All authors read and approved the final manuscript.

Author information

Author notes

  1. These authors contributed equally: Qiaoli Cui, Xiaoyu Liu

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China

    Qiaoli Cui, Quanya Sun, Wanwan Sun, Hangping Zheng, Min He, Zhaoyun Zhang, Yiming Li, Hongying Ye & Shuo Zhang

  2. School of Life Sciences, Fudan University, Shanghai, 200438, China

    Xiaoyu Liu

  3. College of Life Sciences, Inner Mongolia University, Hohhot, 010021, Inner Mongolia, China

    Xiaoyu Liu

  4. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China

    Zengyi Ma, Ming Shen, Xuefei Shou, Yao Zhao & Yongfei Wang

Authors
  1. Qiaoli Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Quanya Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wanwan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hangping Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min He
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhaoyun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zengyi Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ming Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xuefei Shou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yao Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yiming Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yongfei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hongying Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shuo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hongying Ye or Shuo Zhang.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cui, Q., Liu, X., Sun, Q. et al. The recovery time of hypothalamic-pituitary-adrenal axis after curative surgery in Cushing’s disease and its related factor. Endocrine 81, 349–356 (2023). https://doi.org/10.1007/s12020-023-03405-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-023-03405-8

Keywords

Search

Navigation