ACTH and gonadotropin deficiencies predict mortality in patients treated for nonfunctioning pituitary adenoma: long‐term follow‐up of 519 patients in two large European centres

Abstract

SummaryContext and ObjectiveNonfunctioning pituitary adenomas (NFPAs) are the most common subtype of pituitary tumour. Hypopituitarism is observed in NFPAs due to tumour‐ or treatment‐related factors and may increase mortality risk. Here, we analysed the associations of hypopituitarism, hormone replacement and mortality in a large NFPA cohort derived from two large European centres.Design, Setting and ParticipantsCase note review of all patients treated for NFPA in University Hospitals Birmingham and Beaumont Hospital Dublin between 1999 and 2014 was performed.Main Outcome MeasuresClinical presentation, treatment strategies, pituitary function and vitality status were recorded in each patient. A multivariate Cox regression model was used to examine the association between hypopituitarism, hormone replacement and premature mortality.ResultsA total of 519 patients were included in the analysis. Median duration of follow‐up was 7·0 years (0·5–43). A total of 81 deaths were recorded (15·6%). On multivariate analysis, adrenocorticotropic hormone (ACTH) and gonadotropin (Gn) deficiencies were associated with an increased relative risk of death (OR 2·26, 95% CI 1·15–4·47, P = 0·01 and OR 2·56, 95% CI 1·10–5·96, P = 0·01, respectively). Increased hydrocortisone (HC) (P‐trend = 0·02) and lower levothyroxine (LT4) doses (P‐trend = 0·03) were associated with increased risk of death. Mortality increased with the degree of pituitary failure observed (P‐trend = 0·04).ConclusionACTH and gonadotropin‐deficient patients have higher mortality rates compared to those with intact hormonal axes. Excessive HC and suboptimal LT4 replacement may also increase risk of death. Complex associations between hormone deficiency and replacement underpin the increased mortality risk in NFPA patients.

Long‐term follow‐up of a large prospective cohort of patients with nonfunctioning pituitary adenomas: The outcome of a conservative management policy

“…The debate regarding the long‐term risks of RT in NFPA has been well rehearsed . Two recent well‐designed large retrospective cohort studies have examined the mortality of patients with NFPA . The predictors of mortality were found to be age as well as ACTH and gonadotrophin (Gn) deficiency .…”

“…Two recent well‐designed large retrospective cohort studies have examined the mortality of patients with NFPA . The predictors of mortality were found to be age as well as ACTH and gonadotrophin (Gn) deficiency . RT was associated with lower age of death, higher relative risk of death and a trend towards a higher relative risk of cerebrovascular death.…”

Factors impacting on the action of glucocorticoids in patients receiving glucocorticoid therapy

“…Two large registry-based studies of patients with PAI have shown that despite adequate glucocorticoid replacement, the relative risk of death for these patients is more than double that of the background population. [15][16][17] Two large cohort studies of patients with hypopituitarism (one study comprising of patients with acromegaly and the other patients with nonfunctioning pituitary adenomas) have shown that ACTH deficiency and higher doses of hydrocortisone are associated with increased mortality. 12,14 Patients with SAI also have increased morbidity and mortality.…”

“…[11][12][13] Leading causes of death are adrenal crisis, infections, cardiovascular disease and malignancy. 16,17 It is possible that even subtle increases in glucocorticoid exposure in patients on replacement therapy over prolonged periods of time may contribute to increased morbidity and mortality, as occurs in patients with Cushing's syndrome. [15][16][17] Two large cohort studies of patients with hypopituitarism (one study comprising of patients with acromegaly and the other patients with nonfunctioning pituitary adenomas) have shown that ACTH deficiency and higher doses of hydrocortisone are associated with increased mortality.…”

“…12,14 Patients with SAI also have increased morbidity and mortality. [15][16][17] Two large cohort studies of patients with hypopituitarism (one study comprising of patients with acromegaly and the other patients with nonfunctioning pituitary adenomas) have shown that ACTH deficiency and higher doses of hydrocortisone are associated with increased mortality. 16,17 It is possible that even subtle increases in glucocorticoid exposure in patients on replacement therapy over prolonged periods of time may contribute to increased morbidity and mortality, as occurs in patients with Cushing's syndrome.…”