Recovery of the Hypothalamic-Pituitary-Adrenal Axis in Children and Adolescents after Surgical Cure of Cushing's Disease

Abstract

Context:

Recovery of the hypothalamic-pituitary-adrenal axis (HPAA) after transsphenoidal surgery (TSS) for Cushing's disease (CD) in children has not been adequately studied.

Objective:

Our objective was to assess time to recovery of the HPAA after TSS in children with CD.

Design and Setting:

This was a case series at the National Institutes of Health Clinical Center.

Patients:

Fifty-seven patients with CD (6–18 yr, mean 13.0 ± 3.1 yr) given a standard regimen of glucocorticoid tapering after TSS were studied out of a total of 73 recruited.

Interventions:

ACTH (250 μg) stimulation tests were administered at approximately 6-month intervals for up to 36 months. Age, sex, pubertal status, body mass index, length of disease, midnight cortisol, and urinary free cortisol at diagnosis were analyzed for effects on recovery.

Main Outcome Measure:

The main outcome measure was complete recovery of the HPAA as defined by a cortisol level of at least 18 μg/dl in response to 250 μg ACTH.

Results:

Full recovery was reached by 43 (75.4%) of 57 patients, with 29 of the 43 (67.4%) and 41 of the 43 (95.3%) recovering by 12 and 18 months, respectively. The overall mean time to recovery was 12.6 ± 3.3 months. Kaplan-Meier survivor function estimated a 50% chance of recovering by 12 months after TSS and 75% chance of recovering within 14 months. By receiver operating characteristic curve assessment, the cutoff of at least 10–11 μg/dl of cortisol as the peak of ACTH stimulation testing at 6 months after TSS yielded the highest sensitivity (70–80%) and specificity (64–73%) to predict full recovery of the HPAA at 12 months. Two of the four patients that recovered fully within 6 months had recurrent CD.

Conclusions:

Although this is not a randomized study, we present our standardized tapering regimen for glucocorticoid replacement after TSS that led to recovery of the HPAA in most patients within the first postoperative year. Multiple factors may affect this process, but an early recovery may indicate disease recurrence.

Recovery of normal pituitary function is essential for resumption of growth and development of children that undergo transsphenoidal surgery (TSS) for Cushing's disease (CD) (1, 2). Hypercortisolism suppresses hypothalamic and pituitary functions preoperatively. Unless TSS was complicated by multiple procedures and other untoward effects, hypercortisolism (and not surgery) appears to be mostly responsible for the pituitary hormone deficiencies seen postoperatively (3, 4). It takes anywhere from 4–12 months for recovery of normal GH and TSH secretion after successful, uncomplicated TSS in a child or adolescent with CD (5, 6).

Interestingly, there are no adequate data for the length of time required for recovery of the hypothalamic-pituitary-adrenal axis (HPAA) after successful TSS in children with CD. The classic study by Graber et al. (7) on the HPAA recovery of patients withdrawn from exposure to excess endogenous or exogenous glucocorticoids was followed by numerous studies on this issue (8–12), but little has been reported exclusively in children after TSS for CD. Recovery of the HPAA depends on the hypothalamic secretion of CRH and not on the pituitary corticotrophs (13). The ACTH-stimulated (250 μg Synacthen) cortisol value (at 30 or 60 min) is considered the test of choice for documenting HPAA recovery during the postoperative time (13–15). In the majority of adult patients, HPAA recovers during the first postoperative year (11, 12, 16, 17), but there is controversy about the exact regimen of replacement.

This study presents our center's experience with a standardized regimen of glucocorticoid replacement and HPAA testing that was adopted in the early 1990s; to date, we have treated a large number of children with CD that have followed this regimen. Factors that may influence HPAA recovery were evaluated including age, sex, pubertal status, body mass index (BMI) Z-score, length of disease, midnight cortisol, and urinary free cortisol (UFC) at diagnosis. The present study offers a guide for the clinicians managing children with CD and has important implications for their care, although it does not recommend a regimen that has been studied in a prospective and/or randomized manner. Nevertheless, with the tapering schedule we followed at the National Institutes of Health (NIH), more than half of our patients fully recovered their HPAA function by the end of the first year postoperatively. Another important message from this study is that children that recover their HPAA function early in the first year should be studied for possible recurrence of their disease.

Subjects and Methods

Subjects and protocol

Seventy-three children aged 6–18 yr with the diagnosis of CD presented for treatment at the NIH between 1997 and 2007. Of these, 57 met the criteria for analysis, which included having undergone successful TSS at the NIH; patients with previous pituitary radiation or surgery or pituitary hormone deficiencies were excluded from this analysis, as were patients with persistent disease after TSS or disease recurrence during the first 6 months after TSS. Patients lost to follow-up and whose recovery status could not be determined were also excluded from this analysis. Thus, a total of 16 patients did not meet one or more criteria, as detailed in Table 1, and were excluded from the study. Of these 16 patients, two had persistent hypercortisolemia immediately after their TSS, five patients had recurrent CD before their 6-month visit, and nine had no follow-up at the NIH after discharge from their TSS. Of the remaining 57 patients, 43 patients reached full recovery in the course of the study, and 14 were still on replacement when we closed the investigation. All studies were conducted under clinical protocol 97-CH0076 that was approved by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Institutional Review Board. Informed consent from the patients' parents (and assent from older children) was obtained for all patients.

Table 1.

Complete patient cohort characteristics

	Total number of patients (n = 73) A	Patients excluded from study (n = 16)			Patients included in study (n = 57)
		B	C	D	E	F	G	H	I
Number of patients	73	2	5a	9	4b	25	12	2	14
Total number of patients who followed up at each interval	NA	NA	NA	NA	18	47	16	2	NA

A, Number of patients diagnosed with CD; B, patients with persistent CD immediately after TSS; C, patients that recurred before 6 months; D, patients with no follow-up; E, patients who reached a peak cortisol of at least 18 μg/dl at 6 months; F, patients who reached a peak cortisol of at least 18 μg/dl in the interval between 7 and 12 months; G, patients who reached a peak cortisol of at least 18 μg/dl in the interval between 13 and 18 months; H, patients who reached a peak cortisol of at least 18 μg/dl in the interval between 19 and 36 months; I, patients who did not fully recover their HPAA. NA, Not applicable.

^aOne patient with TSS before coming to NIH.

^bTwo patients with recurrent CD at least 6 months after TSS.

Study design

The study sought to answer the question of how many subjects recovered HPAA function as defined by a cortisol level of at least 18 μg/dl in response to 250 μg ACTH. The study also evaluated the time to recovery in the 43 patients who did reach full recovery. Diagnosis of CD was confirmed, as previously described (2). Diurnal plasma cortisol was obtained by placing an iv tube at least 2 h before the test; cortisol levels were drawn at 2330 and 2400 h and at 0730 and 0800 h, while the patient was asleep. Plasma cortisol was measured by chemiluminescence immunoassay. Twenty-four-hour UFC was averaged from two separate preoperative measurements. Immediate postoperative evaluation of these children has been previously described (18). The 24-h UFC was measured on postoperative d 5–9. Serum cortisol was measured beginning on postoperative d 5 and was repeated daily until postoperative d 10. During this postoperative period, dexamethasone (at the replacement dose of 500 μg/70 kg weight) was administered to patients who required replacement. Patients were defined as cured of disease by postoperative measurements of UFC less than 10 μg/24 h, plasma cortisol less than 2 μg/dl, and/or adrenocortical insufficiency for which they received replacement, as previously described (18, 19).

After their discharge from the hospital, all patients included in this analysis were started on glucocorticoid replacement (hydrocortisone) at 8–12 mg/m² · d divided twice daily with a larger dose in the morning (approximately two thirds of the total dose was given in the morning). In nearly every case, patients were given a standard regimen of hydrocortisone tapering; after 4 months, their dose was reduced by 2.5 mg every 4–6 wk until on only 5 mg/d. Whenever possible, patients were brought back to the NIH Clinical Center for follow-up visits. The numbers of patients returning for ACTH stimulation testing are as follows: 18 patients at 0–6 months after TSS, 47 patients at 7–12 months after TSS, 16 patients at 13–18 months after TSS, and two patients at 19–36 months after TSS.

At the 6-month and 1-yr follow-up visits, patients were tested with an iv administration of 250 μg corticotropin (ACTH, Synacthen). Plasma cortisol was measured at 30 and 60 min after ACTH administration. In patients with continuing need for replacement, HPAA function testing took place thereafter approximately every 6 months until recovery had been achieved. Complete HPAA recovery was defined by cortisol level of at least 18 μg/dl (500 nmol/liter) on ACTH testing (20). Duration of follow-up for these children ranged from 6–36 months. Follow-up data included: 1) clinical stigmata of Cushing's syndrome; 2) biochemical testing (UFC and cortisol circadian rhythm); 3) current medications; and 4) requirement of additional treatment for CD.

Statistical analysis

Frequency distributions and simple descriptive statistics described the data. Continuous data between groups or categories were compared by t tests or Wilcoxon rank-sum tests, and paired data used paired t tests or Wilcoxon signed-rank tests, as appropriate. Categorical data were compared between groups or categories by Fisher's exact tests, or if singly ordered, by the Kruskal-Wallis test. Regression models assessed relationships between continuous variables. Kaplan-Meier survival analysis and Cox proportional hazards models were used to analyze time to recovery data. Sensitivity and specificity data were computed, and a receiver operating characteristic (ROC) curve was plotted to determine the optimal cortisol cutoff at 6 months for predicting full recovery by 12 months. Data are presented as mean ± sd, unless otherwise indicated, or if data were not approximately normally distributed, in which case median (25th percentile, 75th percentile) were used. Multiple comparisons corrections used the Bonferroni method. Data were analyzed using SAS system software version 9.2 (SAS Institute Inc., Cary, NC) and Stata version 10.1 (StataCorp, College Station, TX). A two-sided P value ≤0.05 was considered statistically significant.

Results

Time to recovery of HPAA

Baseline characteristics of the 57 patients included in the analysis are presented in Table 2. Using a cutoff value of peak cortisol of at least 10 μg/dl to indicate partial HPAA recovery, 55 of 57 patients (96.5%) demonstrated partial recovery during follow-up. The two patients who did not reach a cortisol value of 10 μg/dl had unique clinical circumstances. One patient suffered a perioperative hypothalamic cerebral accident and was continued on full replacement doses of hydrocortisone at her 12-month follow-up. The second patient had persistent hypercortisolism after the first surgery and required a second exploration of her pituitary 9 d later in an attempt to provide remission of CD, which proved to be successful, but left her with lasting hypopituitarism.

Table 2.

Patient characteristics

Patient characteristics (n = 57)	Mean ± sd or n (%)
Females/males	28 (49)/29 (51)
Age (yr), n = 57	13.0 ± 3.1
Pubertal status (Tanner stage), n = 55
Male
T1–3	22 (81.5)
T4 and 5	5 (18.5)
Female
T1–3	13 (46.4)
T4 and 5	15 (53.6)
BMI sd Z-score, n = 57	1.9 ± 0.8
Midnight cortisol (μg/dl), n = 57; normal range, <4.4 μg.dl	17.9 ± 8.2
Mean UFC (μg/24 h), n = 57; normal range, 4.0–56 μg/24 h	330.1 ± 366.2
Length of disease (months), n = 57	28.3 ± 15
Time to full recovery (by peak cortisol of ≥18 μg/dl)
Mean time (months)	12.6 ± 3.3
By interval
0–6 months	4 (9.3)
7–12 months	25 (58.1)
13–18 months	12 (27.9)
19–36 months	2 (4.7)

Five patients with recurrent disease within the first 2–3 months after TSS and the two patients with persistent disease immediately after TSS were omitted from this analysis as described in the Subjects and Methods. Of those individuals included in the study, two of the four patients who reached a peak cortisol of at least 18 μg/dl at 6 months did in fact have recurrence of disease during the course of this investigation; one of these patients is a 10-yr-old male with multiple endocrine neoplasia type 1 and both a prolactinoma and ACTH-producing pituitary adenoma. The patient underwent TSS where multiple discrete masses of tissue were resected. Immediately after his surgery, he had lower serum cortisol levels. At his 1-yr follow-up, he exhibited marked reduction in his Cushing's symptoms with weight loss and improved growth velocity, yet with urinary cortisol levels in the range of CD. The patient has since been lost to follow-up, but he is off any glucocorticoid replacement and by all diagnostic standards, he has CD. The second patient underwent TSS and initially had biochemical evidence for cure; however, after the first 6 months after TSS, he showed biochemical signs of recurrence and ultimately required pituitary radiation within the first postoperative year.

Full recovery by definition of reaching a peak cortisol of at least 18 μg/dl was reached by 43 (75.4%) of the patients, whereas 14 patients (24.6%) did not fully recover their HPAA (Fig. 1). At 6 months, four of the 18 patients that were tested had recovery of their HPAA. Between 7 and 12 months, 25 of the 47 patients tested had recovery of their HPAA. Of note, 10 of the patients who did not recover their HPAA by 7–12 months were not tested subsequently; thus, it is not known whether they would have recovered if tested at later time points. Between 13 and 18 months, 12 of the 16 patients that were tested had recovery of their HPAA, and between 19 and 36 months, the two patients tested showed recovery of their HPAA. These two patients were were not tested between 13 and 18 months. The patient tested at 19 months reached a value of 22.7 μg/dl; this patient was previously tested at 6 months and reached a value of 17.2 μg/dl. The patient tested at 36 months peaked at 34 μg/dl; this was the only follow-up time point for this patient. The mean time to recovery was 12.6 (±3.3) months, with Kaplan-Meier survivor function estimates yielding 50% chance of recovering by 12 months after TSS and 75% chance of recovering within 14 months (Fig. 2).

Fig. 1.

Maximal cortisol levels by test month. A, Peak cortisol value in micrograms per deciliter reached by each subject on each 250 μg ACTH test performed as a function of time in months since TSS for CD. The dotted horizontal line represents a cutoff value of 18 μg/dl of cortisol used to define recovery of the HPAA. Of note, four patients did recover by 6 months; what appears as a single point is in fact two patients that had very similar, almost identical values at 22.7 and 22.9 μg/dl. B, First cortisol measurement of at least 18 μg/dl reached by each of the 43 patients who showed evidence for recovery. In the 14 subjects who did not show evidence of recovery, the single peak cortisol level reached by each patient over the entire period of follow-up is plotted Of note, four people tested between 13 and 18 months did not recover HPAA function; these four patients are represented in panel A, and their values are 16 μg/dl at 14 months, 12 μg/dl at 14 months, 11.1 μg/dl at 18 months, and 11.5 μg/dl at 18 months. Only one of these four points is shown in panel B because three of these patients had earlier cortisol values that were slightly higher; i.e. the patient with an 18 month value of 1.1 μg/dl had a 12-month value of 15 μg/dl, the patient with an 18-month value of 11.5 μg/dl had a 12-month value of 11.6 μg/dl, and the patient with a 14-month value of 12 had a 12-month value of 12.5 μg/dl. In addition, a peak value on panel A in the 13- to 18-month time period is correctly omitted on panel B because this person has an earlier cortisol level above18 μg/dl that is represented elsewhere on panel B; this individual reached a value of 26.6 at 12 months and a value of 28.2 at 18 months. C, Paired cortisol data in patients who had repeated ACTH stimulation testing performed.

Fig. 2.

Kaplan-Meier survival estimate of time to recovery failure. A, Time to recovery (≥18 μg/dl cortisol) failure of the HPAA in children and adolescents after TSS for CD; B, same as A, stratified by gender; C, same as A, stratified by Tanner stage. The curves in panels A–C represent incidence rate of patients not yet recovered at each time interval in 43 patients with known recovery of the HPAA as defined by reaching a peak cortisol level of at least 18 μg/dl in the ACTH stimulation test. The n values at the bottom represent the numbers of individuals tested at each of the intervals who ultimately recovered to a peak stimulated cortisol above 18 μg/dl, because the Kaplan Meier survival curve effectively censors all individuals who never recovered from the analysis. The numbers of individuals tested at each of the intervals who ultimately recovered to a peak stimulated cortisol of at least 18 μg/dl are depicted on the y-axis as follows: 0–6 months, 12; 7–12 months, 34; 13–18 months, 12; 19–36 months, two. In the 43 children who reached a peak cortisol of at least 18 μg/dl, four patients (9.3%) recovered by 6 months after TSS, 25 patients (58.1%) recovered between 7 and 12 months, 12 patients (27.9%) recovered between 13 and 18 months, and two (4.7%) recovered between 19 and 36 months.

Factors predicting recovery of the HPAA

When examining the characteristics of the 43 patients who had full recovery of their HPAA, there was an equal proportion of males [n = 21 (48.8%)] and females [n = 22 (51.2%)]. Age at time of diagnosis of CD was not associated with the overall likelihood of recovery. Baseline characteristics, including tanner stage, BMI Z-score, length of disease, midnight cortisol, and UFC at time of diagnosis were not statistically different between the group of patients who recovered their HPAA completely (n = 43) vs. those who did not (n = 14).

Lower UFC at the time of diagnosis of CD were related to partial recovery of the HPAA. Six months after TSS, patients with partially recovered HPAA function and stimulated cortisol value of at least 4 μg/ml had lower UFC at diagnosis, median [224.1 (143.5, 343.0) vs. 702.2 (403.2, 1424.0); n = 18; corrected P value = 0.0198]. Because no accepted definitions of cortisol values exist to apply to partial recovery of the HPAA, we also explored cutoffs of 7 and 10 μg/dl and corrected for multiple comparisons.

Patients exhibited significant recovery between 6 and 12 months after TSS. The mean peak cortisol in those patients who returned for follow-up between 6 and 8 months after TSS was 12.6 μg/dl (±8.7; n = 21), whereas the mean peak cortisol in the patients who returned at 11–14 months after TSS was 21.1 (±7.0; n = 48).

In subjects with paired data (n = 16), there was a significant increase in mean peak cortisol between 6 and 12 months of follow-up (Δ 10.2 ± 8.5, P < 0.0001); this increase was not related to any of the studied parameters, including gender, age, tanner stage, BMI Z-score, length of disease, midnight cortisol, or UFC at time of diagnosis (Fig. 1C).

We generated a ROC curve to determine the optimal cutoff cortisol level on stimulation test at 6 months that predicted recovery of the HPAA by 12 months of follow-up. Sensitivity and specificity were highest (70–80 and 64–73%, respectively) at the cutoffs of at least 10–11 μg/dl of cortisol as the peak of ACTH stimulation testing at 6 months after TSS, to predict full recovery of the HPAA at 12 months after TSS (Fig. 3). The likelihood of recovery during follow-up status or after TSS as defined by peak cortisol of at least 18 μg/dl was greater in those subjects with a peak cortisol at 6 months after TSS of at least 10 μg/dl (P = 0.0158).

Fig. 3.

ROC curve for recovery of HPAA by 12 months after TSS. The arrow indicates optimal cutoff for the cortisol level, indicating that cortisol levels from 10–11 μg/dl on ACTH stimulation test at 6 months has the highest sensitivity (70–80%) and specificity (64–73%) in predicting recovery of HPAA by 12 months.

Discussion

Successful TSS for CD leads to transient secondary adrenal insufficiency in most patients, resulting from hypothalamic suppression due to the preceding hypercortisolism (13, 21). In most adults, as well as in children, adrenal responsiveness is restored to normal over a period of several months to a year. In our study, half of all cured patients with CD recovered HPAA function within 12 months and two thirds within 18 months after TSS. However, several important limitations to our study must be addressed. One limitation of our study is that not all patients returned for each follow-up interval; thus, it is impossible to know whether they may have recovered at an earlier or later time. Another limitation of our study is the use of an empiric tapering regimen without comparison to other tapering methods and how they may affect time to recovery.

Uncertainty remains surrounding the optimal regimen of postoperative glucocorticoid replacement. The tapering mode of glucocorticoids, timing and type of HPAA testing, and biochemical diagnostic factors that influence normalization of HPAA function remain largely uncharacterized. In our institution, we established a standardized protocol for tapering replacement after TSS. We then performed this retrospective review of the largest cohort of pediatric patients with CD studied to date and hypothesized that degree of hypercortisolism, tanner stage, BMI, and length of disease are correlated with HPAA recovery after TSS.

The HPAA suppression after treatment with exogenous glucocorticoid therapy is related to the patient's glucocorticoid dosage, although the duration of dose and cumulative dose may only roughly predict HPAA suppression (22). In children, adrenal insufficiency remains a cause of morbidity and mortality related to blunted cortisol response to stress; ensuring that the HPAA is no longer suppressed before withdrawing glucocorticoid replacement therapy is crucial (23). A number of prospective studies have assessed HPAA function after high-dose glucocorticoid therapy in children (24, 25). The question remains as to the optimal method of tapering glucocorticoids to avoid overtreatment that slows recovery while balancing the risk of undertreatment and possible adrenal crisis and steroid withdrawal syndrome.

The NIH protocol for tapering glucocorticoids in pediatric patients after TSS for CD is outlined in Fig. 4. Post-TSS patients are placed on 8–12 mg/m² · d of hydrocortisone (physiological replacement of endogenous cortisol production) divided twice daily with a larger dose in the morning (usually two thirds in the morning and one third in the afternoon). After 4 months, the dose is reduced by 2.5 mg every 4–6 wk until the patient is on only 5 mg/d. The afternoon dose is reduced first and gradually eliminated; this is then followed by reductions of the morning dose. HPAA function testing takes place approximately every 6 months until recovery has been achieved. Hydrocortisone is held on the day before, replaced by the equivalent dexamethasone replacement dose, and no replacement is given on the morning of the ACTH stimulation test. Glucocorticoid therapy is discontinued completely when cortisol level in response to ACTH is greater than 18 μg/dl. Stress coverage is continued for another 6 months to allow for the possibility of residual HPAA dysfunction; patients and/or parents are instructed to triple their starting maintenance hydrocortisone dose in case of illness and are taught to inject 100 mg hydrocortisone in emergency situations. Throughout the entire period, patients are also instructed to wear a bracelet (or necklace) alerting to the presence of adrenal insufficiency. Patients are requested to document signs or symptoms of glucocorticoid withdrawal, including nausea, anorexia, malaise, fatigue, depression, and joint pain. This tapering regimen avoids continued suppression of the HPAA and the Cushing's syndrome features associated with higher doses. The majority of patients, however, are expected to experience some symptoms of adrenal insufficiency during the course of their hydrocortisone wean, particularly during the first 3–4 months after TSS. Patients were instructed to contact the protocol team or their primary endocrinologist if they experienced prolonged or severe symptoms of adrenal insufficiency. A minority of patients (<6%) required individualized modification to their taper schedule due to severity of their symptoms. However, none of the patients required hospitalization for adrenal insufficiency-related symptoms during the course of the tapering process. Our protocol of gradual cessation of glucocorticoid therapy allows for the recovery of HPAA function in a safe and well-controlled manner and may potentially be adapted for management of HPAA suppression after treatment with glucocorticoids for other pediatric conditions.

Fig. 4.

The NIH hydrocortisone (HC) tapering regimen after TSS in children with CD.

Using this standard regimen of hydrocortisone replacement, the majority of cured children with CD recovered spontaneous HPAA function within 12 months, and a significant recovery was seen between 6 and 12 months. Parameters that would seem to intuitively negatively influence recovery such as prolonged length of disease before diagnosis and higher BMI did not have any correlation with recovery time. On the other hand, severity of hypercortisolemia did appear to influence recovery; greater elevations of UFC at the time of diagnosis of CD were correlated with a lower likelihood of partial recovery of the HPAA function when measured 6 months postoperatively, corresponding with the finding that patients who are exposed to higher doses of exogenous glucocorticoids take longer to recover their HPAA and recommendations to taper these patients more slowly.

It is important to note that of those individuals included in our study, two of the four patients who reached a peak cortisol of at least 18 μg/dl at 6 months did in fact have recurrence of disease. In addition, four children with CD reported by Batista et al. (18) who had shown full recovery of the HPAA by 6 months were actually children with recurrent CD. Our two patients together with the Batista et al. (18) report suggest that early recovery of the HPAA may be in fact a sign of recurrent CD. It is often challenging to balance replacement and tapering of hydrocortisone during follow-up with surveillance for recurrent CD. Other factors that help to predict those patients who may be at risk for recurrent CD include a normal response to CRH testing and/or normal morning ACTH and cortisol values after TSS (18). Patients should be monitored for classic signs and symptoms of CD, because the level of hydrocortisone in physiological replacement would not be expected to cause cushingoid features. When patients do stimulate to a value of at least 18 μg/dl at 6 months or sooner after TSS, measurement of UFC and midnight serum cortisol may be warranted, and patients should be switched to dexamethasone to avoid interference of the hydrocortisone with the cortisol assay.

First-line treatment for CD in childhood is surgical and is 90% curative in a facility with expertise in treating CD yet results in secondary adrenal insufficiency. The supraphysiological levels of glucocorticoids suppress the secretion of CRH and ACTH, leading to secondary adrenal cortical atrophy and delayed recovery of the HPAA (22, 26). Surgical manipulation and radiation therapy for CD also contribute to pituitary hormone deficiencies. Impairment of adrenocortical function can last from a few months to 1 or more years in patients with CD. Our group has previously reported the recovery time to GH axis and thyroid axis; here we show a comparable recovery time for the HPAA in children after TSS. Finally, using the cutoff of at least 10–11 μg/dl of cortisol as peak of ACTH stimulation testing at 6 months after TSS, the ROC curve has a high sensitivity and specificity to predict subsequent full recovery of the HPAA at 12 months after TSS and may be used to guide clinicians as they counsel patients and taper glucocorticoids.

In summary, this study proposes that an empirically made but standardized regimen for replacement and tapering of glucocorticoid replacement after TSS for CD leads to safe recovery of HPAA function within 12 months after TSS in most patients; our data also identify severity of hypercortisolemia before TSS as a factor that influences recovery, whereas early recovery is highly suspicious for failed surgical treatment.