Adrenocortical Function Recovery from Secondary Adrenal Insufficiency After ACTH Therapy in a Patient with West Syndrome: A Case Report and Literature Review

ABSTRACT

We report a 1-year-7-month-old boy with West syndrome who had associated secondary adrenal insufficiency as a side effect of synthetic ACTH therapy. Serial investigation using corticotropin-releasing hormone (CRH) stimulation tests revealed the time course of his hypothalamic-pituitary-adrenal (HPA) axis recovery after the secondary adrenal insufficiency. Three days after completion of the ACTH therapy, the basal cortisol, peak cortisol, and peak ACTH levels were all low. One month after ACTH therapy, the basal cortisol level exceeded the cutoff level for intact adrenocortical function, and the peak ACTH level had improved. Five months after ACTH therapy, the peak cortisol level exceeded the cutoff level for intact adrenocortical function. The secondary adrenal insufficiency after ACTH therapy and the four months’ time lag between the recovery timing of the basal and peak cortisol levels on CRH stimulation tests were notable findings. This follow-up data is valuable information for understanding the timeline for the process of recovery of the HPA axis from secondary adrenal insufficiency, that should lead to appropriate protocols for adrenal testing and adrenocorticosteroid replacement for patients who have undergone ACTH therapy. We also reviewed previous studies on secondary adrenal insufficiency after ACTH therapy in terms of incidence rate, onset risk factors, and recovery from it. Based on our own experience and previous reports, we suggest secondary adrenal insufficiency after ACTH therapy as follows: regarding the total synthetic ACTH dose administered, approximately 0.2 mg/kg of ACTH could cause secondary adrenal insufficiency. As for the required period for convalescence from secondary adrenal insufficiency, it would take from two to five months.

West syndrome is a severe epilepsy syndrome comprising the triad of a specific seizure type called infantile spasms, an interictal electroencephalogram pattern termed hypsarrhythmia, and developmental regression or delay.¹ The term infantile spasms has been used in the literature to describe a seizure type, an epilepsy syndrome, or both. In this article, the term infantile spasms is synonymous with West syndrome.² We report a boy with infantile spasms (West syndrome) who had associated secondary adrenal insufficiency as a side effect of hormonal therapy involving synthetic ACTH, which is commonly used and covered with health insurance covered with health insurance in Japan for West syndrome. Corticotropin-releasing hormone (CRH) stimulation tests were repetitively performed during his recovery from the secondary adrenal insufficiency. We document here a case in whom we observed the process of the hypothalamic-pituitary-adrenal (HPA) axis recovery from secondary adrenal insufficiency following ACTH therapy.

PATIENT REPORT

An 11-month-old Japanese boy was introduced to our hospital for developmental retardation that had become evident at 10 months of age. Corpus callosum agenesis, hydrocephalus and brain atrophy were revealed on brain magnetic resonance imaging, with no morphological pituitary dysplasia. He exhibited no chromosomal abnormality on analysis by G-band karyotyping. While for family reasons his visit to a professional medical organization was delayed, he gradually began to present epileptic spasms occurring in clusters with interictal epileptic discharges of hypsarrhythmia on electroencephalographic examination. He was diagnosed as having West syndrome and we decided to initiate ACTH therapy, as follows: time of initiation of ACTH therapy, 1-year-6-months-old; intramuscular injection of tetracosactide acetate zinc suspension (Cortrosyn®Z); total synthetic ACTH dose administered, 0.224 mg/kg; once daily ACTH dose, 0.014 mg/kg; actual number of administrations, 16; duration of ACTH administration, 25 days; and concurrent medication, sodium valproate, vitamin B6 and clobazam. The ACTH therapy was effective, causing disappearance of the epileptic spasms and hypsarrhythmia. The serum cortisol levels between 8 am and 9 am were 26.7, 4.2, 1.0 and 1.2 μg/dL at 6, 12, 17 and 24 days after initiation of ACTH therapy, respectively. The clinical course during his hospitalization is shown in Fig. 1. We suspected that he had associated secondary adrenal insufficiency, and so investigated his HPA function using CRH stimulation tests conducted between 7 am and 8 am according to the simplified method.³ The patient was requested not to take any hydrocortisone on the previous night nor in the morning of each CRH stimulation test to avoid the effect of the glucocorticoid on the HPA system.⁴ A dose of 1.5 μg/kg of human CRH was administered intravenously, and the serum cortisol and plasma ACTH levels were measured after 0, 15, 30 and 60 min. Time-course changes of the results of CRH stimulation tests are shown in Fig. 2. We posited the cutoff levels for basal and peak serum cortisol of 5 μg/dL and 15 μg/dL for intact adrenocortical function, respectively, according to previous reports.^{5, 6} Three days after completion of the ACTH therapy, both the basal and peak serum cortisol levels were low, and the response of the plasma ACTH to CRH stimulation was poor, indicating pituitary-adrenocortical insufficiency. One month after ACTH therapy, the basal cortisol level exceeded the cutoff level, and the peak ACTH level had improved. Five months after ACTH therapy, the peak cortisol level had recovered enough, i.e., 16.1 μg/dL, exceeding the cutoff level, to judge his adrenocortical insufficiency had resolved. The patient took peroral hydrocortisone (7.5 mg/m²/day) daily from five days after ACTH therapy completion for five months. He had no clinical symptom that suggested adrenocortical insufficiency within one year after ACTH therapy. There was no critical adverse effect of ACTH therapy except subclinical adrenocortical insufficiency.

Fig. 1.

 Endocrinological clinical course of the patient during his hospitalization. F, cortisol.

Fig. 2.

 Time-course changes of the results of corticotropin-releasing hormone (CRH) stimulation tests. The upper panel shows plasma ACTH levels, closed and open circles indicating basal and peak levels, respectively. The lower panel shows serum cortisol levels, closed and open circles indicating basal and peak levels, respectively. The basal and peak cortisol levels exceeded the cutoff levels one month and five months after ACTH therapy, respectively. In the lower panel, the solid and dashed lines indicate the cutoff levels of the basal and peak serum cortisol levels on CRH stimulation tests, respectively. F, cortisol.

DISCUSSION

While ACTH therapy is recommended as the most effective medical treatment for West syndrome, secondary adrenal insufficiency has been reported as one of the critical side effects of ACTH therapy.^{7, 8} This iatrogenic adrenocortical insufficiency exhibits great individual variability and is unpredictable.⁸ We evaluated the time-course changes of HPA axis function in a patient with secondary adrenal insufficiency after ACTH therapy. Although precise evaluation of the HPA axis should be performed with the insulin tolerance test, we conducted CRH stimulation tests to avoid severe hypoglycemia due to the test itself.

There have been many more studies on the effect of exogenous glucocorticoid on the HPA axis and timing of recovery than of ACTH. Younes et al. describe the recovery of steroid-induced adrenal insufficiency as follows in their review article.⁹ Following glucocorticoid therapy in childhood leukemia and hemangioma, most patients demonstrated recovery of the HPA axis between 4-10 weeks and by 10-12 weeks, respectively, after cessation of glucocorticoid therapy. In some cases, the recovery can take anywhere from 6 to 12 months. Another study on HPA axis recovery from secondary adrenal insufficiency following long-term corticosteroids therapy, by Graber et al., revealed the natural history of HPA axis function to be as follows. The ACTH level was the first to normalize, followed by the morning serum cortisol level, and finally the cortisol level after adrenal stimulation with ACTH.¹⁰ The process of recovery of the HPA axis from secondary adrenal insufficiency in our case was consistent with Graber’s report, i.e., one month after ACTH therapy the response of the ACTH level to CRH stimulation and the basal cortisol level, and subsequently, five months after ACTH therapy the response of the peak cortisol level to CRH stimulation normalized.

We compared our case’s clinical features with in Sakaguchi et al.’s study,⁸ which is the largest one of HPA axis function following synthetic ACTH therapy using stimulation tests. They retrospectively investigated 35 patients who underwent CRH stimulation tests out of 37 with West syndrome treated with ACTH therapy. Of those 35 patients, four exhibited secondary adrenal insufficiency on CRH stimulation tests. In comparison with in their study (Table 1), in our case, the ages at the onset of West syndrome, initiation of ACTH therapy and CRH stimulation tests were higher. The total dosage of ACTH was the same, whereas the duration of ACTH administration was shorter, i.e., he underwent relatively intensive ACTH medication. As for the results of CRH stimulation tests, both the basal and peak serum cortisol levels on the first CRH stimulation test after ACTH therapy were lower in our case than in the adrenal insufficiency group in their study, indicating our case’s more serious adrenal insufficiency. In addition to these clinical features, hydrocortisone replacement therapy during the adrenal recovery process, and central nerve system comorbidities, i.e., corpus callosum agenesis, hydrocephalus and brain atrophy, are also clinical features that we should take into account as factors affecting his HPA axis.

Table 1.  Comparison of patient characteristics and adrenocortical function after ACTH therapy between our present case and a previous study.

	Our case	Sakaguchi et al.’s study8
		Normal adrenal function	Adrenal insufficiency
Patient characteristics
Onset of infantile spasms (age in months)	10	5.7 (0.402–0.540)	5.8 (0.393–0.607)
Initiation of ACTH therapy (age in months)	18	7.0 (5.2–8.4)	7.9 (5.6–11.8)
Total dosage of ACTH (mg/kg)	0.224	0.212 (0.202–0.246)	0.227 (0.221–0.247)
Duration of ACTH administration (days)	25	28 (26-30.5)	31 (28.75-34.0)
CRH stimulation test (age in months)	19	8.7 (0.580–1.043)	8.5 (0.644–0.752)
Interval between ACTH therapy and stimulation test (days)	3	10 (6–15.5)	10 (5.5–17.0)
Results of the first CRH stimulation test after ACTH therapy
Basal F (μg/dL)	2.6	8.3 (6.0–12.2)	5.7 (4.7–7.4)
Peak F (μg/dL)	7.7	18.8 (16.5–23.2)	12.1 (10.9–13.1)
Basal ACTH (pg/mL)	9.8	10.6 (4.9–20.6)	7.7 (5.8–11.2)
Peak ACTH (pg/mL)	18.6	25.3 (20.2–36.5)	18.0 (11.8–27.0)

All values are medians (25–75 percentile). CRH, corticotropin-releasing hormone; F, cortisol.

We reviewed previous studies on secondary adrenal insufficiency after ACTH therapy confirmed using adrenal stimulation tests (Table 2).^{2, 7, 8, 11,12,13,14,15} The drug formulation used, i.e., natural or synthetic, dose and duration of ACTH therapy, weaning protocol, and the diagnostic tests used to assess adrenal function vary greatly among studies. The incidence varies from 0% to 67% of the patients treated with ACTH. Two studies investigated the predictors of the risk of onset of adrenal insufficiency after ACTH therapy in terms of patient’s age, sex, etiology of infantile spasms, anterior corticosteroid use, concomitant medication, presence of other critical side effects besides adrenal insufficiency, total ACTH cumulative dose and duration of ACTH treatment, but no predictor was identified in either study.^{8, 14} We charted the age distribution of the patients subjected to ACTH therapy in four studies and our case, comparing with and without secondary adrenal insufficiency (Fig. 3), but found no correlation between the patient’s age and development of adrenal insufficiency.^{8, 11, 13, 15} Further clinical studies are needed to reveal patients’ risk factors for onset of secondary adrenal insufficiency.

Table 2.  Incidences of secondary adrenal insufficiency after ACTH therapy confirmed using adrenal stimulation tests.

Study	Ross et al.11	Perheentupa et al.12	Rao and Willis13	Mytinger et al.7	Sakaguchi et al.8	Doré-Brabant et al.14	Bistritzer et al.2	Abe et al.15
Number of patients	5	10	9	9	35	12	5	6
Secondary adrenal insufficiency	1 (20%)	#1	5 (56%)	1 (11%)	4 (11%)	8 (67%)	0	1 (17%)
Baseline characteristics
Age	median 20 mo	mean 9 mo#2	median 5 mo	median 6 mo#3	median 8 mo #4	mean 8 mo#4, 5	median 6.5 mo#4	median 1 yr 3 mo
Age range	8 mo to 8 yr	5 to 22 mo	7 wks to 16 mo	5 to 12 mo	2 to 25 mo	1.6 to 21.1 mo	4 to 9 mo	4 mo to 5 yr 2 mo
Treatment	natural ACTH	synthetic ACTH	natural ACTH	natural ACTH	synthetic ACTH	synthetic ACTH	synthetic ACTH	synthetic ACTH
Dose		80 IU/day		150 IU/m2/day		1.9 mg/m2 every other day#6	30 IU/day
Dose range	1.1 to 9 IU/kg/day	6.6 to 13.1 IU/kg/day	20 to 40 IU/day		0.01 to 0.0125 mg/kg/day		2.1 to 5 IU/kg	0.0125 to 0.025 mg/kg/day
Duration	1 to 3 mo	42 days	30 to 66 days	2 wks#7	2 wks#8	mean; 50 days, SD; 22 days	2 wks#9	2 wks#10
Adrenal stimulation test
Stimulation agents	insulin	vasopressin + ACTH	metyrapone	glucagon or ACTH#11	CRH	ACTH	low dose ACTH	CRH
Diagnostic criterion for adrenocortical insufficiency	no description of peak F	#12	peak11-deoxycortisol < 7 mg/dL	peak F < 18 mg/dL	peak F < 15 mg/dL	no description#13	peak F < 18 mg/dL	peak F < 20 mg/dL
Timing of testing from ACTH therapy completion	immediately#14	3 days, 1 and 2 wks	2 days	mean 8.9 wks#15	median 10 days	mean 49 days	median 2 days
					range; 3 to 33 days	range; 2 to 192 days	range; -15 to 11 days	range; 3 to 16 days

#1: No data of individual morbidity. Two weeks after ACTH therapy, serum F 120 minutes after stimulation was low in five out of seven (71%).

#2: Ages on admission.

#3: Corrected ages at initiation of ACTH therapy.

#4: Ages at initiation of ACTH therapy.

#5: Including patients treated with ACTH alone, corticosteroid alone and combined treatment (ACTH, corticosteroid).

#6: Total cumulative dose, mean (SD); 19.31 (9.82) mg/m².

#7: Followed by a tapering over 15 days.

#8: Followed by a tapering of two weeks.

#9: With weekly downward titration.

#10: Then on alternate days for 14 days.

#11: Two and seven patients were evaluated by means of glucagon stimulation tests and ACTH stimulation tests, respectively.

#12: Peak F; < 23.9 μg/dl after vasopressin stimulation or < 29.8 μg/dl after ACTH stimulation.

#13: Peak F of the patients diagnosed as having adrenal insufficiency was median 200 nmol/L, range 0 to 481 nmol/L.

#14: Within 48 hours after tapered withdrawal of ACTH.

#15: Median after 9 wks, range; 2 to 18 wks.

F, cortisol.

Fig. 3.

 The age distribution of the patients for whom pituitary-adrenocortical function was evaluated with stimulation tests after ACTH therapy in the previous studies and our case. Groups A and B indicate patients with normal adrenal function and adrenal insufficiency, respectively. The open and closed circles indicate male and female, respectively. The authors drew this figure based on the data given in three papers^{11, 13, 15} and individual characteristics of the patients who were analyzed in the previous study.⁸ Sakaguchi et al.’s data was personally provided by the corresponding author of the paper with permission of all coauthors. *The authors do not mention at which points of their clinical courses the recorded patients’ ages were. **Patients’ age means the age at ACTH therapy.

We summarize the cases with recovery from secondary adrenal insufficiency after ACTH therapy in Table 3.^{7, 8, 11, 13} In four different studies, there was a total of six cases. The timing of adrenal stimulation re-examination, i.e., period between the first examination or ACTH therapy completion and the second stimulation test, varied from 6 weeks to 255 days, and consequently the results on re-examination were all normal. However, none of them evaluated the time-course changes of HPA axis function. Further case accumulation will reveal the endocrinological process of HPA axis recovery from secondary adrenal insufficiency and the required period for convalescence.

Table 3.  Recovery from secondary adrenal insufficiency after ACTH therapy .

Study	Ross et al.11	Rao and Willis13	Mytinger et al.7	Sakaguchi et al.8
Number of patients in whom
adrenal function recovery was
confirmed using stimulation tests	1	1	1	3
Adrenal stimulation test
Stimulation agent	insulin	metyrapone	ACTH	CRH
Timing of re-exam	6 wks#1	2 mo#1	8 mo#1, 2	61, 161, 255 days#3
The result of re-exam	normal	normal	normal	normal in all cases

#1: Interval between first examination and re-examination.

#2: Physiological replacement hydrocortisone was slowly tapered for about 7 months, repeat adrenal stimulation test was conducted 1 month after weaning off hydrocortisone.

#3: After ACTH therapy completion.

The knowledge concerning secondary adrenal insufficiency after ACTH therapy is very limited when compared to that after prolonged glucocorticoid administration. Although our patient fortunately presented no clinical symptom of adrenocortical insufficiency, subclinical failure of HPA axis function can lead to adrenal crisis under stressful conditions, i.e., at the onset of fever due to infection or inoculation. We clinicians should pay sufficient attention to not only apparent but also subclinical adrenocortical insufficiency. Based on our own experience and previous reports, we suggest secondary adrenal insufficiency after ACTH therapy as follows: regarding the total synthetic ACTH dose administered, approximately 0.2 mg/kg of ACTH could cause secondary adrenal insufficiency. Also, the required period for convalescence from secondary adrenal insufficiency would take from two to five months. Understanding of a patient’s risk factor for developing secondary adrenal insufficiency and the recovery of HPA axis function from it, and creating appropriate adrenal testing protocols are crucial goals. This should avoid unnecessary glucocorticoid replacement, and the missing of a diagnosis of secondary adrenal insufficiency with possible adrenal crisis.