RECOVERY OF ADRENAL FUNCTION AFTER TREATMENT OF ADRENOCORTICAL CARCINOMA WITH o,p’-DDD
F. GREIG, S.E. OBERFIELD, L. S. LEVINE, F. GHAVIMI, S. PANG AND M. I. NEW
Department of Pediatrics, Division of Pediatric Endocrinology, The New York Hospital-Cornell Medical Center, New York, NY 10021, Department of Pediatrics, Memorial-Sloan Kettering Cancer Center, New York, NY 10021, USA
( Received 18 July 1983; revised 29 September 1983; accepted 30 September 1983 )
SUMMARY
The adrenolytic agent, 2,2-bis [2-chlorophenyl-4-chlorophenyl] 1,1 dichloroeth- ane (o.p’-DDD), was used over a 20-month period following surgery in a 2 3/12-year-old girl for treatment of adrenocortical carcinoma. The child remained free of disease and was maintained on glucocorticoid and mineralo- corticoid supplements for 7 years. Hormonal evaluation was undertaken at 9 9/12 years of age to determine remaining adrenal steroidogenic capacity. Following discontinuation of both hydrocortisone and 9x-fludrocortisone, she remained stable and asymptomatic. Immediately after discontinuing 9x-fludro- cortisone, the adrenal glomerulosa was able to respond to stimulation by the renin-angiotensin system as shown by the ability to achieve renal sodium conservation on a restricted sodium intake ( < 10 mEq/d for 5 d). The response of the adrenal fasciculata to ACTH stimulation showed a slower recovery. Baseline levels of cortisol were in the low normal range, but there was no increase in plasma cortisol or urinary 17-hydroxysteroids following stimulation with ACTH. The responses of cortisol, deoxycorticosterone, and corticosterone to ACTH stimulation gradually improved to achieve normal stimulated levels 18 months after stopping medications. Serum testosterone and 44-androstene- dione were initially increased for level of puberty, while levels of dehydroepian- drosterone were prepubertal. Testosterone and 44-androstenedione did not suppress with dexamethasone (2 mg/d for 2 d; 4 mg/d for 2 d), and dehydroepiandrosterone decreased only slightly. However, administration of norethindrone (Norlutin) (10 mg orally, three times a day for 3 d) resulted in suppression while human chorionic gonadotrophin (hCG; 5000 U i.m. daily for 3 d) produced stimulation of testosterone, 44-androstenedione and dehydro- epiandrosterone. Thus the androgens were felt be predominantly of ovarian origin. Dehydroepiandrosterone rose to low normal levels by 18 months after
This work was presented at the 65th Annual Meeting of the Endocrine Society, San Antonio, Texas, 1983. Correspondence: Sharon E. Oberfield, M.D., Division of Pediatric Endocrinology, The New York Hospital-Cornell Medical Center, 525 East 68th Street, N-236 New York, NY 10021, USA.
discontinuation of hydrocortisone. We thus demonstrate for the first time that both the adrenal glomerulosa and fasciculata have the capacity to recover normal function following treatment with o,p’-DDD. Further, we suggest that early exposure to excess adrenal androgens may result in mild alteration of gonadal function.
Adrenocortical carcinoma is a rare disorder in childhood, which has proved difficult to treat. The use of the adrenolytic agent o.p’-DDD (2,2-bis [2-chlorophenyl-4-chloro- phenyl] 1,1 dichloroethane) in a few cases has been very effective therapy with resolution of pulmonary and hepatic metastases, and even apparent cure (Fisher et al., 1963; Helson et al., 1971; Exelby, 1975; Ostuni & Roginsky, 1975; Becker & Schumacher, 1975; Benaily et al., 1975; Korth-Schutz et al., 1977; Rappaport et al., 1978). O,p’-DDD has also been used to reduce excessive adrenal activity in patients with Cushing’s disease, presumably also by destruction of adrenal tissue (Luton et al., 1979). The mode of action of o,p’-DDD on the adrenal is still unclear; anatomical studies have reported destructive changes and atrophy (Tullner, 1970), but the long term effect of such lytic action on the function of the adrenal gland is not well documented. Many patients remain on maintenance steroids because of uncertainties of adequate residual function. We present the first report of long term evaluation of the functional capacity of the glomerulosa and fasciculata of the remaining adrenal gland in a child previously treated for metastatic adrenocortical carcinoma with both surgery and o,p’-DDD.
CASE REPORT
This Oriental girl presented at age 2 8/12 years with virilisation, accelerated growth, and a large, calcified abdominal mass in the right upper quadrant. Urinary 17-ketosteroids (96-0-150.0 mg/d) and serum testosterone (100 ng/dl) were both very elevated. She was not Cushingoid, and urinary 17-hydroxysteroids were normal. However, she was hypertensive (150/100 mmHg). Bone age was advanced (5 9/12 years). Radiographic studies showed a markedly elevated right hemi-diaphragm and a large mass which displaced the kidney downward and laterally. The chest X-ray showed clear lung fields. Selective arteriography showed grossly abnormal vascular patterns stretching over the mass and with some tumour staining. At surgery a large right adrenal adenocarcinoma was found, depressing the right kidney inferiorly, with compression of the inferior vena cava without apparent invasion; the poorly encapsulated tumour was closely adherent to the right lobe of the liver and to the dome of the diaphragm. Resection of the tumour mass, which included the lateral segment of the right lobe of the liver and part of the diaphragm, was felt to be complete. However, intraoperative spillage of friable, necrotic tumour was reported. Pathology revealed that the adrenal cortex and medulla were replaced by a diffusely growing, anaplastic carcinoma. By 10 days postoperatively, urinary 17-ketosteroids (2.5 mg/d) and serum testosterone (17 ng/dl) had declined almost to within the normal range. Blood pressure continued to be moderately elevated for three months, and then also declined to normal levels for age. Three weeks after surgery, treatment with o,p’-DDD was begun, and continued over a 20-month period with four short interruptions. Doses of 0.5-2.0 g/day were used, with an average dose of 1.53 g/d of treatment. She was also maintained on replacement hydrocortisone (15 mg/d), and after three months fludrocortisone (50 µg every other day) was added. During treatment,
she had several admissions for fever and symptoms of adrenal insufficiency. After three months on treatment, she developed ataxia which was ascribed to central nervous system toxicity of o,p’-DDD. Chemotherapy was withheld for three weeks and then restarted at a lower dose without recurrence of symptoms. Following discontinuation of o,p’-DDD (at age 4 5/12 years), there has been no recurrence of the tumour. Her growth has remained between the 75-90 percentile. Bone age continued to be slightly advanced, but with recent acceleration in the year prior to her present endocrine evaluation (Fig. 1).
Age (years)
4
6
8
10
12
14
16
195
T
Bone age 7 years 10 months
Bone age 7 years 10 months-
8 years 10 months
Bone age 14-15 years
185
175
95
90
75
165
50
Bone age 5 years 9 months
Bone age 7 years 10 months
Bone age 13 years 6 months
Bone age Il years
155
5
145
Length (cm)
135
85
95
125
75
90
Weight (kg)
115
Menarche
75
65
105
50
55
95
5
45
85
75,
o,p’- DDD
Hydrocortisone
1
9a Florinef
!
She was admitted to the Paediatric Clinical Research Center at The New York Hospital at age 9 9/12 years for evaluation of residual adrenal function, and evaluation of the recent acceleration of bone age and onset of further pubertal changes. On admission, her height was 143.6 cm (75-90%), weight 36-8 kg (75%), BP 90/60, and pulse 100/min. Her skin was without abnormal pigmentation; there was minimal body hair. She had Tanner IV breast development and Tanner III pubic hair. Her clitoris was slightly enlarged, 2 x 1 cm; there was no labial fusion. Her current medications were hydrocortisone, 15 mg/d (12 mg/m2/d), and fludrocortisone, 25 µg every third day.
Abdominal computerized tomography did not identify any masses or the remaining adrenal gland; liver, spleen, and kidneys appeared normal. An intravenous pyelogram was normal. Pelvic sonography indicated that the uterus was normal size for an immediately pre-menarchal girl; there were multiple small cysts bilaterally in the adnexal region. Vaginal smear showed a moderate oestrogenic effect. At the chronological age of 9 9/12 years her bone age was 13 6/12 years.
METHODS
All steroid analyses were performed according to modifications of previously described methods by radioimmunoassay (RIA) as indicated; aldosterone and urinary pHI aldosterone (Chakmakjian et al., 1974), plasma deoxycorticosterone, corticosterone, cortisol (Abraham et al., 1972), and androgens (Korth-Schutz et al., 1976). Plasma renin activity was measured by RIA (Sealey & Laragh, 1975).
RESULTS
Periods of inpatient study are shown in Fig. 2. Adrenal and ovarian function were tested under conditions of stimulation and suppression. (See Table 1 for normal ranges).
Evaluation of adrenal glomerulosa function (Fig. 2, Panels A-C)
Baseline while receiving hydrocortisone and fludrocortisone. Plasma cortisol and aldosterone were unmeasurable prior to the morning dose of hydrocortisone. Androgens showed an increase in testosterone and 44-androstenedione for her Tanner stage of puberty, while dehydroepiandrosterone levels were prepubertal. Plasma renin activity was 7.5 ng/ml/h.
Discontinuation of fludrocortisone. Blood pressure, weight, and electrolytes remained stable during this period and throughout all subsequent test periods. She remained in positive sodium balance. A plasma renin activity of 18 ng/ml/h was recorded.
Low sodium intake ( < 10 mEq|d for 5 d). The patient was able to achieve salt balance. A clear increase in urinary aldosterone was not observed, but levels were within the normal range for reduced salt intake. Plasma renin activity rose minimally to 20 ng/ml/h. Serum aldosterone increased from an undetectable level to 10-4 ng/dl. The patient developed varicella and was discharged and later readmitted to complete the studies.
Interpretation of Fig. 2, Panels A-C
After discontinuing mineralocorticoid supplements, plasma renin activity was as high as 18 ng/ml/h in the absence of clinical signs of salt wasting. Although a distinct increase
A
B
c
D
E
F
G
H
Hydrocortisone
Dexamethasone
15
30 15
4
:
2
Base line
Low salt
ACTH
Norlutin HCG
T (ng/dl )
100
50
Δ4Α (ng /dl )
300
100
DHEA (ng/dl)
100
50
8
17KS (mg/d )
4
15
10
F (µg /dl)
170HS (mg/d)
5
6
2
DOC (ng /dl)
15
5
0.6
B (µg/dl)
0.2
30
Aldo (ng/dl)
10
Aldo ( mg/dl)
15
5
PRA (ng/ml/h)
20
4
K (meq/d)
60
20
140
Na (meq/d)
100
60
20
5
7
9
HI
13
15
12
28
30
1/2
4
6
8
10
November
December
January
1980
1981
| Mean ± standard deviation | ||||||
|---|---|---|---|---|---|---|
| Androgens | Tanner I female | Tanner II female | Tanner III female | Tanner IV female | Tanner V female | |
| <7 yrs | > 7 yrs | |||||
| Testosterone | 5.9± 2 | 4.3±2 | 10.3±4.6 | 33±21 | 27±12 | 40±22 |
| (ng/dl) | ||||||
| 44-androstenedione (ng/dl) | 18±12 | 37±23 | 59±42 | 68±42 | 140± | 56 |
| Dehydroepiandros- | 43±28 | 123±89 | 283±160 | 273±181 | 442±220 | |
| terone (ng/dl) | ||||||
| Dehydroepiandros- | 16±17 | 45±27 | 115±54 | 114±73 | 233±100 | |
| terone sulfate | ||||||
| (µg/dl) | ||||||
| Deoxycorticosterone | All Tanner Stages 11±10.33 | |||||
| (ng/dl) | ||||||
| Corticosterone | 0·47±0.51 | |||||
| (µg/dl) | ||||||
| Cortisol | 11.38 ± 5.43 | |||||
| (µg/dl) | ||||||
| Aldosterone | 9·11 ±6.62 | |||||
| (ng/dl) | ||||||
* Normal values are unpublished data from this laboratory.
in plasma renin activity was not observed with sodium deprivation both plasma renin activity and aldosterone levels were within the range previously noted in this laboratory in normal patients under these conditions (M.I. New et al., unpublished data; see Table 1). Thus, the adrenal glomerulosa was capable of an adequate response to stimulation from the renin-angiotensin system and renal sodium conservation occurred. This response indicated that the low replacement dose of mineralocorticoid did not cause significant suppression of the adrenal glomerulosa.
Evaluation of adrenal fasciculata function (Fig. 2, Panels D and E, Fig. 3)
a) Initial evaluation of adrenal fasciculata function after discontinuation of hydrocorti- sone.
Discontinuation of hydrocortisone. The patient remained asymptomatic. There was a slight increase in morning cortisol to low-normal levels.
ACTH stimulation. Cortrosyn (1-24 ACTH), 0-4 mg in 250 ml 5% dextrose in water was administered by i.v. infusion over 6 h. The responses of plasma cortisol, deoxycorticoster- one, corticosterone, androgens, and aldosterone were minimal (Fig. 3, No. 1).
b) Subsequent evaluation of adrenal fasciculata function (Fig. 3: No. 2, 6 months; No. 3, 12 months; No. 4, 18 months after discontinuation of hydrocortisone).
Baseline levels of serum cortisol were in the normal range. In response to ACTH
ACTH stimulation
0h
6 h
30
4
Cortisol (ug/dl)
20
3
2
10
1
0
40
4
30
DOC (ng/dl)
20
32
I
10
0
1-6
4
1.2
B (µg/dl )
0-8
3
2
0-4
1
0-0
160
4
DHEA (ng/dl)
140
120
1
100
2
80
stimulation (0-4 mg Cortrosyn i.v. over 6 h), the adrenal response of cortisol was still absent at 6 months, demonstrated a moderate response at 12 months, but showed an adequate rise by 18 months after discontinuation of medications. Responses of similar magnitude were seen in serum deoxycorticosterone, corticosterone, and dehydroepian- drosterone.
Interpretation of Fig. 2, Panels D and E, and Fig. 3
Eighteen months after discontinuation of hydrocortisone therapy the adrenal fascicu- lata was capable of responding to the stimulus of ACTH.
Evaluation of ovarian function (Fig. 2, Panels F, G and H)
Dexamethasone suppression (2 mg/d for 2 d; 4 mg/d for 2 d). Plasma cortisol, deoxycorticosterone and urinary 17-hydroxysteroids suppressed, but serum testosterone and 44-androstenedione levels remained unchanged. There was a slight decrease in dehydroepiandrosterone.
Dexamethasone 4 mg/d continued with Norlutin 10 mg orally three times a day for 3 d. Suppression of LH was documented. (Prior to Norlutin, FSH was 7.2 mIU/ml and LH was 3.4 mIU/ml; following Norlutin, FSH was not measured due to insufficient sample size, and LH was 1·1 mIU/ml.) Testosterone and 44-androstenedione showed clear suppression, and there was further decrease in dehydroepiandrosterone.
Dexamethasone 4 mg/d continued with hCG 5000 U IM |d for 3 d. Serum androgens were restored to their previous level.
Interpretation of Panels F, G and H
Baseline levels of 44-androstenedione and testosterone were increased for Tanner stage of puberty, and were not suppressed with dexamethasone or stimulated with ACTH (as noted in panel E). Suppression and stimulation of these androgens seen after administra- tion of Norlutin and HCG respectively indicates their ovarian origin. Deficiency of an adrenal contribution probably accounts for the low levels of dehydroepiandrosterone, but a dehydroepiandrosterone response similar to that found in testosterone and 44-androstenedione to Norlutin and HCG also indicates an ovarian contribution.
Menarche occurred at age 10 years, and she has had monthly periods thereafter. Testosterone and 44-androstenedione levels have remained elevated for Tanner IV to V stage of puberty.
DISCUSSION
This child presented with metastatic spread of adrenocortical carcinoma. Although surgical resection was felt to be complete, her prognosis was guarded since the tumour was characterized pathologically as an aggressive type. Previous reports have indicated the frequent emergence of metastases following the excision of all visible tumour (Fisher et al., 1963; Hutter & Kayhoe, 1966a; Helson et al., 1971; Ostuni & Roginsky, 1975). Postoperatively therefore she was treated with o,p’-DDD (Exelby, 1975). The initial studies in the use of this drug described a clinical response and regression of metastases in 34-61% of patients (Bergenstal et al., 1960; Hutter & Kayhoe, 1966b; Lubitz et al., 1973). Later reports have described few short or long term benefits in the majority of patients (Hogan et al., 1980; Bertagna et al., 1981). In the literature, paediatric cases have not been distinguished from the adult population either in the course of the disease or response to o,p’-DDD. However, the majority of reported cases with a sustained response to o,p’-DDD, and those with apparent cures including the patient described here, are in the paediatric age group (Fisher et al., 1963; Helson et al., 1971; Exelby, 1975; Ostuni &
Roginsky, 1975; Becker & Schumacher, 1975; Benaily et al., 1975; Korth-Schutz et al., 1977; Rappaport et al., 1978).
Hormonally active lesions are reported to be more responsive to o,p’-DDD (Hogan et al., 1980). Furthermore, it is possible that the diagnosis is made earlier in children with such tumours, even those with metastatic disease at the time of diagnosis, because of the readily apparent abnormalities in growth and virilisation due to the inappropriate excess of hormones.
The exact mode of action of o,p’-DDD is unclear. In dogs, administration of o,p’-DDD was associated with necrosis of the adrenal cortex, which was marked after 6 weeks and complete after 3 months of the drug. Regeneration of the cortex was noted after discontinuation of the drug, if destruction was incomplete (Tullner, 1970). In humans, atrophy and fibrosis has been described after treatment with o,p’-DDD, which was distinguished from the histological changes associated with suppressive effect of glucocorticoids (Bergenstal et al., 1960). In one patient, no adrenal tissue could be identified at autopsy 9 years after treatment with o,p’-DDD; this patient had also been maintained on glucocorticoids (Ostuni & Roginsky, 1975). Decrease in levels of androgens, glucocorticoids, and mineralocorticoids have been noted.
During treatment with o,p’-DDD, the clinical picture of glucocorticoid deficiency appears to be earlier and is often more prominent than that of mineralocorticoid deficiency (Bergenstal et al., 1960; Hutter & Kayhoe, 1966b; Helson et al., 1971; Lubitz et al., 1973; Hogan et al., 1978). Biochemically, inhibition of 11ß-hydroxylase activity in vivo has been demonstrated with a significant increase in ratios of plasma 11-deoxycortisol: cortisol and deoxycorticosterone:corticosterone in patients with Cushing’s disease treated with o,p’-DDD (Brown et al., 1973). Results of in vitro studies on glands of patients treated with o,p’-DDD have demonstrated a decrease in 110-hydroxylase activity, with reduced synthesis of cortisol. Also, an effect on the zona glomerulosa has been shown with a reduction in synthesis of 18-hydroxycorticosterone and aldosterone from corticosterone, indicating decreased 18-hydroxylase activity (Touitou et al., 1978).
Use of o,p’-DDD in Cushing’s disease, either alone or in combination with pituitary irradiation, is reported to result in a good clinical response in the majority of patients, thus avoiding the need for adrenalectomy (Luton et al., 1979). However, neither the short nor long term effect of o,p’-DDD in Cushing’s disease can be clearly compared with the effect on the contralateral adrenal of the patient with adrenocortical carcinoma. In Cushing’s disease, both adrenal glands are hyperstimulated, whereas in the case of unilateral excess steroid production in adrenocortical carcinoma, the secretory function of the contrala- teral gland is presumably suppressed.
After completion of treatment with o,p’-DDD many patients with adrenocortical carcinoma have been maintained on steroid replacement with the assumption that there was defective residual adrenal function in the contralateral gland due to the lytic action of the drug. Dynamic function of the adrenal following such treatment had only been reported briefly and in a few patients. During treatment with o.p’-DDD, a poor response of plasma corticoids to stimulation with ACTH was noted in humans (Bergenstal et al., 1960), and also in dogs after only two days of treatment (Tullner, 1970). Following treatment with the drug, the response to ACTH stimulation was absent in two patients given prolonged stimulation (Bergenstal et al., 1960), and moderate in one patient after a 48-hour stimulation test (Becker & Schumacher, 1975). An adequate rise in plasma cortisol was noted only in one patient (Fisher et al., 1963). Ability to conserve sodium on a
reduced intake was reported in two out of four patients (Bergenstal et al., 1960). More detailed evaluation of the secretory response of the adrenal gland to provocative stimuli has not been reported.
In our patient there was no clinical evidence of glucocorticoid or mineralocorticoid deficiency in the baseline state after replacement therapy was discontinued. She could achieve sodium balance in response to sodium deprivation. However, the response of the zona fasciculata was initially absent, but an increase in response was shown with time. Eighteen months after medications were stopped, responses in cortisol, deoxycorticoster- one, corticosterone, and dehydroepiandrosterone were essentially normal, although at the lower end of the response range for our standards (M.I. New et al., unpublished data).
Signs of advancing puberty at a relatively early age (9 6/12 years) were of interest. The role of exposure to early and excess androgens in the maturation of the hypothalamic- pituitary-gonadal axis is as yet an unanswered question. Following treatment with o,p’-DDD, normal puberty has been reported in one other patient with adrenocortical carcinoma and two patients with Cushing’s disease (Rappaport et al., 1978; Luton et al., 1979), and normal pregnancies have also been reported (Luton et al., 1979). Our patient had menarche at 10 years of age with normal subsequent cycles.
The serum testosterone and 44-androstenedione levels are greater than normal Tanner V pubertal levels. However, she has shown no physical evidence of increased virilisation or hirsutism. We presume that her hormonal pattern coupled with her ovarian sonography may be compatible with a very mild form of polycystic ovarian disease. The exposure of the prepubertal gonads of this child to excessive androgen levels at the time of tumour diagnosis may be similar to the hormonal milieu noted in patients with untreated or poorly controlled adrenogenital syndrome. Even after adrenal androgen levels are normalised, residual ovarian dysfunction has been observed (Levine et al., 1977).
Thus, essentially normal adrenal function in the remaining adrenal gland is demon- strated during long term follow up after treatment with o,p’-DDD. We suggest that in patients with no evidence of disease, glucocorticoids should be withdrawn, and dynamic testing of residual adrenal capacity be performed. Without chronic glucocorticoid therapy there would be no need for increased steroid coverage during medical stress and thereby allow for less complicated life long management.
ACKNOWLEDGEMENTS
This work was supported in part by USPHS NIH Grants HD-00072, AM 14040, and by a grant (RR 47) from the Clinical Research Centers Program, Division of Research Resources, NIH. Dr Oberfield is the Clinical Associate Physician for the Clinical Research Center at this institution.
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