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Clinical Endocrinology (1980) 13,40144 RAPID COMMUNICATION OESTROGEN DYNAMICS IN ADRENAL VENOUS EFFLUENTS IN CONGENITAL VIRILIZING ADRENAL HYPERPLASIA B. L. WAJCHENBERG, J. GOLDMAN, T. S. KYAN, S. S. ACHANDO, Y. L. THOMSEN AND S. S. LIMA Diabetes and Adrenal Unit, Hospital das Clinicas; Hospital Sirio-Libanez and Institute of Energetic and Nuclear Research (IPEN) , SZo Paulo I Received 17 March 1980; revised 7 May 1980; accepted 28 May 1980) SUMMARY. Four patients with untreated congenital virilizing adrenal hyper- plasia (partial 2 1 -hydroxylase deficiency) were studied by bilateral adrenal vein catheterization. Simultaneous right and left adrenal and peripheral blood samples were collected for determination of oestrone (El) and oestradiol (Ed. The concentrations of both were higher in the adrenal effluents than in the peripheral blood samples, indicating their secretion by the adrenals. All patients were also studied during a sequential test of suppression (0-5 h after i.v. administration of 4 mg dexamethasone) and stimulation (5 min after i.v. administration of 250 pg ACTH 1-24; Synacthen).Mean peripheral E2 concen- trations did not change significantly whereas El increased above control levels after stimulation. In contrast, suppression of adrenal venous blood concentra- tions with dexamethasone, and stimulation with ACTH, was demonstrated for every patient. The results indicate that in congenital adrenal hyperplasia the adrenal glands secrete significant amounts of El and Ez. The steroid content of the adrenal venous effluent has been used to localize steroid- producing tumours and to study the dynamics of steroid secretion in normal and pathological conditions. We have previously presented adrenal vein effluent concentra- tions of cortisol, progestational steroids and androgens in untreated patients with partial 2 1-hydroxylase deficiency (Wajchenberg et al., 1979).Here we report the results of similar studies of oestrone (El) and oestradiol (E2). Material and methods Four untreated female patients (ages 12-28 years) with congenital adrenal hyperplasia (CAH), with the partial form of 21-hydroxylasedeficiency,were studied. The studies were approved by the local ethical committee and informed consent was obtained from the patients or their parents. The patients were studied after a 48 h observation period in hospital. Correspondence: Dr B. L. Wajchenberg, Diabetes and Adrenal Unit, Hospital das Clinicas, S9o Paulo, Brazil. 0300-0664/80/1000-0401S02.00 0 1980 Blackwell Scientific Publications 401

OESTROGEN DYNAMICS IN ADRENAL VENOUS EFFLUENTS IN CONGENITAL VIRILIZING ADRENAL HYPERPLASIA

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Clinical Endocrinology (1980) 13,40144

RAPID COMMUNICATION

OESTROGEN DYNAMICS IN ADRENAL VENOUS EFFLUENTS IN CONGENITAL VIRILIZING ADRENAL HYPERPLASIA

B. L. WAJCHENBERG, J. GOLDMAN, T. S. KYAN, S. S. ACHANDO, Y. L. THOMSEN A N D S. S. LIMA

Diabetes and Adrenal Unit, Hospital das Clinicas; Hospital Sirio- Libanez and Institute of Energetic and Nuclear Research (IPEN) , SZo Paulo

I Received 17 March 1980; revised 7 May 1980; accepted 28 May 1980)

SUMMARY. Four patients with untreated congenital virilizing adrenal hyper- plasia (partial 2 1 -hydroxylase deficiency) were studied by bilateral adrenal vein catheterization. Simultaneous right and left adrenal and peripheral blood samples were collected for determination of oestrone (El) and oestradiol (Ed. The concentrations of both were higher in the adrenal effluents than in the peripheral blood samples, indicating their secretion by the adrenals. All patients were also studied during a sequential test of suppression (0-5 h after i.v. administration of 4 mg dexamethasone) and stimulation (5 min after i.v. administration of 250 pg ACTH 1-24; Synacthen). Mean peripheral E2 concen- trations did not change significantly whereas El increased above control levels after stimulation. In contrast, suppression of adrenal venous blood concentra- tions with dexamethasone, and stimulation with ACTH, was demonstrated for every patient. The results indicate that in congenital adrenal hyperplasia the adrenal glands secrete significant amounts of El and Ez.

The steroid content of the adrenal venous effluent has been used to localize steroid- producing tumours and to study the dynamics of steroid secretion in normal and pathological conditions. We have previously presented adrenal vein effluent concentra- tions of cortisol, progestational steroids and androgens in untreated patients with partial 2 1-hydroxylase deficiency (Wajchenberg et al., 1979). Here we report the results of similar studies of oestrone (El) and oestradiol (E2).

Material and methods

Four untreated female patients (ages 12-28 years) with congenital adrenal hyperplasia (CAH), with the partial form of 21-hydroxylase deficiency, were studied. The studies were approved by the local ethical committee and informed consent was obtained from the patients or their parents. The patients were studied after a 48 h observation period in hospital.

Correspondence: Dr B. L. Wajchenberg, Diabetes and Adrenal Unit, Hospital das Clinicas, S9o Paulo, Brazil.

0300-0664/80/1000-0401S02.00 0 1980 Blackwell Scientific Publications

401

402 B. L. Wajchenberg et al.

Table 1. Clinical and laboratory data on four female patients with congenital viriliing adrenal hyperplasia (partial 2 I-hydroxylase deficiency)

Urine Findings at ~ venography 1 Ovaries§

Age Height Weight 170HCS* 17KSt Patient (years) (cm) (Kg) Bone age (pno1/24 h) RAV LAV Size Cysts

MJPS 28 151.0 51.6 Adult 15.5 182.0 NL +++ N 0 MJSM 26 048.0 40.2 Adtlt 16-2 241.8 ++ ++ + N + ACA 12 143.0 47.5 Adult 7.2 428.7 ++++ ++++ < 0 CNA 14 148.0 56.4 Adult 9.3 92.7 + + + + + +++ + +

All patients presented heterosexual precociouspuberty. In one patient (MJPS) menarche occurred at theage of 16 years, with irregular menses afterwards (I70HCS, 17-hydroxycorticosteroids; 17KS. 17-ketosteroids: RAV, right adrenal vein; LAV, left adrenal vein). * Method of Silber & Porter (1954). Normal values for children above 5 years and adults, 8.3-17.2 umol.m-’ 24 h-’ (unpublished data). t Method of Dreckter er 01. (1952) normal values for adults (females) 20.1-584 umol.24 h-1 (mean 35.3 umol-24 h- I ) . $ NL normal; + to + + f + degree of enlargement. 4 Evaluated by pneumogynaecography and ovarian biopsy. N normal; + to + + + enlargement; < decreased; 0 cysts absept; + cysts present.

Clinical and laboratory data are presented in Table 1, All patients fasted for 12 h before the study. Percutaneous venous catheterization via the femoral vein was performed. The catheters were placed in both adrenal veins between 08.00 h and 09.00 h, under Auoro- scopic control, using xylocaine hydrochloride as a local anaesthetic. Adrenal venograms were performed to confirm correct catheter placement. This was followed by simul- taneous venous blood sampling from the right and left adrenal effluents, and from a peripheral vein. To study the dynamics of the adrenal steroids, all patients received an acute i.v. injection of dexamethasone (4.0 mg). Blood sampling from both adrenal and peripheral veins was carried out 30 min later, ACTH (1-24; Synacthen) (250 pg) was then immediately injected through a peripheral vein, and the sampling procedure was repeated 5 min later. Oestrone (El) and 17-8 oestradiol (E2) were measured in peripheral and adrenal vein samples obtained during the suppression and stimulation tests. All steroids were measured by specific radioimmunoassays, after separation in 5 x 1 cm Sephadex LH-20 columns.

Results The plasma concentrations of El and EZ in peripheral and adrenal venous effluents are

shown in Table 2. The peripheral venous plasma levels of El were not suppressed after dexamethasone but increased significantly after ACTH administration. These differences after suppression and stimulation were greatly magnified in adrenal venous effluents. For Ez, while in the peripheral no significant changes were observed after suppression or stimulation, in the adrenal veins there was a significant increase in its levels after ACTH.

The oestrogen concentrations in the adrenal effluents were higher than the correspond- ing peripheral values, except for some measurements of Ez. The values obtained for the right and left glands were comparable. The meanf 1 SEM for the ratios of the basal

Oestrogens in congenital acirenul hyperplasia 40 3

Table 2. Oestrone (El ) and oestradiol (E2) levels in peripheral and adrenal venous blood in four female patients with CAH

Patient Samples Periods Ei (pg,ml) Ez (pg;ml)

ACA

CNA

MJPS PV

RAV

LAV

MJSM PV

RA V

LAV

PV

RAV

LAV

PV

RAV

LAV

C DEX ACTH C DEX ACTH C DEX ACTH C DEX ACTH C DEX ACTH C DEX ACTH C DEX ACTH C DEX ACTH C DEX ACTH C DEX ACTH C DEX ACTH C DEX ACTH

305.7 285. I 336.3 468.7 290.9

1469.4 506.7 449. I

2 154.0 191.0 150.0 384.4 29 I .O 187.9 695.2 302.2 220. I 823.2 278.2 242.9 352.5 614.9 420.6 961-7

539. I 1141.9

140.2 360.0 310.2 170.3

1'40.4 360. I 210.0 950.2

824- 1

1no.i

49.1 48.9 97.7

70.0 183.4 78.7 73.6

137.7 43.4 30.0 68.3 55.' 26.8 63.7 54.3 34.0 94.7 76.9 82.5 89.0 90.0 74.3

110.4 83.3 83.0

112.2

83.8

86.0 82.4

8 1 . 4

80.4

86, I 90.3

156.5 95.2

120.7

MeankSEM PV C DEX ACTH

DEX ACTH

DEX ACTH

RAV C

LAV C

738.7531.3 204.5 354 358.3 f 10.0 42 I . I + 75.8 267.3 k 57.6

1091.5+ 168.0 498.2 f I 16.8 368. I + 93. I

1292.2 k 300.3

63.8 f 10.0 60.9+ 13.0 85.2 f 6. I 79.8 t 8.3 63.1 t 12.3

128.5k26.3 77.8 f 8.6 67.7f 11.4

116.3 8.9

PV peripheral vein; LAV left adrenal vein; RAV right adrenal vein; C control; DEX after dexamethasone.

404 B. L. Wajchenberg et al.

concentrations of steroids in the adrenal effluents to the corresponding peripheral values corresponding to the right and left adrenal veins were, respectively: El , 1.7kO.1 and 2.9k0.3 and El, 1.2f0.1 and 1.2kO.l.

Discussion In CAH due to partial 21-hydroxylase deficiency, the enzyme defect can be overcome

by the compensatory hyersecretion of ACTH, and a rise in 17-hydroxyprogesterone which, although bringing cortisol production rates towards normal, also results in an increased secretion of adrenal androgens and clinical virilism (Migeon, 1972, Wajchen- berg er al., 1979).

I t is to be expected that the increase in androgen secretion would bring an increased peripheral and adrenal conversion to oestrogens, androstenedione being a more efficient precursor than testosterone, dehydroepiandrosterone and dehydroepiandrosterone sul- phate (MacDonald er a/.. 1967). High values of plasma E l and El were found in children with CAH of either sex (Bidlingmaier er al., 1973).

Direct proof of the secretion of a hormone requires the demonstration of a greater concentration in the venous effluent of the gland than in the artery or, at least, in peripheral blood, and the present study demonstrates the basal secretion El by the adrenal gland. On the other hand, the adrenal contribution of El, if any, was probably minimal under basal conditions, the mean gradient after dexamethasone between the adrenal and peripheral veins being 1.03 and 1 . 1 in the right and left adrenal veins respectively, which increased to 1.50 and 1.36 after ACTH. This observation shows that in CAH the adrenal also contributes directly to the plasma pool of Er and to the pool of El to a much lesser extent.

Adrenal E? and particularly El secretion, has been described in other adrenal disorders (Baird er al.. 1969: Saez ef al.. 1972; Yuen er al., 1974). This study is the first demon- stration of direct adrenal secretion of El in CAH.

Rqfkrences BAIRD. D.T.. UNO. A. & MELBY. J.C. (1969) Adrenal secretion of androgens and oestrogens. Juurnul of

Entlucrinulugy. 45. 133-1 36. BIDLINGMAIER. F., WAGNER-BARNACK, M.. BUTENANDT, 0. & KNORR, D. (1973) Plasma

estrogens in childhood and puberty under physiologic and pathologic conditions. Pediulric Research. 7 ,

DRECKTER. I.J.. HEISER. A,. SCHISM, G.R. . STARN, S. & MrGAVACK. T.H. ( 1952)The determination of urinary steroids. I . The preparation of pigment-free extracts and a simplified procedure for the estimation of total 17-ketosteroids. Journal uf Clinical Endocrinology and Metaholism. 12. 55415.

MAcDONALD. P.C., ROMBAUT. R.P. & SIITERI, P.K. (1967) Plasma precursors of estrogen. I. Extent of conversion of plasma A?-androstenedione to estrone in normal males and nonpregnant normal. cast rate and adrenalectomized females. Journal of Clinical Endocrinology. 27, I 103-1 1 I I .

901 -907.

MIGEON. C.J. (1972) Adrenal androgens in man. American Journalof Medicine, 53,606626. SAEZ. J.M.. MORERA. A.M.. DAZORD. A. & BERTRAND, J . (1977) Adrenal and testicular contribution

to plasma oestrogens. Journal of Endocrinology. 55,41-49. SILBER. R.H. & PORTER, C.C. (1954) The determination of 17.21 dihydroxy-20-ketosteroids in urine and

plasma. Journal Of’Biolugical Chemistry. 210,923-932. WAJCHENBERG, B.L., ACHANDO. S.S.. OKADA, H.. SHIMIZU. T.. WHITE, A,, LIMA, S.S..

PIERONI, R.R. & LEME. C.E. (1979) Adrenal steroid dynamics in congenital adrenal hyperplasia: evaluation by simultaneous bilateral adrenal venous catheterization. Juurnul of Clinical Endocrinology and Metabolism. 49.46-5 I .

YUEN. B.H., KELCH. R.P. & JAFFE. R.B. (1974) Adrenal contribution to plasma oestrogens in adrenal disorders. Acta Enducrinulogica. 76, I 17- 126.