CLIN. AND EXPER.-THEORY AND PRACTICE, A8(4&5), 787-791 (1986)

BLOOD PRESSURE BEHAVIOUR AND CONTROL IN TURNER SYNDROME

R. Virdis, M.C. Cantu', L. Ghizzoni, A. Ammenti, C!. Nori, C. Volta, C. Cravidi, M. Vanelli, P. Balestrazzi, S. Bernasconi

and G. Giovannelli. Department of Pediatrics - University of Parma.

43100 PARMA - ITALY.

Key words: Turner syndrome, hypertension, rfnin

ABSTRACT Adult Turner syndrome (TS) patients frequently present hypertension. To clarify the pathogenesis of this hypertension we examined the blood pressure (BPI behaviour and the renin- angiotensin-aldosterone system in 31 TS patients (2-22 years of age). BP levels were occasionally elevated in 47% of the subjects and constantly elevated in 23%. Most of the patients were on estrogen replacement therapy,but 26% of them presented with elevated levels since childhood. Supine and upright plasma renin activity (PRA) values were higher in TS compared to controls and more elevated in hypertensive TS than in the normotensive ones. At Captopril challenge TS showed different PRA responses regardless of the karyotype and clinical features. Patients on estrogen therapy,however,exhibited higher increments of PRA after Captopril. Conclusions: 1) TS patients show high frequency of hypertension in pediatric age. 2) Estrogen therapy is an outbreaking and worsening factor. 3 ) An estrogen independent role of the renin-angiotensin- aldosterone system in the pathogenesis of TS hypertension is still uncertain.

INTRODUCTION Patients with Turner syndrome (TS) often present hypertension which can be secondary to aorta coarctation or essential (1,2). In the literature there are no extensive studies on the incidence and mechanisms of "essential hypertension" in this syndrome. We studied a large group of TS patients selected from our endocrine and genetic clinic in order to estimate the frequency of hypertension in TS children and adolescents, the behavioiir of the renin-angiotensin system and the possible role of endogenous (renal and cardiovascular anomalies) and exogenous (estrogen therapy) factors involved in the hypertensive process.

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Copyright 0 1986 by Marcel Dekker, Inc. 0730-0077/86/0804-0787$3.50/0

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788 VIRDIS ET AL.

MATERIALS AND METHODS Thirty one female patients (2 to 22 years of age) with TS were studied. The karyotypes were 45,XO in 17; 45,XO/46,XX in 6; other mosaicisms and / or X chromosome pathology in 8. Replacement therapy with estrogens was begun in 20 adolescent girls and then treatment was changed to estrogen-progesterone combination regimen. In 5 patients the therapy was interrupted because of the onset of hypertension.

Seventeen girls underwent extensive cardiological evaluation, including echocardiography, which showed the presence of anomalous aortic valve (bicuspid and/or stenotic) in 6 of them. No aortic coarctation was found. In the remaining subjects the existence of coarctation was excluded by simultaneous blood pressure (BP) measurement in the four limbs in the absence of cardiac and ECG abnormalities.

BP was measured by mercury sphigmomanometers during periodical clinical controls.

Plasma renin activity (PRA) and plasma aldosterone levels were determined in blood samples collected from patients in upright position in 6 and in both supine and upright position in 18. In 17 patients PRA and aldosterone levels in the sitting position were also assayed one hour before and one hour after a single oral dose of 25 mg of Captopril.

PRA and aldosterone were measured by radioimmunoassay with commercial kits from CIS-SORIN (Italy). Statistical tests used were the Student t-test and the linear regression analysis. RESULTS Fourteen girls (47%) occasionally showed BP levels above the 95th percentile,and seven of them (23%) had constantly elevated BP. Most of these patients (10/14) were on estrogen therapy,but 8 presented with occasional elevated levels in prepuberty before estrogen therapy.

TABLE 1

Con t ro 1 s

TS

PRA LEVELS (ng/ml/hr) SUPINE UPRIGHT

1.4 - + 1.2 (n=35) 3.0 - + 2.7 ( ~ 1 8 )

3.5 - + 1.0 (11-35) 5.2 - + 2.7 (11-24)

p<O. 005 p<O. 005

Hypertensive TS

Normotensive TS

Estrogen treated TS 3.1 If: 1.6 (n=8)

Untreated TS

2.1 - + 1.1 (n=6) 3.4 - + 3 . 3 (n-10)

6.4 - + 2.1 (n-10)

4.6 5 2.9 (11-13)

5.2 - + 2.8 (n=15)

5.2 5 2.7 (n-9)

n.6. p<O. 005

n.a. n.8. 3.0 - + 3.4 (n=10)

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BLOOD PRESSURE CONTROL IN TURNER SYNDROME 789

Captopril Test

Hypertensive TS Renal malformation

1 Pro Post Re post Estrogen treated TS Untreated TS

FIGURE 1

PRA Responses to Captopril in 8 Estrogen Treated and 9 Untreated Turner Syndrome Patients.

Supine and upright PRA levels were more elevated in TS than in controls (table 1). The mean supine and upright PRA levels of 10 hypertensive patients were compared with those of 13 normotensive TS and found significantly higher only in upright. No differences were found between patients on and o f f estrogens therapy.

Plasma aldosterone levels,determined in fewer patients were similar to those found in contro1s:supine (n=10> 153 2 124 pg/ml

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VIRDIS ET AL. 790

vs. ( ~ 3 5 ) 133 5 81 pg/ml;upright ( ~ 1 5 ) 185 5 125 pg/ml vs. (n=35) 191 - + 137 pg/ml.

Captopril chal1enge:TS patients showed different PRA responses to the Captopri1,without any relationship to karyotype,renal or cardiac anomalies and hypertension (Fig. 1). The PRA increments expressed as ratio of the PRA levels after and before the Captopril admini~tration~were higher than 3.5,as in nephrovascular hypertension,in 35% of all TS subjects and in 50% of the estrogen treated TS. In 8 of the girls on estrogen replacement the PRA levels after Captopril and the increments in PRA were significantly higher compared to those of 9 untreated patients. (PRA after Captopril: 12.8 + 7.5 ng/ml/hr vs. 4.6 + 3.1 ng/ml/hr, p<O.OOl; increments: 3.6 - T 1.9 vs. 1.8 5 0.7, p<0.02).

DISCUSSION The hypertensive trend of TS is well known (1,2),but no studies are available on the etiology and pathogenesis of the presumed essential hypertension in this syndrome. Our patients sometimes present elevated BP in prepuberty with an increased frequency of hypertension in adolescence related to the estrogen replacement therapy.

Estrogens or a combination of estrogens and progesterone therapy lead to increased PRA levels in normal women through an augmented production of renin substrate (3,4). This process may play a major role in the development of hypertension in women on contraceptive therapy, but PRA increases at the same degree also in those who remain normotensive (3,4). The estrogen treated TS show higher frequency of hypertension compared to normal young females while on contraceptive therapy (5). Moreover, regardless of the BP levels, the PRA responses to Captopril are also elevated in these patients and often are in the range o f nephro-vascular renin- dependent hypertension.

In conclusion this study confirms the hypertensive genetic susceptibility of TS patients and indicates that estrogen replacement therapy is probably the major exogenous factor related to the onset of hypertension in adolescence. An estrogen- independent role of renin-angiotensin system in TS hypertension still remains unclear. Renal and cardiac malformations, with the exception of aorta coarctation, are not related to the BP elevation.

REFERENCES 1) Haddad, H.M., Wilkins,L. Congenital anomalies associated with gonadal aplasia. Review of 55 cases. Pediatrics 1959;23:885-902. 2) Engel,E., Forbes, A.P. Cytogenetic and clfnical findings in 48 patients with congenital defective or absent ovaries. Medicine 1965;44:135-164. 3) Laragh,J.H., Sealey, J.E., Ledingham, J.J.G., Newton, M.A. Oral contraceptives: renin, aldosterone and high blood pressure. JAMA 1967;201:918-922. 4) Crane,M.G. Iatrogenic hypertension. In "Hypertension" Eds. Genes t , J. , Kuchel ,O. , Hamet ,P. , Cant in,M. 2nd Edit ion, McGraw-Hi11 Book Co., New York,1983:976-988.

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BLOOD PRESSURE CONTROL IN TURNER SYNDROME 791

5) Finnerty,F.A. jr. Contraception and pregnancy in the young female hypertensive patients. Pediat Clin North Am 1978;23:119-126.

This paper was supported by a grant of C.N.R. (Rome - Italy) n. 85.00610.56.

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