J. Endocrino/. Invest. 2: 13, 1979
Plasma renin activity and urinary aldosterone in acromegaly F. Mantero, G. Opocher, D. Armanini, G. Paviotti, M. Boscaro, and M. Muggeo* *Istituto di Semeiotica Medica and Istituto di Medicina Clinica , University of Padova, Italy ABSTRACT. The behaviour of the renin-angiotensin-aldosterone system was evaluated in 16 acromegalic patients, of whom 7 were hypertensive. The patients were studied in basal conditions, after suppression with 9a-fluorohydrocortisone, and after stimulation with furosemide. Baseline and after furosemide PRA were significantly lower in acromegalic hypertensive patients than in the normotensive group. Mean urinary aldosterone excretion was found at the upper limits of the normal range; it was occaSionally elevated, but the values were not statistically different in the two groups. There was a suppression after 9 a fluorohydrocortisone in both groups, though it did not rea(fhed the 50%. These data show that there is a disorder of the renin-angiotensin-aldosterone system in acromegalic subjects. This defective regulation is sometimes similar to that present in primary aldosteronism. In fact in two patients a typical phlebographic and scintigraphic picture of primary aldosteronism has been found; surgery, performed in both patients, revealed a large cortical adenoma in one case and a macronodular hyperplasia in the second case. However, the relationship between this adrenal abnormalities and hypertension in acromegaly are not yet completely clarified. hypertension. In those patients surgery revealed an adrenal adenoma. Another case of associated acromegaly and Conn's syndrome has been previously reported by Dluhy and Williams (9). The present study was undertaken to further elucidate the type of disorder of the renin-angiotensin-aldosterone system, present in acromegaly. PRA and aldosterone were evaluated both in basal condition and after stimulatory and suppressive maneuvers in two groups of acromegalic patients, respectively with normal and elevated blood pressure,
INTRODUCTION Arterial hypertension in acromegaly is quite common (up to 30% of the cases) (1-3). It has not yet been clarified if this frequent association is merely coincidental or related to the chronic hypersecretion of growth hormone (GH) or to sOr1)e other factors. Previous studies have demonstrated an elevated cortisol (F)'secretion rate along with increased excretion of 17 -ketosteroids (1 7-KS) and 17 -hydroxycorticosteroids (17-0HCS); however in most cases the plasma levels and the diurnal rhythm of F were normal (4). Plasma volume, total body water and exchangeable sodium have been found increased in acromegaly (5, 6). Similar findings are typical for primary aldosteronism, where they are associated with a decreased exchangeable potassium. Only very few studies have been dedicated to clarify the role of angiotensin and aldosterone in the pathogenesis of the hypertension in acromegaly. Cain et al. (7) have found normal basal values of plasma renin activity (PRA) and aldosterone secretion rate, but the aldosterone and PRA response to sodium depletion and furosemide was subnormal in the hypertensive acromegalics. Strauch et al. (8) have shown a normal behaviour of the renin-angiotensin-aldosterone system in normotensive acromegalic patients, but a typical picture of primary aldosteronism in 4 of 5 patients with
MATERIALS AND METHODS Sixteen patients with active acromegaly, aged from 36 to 66 years, 11 females and 5 males, were studied (Table 1 ). All treatment was stopped at least 11 days before beginning the studies. Five patients (no. 7, 8, 10, 12, 1 3) had previously undergone pituitary irradiation, whereas the other were untreated. In all the patients the entity of the disease was well documented by clinical criteria, high basal levels of serum GH and lack of appropriate suppression during glucose tolerance test. There were no cases of adrenal insufficiency, as shown by the levels of 17 -OHCS and 17 -KS excretion; in two cases 17-KS were above normal (no. 3 and 6). Two patients (no. 5 and 10) had simple goiter; thyroid function, evaluated by measurement of T4 and T3 test, basal metabolic rate and occasionally by 1131 uptake test was normal in all patients. The patients were divided in two groups according to their blood pressure: group 1 included 9 normotensive acromegalic patients, aged from 36 to 60 years (mean ± SE: 47 ± 2.6); group 2 the remaining 7 patients, aged
Key-words. acromegaly; PRA; aldosterone; growth hormone; hypertension. Correspondence. Dr. Franco Mantero - Istituto di Semeiotica Medica - Via Ospedale Civile, t05 - 35tOO Padova, Italia. Received January 30, 1978; accepted November 7, 1978.
13
F. Mantero, G. Opocher, D. Armanini, G. Paviotti, et a/.
Table 1 - Clinical and endocrine studies in 16 patients with acromegaly Patients
normotensive 1 R.G. 2 G.G. 3 Z.G. 4 V.G. 51.C. 6 A.A. 7 S.E. 8D.M. 9 R.N. hypertensive 10 SA 11 ZA 12 P.M. 13 P.R. 14 R.M. 15 F.M. 16 T.U.
Duration Blood Creatin. Blood Serum Serum Basal Min. val. 170HCS 17KS K+ of the pressure mg/ dl glucose NA+ GH GH (mg/ (mg/ (g/I) (meq/I) (meq/I) (ng/ml) after day) disease mm Hg day) (yr) (n.v. OGTT (n.v. (ng/ml) 4-15) 6-15)
Age (yr)
Sex
55 55 46 40 44 45 36 60 42
F F M M F M F F F
3 6 2 10 3 3 8 20 2
140/85 140/90 120/90 120/80 120/85 120/80
46 64 66 54 49 48 63
F F F F F M M
19 5 8 34 8 14 9
160/110 160/100
120175
130/90 140/90
160/110 170/110
145/100 180/110 180/110
1.10 0.90 1.20 1.00 0.80 1.20 1.10 1.10 0.80
0.69 0.90 0.92 0.96 0.77 0.99 0.94 1.31 0.70
146 150 138 140 146 139 143 143 148
4.4 4.2 5.2 4.4 4.7 4.4 3.9 4.5 3.7
80.0 9.0 31.0 48.0 42.0 36.0 100.0 13.7 32.0
34.5 8.0 17.8 46.0 27.0 25.0 71.1 35.0 18.0
11.8 11.0 9.2 8.4 5.2 4.3 10.4 8.7 3.4
14.0 6.9 17.2 15.7 7.0 30.9 16.2 13.4 5.1
1.00 1.30 1.40 1.20 1.20 1.00 1.40
0.69 0.69 0.95 1.05 1.22 0.80 1.01
143 146 145 140 140 139 139
4.7 4.7 4.1 3.8 3.8 3.9 4.0
51.0 9.6 45.4 100.0 12.0 320.0 6.0
27.6 4.6 14.3 70.0 4.0 128.0 2.5
6.0 6.4
9.5 10.8
8.3
6.4
3.6
8.1
from 48 to 66 years (mean: 55.7 ± 3.1 ), who where hypertensive (diastolic blood pressure over 100 mmHg). In this last group a renal pathogenesis of the hypertension was highly unlikely, considering the normal i.v. pyelogram and renal function test. None had hypertensive retinopathy. In normotensive patients the basal values of serum GH ranged from 9 to 100 ng/ml (mean: 43.5 ± 9.8) and in the hypertensive group from 9.6 to 320 ng/ml (mean: 78.4 ± 42). Sodium and potassium were determined by an atomic absorption spectrophotometer. Urinary 17 -OHCS were measured by a modification of the Porter-Silber's method (normal values 4-15 mg/24h). Aldosteroneexcretion (3-oxo conjugate) was measured by the double isotope derivative technique of Kliman and Peterson (1 0) (normal values 5-15 jlg/24h). PRA was measured as amount of angiotensin I generated in 1 ml of plasma after 3h of incubation at pH 5.5 and 37 C; angiotensin was measured by radioimmunoassay using a specific antiserum, according to a modification (the boiling step was avoided) of the method of Stockigt et al. (11) for PRA (normal values: standing 3-7 ng/ml/3h; mean 4.6 ± 0.7). The results are reported as mean ± SE. The acromegalic patients were placed at admission on a costant diet containing 120 meq of Na and 60 meq of K a day. All drugs were discontinued at least one week before admission. The studies began on the 5th day after admission. A 24h urine sample for analysis of urinary aldosterone was collected and a blood sample for PRA determination was drawn after 3h of upright posture. In the following days, while the patients remained on costant diet, the renin-angiotensin-aldosterone sys-
tem was evaluated by the following maneuvres: i) suppression test by 9 a fluorohydrocortisone (9 aFF) (0.4 mg/day orally, for 3 days): the urines for aldosterone determination were collected on the 3rd day and blood sample for standing PRA was drawn in the morning of the 4th day. ii) stimulatory test by sodium and volume depletion: furosemide (80 mg/ day, orally) was administered ft;Jr 3 days; urinary aldosterone was measured on the 3rd day and upright PRA in samples obtained in the morning of the 4th day. An adrenal scintiscan with 1311-iodocholesterol and an adrenal venography was performed in two hypertensive patients (no. 13, 16).ln patient no. 13 also a computerized axial tomography (CAT.) was performed.
RESULTS Basa/ condition (Figs. 1, 2, 3): on a costant diet PRA, measured after 3h standing, ranged in the acromegalic patients from 0.1 to 16 ng/ ml/3h with a mean value of 3.8 ± 1.0 ng/ ml/3h, not significantly different from normal (mean 4.6 ± 0.7 ng/ m1/3h, p >0.1 ). However the acromegalic hypertensive group had a mean PRA (1.48 ± 0.68 ng/ml/3h) significantly lower (p < 005) than the normotensive group (mean 5.6 ± 1.6 ng/ml/3h). The mean urinary aldosterone was 15.07 ± 2.6 jlg/24h, ranging from 3.3 to 37 J..I9/ 24h, and was significantly higher (p
..
Z
-Z a
~ .~ NS . ...
.. .. .
12
...J
-
a: 8
NS
« z
~ 4
•• •
:. ~. :- :.:.: o
BASAL 9a·FF normotensive hypertensive
FUROSEMIDE
BASAL
9 0- FF
DISCUSSION
FUROSEMIDE
Fig. 3 - Comparison between mean values of PRA and urinary aldosterone in hypertensive and normotensive acromegalic patients in control conditions and after stimulatory and suppressive maneuvers.
(18) and of Mayberry et al. (19) , which support a direct effect of GH on aldosterone secretion. Moreover the increase of exchangeable Na and extracellular fluid induced by GH may be obtained also in adrenalectomized patients (20) being apparently due to a direct effect of GH on renal tubular sodium reabsorption.
Our findings may be summarized as follows: i) the basal PRA, in upright position, is usually normal in acromegaly, but in the hypertensive group the PRA is partially suppressed. Acromegalic patients, irrespective to the blood pressure levels, have a mean urinary aldosterone at the upper level of the normal range, and in isolated patients it may be found elevated.
Similar changes in body compartments have been shown also in acromegaly (5 , 6, 8). These changes could be responsible for the high incidence of hypertension in this disease. In that case , one would expect to find a suppression of PRA and aldosterone in acromegaly, at least in the hypertensive group. In fact PRA was undetectable in 317. acromegalic patients with hypertenSion and a blunted response of PRA after furosemide was found in more than half of acromegalic patients. This is similar to what is seen in patients with primary aldosteronism where the PRA suppression is due to the volume expansion induced by mineralocorticoids. The GH could playa similar role, when secreted in excess. Also the slight response of aldosterone to furosemide could be due to these same phenomena , as it is assumed that the changes in aldosterone production after volume depletion are renin -dependent.
ii) after furosemide there is a blunted response of PRA in acromegalic patients; this is particularly evident in the hypertensive group, where PRA remained low in 4 of the 7. patients. iii) after 9 a-FF administration there is a suppression of aldosterone in both groups of acromegalic patients, but the degree of this suppression is lower than 50% , as may occur in primary aldosteronism. Therefore it appears that there is in acromegaly a regulatory disorder of the renin-angiontensin aldosterone system. The controversial aspects of our knowledge on the relationship between GH and aldosterone makes it particularly difficult to understand the nature of this disordered mechanism . Although the role of GH on aldosterone regulation is well demonstrated in rats (12) , studies in man do not allow similar conclusions. In hypopituitarism the stimulation of aldosterone excretion obtained by GH administration and the lack of the response of aldosterone to sodium restriction which are reported to be independent from ACTH deficiency (13, 14), could support the hypotesis of role of GH on aldosterone regulation. However Dahl et al. (15) reported that in patients with isolated GH deficiency there is a normal aldosterone response . Moreover the studies made by Finkelstein et al. (16) on hypopituitaric subjects and by Birkhauser et al. (17.) on normal subjects are in contrast with the previous results of Beck et al.
Furthermore, the presence of this behaviour also in a substantial percentage of hypertensive patients (lOW renin essential hypertension) leads one to believe that a similar disorder of the renin-angiotensin-aldosterone system could well be related to the frequent incidence of hypertension in acromegaly. Our findings are similar in part to those obtained by Cain et al. (7.) ; they suggested that this disorder in aldosterone regulation was directly related to the GH action on sodium and water balance. Moreover it may be of some interest that 4 of our 7. pa16
PRA and aldosterone in acromegaly
case, and a macronodular adrenal gland in the second case. In both cases the slight post-operative changes on blood pressure, as well as the only partial antihypertensive effect of spironolactone, seen in this patients, may be considered as an evidence against predominant role of aldosterone in the pathogenesis of the hypertension. Furthermore the findings of abnormalities of the renin-angiotensin-aldosterone system also in other acromegalics without signs of primary aldosteronism suggest that the occurence of a latter disease seems more likely due to an evolution of the previous disorder than to an occasional association. From our results it may be concluded that an evaluation of the PRA and aldosterone pattern should be routinely performed in hypertensive acromegalics, since the presence of an aldosteronoma, or a nodular hyperplasia could be more frequent than previously thought. The possibility that prolactin and some other unknown pituitary factor could be involved in the pathogenesis of this sindrome cannot be ruled out.
tients with hypertension, presented, besides the undetectable PRA, values of urinary aldosterone excretion at the upper normal limits, or frankly elevated. Also 1 normotensive patient with normal PRA showed elevated urinary aldosterone levels; this is more similar to what is seen in primary aldosteronism that in low renin essential hypertension, where aldosterone is normal or even low. Strauch et al. (8, 21) found a similar pattern in 4/5 hypertensive patients with acromegaly. They suggested that, if we do not accept a direct stimulatory effect of GH on adrenals, we may be faced with a new form of endocrine polyadenomatosis. In fact other acromegalic patients have nodular goitre (2 in our series) and parathyroid adenomas. The fact that in our patients aldosterone was only partially suppressible by 9 a-FF is further evidence on the autonomy of aldosterone secretion. A direct stimulatory effect of GH on adrenal activity may still be kept in mind. Charro et al. (22) demonstrated recently a hyperactivity of the adrenal glands, as shown by the increases of 17 -OHCS and 17 -KS excretion in active acromegaly. Also a possible role of prolactin may be evoked, since it has been found often increased in acromegaly. This hormone has an important role in regulating fluids and electrolytes and a trophic influence of steroidogenic organs in animals (23), but results obtained in humans are controversial (23). Finally a less likely hypothesis could consist in a direct opposite effect of potassium retention (24) in acromegaly on both PRA and aldosterone, being the latter increased by potassium, while the former is decreased. However in our acromegalic patients no serum K abnormalities were found, and hypokalemia was seen by Strauch et al. (8, 21) in the patients with associated aldosteronoma. A study in exchangeable potassium has been undertaken in our patients, but no conclusions can be made at this time because of the limited number of cases studied. From the results of our own and the similar studies existing on this subjects no definitive conclusions can be reached. A possibility to reconcile these seemingly contradictory results may be reached be accepting a double regulatory theory. The sodium retaining activity of GH would lead to a decreased PRA and aldosterone response to furosemide, as in low renin essential hypertension. However in some cases or at some time during their disease, the direct stimulatory effect of GH adrenals would overcome this mechanism, leading to an excessive aldosterone secretion and PRA suppression as in primary aldosteronism. In fact, 2 of these hypertensive patients in whom an adrenal venography, aldosterone assay in blood taken from the adrenal veins, and 1311-19-iodo-cholesterol scintiscans were performed, clear signs of unilateral hyperactivity were obtained. These patients have been chronically treated with bromocriptine (25); surgery, performed in both patients, revealed an adrenocortical adenoma in one
REFERENCES 1. Bricaire H., Chiche P., Acar J. Manifestation cardiovasculaires de I'acromegalie. Nouv. Pre sse Med. 70: 521, 1962. 2. Souadjian J.v., Schirger A. Hypertension in acromegaly. Am. J. Med. Sci. 254: 629, 1967. 3. Snow M.H .. Piercy D.A., Robsor:tv', Wilkinson R. An investigation into the pathogenesis of hypertension in acromegaly. Clin. Sci. Mol. Med. 53: 87, 1977. 4. Roginsky M.S .. Shaver I.C.. Christy N.P. A study of adrenal cortical function in acromegaly. J. Clin. Endocrinol. Metab. 26: 1101, 1966. 5. Ikkos D.. Lul! R., Sjogren B. Body water and sodium in patients acromegalics. J. Clin. Invest. 33: 989, 1959. 6. Aloia I. F., Roginsky M.S .. Jowsey J., Dombrowsky C.S .. Shukla K.K., Conn S.H. Skeletal metabolism and body composition in acromegaly. J. Clin. Endocrinol. Metab. 35: 543, 1972. 7. Cain J.P .. Williams G.H., Dluhy R.G. Plasma renin activity and aldosterone secretion in patients with acromegaly. J. Clin. Endocrinol. Metab. 34: 73. 1972. 8. Strauch G .. Vallotton M.B., Touitou Y., Bricaire H. The renin-angiotensin-aldosterone system in normotensive and hypertensive patients with acromegaly. N. Engl. J. Med. 287: 785, 1972. 9. Dluhy R.G .. Williams G.H. Primary aldosteronism in a hypertensive acromegalic patient. J. Clin Endocrinol. Metab. 29: 1319, 1969. 10. Kliman B., Peterson R.E.
17
F. Mantero, G. Opocher, O. Armanini, G. Paviotti, et a/.
Double isotope derivative assay on aldosterone in biological extracts. J. BioI. Chem. 235: 1963, 1960.
rone, cortisol, corticosterone and growth hormone in man. Acta Endocrinol. (Kbh.) 79: 16, 1975. 18. Beck J.C., McGarry E.E., Dyrenfurth L., Morgan R.O., Bird E.D., Veming EH. Primate growth hormone studies in man. Metabolism 9: 699, 1960.
11. Stockigt J.A., Collins A.D., Biglieri E.G. Determination of plasma renin concentration by angiotensins I radioimmunoassay: diagnostic import of precise measurement of subnormal renin in hyperaldosteronism. Circ. Res. 28: 1 76, 1971.
19. Mayberry H.E., Von den Brande J.L., Von Wyk J.J., Waddell W.S. Early localisation of 1125 -labeled human growth hormone in adrenals and other organs of immature hypophysectomized rats. Endocrinology 88: 1 309, 1 971.
12. Lee T.C., De Wied D. Somatotropin as the non ACTH factor of anterior pituitary origin for the maintenance of echanged aldosterone secretory responsiveness of dietary sodium restriction in chronically hypophysectomized rats. Life Sci. 7: 35, 1968.
20. Biglieri E.G., Watlington C.O., Forsham PH. Sodium retention with human growth hormone and its subfractions. J. Clin. Endocrinol. Metab. 21: 721, 1961.
13. Lieberman A.H., Luetscher J.A. Some effects of abnormalities of pituitary, adrenal and thyroid function on secretion of aldosterone and response to corticotropinic sodium deprivation. J. Clin Endocrinol. Metab. 20: 1004, 1960.
21. Strauch G., Vallotton M.B., Touitou Y., Bricaire H. The renin-aldosterone system in acromegaly: Follow-up report. N. Engl. J. Med. 289: 808, 1973.
14. Williams G.H., Rose L.I., Dluhy A.G., Dingman J.F., Lauer
P. Aldosterone response to sodium restriction and ACTH stimulation in panhypopituitarism. J. Clin. Endocrinol. Metab. 32: 27, 1971.
22. Charro A.L., Hofeldt F.D., Becker N., Levin S.R., Forsham PH. Adrenocortical function in acromegaly. Am. J. Med. Sci. 266: 211, 1973.
15. Dahl V., Heinrich J.J., Rivarola M.A., Bergada C. Secretion de aldosterona en la insuficiencia hypofisaria. Reunion Annual de la Societad Latino Americana de Investigacion Pediatrica. Chile 1969.
23. Nicoll C.S. In: Knobil E., Sawyer W. (Eds.), Handbook of Physiology. American Physiological Society, Section 7, p. 253, 1974. 24. Vander A.'J. Direct effect of potassium on renin secretion and adrenal function. Am. J. Physiol. 219: 455, 1970.
16. Finkelstein J., Kowarski A., Spaulding J.S., Migeon C.S. Effect of various properties of human growth hormone on aldosterone secretion rate of hypopituitaric dwarfs. Am. J. Med. 38: 517, 1965.
25. Mantero F., Opocher G., Armanini D. Acromegaly and primary aldosteronism: report ot two cases. In press.
17. Birkhauser M., Gaillard R., Riondel A.M., Zahnd G.R. Influence of acute administration of human growth hormone and alfa MSH on plasma concentration of aldoste-
18
Plasma renin activity and urinary aldosterone in acromegaly F. Mantero, G. Opocher, D. Armanini, G. Paviotti, M. Boscaro, and M. Muggeo* *Istituto di Semeiotica Medica and Istituto di Medicina Clinica , University of Padova, Italy ABSTRACT. The behaviour of the renin-angiotensin-aldosterone system was evaluated in 16 acromegalic patients, of whom 7 were hypertensive. The patients were studied in basal conditions, after suppression with 9a-fluorohydrocortisone, and after stimulation with furosemide. Baseline and after furosemide PRA were significantly lower in acromegalic hypertensive patients than in the normotensive group. Mean urinary aldosterone excretion was found at the upper limits of the normal range; it was occaSionally elevated, but the values were not statistically different in the two groups. There was a suppression after 9 a fluorohydrocortisone in both groups, though it did not rea(fhed the 50%. These data show that there is a disorder of the renin-angiotensin-aldosterone system in acromegalic subjects. This defective regulation is sometimes similar to that present in primary aldosteronism. In fact in two patients a typical phlebographic and scintigraphic picture of primary aldosteronism has been found; surgery, performed in both patients, revealed a large cortical adenoma in one case and a macronodular hyperplasia in the second case. However, the relationship between this adrenal abnormalities and hypertension in acromegaly are not yet completely clarified. hypertension. In those patients surgery revealed an adrenal adenoma. Another case of associated acromegaly and Conn's syndrome has been previously reported by Dluhy and Williams (9). The present study was undertaken to further elucidate the type of disorder of the renin-angiotensin-aldosterone system, present in acromegaly. PRA and aldosterone were evaluated both in basal condition and after stimulatory and suppressive maneuvers in two groups of acromegalic patients, respectively with normal and elevated blood pressure,
INTRODUCTION Arterial hypertension in acromegaly is quite common (up to 30% of the cases) (1-3). It has not yet been clarified if this frequent association is merely coincidental or related to the chronic hypersecretion of growth hormone (GH) or to sOr1)e other factors. Previous studies have demonstrated an elevated cortisol (F)'secretion rate along with increased excretion of 17 -ketosteroids (1 7-KS) and 17 -hydroxycorticosteroids (17-0HCS); however in most cases the plasma levels and the diurnal rhythm of F were normal (4). Plasma volume, total body water and exchangeable sodium have been found increased in acromegaly (5, 6). Similar findings are typical for primary aldosteronism, where they are associated with a decreased exchangeable potassium. Only very few studies have been dedicated to clarify the role of angiotensin and aldosterone in the pathogenesis of the hypertension in acromegaly. Cain et al. (7) have found normal basal values of plasma renin activity (PRA) and aldosterone secretion rate, but the aldosterone and PRA response to sodium depletion and furosemide was subnormal in the hypertensive acromegalics. Strauch et al. (8) have shown a normal behaviour of the renin-angiotensin-aldosterone system in normotensive acromegalic patients, but a typical picture of primary aldosteronism in 4 of 5 patients with
MATERIALS AND METHODS Sixteen patients with active acromegaly, aged from 36 to 66 years, 11 females and 5 males, were studied (Table 1 ). All treatment was stopped at least 11 days before beginning the studies. Five patients (no. 7, 8, 10, 12, 1 3) had previously undergone pituitary irradiation, whereas the other were untreated. In all the patients the entity of the disease was well documented by clinical criteria, high basal levels of serum GH and lack of appropriate suppression during glucose tolerance test. There were no cases of adrenal insufficiency, as shown by the levels of 17 -OHCS and 17 -KS excretion; in two cases 17-KS were above normal (no. 3 and 6). Two patients (no. 5 and 10) had simple goiter; thyroid function, evaluated by measurement of T4 and T3 test, basal metabolic rate and occasionally by 1131 uptake test was normal in all patients. The patients were divided in two groups according to their blood pressure: group 1 included 9 normotensive acromegalic patients, aged from 36 to 60 years (mean ± SE: 47 ± 2.6); group 2 the remaining 7 patients, aged
Key-words. acromegaly; PRA; aldosterone; growth hormone; hypertension. Correspondence. Dr. Franco Mantero - Istituto di Semeiotica Medica - Via Ospedale Civile, t05 - 35tOO Padova, Italia. Received January 30, 1978; accepted November 7, 1978.
13
F. Mantero, G. Opocher, D. Armanini, G. Paviotti, et a/.
Table 1 - Clinical and endocrine studies in 16 patients with acromegaly Patients
normotensive 1 R.G. 2 G.G. 3 Z.G. 4 V.G. 51.C. 6 A.A. 7 S.E. 8D.M. 9 R.N. hypertensive 10 SA 11 ZA 12 P.M. 13 P.R. 14 R.M. 15 F.M. 16 T.U.
Duration Blood Creatin. Blood Serum Serum Basal Min. val. 170HCS 17KS K+ of the pressure mg/ dl glucose NA+ GH GH (mg/ (mg/ (g/I) (meq/I) (meq/I) (ng/ml) after day) disease mm Hg day) (yr) (n.v. OGTT (n.v. (ng/ml) 4-15) 6-15)
Age (yr)
Sex
55 55 46 40 44 45 36 60 42
F F M M F M F F F
3 6 2 10 3 3 8 20 2
140/85 140/90 120/90 120/80 120/85 120/80
46 64 66 54 49 48 63
F F F F F M M
19 5 8 34 8 14 9
160/110 160/100
120175
130/90 140/90
160/110 170/110
145/100 180/110 180/110
1.10 0.90 1.20 1.00 0.80 1.20 1.10 1.10 0.80
0.69 0.90 0.92 0.96 0.77 0.99 0.94 1.31 0.70
146 150 138 140 146 139 143 143 148
4.4 4.2 5.2 4.4 4.7 4.4 3.9 4.5 3.7
80.0 9.0 31.0 48.0 42.0 36.0 100.0 13.7 32.0
34.5 8.0 17.8 46.0 27.0 25.0 71.1 35.0 18.0
11.8 11.0 9.2 8.4 5.2 4.3 10.4 8.7 3.4
14.0 6.9 17.2 15.7 7.0 30.9 16.2 13.4 5.1
1.00 1.30 1.40 1.20 1.20 1.00 1.40
0.69 0.69 0.95 1.05 1.22 0.80 1.01
143 146 145 140 140 139 139
4.7 4.7 4.1 3.8 3.8 3.9 4.0
51.0 9.6 45.4 100.0 12.0 320.0 6.0
27.6 4.6 14.3 70.0 4.0 128.0 2.5
6.0 6.4
9.5 10.8
8.3
6.4
3.6
8.1
from 48 to 66 years (mean: 55.7 ± 3.1 ), who where hypertensive (diastolic blood pressure over 100 mmHg). In this last group a renal pathogenesis of the hypertension was highly unlikely, considering the normal i.v. pyelogram and renal function test. None had hypertensive retinopathy. In normotensive patients the basal values of serum GH ranged from 9 to 100 ng/ml (mean: 43.5 ± 9.8) and in the hypertensive group from 9.6 to 320 ng/ml (mean: 78.4 ± 42). Sodium and potassium were determined by an atomic absorption spectrophotometer. Urinary 17 -OHCS were measured by a modification of the Porter-Silber's method (normal values 4-15 mg/24h). Aldosteroneexcretion (3-oxo conjugate) was measured by the double isotope derivative technique of Kliman and Peterson (1 0) (normal values 5-15 jlg/24h). PRA was measured as amount of angiotensin I generated in 1 ml of plasma after 3h of incubation at pH 5.5 and 37 C; angiotensin was measured by radioimmunoassay using a specific antiserum, according to a modification (the boiling step was avoided) of the method of Stockigt et al. (11) for PRA (normal values: standing 3-7 ng/ml/3h; mean 4.6 ± 0.7). The results are reported as mean ± SE. The acromegalic patients were placed at admission on a costant diet containing 120 meq of Na and 60 meq of K a day. All drugs were discontinued at least one week before admission. The studies began on the 5th day after admission. A 24h urine sample for analysis of urinary aldosterone was collected and a blood sample for PRA determination was drawn after 3h of upright posture. In the following days, while the patients remained on costant diet, the renin-angiotensin-aldosterone sys-
tem was evaluated by the following maneuvres: i) suppression test by 9 a fluorohydrocortisone (9 aFF) (0.4 mg/day orally, for 3 days): the urines for aldosterone determination were collected on the 3rd day and blood sample for standing PRA was drawn in the morning of the 4th day. ii) stimulatory test by sodium and volume depletion: furosemide (80 mg/ day, orally) was administered ft;Jr 3 days; urinary aldosterone was measured on the 3rd day and upright PRA in samples obtained in the morning of the 4th day. An adrenal scintiscan with 1311-iodocholesterol and an adrenal venography was performed in two hypertensive patients (no. 13, 16).ln patient no. 13 also a computerized axial tomography (CAT.) was performed.
RESULTS Basa/ condition (Figs. 1, 2, 3): on a costant diet PRA, measured after 3h standing, ranged in the acromegalic patients from 0.1 to 16 ng/ ml/3h with a mean value of 3.8 ± 1.0 ng/ ml/3h, not significantly different from normal (mean 4.6 ± 0.7 ng/ m1/3h, p >0.1 ). However the acromegalic hypertensive group had a mean PRA (1.48 ± 0.68 ng/ml/3h) significantly lower (p < 005) than the normotensive group (mean 5.6 ± 1.6 ng/ml/3h). The mean urinary aldosterone was 15.07 ± 2.6 jlg/24h, ranging from 3.3 to 37 J..I9/ 24h, and was significantly higher (p
..
Z
-Z a
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.. .. .
12
...J
-
a: 8
NS
« z
~ 4
•• •
:. ~. :- :.:.: o
BASAL 9a·FF normotensive hypertensive
FUROSEMIDE
BASAL
9 0- FF
DISCUSSION
FUROSEMIDE
Fig. 3 - Comparison between mean values of PRA and urinary aldosterone in hypertensive and normotensive acromegalic patients in control conditions and after stimulatory and suppressive maneuvers.
(18) and of Mayberry et al. (19) , which support a direct effect of GH on aldosterone secretion. Moreover the increase of exchangeable Na and extracellular fluid induced by GH may be obtained also in adrenalectomized patients (20) being apparently due to a direct effect of GH on renal tubular sodium reabsorption.
Our findings may be summarized as follows: i) the basal PRA, in upright position, is usually normal in acromegaly, but in the hypertensive group the PRA is partially suppressed. Acromegalic patients, irrespective to the blood pressure levels, have a mean urinary aldosterone at the upper level of the normal range, and in isolated patients it may be found elevated.
Similar changes in body compartments have been shown also in acromegaly (5 , 6, 8). These changes could be responsible for the high incidence of hypertension in this disease. In that case , one would expect to find a suppression of PRA and aldosterone in acromegaly, at least in the hypertensive group. In fact PRA was undetectable in 317. acromegalic patients with hypertenSion and a blunted response of PRA after furosemide was found in more than half of acromegalic patients. This is similar to what is seen in patients with primary aldosteronism where the PRA suppression is due to the volume expansion induced by mineralocorticoids. The GH could playa similar role, when secreted in excess. Also the slight response of aldosterone to furosemide could be due to these same phenomena , as it is assumed that the changes in aldosterone production after volume depletion are renin -dependent.
ii) after furosemide there is a blunted response of PRA in acromegalic patients; this is particularly evident in the hypertensive group, where PRA remained low in 4 of the 7. patients. iii) after 9 a-FF administration there is a suppression of aldosterone in both groups of acromegalic patients, but the degree of this suppression is lower than 50% , as may occur in primary aldosteronism. Therefore it appears that there is in acromegaly a regulatory disorder of the renin-angiontensin aldosterone system. The controversial aspects of our knowledge on the relationship between GH and aldosterone makes it particularly difficult to understand the nature of this disordered mechanism . Although the role of GH on aldosterone regulation is well demonstrated in rats (12) , studies in man do not allow similar conclusions. In hypopituitarism the stimulation of aldosterone excretion obtained by GH administration and the lack of the response of aldosterone to sodium restriction which are reported to be independent from ACTH deficiency (13, 14), could support the hypotesis of role of GH on aldosterone regulation. However Dahl et al. (15) reported that in patients with isolated GH deficiency there is a normal aldosterone response . Moreover the studies made by Finkelstein et al. (16) on hypopituitaric subjects and by Birkhauser et al. (17.) on normal subjects are in contrast with the previous results of Beck et al.
Furthermore, the presence of this behaviour also in a substantial percentage of hypertensive patients (lOW renin essential hypertension) leads one to believe that a similar disorder of the renin-angiotensin-aldosterone system could well be related to the frequent incidence of hypertension in acromegaly. Our findings are similar in part to those obtained by Cain et al. (7.) ; they suggested that this disorder in aldosterone regulation was directly related to the GH action on sodium and water balance. Moreover it may be of some interest that 4 of our 7. pa16
PRA and aldosterone in acromegaly
case, and a macronodular adrenal gland in the second case. In both cases the slight post-operative changes on blood pressure, as well as the only partial antihypertensive effect of spironolactone, seen in this patients, may be considered as an evidence against predominant role of aldosterone in the pathogenesis of the hypertension. Furthermore the findings of abnormalities of the renin-angiotensin-aldosterone system also in other acromegalics without signs of primary aldosteronism suggest that the occurence of a latter disease seems more likely due to an evolution of the previous disorder than to an occasional association. From our results it may be concluded that an evaluation of the PRA and aldosterone pattern should be routinely performed in hypertensive acromegalics, since the presence of an aldosteronoma, or a nodular hyperplasia could be more frequent than previously thought. The possibility that prolactin and some other unknown pituitary factor could be involved in the pathogenesis of this sindrome cannot be ruled out.
tients with hypertension, presented, besides the undetectable PRA, values of urinary aldosterone excretion at the upper normal limits, or frankly elevated. Also 1 normotensive patient with normal PRA showed elevated urinary aldosterone levels; this is more similar to what is seen in primary aldosteronism that in low renin essential hypertension, where aldosterone is normal or even low. Strauch et al. (8, 21) found a similar pattern in 4/5 hypertensive patients with acromegaly. They suggested that, if we do not accept a direct stimulatory effect of GH on adrenals, we may be faced with a new form of endocrine polyadenomatosis. In fact other acromegalic patients have nodular goitre (2 in our series) and parathyroid adenomas. The fact that in our patients aldosterone was only partially suppressible by 9 a-FF is further evidence on the autonomy of aldosterone secretion. A direct stimulatory effect of GH on adrenal activity may still be kept in mind. Charro et al. (22) demonstrated recently a hyperactivity of the adrenal glands, as shown by the increases of 17 -OHCS and 17 -KS excretion in active acromegaly. Also a possible role of prolactin may be evoked, since it has been found often increased in acromegaly. This hormone has an important role in regulating fluids and electrolytes and a trophic influence of steroidogenic organs in animals (23), but results obtained in humans are controversial (23). Finally a less likely hypothesis could consist in a direct opposite effect of potassium retention (24) in acromegaly on both PRA and aldosterone, being the latter increased by potassium, while the former is decreased. However in our acromegalic patients no serum K abnormalities were found, and hypokalemia was seen by Strauch et al. (8, 21) in the patients with associated aldosteronoma. A study in exchangeable potassium has been undertaken in our patients, but no conclusions can be made at this time because of the limited number of cases studied. From the results of our own and the similar studies existing on this subjects no definitive conclusions can be reached. A possibility to reconcile these seemingly contradictory results may be reached be accepting a double regulatory theory. The sodium retaining activity of GH would lead to a decreased PRA and aldosterone response to furosemide, as in low renin essential hypertension. However in some cases or at some time during their disease, the direct stimulatory effect of GH adrenals would overcome this mechanism, leading to an excessive aldosterone secretion and PRA suppression as in primary aldosteronism. In fact, 2 of these hypertensive patients in whom an adrenal venography, aldosterone assay in blood taken from the adrenal veins, and 1311-19-iodo-cholesterol scintiscans were performed, clear signs of unilateral hyperactivity were obtained. These patients have been chronically treated with bromocriptine (25); surgery, performed in both patients, revealed an adrenocortical adenoma in one
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19. Mayberry H.E., Von den Brande J.L., Von Wyk J.J., Waddell W.S. Early localisation of 1125 -labeled human growth hormone in adrenals and other organs of immature hypophysectomized rats. Endocrinology 88: 1 309, 1 971.
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14. Williams G.H., Rose L.I., Dluhy A.G., Dingman J.F., Lauer
P. Aldosterone response to sodium restriction and ACTH stimulation in panhypopituitarism. J. Clin. Endocrinol. Metab. 32: 27, 1971.
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23. Nicoll C.S. In: Knobil E., Sawyer W. (Eds.), Handbook of Physiology. American Physiological Society, Section 7, p. 253, 1974. 24. Vander A.'J. Direct effect of potassium on renin secretion and adrenal function. Am. J. Physiol. 219: 455, 1970.
16. Finkelstein J., Kowarski A., Spaulding J.S., Migeon C.S. Effect of various properties of human growth hormone on aldosterone secretion rate of hypopituitaric dwarfs. Am. J. Med. 38: 517, 1965.
25. Mantero F., Opocher G., Armanini D. Acromegaly and primary aldosteronism: report ot two cases. In press.
17. Birkhauser M., Gaillard R., Riondel A.M., Zahnd G.R. Influence of acute administration of human growth hormone and alfa MSH on plasma concentration of aldoste-
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