Cushing's Syndrome and Hypertension - …hyper.ahajournals.org/content/hypertensionaha/8/3/258.full.pdf · Clinical Conference Cushing's Syndrome and Hypertension Principal Discussant

Clinical Conference

Cushing's Syndrome and HypertensionPrincipal Discussant

CELSO E. GOMEZ-SANCHEZ, M.D.

University of South Florida College of Medicine, and James A. HaleyVeterans Administration Hospital, Tampa, Florida

HYPERTENSION CLINICALCONFERENCE

EDITORSEdgar HaberVictor J. DzauRobert M GrahamRandall M Zusman

MANAGING EDITORNancy Phinney

Beth Israel Hospital, Brtgham and Women's Hospital,Massachusetts General Hospital, Hanard Medical School

Case PresentationA 69-year-old man was admitted to the Massachu-

setts General Hospital in December 1983, followingreferral from another hospital, for evaluation of hypo-proteinemia, peripheral edema, and weakness. He wasknown to have type II diabetes when he underwent agastroenterostomy and, later, a vagotomy, two-thirdsgastrectomy, and gastroenterostomy in 1972 for pepticulcer disease. His blood glucose levels had been wellcontrolled with an oral hypoglycemic agent until Sep-tember 1983, when he was admitted to another hospitalfor investigation and treatment of uncontrolled hyper-glycemia (blood glucose level, 543 mg/dl) and lowerextremity edema. He was commenced on a regimen ofNPH insulin, and an evaluation of his edema led todiscovery of diffuse hypoproteinemia (total protein,5.6 g/dl; albumin, 2.7-3.3 g/dl). Initially, the hypo-proteinemia was thought to be due to a protein-losingenteropathy, but this suspicion could not be substanti-ated.

Address for reprints: Celso E. Gomez-Sanchez, M.D., James A.Haley VA Hospital, 13000 N. 30th Street (111-M), Tampa, FL33612.

Over the course of a long hospitalization in Septem-ber and again in November 1983, he was noted to havenew-onset hypertension (blood pressure, 170-200/95-105 mm Hg), hypokalemia (K+, 2-3 mEq/L), se-vere muscle wasting, an increased alkaline phospha-tase level (336 IU/L), a normal plasma aldosteronelevel, a cortisol level of 28 /Ag/dl, a low thyroid-bind-ing globulin level, but normal free thyroxine and thy-roid-stimulating hormone levels. Results of a smallbowel biopsy were normal, and computed tomograph-ic abdominal and liver/spleen scans were reportedlynormal.

The patient was unable to give a detailed history, buton questioning thought his skin had become darkerrecently and was particularly concerned about muscleweakness, mild insomnia, fatigue, and a 40-poundweight loss over the preceding 6 months. There was nofamily history to suggest multiple endocrine neopla-sias. An aunt and his mother had had diabetes mellitus,and a daughter had undergone a thyroid operation. Thepatient did not drink alcohol and had not smoked forthe past 20 years. There was no history of cough,hemoptysis, melena, abdominal pain, hematuria, visu-al disturbances, headaches, or chest pain. Medicationson admission were KC1, 40 mEq, and NPH insulin, 16units administered subcutaneously, every day.

Physical examination of the patient revealed mildcachexia, severe proximal myopathy, profuse petech-iae and ecchymoses, deeply pigmented areolae andpigment deposition in his abdominal scars, mild prop-tosis, normal-sized thyroid gland and testes, basilarrales, mild pitting edema of the lower extremities, anda distal lower extremity sensory neuropathy. The visu-al fields were full to confrontation, and no abdominalmasses or organ enlargement was detected. The pulsewas 100/min and irregularly irregular. The blood pres-sure was 170/100 mm Hg, and auscultation of theprecordium revealed only physiological heart sounds.There was no gynecomastia or truncal obesity.

Initial investigations disclosed the following values:hematocrit, 35%; hemoglobin, 11.8 g/dl; white bloodcell count, 4.7 x lOVmm3; mean corpuscular volume,81 /i.m3; platelet count, 128,000/mm3; prothrombintime, 10.6/10.8 sec; partial thromboplastin time, 27

358

by guest on May 2, 2018

http://hyper.ahajournals.org/D

ownloaded from

http://hyper.ahajournals.org/

HYPERTENSION IN CUSHING'S SYNDROMEJGomez-Sanchez 259

sec; erythrocyte sedimentation rate, 15 mm/hr; Na+,143 mEq/L; K+, 2.0 mEq/L; CL", 97 mEq/L; CO2, 35mEq/L; blood urea nitrogen, 17 mg/dl; blood glucose,71 mg/dl (fasting); Ca2+, 7.2 mg/dl; PO4, 3.5 mg/dl;Mg2*, 3.5 mEq/L; creatinine, 0.7 mg/dl; total pro-teins, 5.1 g/dl (albumin, 2.6 g/dl; globulin, 2.5 g/dl);aldolase, 8.8 U/L; 17-ketosteroids, 58 mg/24 hr; 17-hydroxysteroids, 55 mg/24 hr (urine volume, 700ml/24 hr); cortisol, 90 at 0735 and 81.2 pig/dl at 1445;T4, 1.1 /ig/dl; T3 resin uptake, 40%; thyroid-stimulat-ing hormone, <0.5 /*U/ml; urinary Na+, 6 mEq/L;urinary K+, 105 mEq/L. A gastrointestinal series wasnormal. Computerized body tomography of the medi-astinum revealed multiple low-density lesions withinthe liver and bilateral adrenal masses; low lung vol-umes and bibasilar subsegmental atelectasis withoutevidence for a lung lesion; a small anterior pericardialeffusion, a normal mediastinum, and calcification ofthe tail of the pancreas.

After admission the patient's blood pressure fluctu-ated widely, ranging from 148/90 to 200/120 mm Hg.The plasma cortisol level remained above 50 /ng/dldespite the administration of 1, 2, and then 8 mg ofdexamethasone. The urinary free cortisol level was3162 and 1407 fxg/24 hr on the seventh and eighth daysafter admission, and adrenocorticotropic hormone(ACTH) levels were 500, 375, and 325 pg/ml on thethird, fifth, and sixth days, respectively, after admis-sion. A regimen of metyrapone, 500 mg t.i.d., anddexamethasone, 0.5 mg in the moming and 0.25 mg atbedtime, was begun on the eighth day after admission.The plasma cortisol and 11-deoxycortisol levels 3 , 5 ,and 7 days after therapy were 51, 28, and 18 /xg/dl and22.8, 29.2, and 19.9 /xg/dl, respectively.

Despite therapy, the patient's condition continued todeteriorate, and he became confused and disorientedapproximately 12 to 14 days after admission. How-ever, his blood pressure remained moderately high,ranging from 130/90 to 150/110 mm Hg. On the seven-teenth day after admission, the patient becamehypotensive (blood pressure, 80/50 mm Hg), febrile(38.4 °C), and obtunded. A urine specimen showedabundant bacteria and many white blood cells. Antibi-otic therapy was begun, but the patient remained hypo-tensive, became apneic, and died that day. Permissionfor an autopsy was denied.

Case DiscussionThe clinical presentation of this 69-year-old man is

the most frequent for ectopic Cushing's syndrome. Hehad a 6-month history of muscle weakness, fatigue,weight loss, and perhaps, increased pigmentation ofthe skin. Three months before his death, his diabetesmellitus type II, which had been reasonably well con-trolled with orally administered hypoglycemics, be-came markedly worse and he was started on a regimenof insulin. During his September and November 1983hospitalizations new onset of moderate hypertension,rather severe hypokalemia, hypoproteinemia, and ele-vated alkaline phosphatase were noted. Although the

diagnostic impression during these two hospitaliza-tions is unknown, the attending physicians were moti-vated to obtain what seems to be random plasma aldo-sterone and cortisol measurements. Aldosterone levelwas reported to be normal, and cortisol level wasfound to be 28 /ig/dl, which is elevated; however,random samples are seldom diagnostic.

The patient was transferred to Massachusetts Gener-al Hospital (probably because the suspected diagnosiswas ectopic Cushing's syndrome caused by an unlocat-ed tumor) where the patient received a thorough ex-amination. He was found to have marked increases inthe urinary excretion of 17-ketosteroids and 17-hydrox-ysteroids and extremely high moming cortisol levelswith no significant decrease in the afternoon. A lowand high dose dexamethasone suppression test re-vealed no significant changes in plasma cortisol level.His plasma ACTH level was clearly elevated on sever-al occasions. Diagnostic imaging revealed multiplelow density lesions within the liver and bilateral adren-al masses and calcifications in the tail of the pancreas.

The diagnosis of a neoplasm with ectopic produc-tion of ACTH was evident, and therapy of the hyper-cortisolism was started, using metyrapone, 500 mgt.i.d., combined with replacement doses of dexameth-asone. The metyrapone produced marked inhibition ofthe 11/3-hydroxylases, a decreased plasma cortisol lev-el (from 51 to 18 /xg/dl) and a concurrent elevation of11-deoxycortisol levels. As would have been predicted,the patient continued to deteriorate, became febrile,and most likely died of gram-negative septic shock.

The clinical manifestations of ectopic ACTH produc-tion depend on the biological nature of the tumor. Slowlygrowing malignant or benign tumors tend to give clinicalmanifestations of Cushing's syndrome, while rapidlygrowing or aggressive tumors present with manifesta-tions similar to those shown by this patient: markedweakness, hypertension, hypokalemic alkalosis, andrapid deterioration.' The type of rumor this patient had isnot immediately apparent. Although no evidence for atumor was found during his first admission, metastaticlesions in the liver, as well as bilateral adrenal masses,were found on the final evaluation. The adrenal glands inectopic ACTH syndrome usually weigh 14 to 16 g, al-though they may weigh more than 20 g. Normal adrenalgland weights in instances of sudden death without priorillness are between 2.8 and 5.5 g. If death is preceded byprolonged illness, adrenal gland weights vary between2.7 and 9.4 g.2

The source of the primary tumor is unclear from thehistory. The following list summarizes the types andincidence of tumors that can produce ACTH13:

Carcinoma of the lung (50%)Oat cell (38%)Large cell (4%)Adenocarcinoma (6%)Squamous (2%)

Carcinoid (16%)Bronchus (8%)Thymus (2%)Gastrointestinal (6%)



ownloaded from


260 HYPERTENSION VOL 8, No 3, MARCH 1986

Thymus (10%)Pancreas (islet cell) (6%)Medullary carcinoma of thyroid (6%)Pheochromocytoma (2%)Other (10%)

The tumors can be divided into two general groups:amine precursor uptake and decarboxylation (APUD)tumors, which constitute over 80% of the list, andother miscellaneous tumors of non-APUD origin*which include a wide variety of cancers such as squa-mous cell carcinoma, adenocarcinomas, and hepato-mas. In children, ectopic ACTH production is lessfrequent and originates from tumors common to thisage group including paragangliomas, neuroblastomas,ganglioneuroblastomas, pheochromocytomas, andthymic and islet cell tumors.4

Extraadrenal or pituitary tumors can produce hyper-cortisolism by secreting excessive quantities of ACTHor corticotropin-releasing hormone (or both),5'6 whichin turn stimulates the pituitary secretion of ACTH,which then acts on the adrenal gland. A case of medul-lary carcinoma of the thyroid has been described thatproduced a bombesin-like peptide that was assumed tobe responsible for an ectopic ACTH-like syndrome.7

The production of ACTH by tumors is more commonthan is the presence Of hypercortisolism.8 Immuno-reactive ACTH is found in most carcinomas of thelung; however, few of these have manifestations ofCushing's syndrome.9 Most of these tumors have highmolecular weight ACTH of little biological activity.

The ACTH molecule is known to be a cleavageproduct, along with /3-lipotropin, from a common pre-cursor molecule, pro-opiomelanocortin.10 In the pitu-itary, pro-opiomelanocortin is cleaved into a 16K frag-ment, ACTH, /3-lipotropin, and other fragments ofunknown function. The /3-lipotropin is split furtherinto y-lipotropin (1-58) and /3-endorphin (61-91), andthese latter two fragments can also be found in tumortissue." A portion of the 16K fragment, y-melanocyte-stimulating hormone, may play a physiological role inadrenal growth12 and potentiation of the adrenal actionof ACTH.13'14 In addition, ACTH can be converted toa-melanocyte-stimulating hormone and corticotropin-like intermediate-lobe peptide in the intermediate lobeof the pituitary,10 and these substances have been dem-onstrated in some tumors.15 The secretion of ACTH,/?-lipotropin, and the N-terminal proopiocortin (pro-y-melanocyte-stimulating hormone) is equimolecular.16

The plasma concentration of high molecular weightACTH immunoreactivity produced by most ectopicACTH tumors tends to be greater than that of thesmaller biologically active ACTH as compared to pitu-itary Cushing's disease; however, this is not always thecase.9'17

The diagnosis of hypercortisolism secondary to ec-topic production of ACTH is usually straightforwardwhen a tumor is evident but can be more difficult inbenign or slowly growing malignant tumors. The diag-nosis is established by a finding of an elevated secre-tory rate of cortisol, as reflected by elevated excretionof 17-hydroxy steroids and 17-ketosteroids, urinary

free cortisol, and plasma cortisol. In addition, plasmaACTH levels are usually greater than those seen inpatients with Cushing's disease18 and cortisol is notsuppressed by high doses of dexamethasone. The re-sponse to corticotropin-releasing hormone stimulationis also blunted in ectopic ACTH production.19 Rarely,patients with Cushing's disease also have elevatedplasma ACTH concentrations and the concomitant ele-vated levels of urinary 17-hydroxy steroids and serumcortisol that are not suppressed by high doses of dexa-methasone.20 In these patients, the absence of a tumorafter a thorough search or the removal of a tumorwithout the relief of the syndrome21 raises suspicion.The diagnosis can be established by selective catheter-ization and sampling of the petrosal vein effluent andmeasurement of ACTH.21

Cushing's Syndrome and HypertensionModerate to severe hypertension was recognized by

Harvey Cushing22 as early as 1912 and reported in1932. In 1924, Oppenheimer and Fishberg23 reported afew cases of adrenal tumors and hypertension that, inretrospect, must have been Cushing's syndrome. Theincidence of hypertension in Cushing's syndrome isvery high and depends in part on the cause, as can beseen in the following list:24 M

Incidence ofhypertensionType

Cushing's diseaseCushing's syndrome

Adrenal adenomasAdrenal carcinomaEctopic ACTHIatrogenic

SteroidsACTH

8310055

1727

Although the blood pressure tends to be greater inpatients with adrenal carcinomas,24 elevated bloodpressure is seldom the cause for the initial consulta-tion.25 The death rate attributable to cardiovascularcomplications of Cushing's syndrome before effectiveantihypertensive drugs were available was 40%.M

The mechanism by which hypertension is producedin Cushing's syndrome is not well understood butclearly involves the hypersecretion of glucocorticoids,mineralocorticoids, and perhaps, "hypertensinogenic"steroids.27 Over the years, the effects of mineralocorti-coids and glucocorticoids on blood pressure have beenstudied extensively, primarily in experimental animalsin which there are species-dependent differences in theeffect of steroids, particularly glucocorticoid, on bloodpressure regulation. For example, synthetic glucocor-ticoids elevate blood pressure in the rat28 but have noeffect in sheep29 or dog.30 Synthetic glucocorticoidsalso seem to have minimal or no effect on blood pres-sure elevation in humans,3132 nor is the incidence ofhypertension in patients receiving ACTH as high asthat in patients with endogenous Cushing's syn-drome.31 Therapeutic use of ACTH is usually intermit-tent, however, which might explain this difference inthe incidence of hypertension.



ownloaded from



Mechanisms of Hypertension inCushing's Syndrome

The following list summarizes the various mecha-nisms postulated for the blood pressure elevation seenin Cushing's syndrome:

Mineralocorticoid overproductionMineralocorticoid effects of cortisol overproductionOveractivity of the renin-angiotensin systemIncreased vascular reactivity induced by glucocorticoidsPresence of hypertensinogenic steroids

Mineralocorticoid OverproductionPlasma potassium concentrations are normal in over

90% of patients with Cushing's disease or Cushing'ssyndrome due to an adrenal adenoma but tend to below in patients with adrenal carcinomas24 and in ec-topic ACTH production.33 Although urinary or plasmaaldosterone levels have been found to be normal inmost patients with Cushing's syndrome, they can below or high.34'33 Levels of the ACTH-dependent min-eralocorticoid deoxycorticosterone are increased in asignificant number of patients with Cushing's syn-drome.34- x The excretion of urinary "free" deoxycorti-costerone is elevated in a significant number of pa-tients with Cushing's disease and tends to be highest inpatients with adrenal carcinomas. The excretion of freedeoxycorticosterone correlates with and tends to paral-lel that of free cortisol.37 The degree of abnormal pro-duction of deoxycorticosterone and corticosterone cor-relates with the hypokalemic alkalosis and is greaterin patients with adrenal carcinomas and in ectopicACTH-producing tumors.34 The mechanism by whichmineralocorticoids induce hypertension is incomplete-ly understood, but it involves increases in total bodysodium levels and peripheral resistance.38

Mineralocorticoid Effects of Cortisol OverproductionSeveral studies have shown a good correlation be-

tween hypokalemic alkalosis and cortisol produc-tion.3339 Although cortisol is predominantly a gluco-corticoid, it has marked mineralocorticoid activity athigher concentrations. Hypokalemic alkalosis occursin a minority of patients with Cushing's syndrome andat a lower frequency than that of hypertension. In a fewpatients with Cushing's syndrome, especially thosewith adrenal adenomas, cortisol is the only steroid thatis markedly elevated33; this supports the argument thatcortisol alone is the predominant cause of the hyperten-sion that occurs with Cushing's syndrome. Cortisoladministration to rats elevates the blood pressure by amechanism that is not dependent on sodium intake.40

Corticosterone, which is somewhat similar to cortisolin its glucocorticoid and mineralocorticoid activity,produces increased plasma volume, extracellular fluidvolume, and blood pressure.

In contrast to the effects produced by excess miner-alocorticoid administration, short-term administration ofcorticosterone produces a negative sodium and waterbalance due to the shift of sodium from the intracellularto the extracellular space.41 This effect is also seen inhumans after administration of ACTH or cortisone.42

Overactivity of the Renin-Angiotensln SystemThe renin-angiotensin system has been studied ex-

tensively in patients with Cushing's syndrome; thesefindings are summarized in Table 1. In Cushing's syn-drome, plasma renin activity tends to be normal (andoccasionally elevated) or low and responds normally tostimulation with furosemide.33-43 Synthetic glucocorti-coid administration to rats elevates their blood pressureand plasma renin activity.28 Short-term administrationof ACTH elevates plasma renin activity in humans44

but decreases plasma renin activity in sheep.27

TABLE 1. Renin-Angiotensin System Alterations in Cushing'sSyndrome and During Excess Glucocorticoid and Adrenocortico-tropic Hormone Administration

Condition

Cushing's syndrome

Excess synthetic glucocorticoids

Excess ACTH

Acute

Chronic

Plasma

Activity

Variable

Increased

Increased

Decreased

renin

Substrate

Increased

Increased

Unchanged

Increased

ACTH = adrenocortjcotropic hormone.

The increase in plasma renin substrate levels is moreuniform in clinical and experimental ACTH or gluco-corticoid excess28-43 and is due to the stimulation ofsynthesis in the liver.43 Plasma renin substrate level isabout twice normal in Cushing's syndrome or synthet-ic glucocorticoid excess.43 For kinetic reasons this ele-vation in substrate increases the velocity of the reninreaction by 20 to 30%.

Administration of saralasin, an angiotensin II an-tagonist, was reported to cause marked decreases inblood pressure in some patients with Cushing's syn-drome43 and in experimental glucocorticoid hyperten-sion.28 However, several subsequent reports haveshown that saralasin either does not reduce the bloodpressure or has a mild pressor effect in patients withCushing's syndrome and normal or low plasma reninactivity.46 Converting enzyme inhibition with captoprilalso has been shown to reduce the blood pressure inexperimental glucocorticoid hypertension.47 However,captopril was not effective in reducing the blood pres-sure in a group of patients with Cushing's syndrome.24

Thus, the renin-angiotensin system, which is usuallynormal in patients with Cushing's syndrome, may playa role in the hypertension of a minority of patients,particularly the few with high plasma renin activity.

Increased Vascular Reactivity Induced by GlucocorticoidsThe lack of adrenal steroids diminishes cardiovascu-

lar reactivity to pressor substances.48 Patients withCushing's syndrome, both spontaneous and iatro-genic, have an increased digital vascular responsive-ness to catecholamines.49 Glucocorticoids can inducethis increased responsiveness in vitro,50 and they alsohave an important role in the control of phenylethanol-amine A'-methyltransferase activity in the adrenal me-



ownloaded from



dulla.51 This enzyme catalyzes the conversion of nor-epinephrine to epinephrine. The concentration ofcortisol in the normal adrenal medulla is very high";however, children with ACTH deficiency have lowlevels of plasma epinephrine.4* Thus, it is possible thatincreased epinephrine synthesis occurs in Cushing'ssyndrome and plays a major role in hypertension.

While enhanced vascular responsiveness is ob-served in regional vascular beds and in vitro, systemicpressor alterations have not been uniformly demon-strated.52 In addition, ACTH-induced hypertension insheep does not change or reduce plasma levels of epi-nephrine and norepinephrine.27

Presence of Hypertensinogenic SteroidsThe concept of hypertensinogenic steroids was pro-

posed by Scoggins et al ." to explain ACTH-inducedhypertension in sheep. Chronic administration ofACTH produces an adrenal-dependent rise in bloodpressure in sheep,54 rats,55 and humans.56 In sheep, therise in blood pressure occurs within 24 hours and isassociated with an increase in cardiac output and heartrate. Blood pressure remains elevated throughout theadministration of ACTH. The induced hypertensionhas features of both glucocorticoid and mineralocorti-coid excess, but administration of either class of ste-roid alone or together does not reproduce the temporalpattern or amplitude of the rise in blood pressure.29

In sheep, infusion of a mixture of cortisol (5 mg/hr),corticosterone (0.5 ng/hr), 11-deoxycortisol (1 mg/hr),deoxycorticosterone (25 pig/hr), and aldosterone (3/ng/hr) produced blood concentrations similar to thoseobtained after ACTH administration but failed to in-crease the blood pressure.57 Subsequent studies demon-strated the adrenal production of 17a-hydroxyprogester-one and 17a, 20a-dihydroxyprogesterone.53 Although17a-hydroxyprogesterone and 17a, 20a-dihydroxypro-gesterone possess no measurable hypertensive or corti-coid effects by themselves, their administration in com-bination with the steroid mixture described abovereproduced the metabolic and blood pressure effects in-duced by ACTH. These steroids have been labeled "hy-pertensinogenic" steroids. In humans, ACTH adminis-tration elevates blood pressure and causes definiteincreases in 17a-hydroxyprogesterone and 17a, 20a-dihydroxyprogesterone.56 The hypertension is increasedby salt loading during ACTH infusions.58

The structural requirements for hypertensinogen-icity have been studied extensively in sheep. Cortisol,dexamethasone, or aldosterone infusions produceminimal elevations of blood pressure,53 while infusionof the synthetic glucomineralocorticoid (0.2 mg/day)9a-fluorocortisol mimics the temporal pattern and am-plitude of the ACTH-induced blood pressure elevationwith minimal, if any, metabolic effects.59 These stud-ies indicate that the actions of glucocorticoids or min-eralocorticoids by themselves cannot explain ACTH-induced hypertension in sheep. Conversely, ACTHdoes not raise blood pressure in the dog, but it doespotentiate the chronic hypertensinogenic effects of an-giotensin II or norepinephrine infusions. Neither corti-sol nor aldosterone infusions can reproduce this po-

tentiation.30 The relevance of these studies in thepathogenesis of hypertension in Cushing's syndromeis unknown because of the marked interspeciesvariations. Similar studies need to be conducted inhumans.

Although these postulated mechanisms offer in-triguing explanations, the exact cause of hypertensionin Cushing's syndrome is unclear. The pathogenesismay vary depending on the various etiologies, the de-gree of the quantitative and qualitative abnormality ofsteroid secretion that occurs in tumors with alteredsteroidogenesis, or the altered secretory activity ofACTH and other components of the pro-opiomelano-cortin molecule that can occur in pituitary or ectopicACTH-producing tumors. Clarification of the patho-genesis of hypertension in Cushing's syndrome maydepend on the study of the hypertension in cases segre-gated according to their etiology.

TherapyTherapy of Cushing's syndrome in ectopic ACTH-

producing tumors depends on the nature of the tumors.Benign or surgically approachable tumors are treatedby resection, which results in improvement or cure ofthe hypertension. Unfortunately, most tumors causingectopic ACTH production are not resectable.

The presence of nonsuppressible hypercortisolism isassociated with a very poor prognosis,60 although ther-apy of the hypercortisolism may improve some of theclinical manifestations and the quality of life. Severalagents have been used to decrease adrenal productionof steroids including mitotane, which destroys thezona fasciculata and reticularis.61 The disadvantage inusing mitotane is that the drug takes 3 to 6 months towork and is not helpful in most cases of ectopic ACTHsyndrome, where a faster decrease in adrenal produc-tion is needed.

Aminoglutethimide is an inhibitor of the cyto-chrome P-450 side chain cleavage enzyme as well asother enzymes.61 It affects zona glomerulosa functionto a greater extent than that of zona fasciculata but iseffective in about 42% of the cases of Cushing's syn-drome.62 Metyrapone is an inhibitor of the cytochromeP^t50 11/3-hydroxylase and side chain cleavage en-zymes.61 The effect on the latter enzyme is of lesserimportance. Aminoglutethimide and metyrapone areused in combination with a glucocorticoid to preventiatrogenic hypoadrenalism.

Another drug that has been used to treat Cushing'ssyndrome is trilostane, an inhibitor of 3/3-ol-dehy-drogenase.63 The initial results were enthusiastic,64 butmore recently trilostane has been found to be relativelyineffective in Cushing's syndrome.65 Ketoconazole, animidazole derivative with antifungal properties, hasbeen shown to block adrenocorticosteroid synthesisand blunt ACTH-induced cortisol release.65 It has beenused in a small group of patients with ectopic ACTHsyndrome and found to be very helpful.66 If the effica-cy of ketoconazole is confirmed in a larger number ofpatients, it will become the treatment of choice formedical (palliative) therapy of Cushing's syndrome be-cause of its easy availability and profile of side effects.



ownloaded from



References1. Imura H. Ectopic hormone syndromes. Clin Endocrinol Metab

1980;9:235-2602. Neville AM, O'Hare MJ. The human adrenal cortex: pathology

and biology •— an integrated approach. Berlin: Springer-Ver-lag, 1982:11-34

3. Azzopardi JG, Williams ED. Pathology of "nonendocrine"tumors associated with Cushing's syndrome. Cancer 1968;22:274-286 .

4. Omenn GS. Ectopic hormone syndromes associated with tu-mors in childhood. Pediatrics 1971 ;47:613-622

5. Upton G, Amatruda TT Jr. Evidence for the presence of tumorpeptides and corticotropin-releasing factor-like activity in theectopic ACTH syndrome. N Engl J Med 1971;285:419-424

6. Asa SL, Kovacs K, Tindall GT, Barrow DL, Horvath E, Vec-sei P. Cushing's syndrome associated with an intrasellargangliocytoma producing corticotropin-releasing factor. AnnIntern Med 1984;101:789-793

7. Howlett TA, Price J, Hale AC, et al. Pituitary ACTH depen-dent Cushing's syndrome due to the ectopic production of abombesin-like peptide by a medullary carcinoma of the thy-roid. Clin Endocrinol (Oxf) 1985;22:91-101

8. Ratcliffe JG, Knight RA, Besser GM, London J, StansfeldAG. Tumor and plasma ACTH concentrations in patients withand without the ectopic ACTH syndrome. Clin Endocrinol(Oxf) 1972; 1:27-44

9. Gerwirtz G, Yalow RS. Ectopic ACTH production in carcino-ma of the lung. J Clin Invest 1974^3:1022-1032

10. Krieger DT. Physiopathology of Cushing's disease. EndocrRev 1983;4:22-43

11. Orth DN, Guillemin R, Ling N, Nicholson WE. Immunore-active endorphins, Hpotropins and corticotropins in humannonpituitary tissue: evidence for a common precursor. J ClinEndocrinol Metab 1978;46:849-852

12. Lowry PJ, Estivariz FE, Silas L, Linton EA, McLean C, Cro-combe K. The case for pro-y-MSH as the adrenal growthfactor. Endocr Res 1984; 10:243-258

13. Pederson RC, Brownie AC. Adrenocortical response to corti-cotropin is potentiated by part of the amino-terminal region ofpro-corticotropin/endorphin. Proc Natl Acad Sci USA 1980;77:2239-2243

14. Al-Dujaili EAS, Hope J, Estivariz FE, Lowry PJ, EdwardsCRW. Circulating human pituitary pro-y-melanotropin en-hances the adrenal response to ACTH. Nature 1981;291:156-159

15. Ratcliffe JG, Scott AP, Bennett HPL, et al. Production of acorticotropin-like intermediate lobe peptide and of corticotro-pin by a bronchial carcinoid tumor. Clin Endocrinol (Oxf)1973;2:51-55

16. Ratter SJ, Gillres G, Hope J, et al. Pro-opiocortin relatedpeptides in human pituitary and ectopic ACTH secreting tu-mors. Clin Endocrinol (Oxf) 1983;18:211-218

17. Odell WD, Wolfen A, Yoshimoto Y. Ectopic peptide synthe-sis: a universal concomitant of neoplasia. Trans Assoc AmPhysicians 1977;90:204-227

18. Besser GM, Edwards CRW. Cushing's syndrome. Clin Endo-crinol Metab 1972; 1:451^*90

19. Chrousos GP, Schulte HM, Oldfield EH, Gold PW, CutlerGB, Loriaux DL. The corticotropin-releasing factor stimula-tion test: an aid in the evaluation of patients with Cushingsyndrome. N Engl J Med 1984;310:622-626

20. Hale AC, Millar JBG, Ratter SJ, Pickard JD, Doniach I, ReesLH. A case of pituitary dependent Cushing's disease withclinical and biochemical features of the ectopic ACTH syn-drome. Clin Endocrinol (Oxf) 1985;22:479-488

21. HiramatSu R, Shimada T, Sato T. A case of dexamethasonenon-suppressible Cushing's disease hardly differentiated fromectopic ACTH syndrome. Endocrinol Jpn 1983;30:85-91

22. Cushing H. The basophil adenomas of the pituitary body andtheirclinical manifestations (pituitary basophilism). Bull JohnsHopkins Hosp 1932;5O:137-195

23. Oppenheimer BS, Fishberg AM. The association of hyperten-sion with suprarenal tumors. Arch Intern Med 1924;34:631-644

24. Greminger D, Tenschert W, Vetter W, Luscher T, Vetter H.Hypertension in Cushing's syndrome. In: Mantero F, Biglieri

EG, Edwards CRW, eds. Endocrinology of hypertension. Ser-ona Symposia. New York: Academic Press, 1982;50:103-110

25. Baker JV, CopeO, Ackerman IP. Surgical experience with thetreatment of hypertension of Cushing's syndrome. Am J Surg1964;107:153-158

26. Plotz CM, Knowlton Al, Ragan C. The natural history ofCushing's syndrome. Am J Med 1952;13:597-614

27. Scoggins BA, Coghlan JP, Denton DA, Mason RT, WhitworthJA. A review of mechanisms involved in the production ofsteroid induced hypertension with particular reference toACTH dependent hypertension. In: Mantero F, Biglieri EC,Edwards CRW, eds. Endocrinology of hypertension. ScronaSymposia. New York: Academic Press, 1982;50:41-67

28. Krakoff LR, Selvadurai R, Sutler E. Effect of methylpredniso-lone upon arterial pressure and the renin angiotensin system inthe rat. Am J Physiol 1975;228:613-617

29. Whitworth JA, Coghlan JP, Denton DA, Graham WF, Hum-phery TJ, Scoggins B A. Comparison of the effects of glucocor-ticoids and mineralocorticoids infusions on blood pressure insheep. Clin Exp Hypertens [A] 1979; 1:649-663

30. Lohmeier TE, Kastner PR. Chronic effects of ACTH and corti-sol excess on arterial pressure in normotensive and hyperten-sive dogs. Hypertension 1982;4:652-661

31. Ragan C. Corticotropin, cortisone and related steroids in clini-cal medicine: practical considerations. Bull NY Acad MedI953;29:355-376

32. Thomas TPL. The complications of systemic corticosteroidtherapy in the elderly: a retrospective study. Gerontology1984;30:60-65

33. Christy NP, Laragh JH. Pathogenesis of hypokalemic alkalosisin Cushing's syndrome. N Engl J Med 1961 ;265:1083-1088

34. Schambelan M, Slaton PE, Biglieri EG. Mineralocorticoidproduction in hyperadrenocorticism: role in the pathogenesis ofhypokalemic alkalosis. Am J Med 1971;51:299-303

35. Ganguly A, Weinberger MH, Grim CE. The renin-angioten-sin-aldosterone system in Cushing's syndrome and pheochro-mocytoma. Horm Res 1983;17:l-10

36. Biglieri EG, Slaton PE, Schambelan M, Kronfield SJ. Hyper-mineralocorticoidism. Am J Med 1968 ;45:170-175

37. Cassar J, Loizou S, Kelly WF, Mashiter K, Joplin GF. Deoxy-corticosterone and aldosterone excretion in Cushing's syn-drome. Metabolism 1980;29:115-120

38. Schalekamp MADH, Wenting GJ, Man in't Veld AJ. Patho-genesis of mineralocorticoid hypertension. Clin EndocrinolMetab 1981 ;10:397-418

39. Prunty FTG, Brooks RV, Duprf J, et al. Adrenocortical hyper-function and potassium metabolism in patients with "non-en-docrine" tumors and Cushing's syndrome. J Clin Endocrinol1963;23:737-746

40. Knowlton Al, Loeb EN. Depletion of carcass potassium in ratsmade hypertensive with desoxycorticosterone acetate (DCA)and with cortisone. J Clin Invest 1957;36:1295-1300

41. Haack D, Mohring J, Mohring B, Petri M, Hackenthal E.Comparative study on the development of corticosterone andDOCA hypertension. Am J Physiol 1977;233:F403-F411

42. Levitt MF, Bader ME. Effect of cortisone and ACTH on fluidand electrolyte distribution in man. Am J Med 1951; 11:715-723

43. Krakoff L, Nicolis G, Amsel B. Pathogenesis of hypertensionin Cushing's syndrome. Am J Med 1975;58:216-220

44. Oelkers W, Kohler A, Belbrien L, et al. ACTH stimulatesplasma renin and angiotensin II in man. Clin Sci 1981 ;61:273S-275S

45. Dalakos TG, Elias AN, Anderson GH, Strceten DHP,Schroeder ET. Evidence for an angiotensinogenic mechanismof the hypertension of Cushing's syndrome. J Clin EndocrinolMetab 1978;46:114—118

46. Vetter W, Vetter H, Beckerhoff R, Redlich B, Cottier P, Sie-genthaler W. The effect of saralasin (l-Sar-8-ala-angiotensinII) on blood pressure in patients with Cushing's syndrome.Klin Wochenschr 1976;54:661-663

47. Elijovich F, Krakoff LR. Effect of converting enzyme inhibi-tion on glucocorticoid hypertension in the rat. Am J Physiol1980;238:H844-H848

48. Rudman D, Moffitt SD, Fernhoff PM, Blackston RD, FarajBA. Epinephrine deficiency in hypocorticotropic hypopituitary



ownloaded from



children. J Clin Endocrinol Metab 1981;53:722-72949. Mendlowitz M, Gitlow S, Naftchi N. Work of digital vasocon-

striction produced by infused norepinephrine in Cushing's syn-drome. J Appl Physiol 1958;13:252-256

50. Kalsner S. Mechanisms of hydrocortisone potentiation of re-sponses to epinephrine and norepinephrine in rabbit aorta. CircRes 1969;24:383-395

51. Weiner N. Control of the biosynthesis of adrenal catechola-mines by the adrenal medulla. In: Greep RO, ed. Handbook ofphysiology: endocrinology; vol 6. Washington, DC: AmericanPhysiological Society, 1975:357-366

52. Krakoff LR, Elijovich F. Cushing's syndrome and exogenousglucocorticoid hypertension. Clin Endocrinol Metab 1981; 10:479-488

53. Scoggins BS, Butkus A, Coghlan JP, et al. ACTH-inducedhypertension in sheep: a model for the study of the effect ofsteroid hormones on blood pressure. Circ Res 1978;43(supplI ) I 7 6 I 8 1

54. Freeman RH, Davis JO, Fullerton D. Chronic ACTH adminis-tration and the development of hypertension in rats. Proc SocExp Med Biol 1980; 163:473-477

55. Whitworth JA, Saines D, Thatcher R, Butkus A, Scoggins BA,Coghlan JP. Blood pressure, renal and metabolic effects ofACTH in normotensive man. Clin Sci 1981;61:269S-272S

56. Fan JSK, Coghlan JP, Denton DA, Oddie CJ, Scoggins BA,Shulkes AA. The effect of intravenous infusions of corticoste-roids on blood pressure, electrolytes and water metabolism insheep. Am J Physiol 1975;228:1695-1701

57. Whitworth JA, Saines D, Scoggins BA. Potentiation of ACTHhypertension in man with salt loading. Clin Exp PharmacolPhysiol 1985;12:239-243

58. Coghlan JD, Butkus A, Denton DA, McDougall JG, ScogginsBA, Whitworth JA. Blood pressure and metabolic effects of9a-fluorocortisone in sheep. Clin Exp Hypertens [A] 1979;1:629-648

59. Bishop MC, Ross EJ. Adrenocortical activity in disseminatedmalignant disease in relation to prognosis. Br J Cancer 1971;25:719-725

60. Gaunt R, Melby JC. The pathophysiology of adrenal inhibitorswith respect to their antihypertensive activity. In: Gross F, ed.Handbook of experimental pharmacology: antihypertensiveagents; vol 39. New York: Springer-Verlag, 1977:495-516

61. Misbin RI, Canary J, Willard D. Aminoglutethimide in thetreatment of Cushing syndrome. J Clin Pharmacol 1976; 16:645-651

62. Taylor AA, Mitchell JR, Bartter FC, et al. Effect of aminoglu-tethimide on blood pressure and steroid secretion in patientswith low renin essential hypertension. J Clin Invest 1978;62:

. 162-16863. Komanicky P, Spark RF, Melby JC. Treatment of Cushing

syndrome with trilostane (WIN 24540), an inhibitor of adrenalsteroid biosynthesis. J Clin Endocrinol Metab 1978;47:1042-1051

64. Dewis P, Anderson DC, Bullock DE, Earnshaw R, Kelly WF.Experience with trilostane in the treatment of Cushing syn-drome. Clin Endocrinol (Oxf) 1983; 18:533-540

65. Pont A, Williams PL, Loose DS, et al. Ketoconazole blocksadrenal steroid synthesis. Ann Intern Med 1982;97:370-372

66. Shepard FA, Hoffert B, Evans WK, Emery G, Trachtenberg J.Ketoconazole use in treatment of ectopic adrenocorticotropichormone production and Cushing syndrome in small-cell lungcancer. Arch Intern Med 1985; 145:863-864

(Hypertension 8: 258-264, 1986)

Presentation and publication of Clinical Conferences are supported by educational grants from Ayerst Laboratories;W. A. Baum Company; Bayer AG; Ciba-Geigy Corporation; Glaxo, Inc.; Hoffman-LaRoche, Inc.; Miles Laboratories,Inc.; Schering Corporation; and The Upjohn Company.



ownloaded from


C E Gomez-SanchezCushing's syndrome and hypertension.

Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 1986 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Hypertension doi: 10.1161/01.HYP.8.3.258

1986;8:258-264Hypertension.

http://hyper.ahajournals.org/content/8/3/258.citationWorld Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://hyper.ahajournals.org//subscriptions/

is online at: Hypertension Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer process is available in the

Request Permissions in the middle column of the Web page under Services. Further information about thisOffice. Once the online version of the published article for which permission is being requested is located, click

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialHypertension Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:



ownloaded from

http://hyper.ahajournals.org/content/8/3/258.citation

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://hyper.ahajournals.org//subscriptions/


Documents

Cushing's Syndrome and Hypertension - …hyper.ahajournals.org/content/hypertensionaha/8/3/258.full.pdf · Clinical Conference Cushing's Syndrome and Hypertension Principal Discussant