Endocrine causes of hypertension in pregnancy—When to start looking for zebras

Endocrine Causes of Hypertension in Pregnancy--When to Start Looking for Zebras Erin Keely

Hypertension is a common medical disorder in pregnancy that may predate or first appear in pregnancy. Endocrine disorders rarely are the cause of the elevated blood pressure. However, it is essential to have a high index of suspicion because they carry much higher fetal and maternal morbidity and mortality risks. Endocrine disorders presenting as hypertension are primarily the result of autonomous production of renin, aldosterone, cortisol, or catecholamines. This report discusses the physiological changes in pregnancy, presentation, investigation, and management of these disorders.

Copyright 9 1998 by W.B. Saunders Company ypertension may predate or first appear in pregnancy and is associated with poor fetal and maternal outcome. The overall incidence of chronic hypertension in pregnancy is approximately 3%. Chronic hypertension in women of child-bearing years is most commonly essential (90%) or caused by renal parenchymal disease, with less than 1% to 2% of cases being caused by endocrine disorders. 1 However, these much rarer secondary causes may be lethal to both mother and fetus, unless recognized and treated in a timely fashion. The diagnosis of endocrine disorders must be based on biochemical criteria (generally a screening test followed by a confirmatory test) followed by localization either by radiographic or further biochemical testing. In pregnancy, the standard algorithms often are not applicable because of both changes in normal values and potential risks to the mother a n d / o r fetus of some dynamic endocrine and radiographical investigations. The interpretation of these investigations must also take into account their diagnostic accuracy. The low prevalence of these disorders increases the risk of a false-positive results despite acceptable sensitivity and specificity of a given test. For example, if a pregnant woman with hypertension has a 0.5% chance of having a pheochromocytoma, and the screening test has a 98% sensitivity and 98% specificity, the chance that the woman with a positive test result will actually have the condition (positive predictive value) is only 20%. 1 Once a positive screening test result is obtained, you are obliged to pursue additional tests, which may be expensive and/or invasive. Thus, it is essential that

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the pretest probability be increased by selecting patients on clinical manifestations before embarking on a path of investigation. However, excluding individuals prematurely who may have the disorder may have disastrous outcomes for fetus and mother. This article outlines an approach to investigation and management of the more common causes of endocrine hypertension that may appear in pregnancy.

Renin-Angiotensin S y s t e m - M e d i a t e d Hypertension Physiology The renin-angiotensin-aldosterone system is a cascade of events that is essential for blood pressure control, regulation of circulating volume, and sodium-potassium homeostasis. Renin, an enzyme that cleaves angiotensinogen, is produced in the granular cells of the juxtaglomerular apparatus from the precursor prorenin. These differentiated smooth muscle cells, located in the renal afferent arteriole, release renin under the control of: (1) renal arteriolar blood pressure via baroreceptors in the afferent arteriole, (2) concentration of sodium in the distal tubule fluid as sensed by the macula densa, and (3) ~adrenergic receptors in the renal symFrom the Department of Medicine, University of Ottawa, Ottawa, Canada. Address reprint requests to Erin Keely, MD, FRCPC, Ottawa General Hospital, 501 Smyth Rd (Box 209), Ottawa, Ontario K1H 8L6, Canada. Copyright 9 1998 by W.B. Saunders Company 0146-0005/98/2206-0004508.00/0

Seminars in Perinatology, Vol 22, No 6 (December), 1998: pp 471-484

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pathetic nervous system. 1 It is the circulating level of renin that is the rate-limiting step in the renin-angiotensin-aldosterone pathway. Any decrease in blood pressure, salt restriction, upright posture, decreased blood flow through a renal artery narrowing, /3-receptor stimulation, and hypokalemia will increase plasma renin levels. O n the contrary, supine posture,/3-blockers, salt overload, and hyperkalemia will inhibit renin release. Prostaglandins may also be important for regulation of renin p r o d u c t i o n as PGE2 and PEI2 stimulate renin release. Inhibition of prostaglandin p r o d u c t i o n by nonsteroidal antiinflammatory agents reduce renin levels. 2 Angiotensinogen, also known as renin substrate, is an a-2 globulin synthesized in the liver. Angiotensinogen levels are increased by estrogen, glucocorticoids, and thyroid h o r m o n e . 3 It is converted via renin to angiotensin I, which is in turn cleaved by angiotensin-converting enzyme (ACE) t ~ angiotensin II. A small a m o u n t of angiotensin II is converted to angiotensin III accounting for 20% of angiotensin activity. Angiotensin II and III are equally p o t e n t in stimulating aldosterone release, whereas angiotensin II is a m o r e p o t e n t vasoconstrictor. T h e r e is direct negative feedback by angiotensin to the juxtaglomerulosa cells to decrease renin production. Aldosterone, the major circulating mineralocorticoid, is p r o d u c e d in the zona glomerulosa of the adrenal cortex and serves to balance electrolytes by p r o m o t i n g sodium reabsorption and potassium and bicarbonate excretion in the distal renal tubule. Cortisol has modest mineralocorticoid activity. Aldosterone production is primarily regulated by angiotensin II and III; however, hyperkalemia, adrenocorticotrophic h o r m o n e (ACTH), and vasopressin also stimulate release, a Direct inhibitors of aldosterone production include dopamine, atrial natriutic factor, and somatostatin. Hypernatremia indirectly decreases aldosterone production through the inhibition of renin. The other mineralocorticoid p r o d u c e d in the adrenal gland, 11-deoxycorticoSterone (DOC), is primarily under ACTH control. Renin levels are measured not by concentration but rather by enzymatic activity. Plasma renin activity (PRA) is expressed as the a m o u n t of angiotensin g e n e r a t e d per unit time. Aldoster o n e is measured by radioimmunoassay. Sodium intake and posture must be controlled because

upright posture and salt restriction will increase levels, whereas saline infusion will lower levels. 1

Changes in Pregnancy Normal pregnancy is associated with many changes in the renin-angiotensin-aldosterone system. Despite the increase in extracellular fluid volume, there is a fourfold increase in plasma renin activity evident by 8 weeks' gestation and plateauing at 20 weeks. 4 By indirect measurements, it is estimated that 50% of the increase in PRA is caused by increases in the concentration of active renin, and the remainder is caused by the three- to sixfold increase in plasma angiotensinogen. 4 However, other studies have reported that active renin levels remain within the normal range. 5 This increase is, at least in part, mediated by a pregnancy-induced increase in PGI2, which is known to increase renal renin production. 6 Sodium loading and mineralocorticoid administration do not lower renin levels; therefore, the salt losing state of pregnancy and the aldosterone antagonizing effect of progesterone are not the mediators. 4 Prorenin, the precursor molecule of renin, is p r o d u c e d in the uterus, ovaries, and placenta. Circulating levels are increased fivefold in the first 4 weeks o f pregnancy. 5 T h e physiological role of this increased p r o r e n i n is unknown because there is no evidence that p r o r e n i n is converted to renin intravascularly. A possible paracrine effect of angiotensin II in the uterus to regulate blood flow has been proposed. 7 Angiotensin II levels are increased approximately threefold by term because of the increasing production of angiotensinogen, s However, c o n c u r r e n t with the rising levels o f angiotensin II there is development of resistance to its pressor effect (ie, more angiotensin II is required to p r o d u c e the same rise in blood pressure) as early as 10 weeks of pregnancy, reaching a maxi m u m by 28 weeks. 3,9 After 30 weeks there is increasing sensitivity, but it does not return to n o n p r e g n a n t values by term. T h e observed increase in prostaglandin E2 p r o d u c t i o n contributes to this resistance. 1~ Aldosterone levels are increased fourfold by 8 weeks and continue to rise to a m a x i m u m 10fold increase at term in response to the increase in renin and angiotensin II levels. 4 T h e production remains responsive to physiological stimuli

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such as changes in intravascular volume, b u t less so than in the n o n p r e g n a n t state. 5 T h e decrease in sodium excretion m e d i a t e d by aldosterone that occurs with upright posture is e x a g g e r a t e d in pregnancy. 7 Progesterone, which is markedly increased in pregnancy, is a competitive inhibitor of aldosterone in the distal tubule. Therefore, the physiological effects of increased aldosterone are attenuated in pregnancy.

Renovascular Hypertension Renal artery stenosis causes reversible hypertension and renal failure. It is the most c o m m o n cause o f secondary hypertension a n d accounts for 5% to 15% of hypertension in y o u n g women. 11 Fibromuscular dysplasia is the m o s t comm o n cause in individuals less than 40 years of age, a n d 75% to 85% of those affected are women. ~2 Atherosclerosis is m o r e c o m m o n in older individuals with o t h e r risk factors. A significant stenosis results in decreased perfusion o f the juxta-glomerular cells causing an increase in renin and stimulation of the renin-angiotensin cascade. A timely diagnosis is essential because there is a high risk of progression to accelerated or malignant hypertension a n d also the potential for irreversible ischemic kidney failureA 3 Clinical Manifestations. Hypertension caused by renal artery stenosis may not be distinguishable f r o m essential hypertension. In the y o u n g w o m a n at risk o f fibromuscular dysplasia, evid e n c e of o t h e r vascular disease is not expected. Blood pressure control may be m o r e difficult to achieve, and there is a greater risk of accelerated hypertension. In fact, renal artery stenosis accounts for u p to 50% of cases of accelerated hypertension. Flank pain and h e m a t u r i a may occur when a renal infarct occurs, but this is distinctly u n c o m m o n . O n physical examination an a b d o m i n a l bruit will be audible in 53% to 80% of cases of fibromuscular dysplasia, x4 However, the ability to detect a bruit in p r e g n a n c y may be decreased. A diastolic c o m p o n e n t increases the likelihood of a significant stenosis (Table 1). Outcome in Pregnancy. T h e r e is a surprising paucity of information a b o u t the effect of renal artery stenosis in pregnancy given the incidence in y o u n g women. A retrospective study by Sellars et aP ~ c o m p a r e d p r e g n a n c y o u t c o m e in three w o m e n before a n d after repair of renal artery

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Table 1. Clinical Clues for Renovascular Stenosis Accelerated or malignant hypertension Blood pressure that is difficult to control medically Evidence of other peripheral vascular disease Abdominal bruit* Rise in serum creatine with ACE inhibitors (not usually applicable in pregnant state) Azotemia with normal urinanalysis Hypokalemia Unilateral small kidney detected incidentally * Flank bruits heard in 80% of individuals with fibromuscular dysplasia but may be less in pregnancy.

stenosis. Before repair there were five p r e g n a n cies. Two of these were s p o n t a n e o u s abortions, and two e n d e d in intrauterine fetal death. T h e one live birth was i n d u c e d for intrauterine growth retardation a n d fetal distress at 37 weeks. After definitive treatment, there were four pregnancies all resulting in live births, two of which were complicated by m a t e r n a l hypertension. Diagnostic Tests. This is the o n e "endocrine" cause o f hypertension in which p r o c e e d i n g to imaging before biochemical confirmation is warranted. Unfortunately all diagnostic tests for renovascular hypertension carry risk or uncertainty in interpretation in pregnancy. Angiography is the gold standard test because it is b o t h highly specific and sensitive. A narrowing o f greater than 50% is considered significant. Is T h e risks to all individuals include worsening renal function caused by the contrast material, idiosyncratic allergic reactions, a n d bleeding. In pregnancy, there is the additional risk o f exposure of the fetus to radiation of approximately 0.01 to 0.02 Gy. In theory, this could increase the risk o f childhood leukemia f r o m 1 in 3,000 to 1 in 1,500.16 Digital subtraction a n g i o g r a p h y (DSA) can be d o n e intravenously or intra-arterially. T h e intraarterial route is the p r e f e r r e d m e t h o d using 10% to 20% o f the a m o u n t o f dye c o m p a r e d with conventional arteriography. T h e r e is, however, p o o r e r resolution o f images. Isotope renal scans are used in the n o n p r e g n a n t state. Using captopril to a u g m e n t the difference between sides, the negative predictive value a p p r o a c h e s 100%. 12 T h e known detrimental effects on the fetus of ACE inhibition precludes using this test. Ultrasound D o p p l e r o f renal b l o o d flow has a sensitivity of 91% a n d a specificity of 95% in o n e

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study. 17 As with many diagnostic tests, the result are o p e r a t o r d e p e n d e n t . T h e gravid uterus together with obesity and overlying bowel gas may make visualization difficult. Comparing the renin concentration in both renal veins using fluoroscopy to position the catheters with or without captopril enhancem e n t has b e e n used. However, the lack of normal values for pregnancy and potential risks make this unfavourable in pregnancy. Magnetic resonance imaging (MR/) has been used with good results--100% sensitivity and 93% specificity, as The main difficulty is inability to see vessels beyond the main renal artery. However, the majority of stenoses are within the visualized area. MRI is considered safe for use during pregnancy. Treatment. Medical therapy may be used to temporize before definitive diagnosis and delivery. It should be n o t e d that medical treatment may be effective for blood pressure control, but renal compromise caused by ischemia may continue. T h e pharmacological agent of choice is a ~blocker, which inhibits renin release. 12 In pregnancy, ~ b l o c k e r s o f choice are those with intrinsic sympathomimetic activity to reduce the incidence of neonatal bradycardia and intrauterine growth restriction (IUGR). a9 ACE-inhibitors through r e d u c t i o n in angiotensin II are also effective agents but contraindicated in pregnancy. O t h e r agents are less efficacious. Percutaneous transluminal angioplasty u n d e r fluoroscopic guidance is the treatment of choice in renal artery stenosis, especially those secondary to fibromuscular dysplasia. In the nonpregnant state there is a 85% to 92% improvement in normalization of blood pressure, z~ T h e major risk o f this p r o c e d u r e is the exposure of the fetus to radiation. Others include renal artery dissection and cholesterol emboli, which are more c o m m o n in atherosclerotic lesions. T h e r e are three case reports of angioplasty p e r f o r m e d at 4 weeks', 17 weeks', and 26 weeks' gestation. H,21,22 O n e infant was delivered at 29 weeks, 3 weeks after the angioplasty, because of IUGR, absent end diastolic velocity, and possible superimposed preeclampsia. H The o t h e r two pregnancies went to term with no evidence of superimposed preeclampsia. One patient required antihypertensive therapy t h r o u g h o u t the pregnancy.

Table 2. Clinical Clues for Hyperaldosteronism Hypokalemia, either spontaneous or provoked Hypertension resistant to conventional therapy Presence of muscle cramps, weakness, headaches or other symptoms suggestive of hypokalemia Hypernatremia, metabolic alkalosis

Renal artery stenosis is a rare but reversible cause of extreme hypertension that should be sought in individuals with chronic hypertension, abdominal bruit, and resistance to medication. All women with significant hypertension continuing postpartum should be considered a potential candidate for further workup for renal artery stenosis. In pregnancy, the diagnosis is best made by DSA or MRI. T h e timing for definitive treatment is uncertain, but if there is accelerated hypertension, angioplasty in pregnancy appears safe. Primary Hyperaldosteronism Primary hyperaldosteronism is a rare cause of secondary hypertension wherein a u t o n o m o u s production o f aldosterone causes hypokalemia, hypertension, elevated plasma aldosterone levels, and suppressed plasma renin. T h e majority of cases (60% to 70%) are caused by unilateral benign adrenal adenomas, with the remaining most commonly caused by bilateral zona glomerulosa hyperplasia. 23 The m u c h rarer causes include adrenal carcinoma, glucocorticoid-remediable aldosteronism, and adrenal rest tissue in the ovaries or kidneys, z3,24 Clinical Manifestations. T h e classic clinical feature of mineralocorticoid induced hypertension is hypokalemia, which may first manifest after administration of diuretics, vomiting, or diarrhea. Approximately 50% o f hypertensive patients with u n p r o v o k e d hypokalemia will have primary aldosteronism. 25 However, 7% to 38% of individuals with hyperaldosteronism will have normal baseline potassium levels, z6 The hypokalemia may cause headache, fatigue, weakness, and muscle cramps (Table 2). Serum sodium levels are generally in the u p p e r normal range, and bicarbonate levels often are increased. 27 In pregnancy there is a mild respiratory alkalosis with a compensatory decrease of 4 m E q / L of plasma bicarbonate changing the reference interval to 18 to 22 m E q / L . Potassium retention o f approximately 350 mEq is required to m e e t

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the demands of the fetus, placenta, breasts, and uterus. This occurs despite increased mineralocorticoid activity likely caused by the antagonizing effect of progesterone on the mineralocorticoid receptors. Outcome in Pregnar~ey. There have been 18 cases reported in the literature of pregnancies complicated by hyperaldosteronism3s-a1 Two of these patients underwent surgical adrenalectomy during the second trimester, and the others were treated conservatively. There were two terminations of pregnancy, one intrauterine fetal death at 32 weeks (caused by abruption), seven preterm deliveries including one at 26 weeks with placental abruption who died at 4 days of age, and eight term deliveries. There was one case of cliteromegaly of uncertain cause, sl There were three cases of superimposed preeclampsia. The two pregnancies during which adrenalectomies were performed both resulted in normalization of blood pressure. In one case, preeclampsia occurred at 36 weeks' gestation after a period of normotension. O/agno~s. Before biochemical diagnosis, hypokalemia should be corrected because a low pot tassium level will suppress aldosterone; high dose ~blockers should be reduced because of their reduction in renin production; all diuretics should be discontinued for a minimum of 2 weeks, and calcium channel blockers should be avoided for 2 to 3 hours before testing because of their inhibition of aldosterone and stimulation of renin35 When hypokalemia has been identified, urine potassium levels are taken to confirm urinary potassium wasting. The urinary potassium loss may be less than one would expect in primary hyperaldosteronism because of the antagonizing effects of progesterone, s2 Plasma aldosterone levels usually are helpful in diagnosis in the nonpregnant state. However, in pregnancy, aldosterone levels rise and are often in the primary hyperaldosteronism range.* Plasma renin levels should be decreased in primary hyperaldosteronism. In pregnancy, plasma renin activity usually is increased and does decrease in the setting of primary hyperaldosteronism3 s However, in pregnancies complicated by chronic essential hypertension or preeclampsia, the plasma renin activity tends to decrease, making differentiation difficult,aa To confirm the autonomous secretion of al-

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dosterone, salt loading studies may be performed. Infusion of 2 L of normal saline over 4 hours in the supine position normally suppresses aldosterone levels, whereas aldosterone levels remain elevated in primary hyperaldosteronism. 23 In pregnancy, the concern of volume overload, worsening hypokalemia, and lack of normal ranges make this test unfavored. A second dynamic test, to determine if renin is suppressed, is to stimulate renin production by upright posture. In pregnancy, prolonged upright posture does result in modest increase in plasma renin activity, thus, if renin activity remains suppressed it is suggestive of primary hyperaldosteronism. However, normal values have not been established in pregnancy. Ultrasonography has poor sensitivity for adrenal lesions, especially in the obese and pregnant patient. Both computed tomography (CT) and MRI can detect adrenal nodules greater than 1 cm. Given the potential risks or radiation, MRI would be the preferred method. Treatment. Medical therapy should be aimed at the inhibition of the action or production of aldosterone together with replacement of potassium. In pregnancy, pharmacological options are limited. Spironolactone, which blocks aldosterone receptors, is contraindicated because of the concern of causing feminization of a male infant. ACE inhibitors, which may be effective if the renin-angiotensin-aldosterone axis is not completely suppressed, also are contraindicated in pregnancy. Aldomet and/3-blockers may not be very effective. Calcium channel blockers, especially dihydropyridines, may be used with some effectiveness because of their effects on blocking aldosterone synthesis and release too gether with their direct vasodilation effect3s If an adrenal adenoma is detected, unilateral adrenalectomy by laparotomy or more recently by laparoscopy is the treatment of choice. However, approximately one third of patients will have persistent hypertension.34 There have been three case reports of adrenalectomy during pregnancy3 9"sl It was performed in the second trimester and successful in all three. Thus, if medical treatment is unsuccessful in controlling blood pressure, surgical intervention in the second trimester may be warranted.

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Pheochromoeytoma P h e o c h r o m o c y t o m a is a rare but potentially fatal t u m o r of chromaffin tissue that results in overp r o d u c t i o n of catecholamines. With early diagnosis and appropriate treatment, fetal and maternal morbidity and mortality are significantly reduced. Physiology Chromaffin cells, which originate from neural crest tissue, have the capability of synthesizing, storing, and secreting catecholamines. Because o f the c o m m o n embryological origin of the sympathetic nervous system and adrenal medulla, extra-adrenal chromaffin cells may be found a r o u n d sympathetic ganglia extending from the carotid body to the pelvis. Catecholamines are p r o d u c e d from tyrosine precursors. They function both as neurotransmitters in the sympathetic nervous systems and as h o r m o n e s when released from the adrenal medulla. T h e adrenal medulla produces predominately e p i n e p h r i n e and n o r e p i n e p h r i n e in a ratio o f 4:1, whereas the postganglionic sympathetic fibers release mostly norepinephrine. Catecholamines released from nerve synapses have a brief biological action because of rapid reuptake. Catecholamines from the adrenal medulla are released into the blood and require degradation and excretion to b e c o m e ineffective resulting in a longer half-life (1 to 2 minutes). Circulating catecholamines are metabolized by two main enzymes--catechol-o-methyltmnsferase (COMT) and monoamine oxidase (MAO). The o r d e r in which these enzymes degrade the catecholamines determines the excreted product. The majority o f circulating catecholamine is initially metabolized by COMT, which results in conversion of n o r e p i n i p h r i n e and epinephrine to n o r m e t a n e p h r i n e and metanephrine, respectively, which are then excreted and are measurable in the urine. 35 The biological actions of catecholamines are d e p e n d e n t on interaction with cell surface adrenergic receptors. T h e classification of these receptors is based on their response to pharmacological stimuli. Stimulation of alpha and beta receptors results in vasoconstriction, increased cardiac contractility, increased cardiac automa-

Table 3. Clinical Clues for Pheochromocytoma Paroxysms of hypertension, headache, palpitations, and diaphoresis Hypertension unresponsive to the usual medical treatment Worsening of the blood pressure with/3-blockade Worsening of blood pressure after anesthesia or labor Positive family history of pheochromocytoma with or without other MEN II symptoms Evidence of neurocrestopathic syndrome, ie, Cafe-au-lait lesion, neurofibromas, retinal hemanglomatosls Presence of diabetes (caused by increased glycolysis) Appearance of hypertension in first trimester Sudden cardiovascular collapse

ticity, accelerated lipolysis, and increased glucose production. 36

Changes in Pregnancy As in the n o n p r e g n a n t state, catecholamine levels will be increased by various physiological and pathological stimuli such as physical illness, mental stress, trauma, and hypoglycemia. Intensive care nurses and female physicians in the third trimester of pregnancy demonstrated a 58% to 64% increase in urinary catecholamine levels on working versus nonworking days. 37 Outside of stressful situations, urinary catecholamine levels are u n c h a n g e d in pregnancy except for a rise from the onset of labor until the seco n d postpartum day. 3s,g9 T h e effect of the increased catecholamines caused by stress during pregnancy is unknown. In pregnancies complicated by hypertension, the data on catecholamine levels are conflicting. Urinary catecholamine levels have been reported to be increased 1.7- to 2.6-fold in hospitalized preeclamptic patients and also in critically ill eclamptic patients. 4~ T h e role of the severity of the illness versus preeclampsia itself c a n n o t be separated. Plasma catecholamine levels have been shown to be decreased or normal in patients with preeclampsia and essential hypertension complicating pregnancy c o m p a r e d with normotensives. 42-44 Clinical Manifestations. T h e incidence of pheochromocytoma in pregnancy is approximately 0.002% (Table 3). 45 Pheochromocytomas may be single (90%) or multiple (10%), adrenal (90%) or extra-adrenal (10%), sporadic (90%)

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Table 4.

Effect o f Time o f Diagnosis and Intrapartum Treatment or Fetal and Maternal Mortality in

Pregnancies Complicated by Pheochromocytoma Time of Diagnosis

During Pregnancy Postpartum Fetal 26/76 (34) 74/131 (56) Maternal 6/76 (8) 55/107 (51)

Treatment

a-Blockade Yes No 1/16 (6) 11/20 (55) 0/16 (0) 2/22 (9.5%)

Surgery <24 wk >24 wk 4/9 (44) 9/41 (22) 1/9 (11) 4/47 (8)

Data expressed as death/cases (%). Data from Schenkerand Granat,48Keely,49and Burgess.6~ or familial (10%). The familial disorders associated with pheochromocytomas include multiple endocrine neoplasia type IIa and IIb; von Hippel Lindau disease, neurofibromatosis, and isolated familial pheochromocytoma. The classic paroxysms of hypertension, headache, palpitations, and diaphoresis occur in only 50% of the patients, and one third will demonstrate sustained rather than episodic hypertension. 46,47 The onset usually is sudden and may last minutes to hours. Episodes may be precipitated by many stimuli including exercise, urination, defecation, and palpation of the abdomen and in pregnancy by the enlarging uterus, uterine contractions, fetal movements, and anaesthesia. This may result in worsening of blood pressure during labor. Treatment of hypertension with/3-blockers may result in a paradoxical rise in blood pressure caused by unopposed a-stimulation. The incidence of convulsions and visual changes is more common in pregnancy. This, together with up to a 20% incidence of proteinuria, can make it difficult to distinguish from preeclampsia. Outcome in Pregnancy. Maternal mortality rates from pheochromocytoma have improved significantly in the last three decades. There continues to be a 4% maternal mortality rate in those cases diagnosed during pregnancy compared with 25% mortality rate in those cases not diagnosed until postpartum. 4s,49A timely diagnosis is essential. Fetal morbidity and mortality rates have also improved but remain at an overall incidence of 32%. 49 Again, recognition during the pregnancy results in significant improvement in survival rate (14% intrapartum diagnosis v 62% postpartum diagnosis; Table 4).48,49 D/agnods. As with most endocrinological disorders, a biochemical diagnosis must precede radiographic localization. Collection of 24-hour

urine in an acidified medium is the standard screening test. Quantification of catecholamine metabolites--vanillyl-mandelicacid (VMA), normetanephrine, and metanephrine may be performed by spectrophotometric methods or preferably by high-pressure liquid chromatography (HPLC). These are not interfered with by diet, unlike earlier methods; however, drugs may alter the results. Alpha-methyldopa and labetalol interfere with spectrophotometric but not HPLC measurement of VMA.5~ Use of aldomet, phenothiazines, and tricyclic antidepressants affect the production of VMA and thus alter resuits. Measurement of norepinephrine and epinephrine in the urine (as opposed to their metabolites) may also be done by HPLC but do not offer any major advantage over metabolite measurement. Although measurement of plasma catecholamines may be useful in the diagnosis of pheochromocytoma, strict attention must be paid to collection of the samples because of the wide fluctuations seen with physiological stimuli such as exercise, stress, and postural changes together with the lability of the hormone in vitro. The results are affected by commonly used antihypertensives in pregnancy. Labetalol will falsely increase results of the HPLC assay, whereas alpha-methyldopa will decrease catecholamine secretion. 51 If baseline biochemical investigations are inconclusive, such as with modest elevation in urinary catecholamines, further testing is warranted. A clonidine suppression test in which 300 ktg of clonidine, a centrally acting a-2 agonist, is administered orally followed by plasma catecholamine levels measured at 1, 2, and 3 hours postingestion may be performed. An abnormal response (lack of suppression of plasma norepinephrine to less than 2.96 n m o l / L [500

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p g / m L ] ) has a sensitivity of 87% to 93% and a specificity of 93% to 96% for diagnosing pheoc h r o m o c y t o m a . 52 However, there is the potential for significant hypotension with this test, especially in those individuals receiving antihypertensives, thus, e x t r e m e caution must be used in pregnancy. After a biochemical diagnosis, imaging is required to localize the lesion. It is necessary to modify the choice of imaging tests in pregnancy. T h e ideal test would have high resolution for adrenal lesions, be able to locate extra-adrenal tumors, be low risk to m o t h e r and fetus, and be readily available. U l t r a s o n o g r a p h y does not have the required sensitivity to detect adrenal masses, especially in the p r e g n a n t state in which the left adrenal gland (because of overlying bowel) a n d paraaortic area (because of the fetus) are n o t well visualized. CT is able to detect 85% to 95% of adrenal lesions bigger than 1 cm. 53 T h e two fetal concerns are exposure to ionizing radiation (approximately 0.016 Gy) a n d contrast material. MRI has a sensitivity of close to 100% in lesions greater than 1.5 era. 54 T h e lack of radiation exposure, elimination of contrast m e d i a use, ability to distinguish p h e o c h r o m o c y t o m a f r o m o t h e r adrenal lesions by virtue of the high intensity signal emitted only f r o m p h e o c h r o m o c y t o mas on Tz-weighted images, a n d ability to detect extra-adrenal tumors m a k e it the imaging test of choice. 55 Metaiodbenzylguanidine scans, a radiolabelled material that is selectively taken up by adrenergic tissues, is contraindicated in pregnancy. It may be useful in p o s t p a r t u m localization, especially w h e n extra-adrenal or metastatic lesions are being sought, because it is a full-body image. T h e sensitivity is 79% to 91% and specificity is 94% to 99%. 56 Treatment. T r e a t m e n t of p h e o c h r o m o c y t o m a is divided into two phases: (1) Pharmacological therapy to block the effect of excess catecholamines a n d (2) Surgery to remove the o v e r p r o d u c i n g tissue. Alpha blockade is the initial t r e a t m e n t modality. This results in a reduction in the catecholamine-mediated vasoconstriction. P h e n o x y b e n z a m i n e may be given initially as 10 m g twice daily followed by 10 to 20 m g i n c r e m e n t s until the desired blood pressure response is observed (evidence of orthostatic fall). Major adverse effects include sedation, ha-

sal stuffiness, postural hypotension, fluid retention, and generalized weakness. 57 Prazosin, a selective a-1 antagonist may be used in an initial dose of 1 m g three times daily, increasing up to 20 m g daily. It results in less postural hypotension, but may be less effective in preventing intraoperative hypertension. 5s P h e n t o l a m i n e mesylate is a p a r e n t e r a l preparation for use in hypertensive crisis and perioperative b l o o d pressure control. It can be titrated against clinical response. Alpha-blockade should be provided for 7 to 14 days before surgical intervention to allow catecholamine-induced volume depletion to reverse. Surgery may be u n d e r t a k e n when blood pressure control is adequate (less than 150/90 with presence of orthostatic drop), a n d there is less than one p r e m a t u r e ventricular contraction every 5 minutes. 59 In pregnancy, the benefits o f adequate a-receptor blockade o n p r e g n a n c y o u t c o m e far outweigh any potential of u n k n o w n teratogenic or long-term effects. Fetal mortality rate is r e d u c e d f r o m 55% to 6%, and m a t e r n a l mortality rate reduced f r o m 9.5% to 0% w h e n a-blockade is used. 6~Although there have b e e n animal data to suggest that a-blockade may affect fetal biophysical assessment, it appears that, based on a case report, fetal h e a r t rate is slowed but does not lose variability a n d that b r e a t h i n g m o v e m e n t s remain n o r m a l until o t h e r indicators of fetal c o m p r o m i s e are present. 6~ After adequate a-blockade is achieved,/3-blockers may be added to control tachycardia and tachyarrhythmias. If added prematurely, the unopposed a-adrenergic stimulation may cause worsening of the hypertension. Dosages should be titrated to maintain a heart rate of 80 to 100 beats per minute. Labetalol has a- and/3-blocking properties in a ratio of 1:5. T h e danger of excess/3-blockade and risk of precipitation of a hypertensive crisis limits its usefulness. Surgical excision of the t u m o r is the definitive t r e a t m e n t for p h e o c h r o m o c y t o m a . T h e timing of this during p r e g n a n c y is controversial. Because of i m p r o v e d outcomes with adequate medical therapy and a 44% risk o f fetal loss in surgery conducted before 24 weeks versus 22% for surgery delayed until after 24 weeks, it is p r u d e n t to treat p r e g n a n t w o m e n medically until fetal viability is present unless there is m a t e r n a l or fetal deterioration. 49,6~ Surgical removal a n d de-

Endocrine Causes of Hypertension

livery may occur u n d e r the same anesthetic. It would appear that a cesarean section carries less risk o f maternal death (19% v 31%) c o m p a r e d with a vaginal delivery and is the delivery route o f choice. 48 T h e choice of anesthetic techniques should be made by an experienced team. T h e choice of anesthetic technique must reflect the potential effects on the fetus and m o t h e r as well as the importance of the prevention o f an intraoperative hypertensive crisis. 59

Hypercortisolemia (Cushing's Syndrome) Physiology Corticotropin-releasing h o r m o n e (CRH) is a 41amino acid peptide that is primarily released from paraventricular nucleus o f the hypothalamus and is the primary secretagogue o f adrenocorticotropin h o r m o n e (ACTH). T h e lungs, liver, gastrointestinal tract, adrenal medulla, and placenta also produce CRH. 6~ T h e role o f this peripherally p r o d u c e d CRH is not clear. ACTH, a 39-amino acid peptide derived from the precursor molecule proopomelanocartin, is released from the anterior pituitary gland primarily in response to CRH and vasopression stimulation. It is released in brief episodic bursts whose amplitude changes t h r o u g h o u t the day. Plasma levels reach their lowest 1 to 2 hours after sleep begins and peak at the time o f wakening. ACTH in turn stimulates glucocorticoid, androgen, and to a lesser extent, mineralocorticoid release from the adrenal cortex. T h e hypothalamic-pituitary-adrenal axis is regulated by negative feedback of glucorticoids at both the hypothalamic and pituitary level. Cortisol circulates 90% b o u n d to cortisolbinding globulin (CBG), 6% b o u n d to albumin, and the r e m a i n d e r circulates free. CBG production is increased twofold to threefold in estrogen excess states, including pregnancy and oral contraceptive use. Decreased CBG levels occur in cirrhosis, hypothyroidism, and protein-losing conditions. Measurement of serum cortisol includes the b o u n d and u n b o u n d fractions and is thus influenced by changes in CBG levels; whereas, urine assays measure only the u n b o u n d fraction.

479

Changes in Pregnancy During pregnancy, CRH levels are increased because of placental production, which enters both the maternal and fetal circulation. 63 It may play a role in fetal organ maturation and initiation o f labor together with a paracrine effect within the placental unit. 64 In contrast to the usual negative feedback glucorticoids have on hypothalamic CRH production, placental production o f CRH is increased. Plasma ACTH levels increase t h r o u g h o u t pregnancy but are significantly lower than in the n o n p r e g n a n t state with the nadir being in the first trimester. T h e r e is a marked increase in ACTH levels during labor, which decreases by the second postpartum day. 65 T h e normal diurnal rhythm is maintained. 66 Some o f the maternal ACTH is placental in origin, which is not suppressible with d e x a m e t h a s o n e and is less responsive to m e t y r a p o n e suppresion. 67 Both total and u n b o u n d plasma cortisol levels and urinary-free cortisol increase in pregnancy approximately threefold. 67 T h e r e continues to be the normal circadian rhythm t h r o u g h o u t pregnancy. 66 Clinical Manifestations. Cushing's syndrome is distinctively rare in pregnancy because of a 75% to 95% incidence o f menstrual disorders secondary to elevated a n d r o g e n levels, abnormal GNRH secretion, and elevated prolactin levels.68.69 Hypertension, which is usually mild, is seen in 75% to 90% o f all cases of Cushing's syndrome. 70 As outlined in the excellent review by Danese and Aron, 7~ the pathogenesis of hypertension in glucocorticoid excess states is likely multifactorial including increased vascular tone, increased extracellular fluid sodium concentration, increased mineralocorticoid activity, and changes in the renin-angiotensin system. T h e distribution o f causes of hypercortisolemia in pregnancy is significantly different from that in the n o n p r e g n a n t state. T h e incidence o f adrenal adenomas is 50% in the pregnant versus 16% in the n o n p r e g n a n t Cushing's syndrome population. In comparison, pituitary adenomas are 33% versus 59% in the p r e g n a n t versus nonp r e g n a n t population. 71 This difference in distribution is likely caused by the menstrual irregularities that are seen more commonly in the A C T H - d e p e n d e n t hypercortisolemic states be-

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Erin Keely

Table 5. Clinical Clues for Hypercortisolemic State Excessive rapid weight gain Proximal myopathy Extensive, wide (>1 cm) striae Spontaneous bruising Hirsutism or acne Psychological disturbances

cause of the stimulation of adrenal a n d r o g e n p r o d u c t i o n and thus anovulation. Adrenal adenomas usually p r o d u c e only one steroid product, and thus, androgens are not elevated. Ectopic ACTH production, which is most commonly secondary to malignancies, is very rare in pregnancy (1.7% v 15.7%), which is not surprising given that the m e a n age of patients with this disorder is 53 years, with a 10:1 p r e p o n d e r a n c e of men.

71,72

Hypercortisolemia results in a wide spectrum of clinical findings. Some, such as central obesity, r o u n d facies, abdominal striae, and glucose intolerance are c o m m o n in normal pregnancies and by themselves do not warrant investigation. In Cushing's syndrome, the striae tend to be wider (greater than 1 cm), darker, and occur in sites other than the abdominal wall, ie, breast, thighs, axillae. O t h e r symptoms of glucocorticoid excess including proximal myopathy, neuropsychiatric disturbances, virilization (hirsutism and acne), spontaneous ecchymosis, and poor wound healing are more specific for hypercortisolemia. These clinical features should raise suspicions and cause one to initiate investigations (Table 5). Because of the hypercortisolemia in normal pregnancy, Cushing's syndrome tends to worsen in the gravid patient. However, there also have been reports o f amelioration of symptoms during pregnancy, which is likely caused by the antagonizing effect of progeterone. 7~ Outcome in Pregnancy. Maternal morbidity in Cushing's s y n d r o m e is increased because o f worsening h y p e r t e n s i o n (67%), s u p e r i m p o s e d preeclampsia (10%), gestational diabetes (33%), a n d congestive heart failure secondary to severe h y p e r t e n s i o n ( 1 0 % ) . 74 Maternal deaths caused by gastrointestinal bleeding, p u l m o n a r y e d e m a , cardiac failure, and sepsis have b e e n r e p o r t e d . 75 Fetal o u t c o m e is also compromised in hypercortisolemic states. In Cushing's disease there is

a p r e t e r m delivery rate of 33% and spontaneous abortion and stillbirth rate of 17%. In cases caused by adrenal a d e n o m a or carcinoma fetal o u t c o m e is worse with a p r e t e r m delivery rate of 50% and spontaneous abortion or stillbirth rate o f 22%. 76 Transient neonatal adrenal insufficiency and one case of a soft palate congenital anomaly have b e e n reported. 77,7s T h e benefit of treatment during pregnancy on maternal and fetal o u t c o m e is difficult to ascertain because o f the few r e p o r t e d cases. Only three cases of transphenoidal surgery during pregnancy have b e e n reported, two of which were successful with early delivery (30 and 37 weeks) for worsening hypertension and one of which resulted in fetal death at 33 weeks, 17 weeks after surgery. 79-m Unilateral adrenalectomies during pregnancy, if d o n e early in the seco n d trimester, appear to reduce p o o r neonatal outcome.

82

Diagnosis. The biochemical diagnosis of Cushing's syndrome is challenging in the nonp r e g n a n t state and even more difficult during pregnancy. The first step is to confirm hypercortisolemia followed by localization o f the source. Screening tests for hypercortisolemia include (1) m e a s u r e m e n t of a 24-hour urine-free cortisol in more than 1 sample, (2) serum cortisol measurement at 0800 and 2300 (diurnal rhythm), and (3) 1 mg overnight dexamethasone suppression test. In pregnancy, the definitive criteria for hypercortisolism are not established. T h e normal rise in 24-hour UFC during pregnancy requires using a higher reference range. T h e overnight dexamethasone suppression test is not accurate in estrogen excess states including pregnancy because o f the elevation in total serum cortisol. T h e normal circadian rhythm of plasma cortisol is maintained, but plasma values will be higher at both times, and thus the criteria of evening levels decreased to less than 50% of m o r n i n g levels should be used. 66,83,84 If the screening tests suggest hypercortisolemia, a definitive biochemical diagnosis is required. A 2-day low-dose (0.5 mg every 6 hours) dexamethasone suppression test should be used. During pregnancy there is normal suppression of urinary cortisol to less than 55 nmol every 24 hours.

TM

Once the diagnosis of hypercortisolemia is confirmed, plasma ACTH levels should be measured to differentiate A C T H - d e p e n d e n t (pitu-

Endocrine Causes of Hypertension

itary and ectopic) causes from ACTH-indep e n d e n t (adrenal source) causes. T h e level is difficult to interpret in pregnancy because o f placental production; however, a value greater than 35 p g / m L (8 p m o l / L ) is suggestive o f A C T H - d e p e n d e n t causes; whereas, less than 5 p g / m L (1.1 p m o l / L ) suggests adrenal patholO~f. 67

Administration of CRH followed by the meas u r e m e n t o f peripheral ACTH and cortisol plasma levels can be useful in the differential diagnosis o f Cushing's syndrome. Pituitary but not adrenal or ectopic sources will demonstrate an increase in ACTH secretion after CRH administration, s5 An increase of ACTH o f greater than 50% or corfisol of greater than 20% from baseline has an 86% to 91% sensitivity and 95% specificity for diagnosing Cushing's disease. Because o f the 10% false-negative rate, one needs to have a low threshold for a second diagnostic test in patients with insufficient response to CRH stimulation, s6 CRH stimulation can be used with inferior petrosal sinus sampling in which catheters are placed via the femoral route in both petrosal sinuses, the venous drainage o f the pituitary gland. Comparison of central versus peripheral levels of ACTH allows localization to the pituitary gland (v ectopic source) and lateralization within the gland, s7 In pregnancy, the ACTH response to CRH is blunted by term, possibly because of placental CRH downregulating receptors in the anterior pituitary gland to exogenous CRH. s8 Inferior petrosal sampling has been rep o r t e d in o n e pregnancy using a modified approach to minimize radiation exposure of the fetus (jugular rather than femoral vein access), which confirmed a pituitary lesion but failed to lateralize the lesion. 89 D e p e n d i n g on the results of the biochemical tests, imaging should be directed toward the appropriate area. It is essential that biochemical confirmation occur first because there is a 10% to 20% incidence of pituitary or adrenal adenomas in the normal population. 9~ MRI is the preferred m e t h o d for imaging the pituitary and adrenal glands in pregnancy because o f the enhanced resolution and absence of radiation exposure to the fetus. The pituitary gland does increase in size during pregnancy, and this must be taken into account when interpreting the films.

481

Treatment. Most patients with hypercortisolemia r e p o r t e d in the literature have not b e e n treated during the pregnancy. However, the p o o r fetal o u t c o m e and high maternal morbidity rate has p r o m p t e d physicians m o r e recently to provide therapy during pregnancy. T r e a t m e n t should be aimed at the cause o f the corfisol excess. Cushing's disease is cured 80% to 90% o f the time with selective transphenoidal adenectomy. ~ T h e r e are three case reports of transphenoidal surgery during pregnancy at 16, 18, and 22 weeks' gestation. T h e r e were two p r e t e r m deliveries and one fetal death many weeks after the s u r g e r y . 79,s~ Unilateral adrenal lesions should be removed surgically during pregnancy unless the diagnosis is made late in the third trimester. This recomm e n d a t i o n is based on a reduction from 12 o f 19 fetal deaths or neonatal complications in a group in which surgery was not p e r f o r m e d versus one o f seven in which surgery was p e r f o r m e d during pregnancy, s2 Expert surgical and anesthetic teams together with endocrinological support are required. Cortisol replacement is required after both pituitary and adrenal surgery until the hypothalamic-pituitary-adrenal axis returns to normal. If a diagnosis o f adrenal carcinoma is made in the first trimester, consideration should be given to termination of the pregnancy so that definitive therapy can be undertaken. In the second trimester, adrenalectomy should be considered, and in third trimester, medical therapy should be provided until delivery. 67 Metyrapone, which primarily inhibits 1 l ~ h y droxylation, has been shown to decrease placental a r o m a t a s e activity. 9s T h e fetus synthesizes cortisol from precursors supplied by transplacental passage of maternal cortisol. 94 W h e n the total daily dosage is kept between 0.5 and 2.0 g, no fetal or neonatal adrenal dysfunction has been noted. 93 Inhibited adrenal steroidogenesis by ketoconazole has been used in pregnancy. However, experience is limited, and potential fetal risks are unknown. 95 T h e o t h e r adrenal steroidogenesis inhibitors have contraindications to their use in pregnancy. Aminoglutethimide has been associated with virilization of female fetuses, trilostane may precipitate p r e t e r m labor and

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Summary H y p e r t e n s i o n is a c o m m o n m e d i c a l c o m p l i c a t i o n o f p r e g n a n c y . R a r e l y t h e r e is a s e c o n d a r y cause underlying the hypertension. However, t h e h i g h m o r b i d i t y a n d m o r t a l i t y r a t e s associated with these conditions and improvement in outcome with timely diagnosis and treatment m a k e s it i m p e r a t i v e t h a t c l i n i c i a n s c o n s i d e r these possibilities.

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55. Velchik Mg, Alavi A, Kressel HY, et al: Localization of pheochromocytoma: MIBG, CT and MRI correlation. J Nucl Med 30:328-336, 1989 56. Shapiro B: Imaging ofcatecholamine-secreting tumours: Uses of MIBG in diagnosis and treatment. Baillieres Clin Endocrinol Metab 7:491-506, 1993 57. Hoffmann BB, LetkowitzJR: Adrenergic receptor antagonism, in Gilman AG, Rall TW, Nico AS, et al (eds): The Pharmacologic Basis of Therapeutics (ed 8). Tarrytown, NY, Pergaman Press, 1990, pp 221-243 58. Nicholson JP, Vaughn ED, Picketing TG, et al: Pheochromocytoma and prazosin. Ann Intern Med 99:47% 479, 1983 59. Desmonts JM, Marty J: Anaesthetic management of patients with pheochromocytoma. Br J Anaesthesiol 56: 781-789, 1984 60. Burgess GE: Alpha blockade and surgical intervention of pheochromocytoma in pregnancy. Obstet Gynecol 53: 266-269, 1979 61. Devoe LD, O'Dell BE, Castillo RA, et al: Metastatic pheochromocytoma in pregnancy and fetal biophysical assessment after maternal administration of alpha-adrenergic, beta-adrenergic and dopamine antagonists. Obstet Gynecol 68:155-185, 1986 (suppl 3) 62. Taylor AL, Fishman LM: Corticotropin releasing hormone. N EnglJ Med 319:213-222, 1988 63. Goland RS, Wardlaw SL, Stark RI, et al: High levels of corticotropin-releasing hormone immunoactivity in maternal and fetal plasma during pregnancy. J Clin Endocrinol Metab 63:1199-1204, 1986 64. Riley SC, Walton JC, Herlick JM, et al: The localization and distribution of corticotropin-releasing hormone on the human placenta and fetal membranes throughout gestation. J Clin Endocrinol Metab 72:1001-1007, 1991 65. Carr BR, Parker CR, Madden JD, et al: Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol 139:416422, 1981 66. Nolten WE, Lindheimer MD, Rveckert PA, et al: Diurnal patterns and regulation of cortisol secretion in pregnancy. J Clin Endocrinol Metab 51:466-472, 1980 67. Garner PR: Disorders of the adrenal cortex in pregnancy, in Lee RV, Garner PR, Barron WM, et al (eds): Current Obstetric Medicine (2). St. Louis, MO, MosbyYear Book, 1995 68. Boccuzzi G, Angeli A, Bisbocci D, et al: Effect of synthetic LHRH on the release of gonadotropins in Cushing's Disease.J Clin Endocrinol Metab 40:892-985, 1975 69. Caufriez A, Desir D, Szyper M, et al: Prolactin secretion in Cushing's Disease. J Clin Endocrinol Metab 53:843846, 1981 70. Danese RD, Aron DC: Cushing's syndrome and hypertension. Endocrin Metab Clin North Am 23:299-324, 1994 71. Buescher MA, McClamrock HD, Adashi EY: Cushings syndrome in pregnancy. Obstet Gynecol 79:130-137, 1992 72. Orth DN, Liddle GW: Results of treatment in 108 patients with Cushing's syndrome. N Engl J Med 285:243247, 1971 73. Jorgensen PI, Sele V: A case of adrenocortical hyperfunction normalised during the second and third trimester

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