MINI-REVIEW

Primary : Managing Mineralocorticoid Replacement Therapy

Daniela Esposito,1,2,3 Daniela Pasquali,3 and Gudmundur Johannsson1,2

1Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; 2Department of , Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden; and 3Department of Medical, Surgical, Neurological, Downloaded from https://academic.oup.com/jcem/article/103/2/376/4630430 by guest on 26 September 2021 Metabolic Sciences, and Aging, University of Campania “Luigi Vanvitelli,” 80138 Naples, Italy

Context: Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on how MC substitution should be optimized, because MC dosing regimens have only been systematically investigated in a few studies. We review the management of current standard MC replacement therapy in PAI and its plausible impact on outcome.

Design: Using PubMed, we conducted a systematic review of the literature from 1939 to 2017, with the following keywords: adrenal insufficiency, MC deficiency, , cardiovascular disease, hypertension, and heart failure.

Results: The current standard treatment consists of fludrocortisone (FC) given once daily in the morning, aiming at normotension, normokalemia, and plasma renin activity in the upper normal range. Available data suggest that patients with PAI may be underreplaced with FC as symptoms and signs indicating chronic MC underreplacement, such as salt craving and postural dizziness persist, in many treated patients with PAI. Data acquired from large registry-based studies show that glucocorticoid doses for replacement in PAI are higher than those estimated from endogenous production. Glucocorticoid overreplacement may reduce the need of MC replacement but may also be a consequence of inadequate MC replacement.

Conclusions: The commonly used MC replacement in PAI may not be adequate in some patients. Insufficient MC substitution may be responsible for poor cardiometabolic outcome and the failure to restore well-being adequately in patients with PAI. Well-designed studies oriented at optimizing MC replacement therapy are urgently needed. (J Clin Endocrinol Metab 103: 376–387, 2018)

rimary adrenal insufficiency (PAI) is a rare disease, Autoimmune PAI may occur either as an isolated entity Pcharacterized by insufficient secretion of glucocorti- (40% of all cases) or as part of an autoimmune poly- coids (GCs), mineralocorticoids (MCs), and androgens endocrine syndrome (60%) (1). Other etiologies to (1). The most common cause of PAI in industrialized mention are infectious, genetic, metastatic, hemorrhagic, countries is autoimmune adrenalitis, which is associated and infiltrative disorders, surgery, and drugs (3–5). Long- with detection of circulating 21-hydroxylase autoanti- chain fatty acids should be investigated to assess adre- bodies (1, 2). Measurement of these autoantibodies is noleukodystrophy in men with PAI without detectable therefore of value to determine the etiology of PAI (3, 4). antibodies (6).

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: 11b-HSD2, 11b-hydroxysteroid-dehydrogenase type 2; ACTH, adreno- Printed in USA corticotropic hormone; ANP, atrial natriuretic peptide; BP, blood pressure; FC, flu- Copyright © 2018 Endocrine Society drocortisone; GC, glucocorticoid; GPER, G protein–coupled estrogen receptor; HC, Received 30 August 2017. Accepted 10 November 2017. hydrocortisone; HF, heart failure; HPA, hypothalamic-pituitary-adrenal; LV, left ventricular; First Published Online 15 November 2017 MC, mineralocorticoid; MCU, mineralocorticoid unit; MR, mineralocorticoid receptor; PAI, primary adrenal insufficiency; PRA, plasma renin activity; PRC, plasma renin concentration; PV, plasma volume; QoL, quality of life; RAAS, renin-angiotensin-aldosterone system; SAI, secondary adrenal insufficiency.

376 https://academic.oup.com/jcem J Clin Endocrinol Metab, February 2018, 103(2):376–387 doi: 10.1210/jc.2017-01928 doi: 10.1210/jc.2017-01928 https://academic.oup.com/jcem 377

If untreated, PAI can be lethal. Before the availability GPER expression is ubiquitous; in vascular cells, it is pres- of GCs, the majority of patients died within 2 years of ent in both endothelial and smooth muscle cells. Activation diagnosis (5, 7). Treatment of PAI consists of lifelong of GPER mediates rapid endothelium-dependent vasodi- replacement therapy with GCs and MCs, whereas an- lation, whereas MR activation produces vasoconstriction. drogen replacement is less frequent and mainly consid- Thus, the effect of aldosterone on endothelial function can ered in women. MC substitution is needed in PAI to vary depending on the balance between MR and GPER correct hypovolemia, hyperkalemia, hyponatremia, and expression (20, 21). hypotension (3). Secondary adrenal insufficiency (SAI) Aldosterone, like angiotensin II, has other endocrine is a different disease entity caused by a pituitary disorder activities essential for circulatory homeostasis. They disrupting adrenocorticotropic secretion that leads to GC contribute to blood coagulation (22) and vasoconstric- deficiency. Patients with SAI do not need MC replace- tion to preserve arterial pressure in case of hypovolemia Downloaded from https://academic.oup.com/jcem/article/103/2/376/4630430 by guest on 26 September 2021 ment because the secretion of aldosterone is mostly and stimulate thirst. They are also involved in regulating stimulated by the renin-angiotensin-aldosterone system inflammatory and reparative processes that follow tissue (RAAS), with only a minor component under the control injury (19, 22, 23) (Fig. 1). of adrenocorticotropic hormone (ACTH) (3, 8). Here, we present a review on MC replacement in PAI, MC Activity of GCs including the outcomes associated with current therapy, to promote further discussions on the safety and effec- MRs and GC receptors have analogous DNA-binding tiveness of conventional treatment. We searched Medline domains (94% homology for amino acids) and similar for articles published in English until 21 May 2017, with ligand-binding domains (57%) (8). has high the following keywords: adrenal insufficiency, MC de- affinity for the MR allowing for MC activity. However, a ficiency, aldosterone, cardiovascular disease, hyperten- local enzyme, 11b-hydroxysteroid-dehydrogenase type 2 sion, and heart failure (HF). Studies including a detailed (11b-HSD2), which is colocalized with the MR, converts analysis of MC dosing regimens and monitoring were active cortisol to inactive cortisone, protecting MRs from identified and summarized in Table 1. This review focuses its effects (8). on MC replacement in adult patients with autoimmune Fludrocortisone (FC), a synthetic MC used in PAI for adrenalitis. replacement treatment, has a fluorine atom attached to the carbon 9 position that protects the molecule from b Aldosterone Secretion and Regulation rapid conversion by 11 -HSD2. FC exhibits 10-fold higher MC potency than aldosterone (24, 25). Different Aldosterone was discovered in the more GCs have different MC activity (26). Published compar- than 60 years ago (17). Subsequently, it was recognized ative data on MC potency of steroids are scanty. Hy- as a potent stimulus for sodium reabsorption, acting on drocortisone (HC), the most frequently used short-acting the distal segment of the convoluted tubule in the kidney. GC in PAI, exhibits the highest MC potency (24). Oelkers Aldosterone mediates its effects by the MC receptor et al. (11) defined the MC potency of 1 mg FC as 1 MC unit (MR), a member of the nuclear receptor superfamily (MCU). Because the MC potency of HC is about 1/400th widely expressed in tissues not only involved with salt that of FC, 0.4 mg HC may be regarded as 1 MCU (11). balance, including kidney, brain, lung, colon, and sali- Therefore, 15 to 25 mg of HC, the current recommended vary and sweat glands (18). daily dose in PAI (9), corresponds to approximately 0.04 Aldosterone secretion is mainly regulated by the RAAS to 0.06 mg of FC (11, 24). and the potassium ion, whereas ACTH and other pro- A study that investigated the effect of higher vs lower opiomelanocortin peptides are minor modulators (8, 19) GC replacement dose (30 to 40 vs 15 to 20 mg HC/d) on (Fig. 1). Therefore, aldosterone secretion is not impaired the RAAS and blood pressure (BP) in patients with SAI in SAI (4, 19). The MR, upon binding with aldosterone, is showed an increase in BP and a decrease in renin, al- transferred to the cell nucleus where the ligand-receptor dosterone, and potassium levels in the group on the complex interacts with hormone-responsive elements, higher dose (27). These findings are consistent with modulating transcription (8, 18). activation of the MR by HC, suggesting that MC Aldosterone, however, mediates its actions not only substitution may be superfluous in patients using via the “classic” transcriptional mechanisms but also higher doses of HC (30 to 40 mg/d). By contrast, pa- through “rapid” (,15-minute) mechanisms, described as tients treated with synthetic GCs require higher FC nongenomic signaling of MC (20). Therefore, these ef- doses as prednisolone exhibits fourfold lower MC fects seem to be independent of MRs and are mediated by activity than HC and dexamethasone does not exert Gprotein–coupled estrogen receptors (GPERs) (20, 21). any MC activity (26). 378 Esposito et al Mineralocorticoid Replacement in PAI J Clin Endocrinol Metab, February 2018, 103(2):376–387

Table 1. Summary of Studies Investigating MC Substitution in Patients with PAI

No. of PAI Reference Patients Mean Age (y) Etiology of PAI (No. of Patients) Findings Population-based studies Dalin et al. (9) 660 51.5 Autoimmune PAI (660) FC replacement used by 89% of the patients Median FC dose: 0.1 mg/d (range, 0.014–1.0 mg/d) No sex or age differences in the prevalence of FC replacement (P = 0.96) or daily FC dose (P =

0.56) Downloaded from https://academic.oup.com/jcem/article/103/2/376/4630430 by guest on 26 September 2021 No association between daily FC dose and prevalence of hypertension, hyperlipidemia, or T2DM Erichsen et al. (10) 426 53 (18–95) Autoimmune PAI (426) Mean FC dose: 0.1 mg/d Persistent salt craving and postural dizziness were reported in 24% and 15% of treated patients, respectively, suggesting possible chronic MC underreplacement. Dose-monitoring studies Oelkers et al. (11) 45 NA Autoimmune PAI (37) To evaluate PRA as an index of adequacy of MC substitution, PRA and plasma electrolytes were assessed in a subgroup of 15 patients, at least 5 times, once in the untreated state and during substitution with HC and increasing dosages of FC. Adrenal tuberculosis (4) PRA correlated better with MC dose than plasma potassium and sodium levels. Adrenoleukodystrophy (2) PRA was titrated to the upper normal range between 3 and 10 ng/mL/h (0.288–11.01 ng/ mL/h) to achieve the optimal individual MC dose. Other adrenal disorders (2) Smith et al. (12) 10 41 (25–65) Autoimmune PAI (9) Nine patients with PAI had low sodium and PV levels with high levels of PRA (16.0 6 7.9 ng/mL/h) on 0.05–0.1 mg/d of FC. PV levels were measured by means of a standard dose of 125I- labeled albumin with a 10- minute equilibration time. Bilateral adrenalectomy for When the dose was increased to Cushing disease (1) 0.3 mg/d, there was a fall in PRA (7.0 6 2.7 ng/mL/h). Most patients required 0.2 mg/d of FC to maintain adequate sodium and potassium balance (140.5 6 3.2 and 3.6 6 0.12 mmol/L, respectively) at long-term follow-up. Flad et al. (13) 22 39.9 6 4.4 (6SEM) Autoimmune PAI (18) Optimal FC replacement was associated with mildly elevated PRA levels. Bilateral adrenalectomy for The time of day for blood Cushing disease (3) Isolated sampling was not critical for (1) assessment of PRA level. (Continued) doi: 10.1210/jc.2017-01928 https://academic.oup.com/jcem 379

Table 1. Continued

No. of PAI Reference Patients Mean Age (y) Etiology of PAI (No. of Patients) Findings Thompson et al. (14) 8 NA Autoimmune PAI (3) FC replacement therapy was inadequate in two patients based on PRA levels. In four others, PRA remained normal throughout the study even after FC had been discontinued, suggesting that the drug was unnecessary for the

maintenance of normal Downloaded from https://academic.oup.com/jcem/article/103/2/376/4630430 by guest on 26 September 2021 electrolyte balance. Adrenal tuberculosis (2) FC overtreatment was indicated by low plasma potassium levels. Undetermined (3) PRA failed to distinguish between adequate and excessive MC replacement. Cohen et al. (15) 14 43.5 (22–69) NA Fourteen patients receiving their usual GC doses were placed on different FC doses (0, 0.05, 0.1, and 0.2 mg/d) for four 2-week periods. PRC was significantly elevated in patients receiving placebo (54.2 6 57.9 ng/mL/h) compared with those receiving a baseline dose of FC 0.05–0.3 mg/d (24.7 6 42.4 ng/mL/h), 0.1 mg FC (15.2 6 25.9 ng/mL/h), or 0.2mgFC(5.56 5.7 ng/mL/h). PRC is of value in determining MC underreplacement, whereas ANP is a more sensitive index of FC overreplacement. Jadoul et al. (16) 22 50 (28–74) Autoimmune PAI (17) Mean PRA was 3 times the Adrenal tuberculosis (5) upper limit of normal (9.1 6 7.1 ng/mL/h), and mean PV was decreased (87% 6 11%) despite conventional treatment with both FC and cortisone acetate. Inverse correlation between PRA and PV. No correlation between PV and either SBP or DBP. PRA correlated with SBP but not DBP.

Abbreviations: ANP, atrial natriuretic peptide; DBP, diastolic blood pressure; NA, not available; PV, plasma volume; SBP, systolic blood pressure; SEM, standard error of the mean; T2DM, type 2 diabetes mellitus.

Conversely, FC exhibits GC activity, binding to the doses between 0.075 and 0.3 mg inhibited the HPA GC receptor with high affinity. In vitro studies reported response to corticotrophin-releasing hormone (29). Con- that FC exhibited a 10-fold higher GC potency than that versely, 0.05 mg of FC did not modify the corticotrophin- of cortisol (26). Recent clinical trials seem to support this releasing hormone–stimulatory effect on both ACTH hypothesis, showing that FC exerts an inhibitory effect on and cortisol, suggesting that FC exerts inhibitory ac- the hypothalamic-pituitary-adrenal (HPA) axis. Admin- tion on the HPA axis in a dose-dependent manner (29). istration of 0.5 mg of FC in healthy subjects inhibited However, in a study including patients with PAI, 0.1 mg nocturnal HPA axis activity by reducing nighttime cor- of FC did not show any inhibitory effect on ACTH tisol and ACTH levels (28). Administration of FC in secretion (30). 380 Esposito et al Mineralocorticoid Replacement in PAI J Clin Endocrinol Metab, February 2018, 103(2):376–387

vasopressin secretion that leads to worsened hyponatremia. Furthermore, arginine vasopressin secretion may be further increased by GC deficiency (33). Although hyponatremia may also be detected in SAI, hypovolemia, hyper- kalemia, and metabolic acidosis are only observed in PAI, specifically reflecting MC deficiency (33). Adrenal failure seems to progress through four stages of functional im- Downloaded from https://academic.oup.com/jcem/article/103/2/376/4630430 by guest on 26 September 2021 pairment with stage 1 being character- ized by elevated plasma renin activity (PRA) and inappropriately normal or Figure 1. Diagrammatic representation of aldosterone secretion and systemic aldosterone low aldosterone levels (34). In stage 2, a actions. Aldosterone secretion is mainly regulated by the RAAS and the potassium ion. low cortisol response after stimulation + + Aldosterone induces Na and water reabsorption in exchange for K in the distal tubule is detected. Increased ACTH and low and collecting duct of the nephron. Aldosterone is also involved in regulating cardiac remodeling, arterial stiffness, and inflammatory process that follows tissue injury. Renal basal cortisol are distinctive signs in excretion of K+ and Na+ is regulated by several feedback loops within the RAAS. A “short” stages 3 and 4, respectively (34). Al- feedback loop inhibits renin production when sufficient quantities of angiotensin II are dosterone levels and PRA should be formed, whereas a “long” feedback loop regulates changes in volume and BP. Increases in potassium levels stimulate aldosterone production independently of the RAAS. Graphics assessed in all patients with clinical courtesy of www.MedicalGraphics.de under Creative Commons CC BY-ND 3.0 DE license, suspicion of PAI, because MC deficiency and courtesy of Servier Medical ART under Creative Commons CC BY 3.0 license. may be the only sign of adrenal failure in the early stage. In reviewing MC re- Clinical and Biochemical Features of MC placement in PAI, we acknowledge that, in some cases, Deficiency in PAI MC secretion may not be impaired. Both PRA/active renin and aldosterone measurements Common clinical features of PAI are usually nonspecific, have several laboratory challenges with a lack of inter- including weakness, anorexia, depression, anxiety, and nationally accepted standard reference range; therefore weight loss (31). Patients may have episodes of vomiting, interpretation depends on local reference interval provided abdominal pain, and diarrhea, often leading to false di- by the laboratory report (3). A few studies have suggested agnosis of gastrointestinal or psychiatric disease (32). to assess aldosterone response to ACTH stimulation test Hyperpigmentation of the skin and mucous membranes (11); however, current guidelines only recommend basal is a more specific sign due to increased ACTH secretion and melanocortin levels, which is synthesized with ACTH from pre–pro-opiomelanocortin (3). Orthostatic hypo- Table 2. Clinical Features in PAI tension, salt craving, and hyperkalemia are more spe- cifically related to the MC deficiency (Table 2) (10). Frequency (%) A Norwegian population-based observational study Findings At Onset On Therapy reported that hyperpigmentation was present in 74% of Symptoms the patients, hypotension in 64%, and salt craving in Fatigue 95 24 68% at onset (Table 2) (10). The frequency of all symp- Loss of appetite 67 3.6 Salt craving 64 24 toms was markedly reduced after replacement therapy Nausea, vomiting, 62 9.5 (10). However, 24% of treated patients still reported salt or abdominal pain craving and 15% postural dizziness, suggesting that the Postural dizziness 56 15 Muscle pain 40 21 MC replacement may have been inadequate. Because Diarrhea 23 7.3 patients do not report salt craving unless specifically Constipation 10 5.9 asked about it, this symptom is probably underestimated Signs Hyperpigmentation 74 16 in medical textbooks, which report frequencies of 12% to Weight loss 73 3.8 19% (4, 10). Low BP 68 12 Aldosterone deficiency leads to hyponatremia, hypo- Electrolyte disturbances 35 4 volemia, and hypotension, with associated hyperkalemia Anemia 13 3.8 and acidosis. Hypovolemia is a strong stimulus for arginine Adapted from Erichsen et al. (10). doi: 10.1210/jc.2017-01928 https://academic.oup.com/jcem 381 renin and aldosterone measurement (3, 4). All patients Current replacement therapy consists of 0.05 to with confirmed MC deficiency should receive MC re- 0.2 mg of FC (4) given once daily in the morning, as placement therapy, whatever the etiologic cause of damage physiological aldosterone secretion follows a circadian to the adrenal glands (3). rhythm similar to that of cortisol, with peaks at 8:00 AM MC deficiency may also occur in isolated hypo- and nadirs at 11:00 PM (43). A Swedish population-based aldosteronism due to aldosterone synthase deficiency. observational study reported that MC replacement was Assessment of PRA and aldosterone levels is a valuable used by 89% of all patients with PAI, with a median FC tool for diagnosis of this rare congenital disease (8). dose of 0.1 mg/d (range, 0.014 to 1.0 mg/d) (9). Previous analysis of 664 patients with PAI from Norway had Current Treatment and Outcomes shown that the mean dose of FC was 0.1 mg/d (10). The available forms of FC preparation include 0.1- Downloaded from https://academic.oup.com/jcem/article/103/2/376/4630430 by guest on 26 September 2021 A synthetic MC, desoxycorticosterone acetate, was and 0.05-mg tablets that need to be refrigerated according identified in 1937 and introduced for treatment in 1939. to the new formulation instructions (e.g.,forFlorinef), FC, the currently used MC, was discovered and patented even though the decay rate is as low 0.1% over the first 15 years later (31). Since then, few studies aimed at 6 months at room temperature (25). optimizing MC treatment have been published. FC is quickly absorbed and converted to 9a-fluorocortisol, Long-term outcome in PAI on conventional treatment the active molecule. Maximal plasma concentration of was for a long time considered similar to that of healthy FC occurs 90 to 120 minutes after intake and mean subjects (5, 7). Recent studies, however, have shown that plasma half-time is 4.9 hours. Therefore, FC is suitable morbidity is high, life expectancy is reduced mainly due to for once-daily administration. FC is mainly eliminated by cardiovascular diseases (35, 36), and quality of life (QoL) urinary excretion (25). is impaired (37, 38). Whether the poor outcome in PAI is The starting FC dose consists of 0.05 to 0.1 mg daily related to nonphysiological GC replacement, inadequate (3), which is then titrated in steps of 0.025 to 0.05 mg (3, MC substitution, or the underlying conditions per se has 4) (Fig. 2). A higher dose (up to 0.5 mg daily) is needed in not been explained and requires further studies. newborns and children, because their MC sensitivity is Throughout the last two decades, several efforts have lower compared with adults, as well as in the last tri- been performed to optimize GC treatment (37, 39), al- mester of pregnancy, when high levels of progesterone though MC replacement treatment has received little may counteract the effects of MC (4, 25, 44). Otherwise, attention. The current standard replacement consists of dose adjustments are rarely recommended, but this should FC (0.05 to 0.2 mg) given once daily in the morning (3, probably be done more often. Temporary dose increments 39). It is widely recognized that the majority of patients of 50% to 100% may however be recommended in hot with PAI use higher-than-recommended doses of GC climates and conditions that promote excessive sweating, based on endogenous production (9). It may be specu- such as long-lasting exercise (3, 11, 45). Medications that lated that one of the reasons for GC overreplacement may affect BP and electrolytes, including diuretics, acet- be due to inadequate MC replacement (12, 40). Symptoms azolamide, carbenoxolone, NSAIDS, and drospirenone, and signs indicating chronic underreplacement of FC are might necessitate FC dose adjustments (4). Liquorice the persistent salt craving and postural dizziness reported potentiates the MC effect of HC and should be avoided. by 24% and 15% of treated patients, respectively (Table 2) Glycyrrhetinic acid and its metabolite glycyrrhizic acid, (10). In addition, it has been demonstrated that cognitive present in liquorice, are inhibitors of 11b-HSD2, which function and mood in PAI are in part related to MR oc- plays a crucial role in protecting MRs from GC acti- cupation (41); therefore the low QoL in PAI may also vation (46). suggest inadequate MC substitution. Monitoring MC Dosing Regimens Patients with PAI require lifelong steroid therapy, and monitoring is critical to avoid under- or overreplacement. Current replacement therapy MC replacement should be assessed clinically by mea- The synthetic MC, 9a-FC, is used as replacement suring BP, inquiring about salt craving, and identifying therapy in PAI, because neither of the two natural MCs, the presence of peripheral edema, although the latter has 11-deoxycortisol or aldosterone, is suitable (4). The low sensitivity (3). However, more objective markers are former was administered as subcutaneous or intramus- needed. Some biochemical markers appear useful to guide cular injection in sesame or peanut oil, but is not used MC replacement. Sodium, potassium, and PRA/plasma anymore (42). The latter has a rapid hepatic inactivation renin concentration (PRC) levels are valuable tools, al- and a short half-life (25). though data supporting their usefulness are limited. MC 382 Esposito et al Mineralocorticoid Replacement in PAI J Clin Endocrinol Metab, February 2018, 103(2):376–387 Downloaded from https://academic.oup.com/jcem/article/103/2/376/4630430 by guest on 26 September 2021

Figure 2. Suggested flowchart for administration and monitoring of MC replacement in PAI. replacement should aim at normotension, normokale- FC dose (12). The time of the day for blood sampling is mia, and PRA/PRC in the upper normal range (4, 11). not critical, because PRA/PRC levels do not significantly PRC has mostly replaced PRA in clinical practice. It is fluctuate throughout the day (13). known that GC may modify plasma angiotensinogen Some studies have raised doubts about MC moni- concentration, which may increase PRA. Reid et al. (47) toring by measuring PRA levels. Thompson et al. (14) demonstrated that changes in angiotensinogen levels observed eight Addison patients on constant intake of GC had an influence on PRA but not on PRC in adreno- and different doses of FC, evaluating PRA, BP, and po- lectomized dogs. Therefore, assessment of PRC may be tassium levels after 2-week periods on each FC dose. more reliable than PRA in the management of PAI. Interestingly, PRA remained normal throughout the However, a formal comparison between PRA and PRC study in four patients even after FC withdrawal, sug- has not been performed. gesting that the MC substitution was unnecessary for the Published data on the ideal PRA/PRC level in patients electrolyte balance. FC overtreatment was indicated by with PAI are scanty (Table 1). Smith et al. (12) assessed low potassium but not by PRA levels, which failed to MC substitution in 10 patients with PAI, evaluating identify excessive MC substitution (14) (Table 1). electrolytes levels, PRA, and plasma volume (PV). The Cohen et al. (15) suggested that PRC is of value in latter was measured by means of a standard dose of determining MC underreplacement, whereas plasma 125I-labeled albumin with a 10-minute equilibration atrial natriuretic peptide (ANP) is a more sensitive index time. Nine of 10 patients were sodium depleted, with a of FC overreplacement. ANP is a marker of sodium and mean PV 11% below predicted and high levels of PRA water status. It is secreted in response to an increase in despite receiving 0.05 to 0.1 mg/d of FC. There was a intravascular volume. ANP may be complementary to decrease in PRA and in potassium and an increase in PV PRC in the individualization of FC doses. However, both when a daily dose of 0.3 mg of FC was administered. PRC and ANP exhibit high variability, depending on Most patients required 0.2 mg/d to maintain adequate other factors such as sodium intake and renal function. electrolyte balance, PV, and PRA within the normal The clinical utility of these measurements should not be range (12). Oelkers et al. (11) showed that PRA cor- overestimated and they should be evaluated together with related better with the MC dose than potassium and clinical findings (15). sodium levels alone if PRA was targeted in the upper High BP, rapid weight gain, and hypokalemia indicate normal range (Fig. 3). overtreatment. Conversely, weakness, postural hypo- The prolonged administration of MCs produces an tension with a postural drop in arterial BP .20 mm Hg, escape phenomenon from the salt-retaining effect, and a weight loss, dehydration, salt craving, hyperkalemia, and new steady state is obtained after approximately 1 week high PRA/PRC levels indicate undertreatment and the (48). Therefore, electrolyte levels and PRA/PRC should need to adjust the FC dose because underreplacement be monitored not earlier than 1 or 2 weeks after changing may predispose to adrenal crises (Fig. 2). In fact, salt doi: 10.1210/jc.2017-01928 https://academic.oup.com/jcem 383

However, bearing in mind the direct cardiovascular effects of MC through its receptor and the nongenomic action through GPER, MC replacement may also have an important role in a compromised outcome among patients with PAI.

Hypertension Hypertension has been reported in 14% of patients with PAI (9). There is a Downloaded from https://academic.oup.com/jcem/article/103/2/376/4630430 by guest on 26 September 2021 lack of evidence to guide management of MC replacement in this condition. Conversely, the pathophysiological role of aldosterone in essential hypertension has been studied extensively. Aldoste- rone increases BP, exerting its effects on vasculature, brain, heart, and kidneys (19, 51) (Fig. 1). It enhances sympa- thetic nervous system activity, reduces vascular compliance and endothelial- derived vasorelaxation, and increases extracellular volume. There is consid- erable experimental evidence that al- dosterone increases left ventricular (LV) mass and cardiac output and con- tributes to the development of nephro- sclerosis and renal fibrosis (19, 51) (Fig. 1). Exogenous administration of MC has induced lesions of malignant hypertension and stroke in a rat model (52). Conversely, MR antagonists re- duce BP and promote beneficial effects on myocardial fibrosis in patients with hypertension (22, 53). In accordance with this evidence, reduction or even withdrawal of MC replacement has been suggested in patients with PAI that develop hyper- Figure 3. Relationship between MCU (MC potency of 1 mg of FC) and potassium, sodium, tension (16). However, an inappro- and PRA levels in 15 patients with PAI. At least five measurements on different FC dosages were available for each patient. The normal range of PRA was established to be 0.3 to priate decrease or cessation of FC dose 1.8 ng/L/s (1.0 to 6.5 ng/mL/h). Reproduced from Oelkers et al. (11). in euvolemic patients may lead to re- duced PV with consequently increased depletion and consequent hypovolemia are reported to be angiotensin II, exerting an important vasoconstrictor strong triggers for adrenal crises (4). effect that may worsen the hypertension (11, 19, 54) (Fig. 1). Therefore, when a patient with PAI develops MC Replacement and hypertension, MC replacement should not be withdrawn, Cardiovascular Disease but an attempt to optimize both MC and GC replacement should be performed (3, 54). The relative risk of death in PAI is increased and is Supraphysiological doses of GCs may lead to hyper- predominantly related to cardiovascular disease (36). tension independently of any effect on MRs (55). Ad- Supraphysiological doses of GCs increase the preva- ministration of four different synthetic GCs at doses lence of risk factors for cardiovascular disease (49, 50). calculated to be similar for GC activity, but which had 384 Esposito et al Mineralocorticoid Replacement in PAI J Clin Endocrinol Metab, February 2018, 103(2):376–387 low or no MC potency, to six healthy subjects for 5 days echocardiography and electrocardiographic analysis. showed a significant BP increase with all steroids (55). A Heart weight and LV mass were significantly elevated in further study found a significant positive association 6-month adrenalectomized mice, whereas LV function between the HC equivalent dose and the incidence of was significantly decreased when compared with con- hypertension; conversely, no association was found be- trols. Moreover, genome-wide microarray analysis was tween the FC dose and hypertension (9). Buning et al. (27) performed on hearts from 6-month adrenalectomized determined the effects of a higher vs a lower HC re- and control mice, showing an aberrant expression of a placement dose (0.2 to 0.3 mg vs 0.4 to 0.6 mg HC/kg large number of genes associated with cardiovascular body weight) on BP, showing that the higher dose led to disease 6 months after surgery (64). Because PAI di- significant increase in BP. agnosis is often delayed, with the half of patients re- According to these findings, the GC dose should be ceiving the diagnosis more than 1 year after the onset of Downloaded from https://academic.oup.com/jcem/article/103/2/376/4630430 by guest on 26 September 2021 optimized as the first therapeutic step in patients with PAI symptoms (32), we can theorize that patients with PAI and hypertension. Once GC replacement has been ad- may exhibit an aberrant expression of genes associated justed, assessment of electrolytes and PRA/PRC should be to cardiovascular abnormalities that may lead to higher considered to evaluate MC substitution. If signs or cardiovascular comorbidity and mortality, possibly symptoms of overtreatment are detected, the FC dose independently of subsequent replacement therapy. should be reduced (54). If BP is still high, antihyperten- A small case series has reported a high incidence of HF sive medications should be considered in line with in- in PAI, with seven out of 22 patients with PAI developing ternational guidelines (3, 4, 54). A formal comparison HF over 30 years of follow-up (65). The HF was managed between the available antihypertensive agents remains with administration of diuretics in three patients, FC unexplored. However, diuretics, especially aldosterone reduction in five, and FC withdrawal in one. After this antagonists, such as spironolactone or eplerenone, have study, only case reports or smaller case series have been potential adverse effects on PV and potassium excretion published describing HF in PAI, and congestive HF has and should be avoided (54). Because the majority of not been a leading cause of death in epidemiological antihypertensive treatments affect the RAAS, monitor- studies of PAI (9, 10). ing of renin levels is less helpful to guide MC substitu- Isolated case reports have also described acute HF tion when these antihypertensive drugs are being used resulting from FC administration in patients with PAI, (54, 56). with clinical resolution after its withdrawal (66–68). Six cases of PAI with coexisting dilated cardiomyopathy have HF been recently reported (69). Four patients were able to There is considerable experimental and clinical evi- tolerate a careful balance of FC and medical treatments dence that aldosterone and angiotensin II promote cardiac for HF, one needed FC withdrawal, and one was only on fibrosis by inducing myofibroblast proliferation and ac- GC replacement without FC before HF developed (69). cumulation of collagen (19, 51–53, 57–59) (Fig. 1). High No study has so far investigated how to manage MC aldosterone levels are associated with an increased mor- replacement treatment in HF in patients with PAI. tality rate in cohorts of patients with HF (60). Prolonged Therefore, in line with international guidelines for HF, exposure to high aldosterone concentrations have a del- angiotensin-converting enzyme inhibitors, angiotensin II eterious effect on cardiovascular tissues, leading to LV antagonists, or beta-blockers should be used (70). The use hypertrophy, diastolic dysfunction, and cardiovascular of MR antagonists and or discontinuation of FC should events independently of BP (61, 62). The frequency of be decided on an individual basis. Careful hemodynamic cardiovascular events, including nonfatal myocardial in- monitoring is needed, because treatment of HF may in- farction and HF is also higher in patients with primary terfere with the action of FC. aldosteronism than in properly matched controls with essential hypertension, supporting the detrimental effects Conclusions of excessive aldosterone exposure (63). On the other hand, little is known about cardio- The impact of MC replacement in PAI has been sys- vascular abnormalities when adrenal steroids secretion tematically investigated in only a few studies with limited is impaired. Cruz-Topete et al. (64) have evaluated the number of patients (Table 1). The current MC replacement effects of long-term adrenalectomy on cardiac function in PAI may not be adequate in some patients because there in experimental models. Animals were adrenalecto- are data suggesting that many patients with PAI are mized at 1 month of age and maintained on 0.154 M underreplaced and compensated for by overreplacement saline for 3 to 6 months after surgery. The chronic effects with GCs. Long-term outcome in PAI on conventional of GC and MC deficiency were assessed by transthoracic treatment have shown that morbidity remains high and life doi: 10.1210/jc.2017-01928 https://academic.oup.com/jcem 385 expectancy is reduced, mainly due to cardiovascular E, Landin-Olsson M, Elfving M, Waldenstrom ¨ E, Hulting AL, events. In addition, these patients still show a significantly K¨ampe O, Bensing S. Clinical and immunological characteristics of autoimmune Addison’s disease: a nationwide Swedish multicenter compromised QoL despite their replacement therapy. study. J Clin Endocrinol Metab. 2017;102(2):379–389. Over the last two decades, various approaches have been 10. Erichsen MM, Løvas˚ K, Skinningsrud B, Wolff AB, Undlien DE, undertaken to optimize GC treatment (e.g., reducing the Svartberg J, Fougner KJ, Berg TJ, Bollerslev J, Mella B, Carlson JA, Erlich H, Husebye ES. Clinical, immunological, and genetic fea- overall daily cortisol exposure), trying to mimic the tures of autoimmune primary adrenal insufficiency: observations physiological diurnal variation in serum cortisol, whereas from a Norwegian registry. J Clin Endocrinol Metab. 2009;94(12): MC replacement has received little attention. More careful 4882–4890. optimization of MC replacement therapy may be of im- 11. Oelkers W, Diederich S, B¨ahr V. Diagnosis and therapy surveillance in Addison’s disease: rapid adrenocorticotropin (ACTH) test and portance in patients with PAI to restore QoL and improve measurement of plasma ACTH, renin activity, and aldosterone. their long-term outcome. J Clin Endocrinol Metab. 1992;75(1):259–264. 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