Adrenal Suppression and Exogenous Cushing Syndrome After Inhaled and Topical Corticosteroids – Two Clinical Cases and Review of the Subject

The undesirable endocrine effects associated with pharmacological therapy with corticosteroids administered orally or parenterally are well-known in medical practice. However, the degree of vigilance is lower when compartmental corticosteroids are used, and it is a widely held assumption that local glucocorticoids rarely produce adrenal insuffi ciency or exogenous Cushing syndrome. The two cases that we present here demonstrate the appearance of major adrenal suppression and Cushing exogenous syndrome after inadequate use of topical corticosteroids and, the combination of inhaled corticosteroids with nasal glucocorticoids, respectively. The following mini-review shows, from the endocrinologist point of view, the main aspects to be considered by practitioners who recommend local glucocorticoid treatments – i.e. inhaled, topical (cutaneous, oral, nasal, ophthalmic) or intraarticular – to prevent the occurrence of major endocrine syndromes that are met after corticosteroid therapy, tertiary adrenal insuffi ciency and exogenous Cushing syndrome.


INTRODUCTION
Corticosteroid (CS) therapy is used by 1% of world population, especially for non-endocrinological indications. Compartmental administration of CS (i.e. topical, inhaled or intraarticular) was developed to prevent undesired eff ects. Still even these therapies could generate major endocrine syndromes, as our two cases tend to illustrate - Table 1 and Table 2.  Table 2. Case no. 2 description TC, male, born in 1960, was evaluated in May 2016, referred by rheumatologist after radiological evidences of vertebral crushes. Patient, a trained athlete, with psoriasis from the age of 26 was exposed the last two years to intense local glucocorticoid (GC) therapy -daily applications and weekly occlusive therapy ("wrapping") with a highly potent topical agent, class I, clobetasol-propionate cream 0.05% using an average of 200-225 g/week, i.e. 14mg clobetasol/day. 2016, May. Clinical Exam: Height=179 cm; Weight=124Kg; Bodymass index=38.7 Kg/m2; heart rate=68/min, regular; blood pressure = 140/95 mmHg; plethoric facies; Cushingoid fat redistribution and muscular wasting at the level of proximal groups; thin skin, with widespread exfoliation and areas of atrophy at abdominal level, antero-axillar striae and on the flanks; facial telangiectasia and ecchymosis of various ages on the arms and forearms; psoriatic lesions on elbows, knees, legs and the anterior wall of the abdomen; varicosities at the lower members, with stasis dermatitis and venous ulcer on the external part of the right leg.

LOCAL (COMPARTMENTAL) GLUCOCORTICOID ADMINISTRATION -ENDOCRINOLOGIST MINI-REVIEW
According to the pharmaceutical route of administration glucocorticoid (GC) therapy can be divided in: (a) systemic: oral, intravenous, intramuscular, and subcutaneous; (b) local or compartmental: topic (cutaneous, nasal, ophthalmic); inhaled; intraarticular. Th e therapeutic index for GC depends on the systemic absorption of the drug, the metabolism (renal and/or hepatic clearance) and the degree of plasma protein binding.
Topical GC are used for a large spectrum of dermatological conditions and show a great variability in terms of bioavailability and pharmacokinetics (e.g. the fl uorinated compounds, dexamethasone, triamcinolone, betamethasone, and beclomethasone are better absorbed through skin than the unfl uorinated agents like hydrocortisone). Topical GC can be classifi ed according to their potency and the capacity to inhibit HPA axis - Table 3 [based on World Health Organization (WHO) classifi cation]. As a rule, higher dermatological potency will result in higher degree of HPA axis suppression and risk for adrenal insuffi ciency (AI). Super-active agents such as clobetasol ointment 0.05% can produce HPA suppression at doses as low as 2g/ day and can result in Cushing syndrome at doses larger than 50 g/week (our patient in case no. 1 using 200 g/ week). Pharmacological estimation showed that daily topical use of 20 mg clobetasol (= 40 g ointment clobetasol-propionate 0.05%) have the same systemic eff ect as the daily oral dose of 60 mg prednisone. Accordingly, therapy with clobetasol should not exceed 50 g/ week, no longer than 2 weeks on a row.
Children showed a greater sensibility with HPA suppression demonstrated at doses of 14 g/week clobetasol-propionate or 49 g/week betamethasone-dipropionate 5 . Th ere are reported an increasingly number of cases with HPA axis severely suppressed. In our patient (case no. 1), AI persisted even after 20 months since clobetasol suspension.
Inhaled corticosteroids (ICS), are pivotal to achieve asthma control in both children and adults. In Ta-

ENDOCRINE EFFECTS OF COMPARTMENTAL GC ADMINISTRATION
Th e undesired side eff ects after compartmental GC administration could be local, specifi c to type of therapy and systemic, common to all types. Th e endocrine systemic eff ects are: (1) HPA axis suppression; (2) exogenous Cushing syndrome.

(1) HPA axis suppression and adrenal insuffi ciency
GC therapy is the most common cause of adrenal insuffi ciency (AI). GC administration decrease hypothalamic corticoliberin (CRH), as well as pituitary adreno-corticotropic hormone (ACTH) production and induce adrenocortical cells functional inhibition and atrophy. GC use in a dose larger than the equivalent of 20 mg prednisone/day for more than 3 weeks can induce HPA-axis suppression. When are taken at the bed-time even doses of ≥5 mg prednisone/day can induce suppression 12 . Adrenal suppression was documented both after oral GC and after ICS 13 . In a study of HPA function after systemic GC use in 3166 patients, the median prevalence of AI was 37% and the recovery of the normal function occurred in 58.8% patients 1-2 years after systemic GC withdrawal 14 . In a recent study with 404 patients taking oral, topical, intranasal or inhaled GC therapy, 33.2% had a subnormal short Synacthen stimulation test (SST) response 15 . In a meta-analysis conducted on 3753 subjects exposed to ble 4 ICS are sorted according with potency and HPA suppression. One ICS with higher potency needs lower inhaled daily dose for equivalent effi cacy. Th e schematic pharmacokinetic of ICS: (a) -60-90% of the inhaled drug remains in pharynx and it is swallowed; from gut, it is absorbed and inactivated in liver at the fi rst-pass by enzymes linked with CYP3A 2 . Inhibitors for CYP3A cytochrome increase the GC levels and amplifi es systemic eff ects (moderate inhibitors, e.g. diltiazem; tibolone; dronedarone; amiodarone; mifepristone; erythromycin; fl uconazole; grapefruit juice, and strong inhibitors, e.g., ceritinib; indinavir; clarithromycin; itraconazole; ketoconazole). Ciclesonide, fl uticasone and mometasone are virtually completely metabolized, while 11% budesonide and 20-40% beclomethasone escapes the fi rst-pass and reach the systemic circulation. Th erefore, it is better to select one ICS with greater hepatic clearance. (b) -10-40% of the inhaled drug reach the respiratory system and then delivered into circulation (e.g. 20% of inhaled fl uticasone).
In terms of prednisolone equivalency, adrenal suppression with a large dose of budesonide (1000 ug per day) was estimated to be as high as with 8.7 mg of prednisolone 8 . Important dose-eff ect relationship between ICS and urinary cortisol suppression was documented with beclomethasone (8.4% per 100 μg; p =0.029), followed by fl uticasone (3.2% per 100 μg; p <0.001), and budesonide (3.1% per 100 μg; p= 0.001); no signifi cant suppression was associated with ciclesonide 9 . Pharmacological properties of ciclesonide made it the safest ICS [i.e. -160-600 ug/day ciclesonide didn't aff ect cortisol level] 10 . Th e highest risk for adrenal suppression is encountered in children, especially when ICS was fl uticasone 11 , if the ICS were used for more than  until cessation OR testing with SST and stop the GC whenever the test is normal. Proposed algorithm for HPA assessing for practitioners using GC therapysee Table 6. Adrenal crisis is a medical emergency. Adrenal crisis in tertiary AI occur after abrupt discontinuation of GC. Th e frequency of adrenal crisis is higher in tertiary AI, i.e. 15.1 cases in 100 patients/year, than in primary AI, 5.2 cases, or secondary AI, 3.6 cases in 100 patients/year 20 . In Table 7 are presented the updated criteria for diagnosis of adrenal crisis and basic treatment measures.

(2) Exogenous Cushing syndrome
Exogenous Cushing syndrome is the most common form of Cushing syndrome. Th e main features and resemblances with endogenous Cushing syndrome are listed in Table 8. In children, fi rst signifi cant undesired eff ect associated with GC use is diminished linear growth, encountered even with short-term ICS (i.e. 7 days) if high-doses are used 22 .
Glucocorticoid-induced osteoporosis (GIO) is one of most important feature of exogenous Cushing syndrome and the most frequent form of iatrogenic osteoporosis. GC eff ects on bone result in 2 phases: fi rst systemic or local GC, the percentages of tertiary AI were: 48.3% -after systemic GC; 6.8% -after ICS; 4.7% -after topical corticosteroids; 4.2% -after intranasal GC; 52.2% -after intraarticular GC 16 . Th e combined GC therapy (i.e. ICS and intranasal GC) resulted in a higher risk of HPA suppression (e.g. an 19% excess). In a recent article, 61% of patients with adrenal suppression after systemic GC had normal SST after 2 years 17 . In this study, age, gender, body mass index, indications for GC use, and basal corticotropin levels were not predictive of HPA axis recovery; one useful fi nding was that early morning cortisol of 8.8μg/dL predicted a positive SST response.
Specifi c factors for prediction of HPA suppression after local GC are in Table 5.
Th e basic principle for the GC withdrawal is to avoid sudden discontinuation. Instead, the daily dose gradually decreases with 2.5 mg prednisone/day every 3-4 days, until are reached physiological doses (= equivalent of 5-7.5 mg prednisone/day). Estimations are based on physiological cortisol production 5.7-7.4 mg/m 2 /day, corresponding to a daily dose of 10-15 mg hydrocortisone/m 2 /day, orally or 6-8 mg/m 2 /day, intravenous, lower than previously thought 18 . After these doses are reached, taper slower, 1 mg prednisone every 2-4 weeks Step I -Risk estimation Who to screen?
 Cushingoid appearance, OR  suspected AI: weakness, anorexia, nausea, diarrhea, abdominal pain, morning headaches, myalgia, arthralgia, hypoglycemia, hypotension, OR  large ICS doses (i.e. fluticasone or mometasone >400 ug/day; budesonide or beclomethasone >800 ug/day) -for >3 weeks in last 3 months  large topical corticosteroids doses-clobetasol 0.05% >2 g/day or treatment over 2 weeks with >100 g clobetasol /week, OR  association with oral GC >2 weeks continuously or >3 weeks in last 6 months, OR  association with CYP450 3A inhibitors, OR  yearly for any patient using large doses of compartmental GC How to screen?
Step IV -Suppressed HPA axis Cortisol <35 nmol/L (<1.26 ug/dL) → Diagnose adrenal insuffi ciency -no need to perform SST  start substitution therapy or GC; supplements before major surgery;  reduce doses of compartmental GC;  repeat cortisol testing in 3 months.
Note! In patients treated with local GC even excessive amounts, resulting in Cushingoid traits might not result in suffi cient serum concentration in stress situations. That's why local GC withdrawal needs the concomitant use of oral GC with replacement dose and GC supplementation in stressful events. * NOTE. Synacthen is not available in Romania, and insulin-induced hypoglycemia test (ITT), the gold standard for assessing the HPA axis, is cumbersome to use outside endocrinological units. This is the reason why we searched validated basal tests for rapid detection and/or referral of adrenal suppression. HPA = hypothalamic-pituitary-adrenal axis; GC = glucocorticoids; AI = adrenal insuffi ciency; ICS = inhaled corticosteroids; SST = short Synacthen stimulation test. Table 6. Algorithm for HPA-suppression during local GC administration 15,17,19   Plethoric facies In both endogenous and exogenous Cushing Central obesity and fat redistribution. Peripheral myopathy and cardiomyopathy Osteoporosis. Atherosclerosis and thrombosis. Peptic ulceration and digestive bleeding Glucose intolerance and diabetes mellitus. Natrium retention and potassium excretion Psychological changes -lability, insomnia, psychosis, cerebral atrophy Delayed healing. Immunosuppression and lymphopenia; undercurrent infections Diminution of height growth in children FRAX GC-adjusted * ATTITUDE CATEGORY -Adults ≥40 years of age, with GC therapy for ≥ 3 months Low fracture risk -FRAX 10-year risk of major osteoporotic fracture ** <10% and risk of hip fracture ≤1% Prefer optimize calcium intake (0.8-1g/day) and vitamin D intake (600-800 IU/day) and lifestyle modifi cations (balanced diet, smoking cessation, regular weight-bearing or resistance training exercise, limiting alcohol to 1-2 alcoholic beverages/day) over treatment with bisphosphonates, teriparatide, denosumab, raloxifene. Moderate fracture risk -FRAX 10-year risk of major osteoporotic fracture 10-19% or risk of hip fracture 1-3% ORAL BISPHOSPHONATE. Based on cost-effectiveness criteria alendronate and risedronate are preferred. Prefer an oral bis-phosphonate over IV bisphosphonates, teriparatide, denosumab. If oral bisphosphonates are not appropriate, in order: (1) intravenous (IV) bisphosphonates -acid zoledronic; (2) teriparatide *** ; (3) denosumab (4) raloxifene. High fracture risk: Very high-dose GC **** OR FRAX risk of major osteoporotic fracture ≥20% or risk of hip fracture ≥3% OR prior osteoporotic fracture OR hip/spine bone mineral density (BMD) T score ≤ -2.5 in men age ≥50 years or post-menopausal women.

ORAL BISPHOSPHONATE.
Treat with an oral bisphosphonate over IV bisphosphonates, teriparatide, denosumab, or raloxifene. If oral bisphosphonates are not appropriate, in order: (1) IV bisphosphonates [higher risk profi le for IV]; (2) Teriparatide [cost and burden of injections]; (3) Denosumab [lack of safety data in people treated with immunosuppressive agents]; (4) Raloxifene, for postmenopausal women [lack of adequate data on benefi ts (impact on risk of vertebral and hip fractures in GC users) and potential harms (clotting risks, mortality)]. SPECIAL CASES IN THIS CATEGORY Adults age ≥40 years continuing GC treatment who have had a fracture that occurred after ≥18 months of treatment with an oral bisphosphonate or who have had a signifi cant loss of BMD (≥10%/year) → Treat with another class of OP medication (teriparatide or denosumab; or, consider IV bisphosphonate). Adults age ≥40 years who have completed 5 years of oral bisphosphonate treatment and who continue GC treatment and are assessed to be at moderate-to-high risk of fracture → Continue active treatment, with an oral bisphosphonate beyond 5 years or switch to IV bisphosphonate.
CATEGORY -Adults <40 years of age, with GC therapy for ≥3 months Low risk = None of above risk factors other than GC Optimize calcium and vitamin D intake and lifestyle modifi cations over treatment with bisphosphonates, teriparatide, or denosumab. Moderate fracture risk = Hip or spine BMD Z score < -3 OR rapid bone loss (≥10% at the hip or spine over 1 year) + continuing GC at ≥7.5 mg prednisone/day for ≥6 months TREAT WITH AN ORAL BISPHOSPHONATE over calcium and vitamin D alone. Oral bisphosphonate over intravenous (IV) bisphosphonates, teriparatide, or denosumab [oral bisphosphonates preferred for safety, cost, and because of lack of evidence of superior antifracture benefi ts from other medications]. If oral bisphosphonates are not appropriate, in order of preference: (1) IV bisphosphonates; (2) Teriparatide; (3) Denosumab. Estimate the need for sexual hormones therapy in premenopausal women with amenorrhea and in men with hypogonadism.
High fracture risk = Prior osteoporotic fracture(s) * FRAX-GC = FRAX-glucocorticoid adjusted risk -increase the risk generated with FRAX -by 1.15 for major osteoporotic fracture and 1.2 for hip fracture if GC treatment is equivalent >7.5 mg prednisone/day. ** Major osteoporotic fracture includes fractures of the spine, hip, wrist, or humerus. *** Teriparatide is recommended for the failure of bisphosphonate therapy = the occurrence of extra-vertebral fractures or ≥2 vertebral fractures after 12 months of bisphosphonate therapy. **** Very high-dose GC treatment = prednisone ≥30 mg/day and a cumulative dose of >5 g in the past year. equivalent dose/day, <4 weeks of exposure, cumulative dose <0.5 g, and following tapered withdrawal) 26 . Th ere is no clinical guidance for AI occurring after systemic CS and even lesser agreements for AI induced by local GC. Th is data must lead the practitioners using topical, inhaled, or intra-articular GC to an increased alertness level toward the possibility that even compartmental administration could cause signifi cant systemic endocrine eff ects.

Compliance with ethics requirements:
Th e authors declare no confl ict of interest regarding this article. Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008 (5), as well as the national law. Informed consent was obtained from all the patients included in the study. rapid bone mass, 12% in the fi rst 3-12 months followed by a phase of slower bone mass loss, of 2-15% every 12 months. GIO can occur not only after systemic CS, but with ICS 23 and topical GC 24 . One short guide for prevention and treatment of GIO is presented Table 9.

CONCLUSION
It is estimated that approximately 6% of hospitalized patients have GC-induced tertiary AI 25 . In this article, we intended to draw attention to the endocrine eff ects generated by compartmental GC treatments. GC preparations with the so-called local eff ects (e.g. topical, inhaled, intra-articular) have been shown to exert systemic eff ects that can not be neglected, the most important for endocrinologists being exogenous Cushing syndrome and glucocorticoid-induced AI. One meta-analysis showed evidence of AI following low doses and short durations of GC (<5 mg prednisolone