Hypothalamic-pituitary-adrenal Axis Recovery Research Articles

5112 Late-Onset And Reversible Adrenal Insufficiency In Survivors Of Coronavirus Disease 2019: Results From A 24-Month Longitudinal Study

Abstract Disclosure: S.K. Sahoo: None. J.C. Menon: None. S.B. Yadav: None. Purpose We studied the temporal course of hypothalamic-pituitary-adrenal (HPA) dysfunction in patients with corona-virus disease (COVID19). Methods Three-hundred and two patients (median age 54 years [interquartile range 42-64], 76% males, 97 with severe/critical illness) were recruited. HPA axis was evaluated by adrenocorticotrophic hormone (ACTH)-stimulation test (APST) at admission in 243, and 12-months after discharge in 90 patients. Those with adrenal insufficiency (AI) at 12-months were further assessed by APST 6-monthly for recovery of hypoadrenalism. Results The median 0-min cortisol, peak cortisol, and ACTH during COVID19 were 295 (IQR 136-461) nmol/L, 846 (719-1088) nmol/L, and 3.9 (0.8-6.9) pmol/L respectively. AI was present in 21 (8.6%) patients. Plasma ACTH was elevated in five patients with AI, while it was low or inappropriately-normal in rest. Additionally, CIRCI was present in 22% (19/87) patients who had severe illness. At 12-months, AI was seen in 13% (12/90) patients and was hypothalamic-pituitary in origin in all. Nine (75%) of these had late-onset AI, who had normal HPA axis during COVID19. AI diagnosed at admission persisted at 12-months in three patients and resolved in six; the remaining 12 patients were lost to follow-up. The presence of AI at 12-months was independent of severity, and steroid use during COVID19. All the patients showed recovery of HPA axis in ensuing 6-12 months. A lower morning cortisol during COVID19 predicted presence of AI at one year. Conclusion AI was common during acute COVID19 and at 12-months of follow-up. AI can be late-onset, developing after recovery from COVID19. The AI was predominantly hypothalamic-pituitary in origin and resolved in the ensuing 6-12 months. Presentation: 6/1/2024

Glucocorticoid treatment and adrenal suppression in children: current view and open issues.

Glucocorticoids (GCs) are commonly used for several acute and chronic pediatric diseases. However, chronic treatment may result in hypothalamic-pituitary-adrenal axis (HPA) dysfunction. Glucocorticoid-induced adrenal insufficiency (GI-AI) is indeed the most frequent cause of adrenal insufficiency (AI) in children, possibly resulting in a life-threatening event such as adrenal crisis (AC). It is generally underestimated, especially when using non-systemic glucocorticoid formulations. This review aims at summarizing current evidence on the effects of long-term GC treatment on the HPA axis, management of GC tapering and assessment of the HPA recovery. We conducted a narrative review of the relevant literature focusing on pathogenic mechanisms, predictive factors, diagnosis and treatment of GI-AI. All types of GCs, whatever the route of administration, may have suppressive effects on the HPA axis, especially when compounds with higher potency and long half-life are used. Moreover, chronic GC administration is the most common cause of Cushing syndrome in children. In order to overcome the risk of GI-AI, slow withdrawal of GCs is necessary. When approaching the replacement dose, it is recommended to switch to shorter half-life formulations such as hydrocortisone. Assessment of HPA axis recovery with basal and stimulated cortisol levels may help detecting children at risk of AC that may require hydrocortisone supplementation. The management of GI-AI in children is challenging and many areas of uncertainty remain. Improving the knowledge on long-term GC effects on HPA in children, the management of steroid discontinuation and emergency dosing may help preventing GI-AI symptoms and acute hospital admission for AC.

The Glucocorticoid Taper: A Primer for the Clinicians.

Glucocorticoid (GC) therapy can ameliorate debilitating and life-threatening symptoms in several inflammatory/immunological disorders. However, it can also cause significant side effects, especially with higher doses and longer duration of use. Therefore, GCs should be used at the lowest effective dose for the shortest possible time to minimise adverse effects. GC therapy may cause suppression of the endogenous hypothalamic-pituitary-adrenal (HPA) axis and abrupt discontinuation predisposes patients to features of GC-induced adrenal insufficiency. The practice of tapering GC therapy allows for recovery of the HPA axis while minimising the risk of a disease flare-up or symptoms of AI. Moderate-to-high dose GC therapy may be tapered rapidly to near-physiological doses while watching for features of disease reactivation. Once close to the physiological dose, tapering is slower and at longer intervals to allow for recovery of the HPA axis. It is important to use short- or intermediate-acting GC preparations such as hydrocortisone or prednisolone in physiological doses, administered in the morning to mimic the endogenous cortisol rhythm. A general principle to follow is that HPA axis recovery takes longer if the period of suppression has been long. In such cases, tapering should be slower over a few months to even a year. In select cases at high risk of AI or if symptoms appear during tapering, the decision to further taper and discontinue steroids may be based on testing of HPA axis function using basal and/or stimulated serum cortisol. All patients on exogenous steroids should be advised about the need for an appropriate increase in GC doses during acute medical or surgical illness and should carry a steroid alert card to avoid adrenal crisis.

A Retrospective Study on Weaning Glucocorticoids and Recovery of the Hypothalamic-Pituitary-Adrenal Axis.

Glucocorticoids suppress the hypothalamic-pituitary-adrenal (HPA) axis, resulting in tertiary adrenal insufficiency (AI). When weaning patients off glucocorticoids there is no consensus on whether to maintain patients on prednisolone or convert to hydrocortisone. To investigate HPA axis recovery in patients on long-term prednisolone and assess outcome after hydrocortisone conversion. This was a retrospective cohort study at an outpatient endocrine steroid clinic. Patients were on long-term prednisolone and referred for HPA axis testing between 2015 and 2022. The main outcomes measured were (1) HPA axis recovery rate in patients on prednisolone demonstrated by a normal adrenocorticotrophic hormone (ACTH) stimulation test (AST) and (2) HPA axis recovery rate subanalysis of dose-matched patients with confirmed tertiary AI on prednisolone or hydrocortisone were measured. In total, 206 patients on prednisolone were tested for tertiary AI. Of these, 176 remained on prednisolone while 30 were converted to hydrocortisone. The overall HPA axis recovery rate for patients on prednisolone after interval testing was 137/206 (66.5%). The HPA axis recovery rate in dose-matched prednisolone and hydrocortisone conversion groups was 7/10 (70%) and 2/13 (15%) (P = .008), respectively. There was no difference in mean (SD) age (67.1 [12.2] vs 63.4 [11.1] years; P = .464) and baseline cortisol (5.3 [4.2] vs 4.6 [3.1] µg/dL; P = .648) and median [interquartile, IQR] glucocorticoid duration (1213 [1114] vs 2316 [4808] days; P = .693) and baseline ACTH (20.5 [29.0] vs 16.3 [14.8] ng/L; P = .905) between dose-matched prednisolone and hydrocortisone groups. Follow-up duration in the prednisolone group was significantly lower (median [IQR] 348 [975] vs 667 [884] days; P = .012). Patients with glucocorticoid-induced AI maintained on once-daily prednisolone can recover HPA axis function when weaning. There is no apparent advantage to recover HPA axis function in converting to multiple-dosing hydrocortisone.

THU624 Opioid Induced Adrenal Insufficiency (OIAI) Presenting With Altered Mental Status

Abstract Disclosure: D. Bondarenko: None. M. Ahmad: None. G.A. McGrath: None. Background: Opioid suppression of the hypothalamic-pituitary-adrenal (HPA) axis via inhibition of corticotropin releasing hormone secretion leading to secondary adrenal insufficiency (AI) has been described in literature. Biochemical secondary AI is evident in 6-50% of patients on chronic opioids; fewer cases are reported presenting with clinical AI.1 We present a rare case of symptomatic opioid-induced AI (OIAI) with clinical improvement on initiation of hydrocortisone. Clinical Case: A 49-year-old female on daily buprenorphine (20 mg) and naltrexone (5 mg) presented to the hospital with syncope and hypotension (79/49 mmHg). AM cortisol was 6.2 mcg/dL, a cosyntropin stimulation test was performed, but there was technical difficulty with the results. She was started on midodrine 2.5 mg three times daily and referred to outpatient endocrinology for follow up. Weeks later, outpatient cosyntropin stimulation test showed baseline cortisol of 18 mcg/dL with increase to 26 mcg/dL. Simultaneous adrenocorticotrophic hormone (ACTH) was 16.9 pg/mL. AI was ruled out. Seven years later she presented with acute lethargy, confusion, and memory loss over several days. AM cortisol was 1.6 mcg/dL and cosyntropin stimulation test increased cortisol to 15.1 mcg/dL (normal response being 18 mcg/dL or greater). ACTH was 24 pg/mL. The abnormal cosyntropin stimulation test results are consistent with AI, and lack of elevation of morning ACTH is consistent with secondary AI.2 Hydrocortisone therapy was started and midodrine was held due to elevated blood pressure after initiation of steroids. She was discharged on hydrocortisone 15 mg each morning and 5 mg each afternoon. Within 10 days of initiation of glucocorticoid replacement therapy her neurologic symptoms improved and midodrine discontinued. Prescription Drug Monitoring Program (PDMP) review shows reduction of buprenorphine (16 mg) and naltrexone (4 mg). Conclusion: Data on management of OIAI and recovery of the HPA axis with or without cessation of opioid therapy is limited. This case highlights that opioids should be considered as a potential cause of secondary AI. Further follow-up of this case and other OIAI cases would provide insight into management of opioid therapy, continuation of glucocorticoid therapy, and recovery of HPA axis. This data could provide basis for OIAI management recommendations. Reference: (1) Fountas, A., Prof, S.V.U., Karavitaki, N. Opioid-induced endocrinopathies. Lancet Diabetes Endocrinol. 2020;8(1);68-80. (2) Bornstein, S.R., Allolio, B., Arlt, W., et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocr. 2016;101(2);364-389. Presentation: Thursday, June 15, 2023

THU214 Exploratory Study Of The Association Of Genetic Factors With Recovery Of Hypothalamic-Pituitary-Adrenal Axis In Cushing Disease

Abstract Disclosure: M.H. Nguyen: None. W. Zhang: None. N. Pankratz: None. J. Lane: None. P. Chittiboina: None. F.R. Faucz: None. A. Liu: None. J.L. Mills: None. C.A. Stratakis: None. C. Tatsi: None. Successful treatment of endogenous Cushing syndrome (CS) is often followed by a period of adrenal insufficiency of variable duration. Recovery of the hypothalamic-pituitary-adrenal (HPA) axis may range from 6 months to more than 2 years. Previous studies have investigated potential clinical and biochemical factors involved in this process with variable results. We performed an exploratory study on genetic factors potentially involved in HPA axis recovery in patients with Cushing disease (CD). Ninety (90) patients with CD, who were treated with transsphenoidal surgery (TSS), had initial remission, and a follow up of at least 3 months postoperatively, were included in the study. Recovery of the HPA axis was defined as morning cortisol level or peak cortisol during a standard dose (250 mcg) IV corticotropin stimulation test of >18mcg/dL. Genetic data was obtained by whole exome sequencing (WES). Variants 1) in genes potentially involved in the HPA axis, 2) rare in the general population and 3) predicted as possibly or probably damaging in silico, were selected from WES. Statistical analysis was performed for each variant or for each gene (calculating all variants present in the same gene) using a Cox proportional hazard model. Correction for multiple comparisons was assessed with the false discovery rate (FDR) method.We identified 97 variants in 47 genes of interest that met the above criteria. Although five variants showed a trend toward association with shorter duration of postsurgical adrenal insufficiency (AI), no significant association was noted after correction for multiple comparisons. Furthermore, each variant was present in only one patient. At the gene-level, the BAG1 gene showed significant correlation with shorter postsurgical duration of AI (Hazard ratio: 28.7, 95% Confidence Interval: 5.4-151.1, FDR q-value=0.004), but both patients with a BAG1 variant later experienced recurrent disease, which could suggest an independent predictor of shorter recovery time. When we excluded patients with recurrence, no significant association was reported on the gene-level. In this exploratory study, we did not identify a significant genetic modifier of HPA recovery time. Other factors, clinical or surgical, may play a more important role in the recovery process or larger cohort studies may be required. Presentation: Thursday, June 15, 2023

The recovery time of hypothalamic-pituitary-adrenal axis after curative surgery in Cushing's disease and its related factor.

Patients with Cushing's disease (CD) experienced transient central adrenal insufficiency (CAI) after successful surgery. However, the reported recovery time of hypothalamic-pituitary-adrenal (HPA) axis varied and the related factors which could affect recovery time of HPA axis had not been extensively studied. This study aimed to analyze the duration of CAI and explore the factors affecting HPA axis recovery in post-operative CD patients with biochemical remission. Medical records of diagnosis with CD in Huashan Hospital were reviewed between 2014 and 2020. 140 patients with biochemical remission and regular follow-up after surgery were enrolled in this retrospective cohort study according to the criteria. Demographic details, clinical and biochemical information at baseline and each follow-up (within 2 years) were collected and analyzed. Overall, 103 patients (73.6%) recovered from transient CAI within 2 years follow-up and the median recovery time was 12 months [95% confidence intervals (CI): 10-14]. The age was younger and midnight ACTH at baseline was significantly lower, while the TT3 and FT3 levels were significantly higher in patients with recovered HPA compared to patients with persistent CAI at 2-year follow-up (p < 0.05). In persistent CAI group, more patients underwent partial hypophysectomy. TT3 at diagnosis was an independent related factor of the recovery of HPA axis, even after adjusting for gender, age, duration, surgical history, maximum tumor diameter, surgical strategy, and postoperative nadir serum cortisol level (p = 0.04, OR: 6.03, 95% CI: 1.085, 22.508). Among patients with unrecovered HPA axis at 2-year follow-up, 23 CAI patients (62%) were accompanied by multiple pituitary axis dysfunction besides HPA axis, including hypothyroidism, hypogonadism, or central diabetes insipidus. HPA axis recovered in 73.6% of CD patients within 2 years after successful surgery, and the median recovery time was 12 months. TT3 level at diagnosis was an independent related factor of postoperative recovery of HPA axis in CD patients. Moreover, patients coexisted with other hypopituitarism at 2-year follow-up had a high probability of unrecovered HPA axis.

PSAT052 Iatrogenic Cushing's Syndrome With a Remote History of Synthetic Glucocorticoid Use in the Setting of a CYP3A4 Inhibitor – Location Matters

Abstract Introduction The most common cause of Cushing's syndrome is iatrogenic due to the exogenous administration of glucocorticoids (GCs). Exogenous GCs disrupt the hypothalamic-pituitary-adrenal (HPA) axis by reducing ACTH production, thereby suppressing cortisol production by the adrenal gland. The degree of HPA axis suppression and recovery varies by the formulation, dose, duration, frequency, timing, and location of GC administration. It is also well known that the clearance of GCs is delayed by inhibitors of cytochrome P450 (CYP) 3A4 isoenzyme. Here we report a case in which a patient on cobicistat developed iatrogenic Cushing's syndrome (ICS) even with a remote history of GC use. Clinical Case A 34-year-old male with Human Immunodeficiency Virus (HIV) on cobicistat and a history of a motor vehicle accident was referred for evaluation of ICS. The patient was started on triamcinolone epidural injections after the accident and developed a ruddy face, weight gain, posterior neck fat redistribution, and purple abdominal striae. He received a total of nine injections over three months at an unknown dose with the last injection being given two years ago. His symptoms improved after stopping the regimen. He received no GCs again until four months prior to presentation when he completed a 4 mg methylprednisolone taper and the cushingoid phenotype returned. Biochemical workup was consistent with HPA axis suppression: morning cortisol &amp;lt;0.5 mcg/dL (4-22 mcg/dL), ACTH &amp;lt;5 pg/mL (6-50 pg/mL), and DHEAS 18 mcg/dL (106-464 mcg/dL). Synthetic glucocorticoid screen was positive for methylprednisolone 5.3 mcg/dL (n &amp;lt;0.10 mcg/dL) and triamcinolone 0.29 mcg/dL (n &amp;lt;0.1 mcg/dL). The patient denied any surreptitious GC use. We concluded the patient still had unmetabolized triamcinolone even after two years due to drug interactions from cobicistat, which is a CYP3A4 inhibitor. Moreover, epidural triamcinolone has the longest half-life, 523 hours, compared to oral or intraarticular injections. Clinical Lesson: GCs are primarily metabolized in the liver by CYP3A4. Very few cases have been reported with the use of cobicistat and the cushingoid phenotype typically appears within 3-6 months of the GC use. However, our patient had detectable triamcinolone and return of ICS two years after epidural injections. It is not enough to know whether a patient received GCs; it is also essential to know how it was given and the location of the injection as the half-lives vary depending on said location. This case reinforces the importance of pharmacovigilance and performing a thorough medication reconciliation, as even a remote history of steroid use in the setting of CYP3A4 inhibitors could lead to ICS. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

S2329 Iatrogenic Cushing’s Syndrome in Eosinophilic Esophagitis: A Rare Complication of Swallowed Topical Corticosteroids

Introduction: Topical corticosteroids (TCS) are a first-line treatment for eosinophilic esophagitis (EoE), effective at inducing and maintaining disease remission and well-tolerated with uncommon medication-related adverse events. Despite the theoretical risk of adrenal suppression (AS) with prolonged TCS use, data supporting clinically significant adrenal insufficiency in EoE are lacking and the risk of this rare complication is thought to be low. We present a case of iatrogenic Cushing’s syndrome associated with chronic TCS therapy in EoE and an opportunity for steroid-sparing treatment. Case Description/Methods: A 27-year-old woman with a 7-year history of EoE refractory to proton pump inhibitor, 6-food elimination diet, and swallowed fluticasone (FP) achieved disease remission with high-dose oral viscous budesonide (OVB) 4mg. Rapid recurrence of dysphagia, endoscopic findings, and esophageal eosinophilia occurred with lower OVB doses. After FP use for 5 years and transitioning to OVB for 18 months, she developed cushingoid features including prominent pathologic striae on the abdomen, breasts, and thighs, facial rounding, supraclavicular fullness, central obesity, and a dorsocervical hump. Given known exposure to exogenous steroids, features consistent with iatrogenic Cushing’s syndrome, and assumed hypothalamic-pituitary-adrenal axis (HPAA) suppression, the patient began a taper of OVB and steroid-sparing treatment was initiated with dupilumab 300mg weekly. After tapering OVB to 2mg daily over 2 months, assessment (ACTH, morning cortisol, 24-hour urine cortisol) was normal, consistent with HPAA recovery (Figure). Discussion: Topical steroids such as OVB are commonly used and recommended for long-term management of EoE with rare reports of adrenal insufficiency. As data supporting biochemical AS with TCS use in EoE is limited to observational studies with heterogenous testing for AI and lack of symptom assessment, the risk of clinically relevant AS is likely low. However, our case demonstrates that despite the favorable pharmacokinetics, systemic effects of TCS may be understated, particularly with high compliance and prolonged use of high daily doses. Clinicians should counsel patients on the non-negligible risk of AS when prescribing TCS for EoE, and consider assessment of the adrenal axis or use of steroid-sparing agents in those reliant on chronic TCS for disease control.Figure 1.: Endoscopic evidence of (B) active disease on FP (B) disease remission on OVB 4mg daily; (C) Cushingoid features of abdominal striae and dorsocervical hump.

Hypothalamic-pituitary-adrenal axis recovery after treatment of Cushing's syndrome.

After successful treatment for Cushing's syndrome (CS), secondary adrenal insufficiency develops as a result of the prior suppression of the hypothalamic-pituitary-adrenal (HPA) axis by excess cortisol in the body. Until the recovery of the HPA axis, glucocorticoid replacement therapy is required to enable normal functioning of the body and prevent adrenal crisis. Significant variation in the median time of recovery of the HPA axis is found in various cohorts of CS patients ranging from several weeks to years. Despite the use of physiological glucocorticoid replacement, after cure for CS, patients often experience symptoms of glucocorticoid withdrawal syndrome (GWS). The optimal glucocorticoid regimen to reduce GWS needs to be established and requires an individualized approach aiming to avoid overtreatment at one side and minimize the risk of undertreatment and possible adrenal crisis and GWS on the other side.

Morning Serum Cortisol as a Predictor for the HPA Axis Recovery in Cushing's Disease.

Background The suppressed hypothalamic-pituitary-adrenal (HPA) axis after successful surgery for Cushing's disease (CD) will recover in almost all patients. We aimed to identify the predictive factors for HPA axis recovery in CD patients with postoperative remission. Design and Methods. This observational retrospective cross-sectional study enrolled 69 CD patients with postoperative remission in Huashan Hospital from 2015 to 2019. All subjects had a detailed clinical evaluation. The low-dose ACTH stimulation test (LDT) was conducted as the gold standard for assessing the HPA axis function. Results Peak cortisol in LDT was found only to be positively correlative with morning serum cortisol (MSC) (ρ=0.451, p < 0.001). The MSC was higher (p < 0.001), and the median postoperative course was significantly longer (p=0.025) in the patients with the recovered HPA axis function compared with unrecovered patients. The AUC value of MSC for predicting the recovery of the HPA axis was 0.701, and the optimal cutoff was 6.25 μg/dl (sensitivity 85.19% and specificity 47.62%). Other useful cutoff values were 10.74 μg/dl (specificity 100%) and 4.18 μg/dl (sensitivity 100%). Besides, combined with the postoperative course, the AUC values were higher than MSC alone (0.935 vs. 0.701, p < 0.001). Conclusions MSC is a viable first-step diagnostic predictor for HPA axis recovery in CD patients with postoperative remission. For the patients with cortisol levels between 4.18 and 10.74 μg/dl, a confirmatory test should be conducted. When the MSC level was 10.74 μg/dl or greater, the replacement therapy could be discontinued.

Hypothalamic-Pituitary-Adrenal Axis Recovery Following the 1-mg Overnight Dexamethasone Suppression Test in Healthy Volunteers.

BackgroundThe recovery of hypothalamic-pituitary-adrenal (HPA) axis suppression following pharmacological doses of various steroids has been studied previously. However, no study has been conducted using the more commonly used 1-mg dexamethasone in the overnight dexamethasone suppression test (ODST). Hence, we aimed at evaluating HPA axis recovery after the 1-mg ODST.ObjectivesThis study aimed at investigating the pattern and time of recovery of the HPA axis following the 1-mg ODST in healthy subjects.MethodsTen healthy volunteers aged 18 - 40 years, BMI < 30 kg/m2, with neither exposure to steroids nor interfering drugs were included. The 1-mg ODST was performed, and the adrenocorticotropic hormone (ACTH) and cortisol samples were withdrawn at regular intervals. The serum cortisol of < 1.8 µg/dL was considered as HPA axis suppression, whereas the cortisol value equal to or more than baseline was deemed as recovery.ResultsCortisol and ACTH levels were suppressed in all subjects 9 hours following the 1-mg ODST. Although ACTH showed an early increase after 8 hours, the upsurge was noticed following 24 hours (mean ± SD, 34.42 ± 18 pg/mL). Later, cortisol accompanied ACTH, and both reached their baseline after 72 hours (mean ± SD, ACTH, 37.48 ± 12.44 pg/mL; cortisol, 8.45 ± 3.32 μg/dL). A small dip in ACTH and cortisol (mean ACTH, 23.84 pg/mL; mean cortisol, 2.3 μg/dL) was observed after 24 - 36 hours indicating the return of the diurnal rhythm before complete recovery.ConclusionsThe complete recovery of the HPA axis occurs only 72 hours following the 1-mg ODST. ACTH begins to recover as early as 8 hours after the maximal suppression and diurnal rhythm of ACTH and cortisol resume 24 to 36 hours later.

Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma

Mitotane is a steroidogenesis inhibitor and adrenolytic drug used for treatment of adrenocortical cancer (ACC). Mitotane therapy causes adrenal insufficiency requiring glucocorticoid replacement in all patients. However, it is unclear whether chronic therapy with mitotane induces complete destruction of zona fasciculata and whether hypothalamic-pituitary-adrenal (HPA) axis can recover after treatment cessation. Our objective was to assess the HPA axis recovery in a cohort of patients after cessation of adjuvant mitotane therapy for ACC. We retrospectively reviewed patient files with stage I-II-III ACC in two referral centers in Canada and Italy. Data on demographics, tumor characteristics, hormonal profile, and HPA axis were collected. Data from 23 patients with pathologically proven ACC treated with adjuvant mitotane for a minimum of two years were analyzed. Eight patients were males and 15 were females and the median age was 41 years old (range 18 to 73). After mitotane cessation, 18/23 (78.3%) patients achieved a complete HPA axis recovery while 3/23 (13.0%) were unable to tolerate glucocorticoid withdrawal despite having normal hormonal test values and 2/23 (8.7%) never achieved recovery. The mean time interval between mitotane cessation and HPA axis recovery was 2.7 years. A high proportion of patients achieved HPA axis recovery following cessation of mitotane adjuvant therapy. However, complete recovery was often delayed up to 2.5 years and regular assessment of the hormonal profile is required.

Co-activation of SAM and HPA responses to acute stress: A review of the literature and test of differential associations with preadolescents' internalizing and externalizing.

Understanding co-activation patterns of the hypothalamic-pituitary-adrenal axis (HPA) and sympathetic adrenal medullary (SAM) during early adolescence may illuminate risk for development of internalizing and externalizing problems. The present study advances empirical work on the topic by examining SAM-HPA co-activation during both the reactivity and recovery phases of the stress response following acute stress exposure. Fourth and fifth grade boys and girls (N=149) provided cortisol and alpha-amylase via saliva at seven times throughout a 95-min assessment in which they were administered the modified Trier Social Stress Test. Parents reported on adolescents' life stress, pubertal development, medication use, and externalizing problems. Adolescents reported their own internalizing symptoms. Multiple linear regressions tested both direct and interactive effects of SAM and HPA reactivity and recovery on internalizing and externalizing problems. Results from these analyses showed that whereas SAM and HPA reactivity interacted to predict internalizing symptoms, it was their interaction during the recovery phase that predicted externalizing. Concurrent high SAM and HPA reactivity scores predicted high levels of internalizing and concurrently low SAM and HPA recovery scores predicted high levels of externalizing. Implications of the findings for further study and clinical application are discussed.

MON-454 Recovery of the Hypothalamic-Pituitary-Adrenal, Gonadal, and Thyroid Axes Following Trans-Sphenoidal Adenomectomy: A Single Center Experience

Background Hypopituitarism is a potential sequelea of pituitary macroadenoma or trans-sphenoidal adenomectomy (TSA). Recovery of pituitary function can occur post-TSA, and reassessment is required to avoid needless hormonal replacement. The timing and frequency of re-testing is variable across centres and the aim of this study was to determine rate of, and time to recovery of hypothalamic-pituitary adrenal (HPA), gonadal and thyroid axes postTSA. Methods We performed a single-centre retrospective analysis of TSA patients from February 2015 to September 2018. Patients with apoplexy, corticotroph adenomas, redo-surgery, emergency TSA, craniotomy or pituitary radiotherapy were excluded. Thyroid, gonadal and HPA axis adequacy was respectively assessed with TSH/freeT4, FSH/LH/estradiol or testosterone measurement and short synacthen test (SST), performed pre-TSA and at 6-weeks, 3-, 6-, and 9 to 12-months post-TSA. Results Data on 135 patients (mean age 54±17 years; 80M) were analysed. Macroadenomas occurred in 118 (87.4%), microadenoma in 8 (5.9%). Histology confirmed gonadotroph (53%), somatotroph (10.4%), plurihormonal (13.3%), lactotroph (5.2%), meningioma (1.5%), craniopharyngioma (12.6%), thyrotroph (1.5%) and metastatic malignancy (2.2%). 53.7%, 30.2% and 19.1% of patients had pre-op gonadal, thyroid and HPA function deficit respectively. 59% of patients had at least one deficit at baseline. Age was associated with the number of deficits manifested (F=6.026, p<0.001). 6-weeks post-TSA, 31.4%, 20.6% and 32% showed gonadal, thyroid and HPA axis deficit respectively. 35.7% of patients with normal pre-op pituitary function developed at least one new hormonal axis deficit at 6-weeks. Of 19.1% patients with abnormal pre-op HPA function, 30.4 % (7/23) recovered at 6-weeks. Among patients with abnormal HPA function at 6 weeks, 12.2%, 7.3% and 4.9% recovered at 3-, 6-, and 9 to 12-months respectively. 31.6% of patients with abnormal pre-op thyroid and 20% of patients with abnormal pre-op gonadal axes recovered at 6-weeks. Among patients recovering HPA axis function at 6-weeks, the majority also recovered thyroid axis (85.1% vs 14.9%, χ2=4.839, OR 2.643, p=0.03), whereas no association was found between gonadal and HPA axis recovery (54.1% vs 45.9%, p=0.16). Conclusions We demonstrate a significant rate of recovery of pre-operative pituitary deficit following TSA. 6-weeks post-operatively, gonadal failure is the most prevalent deficit. Regaining HPA axis function is a positive predictor for thyroid axis recovery but not gonadal axis recovery. HPA axis normalization can even occur at 9 to 12-months post-TSA, emphasizing the importance of periodic reassessment to avoid unnecessary hydrocortisone replacement in those who could eventually regain function. More longitudinal data are needed to assess the potential for recovery of thyroid and gonadal axes at >6 weeks post-op.

Extensive clinical experience: Hypothalamic-pituitary-adrenal axis recovery after adrenalectomy for corticotropin-independent cortisol excess.

To identify predictors of hypothalamic-pituitary-adrenal (HPA) axis recovery interval and severity of glucocorticoid withdrawal symptoms (GWS) in patients undergoing adrenalectomy for corticotropin-independent cortisol excess. This is a retrospective study of patients with mild autonomous cortisol excess (MACE), moderate and severe Cushing syndrome (CS) who developed adrenal insufficiency after unilateral adrenalectomy between 1998 and 2017. Adrenalectomy was performed in 81 patients (79% women, median age 52years [IQR 42-62]). HPA axis recovery occurred at a median of 4.3months (IQR 1.6-11.4) after adrenalectomy (severe CS vs moderate CS vs MACE: median 11.4 vs 2.8 vs 2.1months, P<0.01). Main predictors of HPA axis recovery interval included: preoperative serum cortisol concentration after 1-mg overnight dexamethasone suppression test >10μg/dL or >276nmol/L (9.7 vs 1.3months if cortisol ≤10μg/dL or ≤276nmol/L, P<0.01); body mass index (for every 3kg/m2 decrease, glucocorticoid taper increased by 1month, P<0.05); age <45 (11.4 vs 2.3months if ≥45years, P<0.05); duration of symptoms prior to diagnosis >1year (11.4 vs 2.8months if ≤1year); moon facies (11.4 vs 2.2months if no rounding of the face); and myopathy (13.1 vs 2.7months if no myopathy, P<0.05). Patients with severe CS had a higher incidence of GWS compared to patients with MACE (66.7% vs 40.0%, P<0.05) with a median of 1 and 0 events/patient, respectively. The HPA axis recovery interval was the longest for patients with severe CS. Surprisingly, patients with moderate CS recovered their HPA axis as quickly as those with MACE. Glucocorticoid withdrawal symptoms were observed in all groups, with more events in patients with severe CS. This study emphasizes the need to counsel patients on expectations for HPA axis recovery and address intervention for GWS based on individual preoperative parameters.

Predicting Recovery Of The Hypothalamic-Pituitary-Adrenal Axis After Prolonged Glucocorticoid Use

Prolonged exposure to glucocorticoids lead to hypothalamic-pituitary-adrenal (HPA) axis suppression that recovers after cessation of treatment. We aimed to identify the predictive factors for HPA axis recovery after prolonged glucocorticoid use. Retrospective review of patients who had undergone first short Synacthen test (SST) to assess HPA axis recovery after prolonged use of glucocorticoids. A total of 61% (20/33) of patients had adequate SST response at a median time of 2 years after diagnosis of adrenal insufficiency. Those who had adequate response during SST had higher ambulatory early morning cortisol ( P<.01), shorter duration of exposure to glucocorticoids ( P = .01), and lower final cumulative hydrocortisone replacement dose ( P = .03). Age, gender, body mass index, indications for glucocorticoid use, and basal adrenocorticotropic hormone levels were not predictive of HPA axis recovery. On multivariate analysis, ambulatory early morning cortisol was the only independent predictor of adequate SST response (odds ratio, 1.02; 95% confidence interval, 1.01 to 1.04; P = .02). Using receiver operating characteristic curve analysis, ambulatory early morning cortisol of 8.8 μg/dL predicted a positive SST response with a sensitivity of 70% and specificity of 93%. Early morning ambulatory cortisol could be used to decide on timely SST in order to prevent complications from unnecessary replacement with glucocorticoids. ACTH = adrenocorticotropic hormone; BMI = body mass index; CV = coefficient of variation; HPA = hypothalamic-pituitary-adrenal; SST = short Synacthen test.

Prospective evaluation of a week one overnight metyrapone test with subsequent dynamic assessments of hypothalamic-pituitary-adrenal axis function after pituitary surgery.

SummaryObjective To determine whether an overnight metyrapone test (OMT) within the first week postpituitary surgery can definitively assess the hypothalamic-pituitary-adrenal (HPA) axis, compared with subsequent dynamic tests and glucocorticoid requirement at 6 months. Design Prospective study measuring morning cortisol levels on days 3 and 4 post-operatively, OMT day 5-7 and week 6, week 6 250 μg short Synacthen test (SST) and week 7 insulin tolerance test (ITT). Patients and Measurements Forty participants who underwent pituitary surgery at a single centre (Cushing's disease excluded) were followed for at least 6 months. 46% had pre-operative adrenal insufficiency. Primary outcome: week 1 OMT compared to glucocorticoid requirement at 6 months. Secondary outcomes: the performance of ITT as a “definitive” test and all tests compared to glucocorticoid requirement at 6 months. Results Week 1 OMT showed concordance with ITT at week 7 of 78% and glucocorticoid requirement at 6 months of 81% respectively which was not significantly different from post-operative morning cortisol levels; 37% of participants with an abnormal OMT on day 6 had a normal OMT at week 6. All HPA axis tests showed similar concordance with glucocorticoid requirement at 6 months of 80%-85%. Conclusions Overnight metyrapone test within the first week after pituitary surgery was no better than an early morning cortisol level at predicting glucocorticoid requirement at 6 months. OMT at week 6 demonstrated recovery of HPA axis in a substantial proportion of participants who failed earlier assessments; thus, definitive testing should be delayed until 6 weeks post-operatively.

Prospective evaluation of a week one overnight metyrapone test with subsequent dynamic assessments of hypothalamic-pituitary-adrenal axis function after pituitary surgery.

To determine whether an overnight metyrapone test (OMT) within the first week postpituitary surgery can definitively assess the hypothalamic-pituitary-adrenal (HPA) axis, compared with subsequent dynamic tests and glucocorticoid requirement at 6months. Prospective study measuring morning cortisol levels on days 3 and 4 post-operatively, OMT day 5-7 and week 6, week 6 250μg short Synacthen test (SST) and week 7 insulin tolerance test (ITT). Forty participants who underwent pituitary surgery at a single centre (Cushing's disease excluded) were followed for at least 6months. 46% had pre-operative adrenal insufficiency. week 1 OMT compared to glucocorticoid requirement at 6months. the performance of ITT as a "definitive" test and all tests compared to glucocorticoid requirement at 6months. Week 1 OMT showed concordance with ITT at week 7 of 78% and glucocorticoid requirement at 6months of 81% respectively which was not significantly different from post-operative morning cortisol levels; 37% of participants with an abnormal OMT on day 6 had a normal OMT at week 6. All HPA axis tests showed similar concordance with glucocorticoid requirement at 6months of 80%-85%. Overnight metyrapone test within the first week after pituitary surgery was no better than an early morning cortisol level at predicting glucocorticoid requirement at 6months. OMT at week 6 demonstrated recovery of HPA axis in a substantial proportion of participants who failed earlier assessments; thus, definitive testing should be delayed until 6weeks post-operatively.

Mifepristone Accelerates HPA Axis Recovery in Secondary Adrenal Insufficiency.

Context. Transient secondary adrenal insufficiency (SAI) is an expected complication following successful adenomectomy of ACTH-secreting pituitary adenomas or unilateral adrenalectomy for cortisol-secreting adrenal adenomas. To date, no pharmacological therapy has been shown to hasten recovery of the hypothalamic-pituitary-adrenal (HPA) axis in this clinical scenario. Case Description. A 33-year-old woman underwent uncomplicated unilateral adrenalectomy for a 3.7 cm cortisol-secreting adrenal adenoma. Postoperatively, she developed SAI and was placed on hydrocortisone 15 mg/day, given in divided doses. In the ensuing six years, the patient's HPA axis failed to recover and she remained corticosteroid-dependent. Quarterly biochemical testing (after withholding hydrocortisone for 18 hours) consistently yielded undetectable serum cortisol and subnormal plasma ACTH levels. While she was on hydrocortisone 15 mg/day, mifepristone was initiated and gradually titrated to a maintenance dose of 600 mg/day after 5 months. Rapid recovery of the HPA axis was subsequently noted with ACTH rising into the supranormal range at 4 months followed by a subsequent rise in cortisol levels into the normal range. After 6 months, the dose of hydrocortisone and mifepristone was lowered and both were ultimately stopped after 8 months. The HPA axis remains normal after an additional 16 months of follow-up. Conclusion. Mifepristone successfully restored the HPA axis in a woman with prolonged secondary adrenal insufficiency (SAI) after adrenalectomy for Cushing's syndrome (CS).