Ovine CRH Stimulation and 8 mg Dexamethasone Suppression Tests in 323 Patients With ACTH-Dependent Cushing's Syndrome.

CONTEXT: Determining the etiology of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) is often difficult. The gold standard test, inferior petrosal sinus sampling (IPSS), is expensive and not widely available. OBJECTIVE: Evaluate the performance of the corticotropin-releasing hormone stimulation test (CRH-ST) and the 8 mg high-dose dexamethasone suppression test (HDDST) in distinguishing Cushing's disease (CD) from ectopic ACTH syndrome (EAS). METHODS: Retrospective review in a tertiary referral center. A total of 323 patients with CD or EAS (n = 78) confirmed by pathology or biochemical cure (n = 15) in 96% underwent CRH-ST and HDDST performed between 1986 and 2019. We calculated test sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value, and diagnostic accuracy (DA) for the diagnosis of CD, and determined optimal response criteria for each test, alone and in combination. RESULTS: The CRH-ST performed better than the HDDST (DA 91%, 95% CI 87-94% vs 75%, 95% CI 69-79%). Optimal response criteria were a ≥40% increase of ACTH and/or cortisol during the CRH test and a ≥69% suppression of cortisol during the HDDST. A ≥40% cortisol increase during the CRH test was the most specific measure, PPV 99%. Seventy-four percent of subjects had concordant positive CRH test and HDDST results, yielding Se 93%, Sp 98%, DA 95%, and PPV 99%, with a pretest likelihood of 85%. A proposed algorithm diagnosed 64% of patients with CD with near perfect accuracy (99%), obviating the need for IPSS. CONCLUSION: CRH is a valuable tool to correctly diagnose the etiology of ACTH-dependent CS. Its current worldwide unavailability impedes optimal management of these patients.

Diurnal Range and Intra-patient Variability of ACTH Is Restored With Remission in Cushing's Disease.

CONTEXT: Single ACTH measurements have limited ability to distinguish patients with Cushing's disease (CD) from those in remission or with other conditions. OBJECTIVE: To investigate the changes in ACTH levels before and after transsphenoidal surgery (TSS) to identify trends that could confirm remission from CD and help establish ACTH cutoffs for targeted clinical trials in CD. DESIGN: Retrospective analysis of CD patients who underwent TSS from 2005 to -2019. SETTING: Referral center. PATIENTS: CD patients (n = 253) with ACTH measurements before and after TSS. INTERVENTIONS: TSS for CD. MAIN OUTCOME MEASURES: Remission after TSS. RESULTS: Remission was observed in 223 patients after TSS. Those in remission had higher ACTH variability at AM (P = .02) and PM (P < .001) time points compared to nonremission. The nonremission group had a significantly narrower diurnal range compared to the remission group (P = <.0001). A decrease in plasma ACTH of ≥50% from mean preoperative levels predicted CD remission after TSS, especially when using PM values. The absolute plasma ACTH concentration and ratio of preoperative to postoperative values were significantly associated with nonremission after multivariable logistic regression (adj P < .001 and .001, respectively). CONCLUSIONS: Our findings suggest that ACTH variability is suppressed in CD, and remission from CD is associated with the restoration of this variability. Furthermore, a decrease in plasma ACTH by 50% or more may serve as a predictor of remission post-TSS. These insights could guide clinicians in developing rational outcome measures for interventions targeting CD adenomas.

Pituitary adenomas evade apoptosis via noxa deregulation in Cushing's disease.

Sporadic pituitary adenomas occur in over 10% of the population. Hormone-secreting adenomas, including those causing Cushing's disease (CD), cause severe morbidity and early mortality. Mechanistic studies of CD are hindered by a lack of in vitro models and control normal human pituitary glands. Here, we surgically annotate adenomas and adjacent normal glands in 25 of 34 patients. Using single-cell RNA sequencing (RNA-seq) analysis of 27594 cells, we identify CD adenoma transcriptomic signatures compared with adjacent normal cells, with validation by bulk RNA-seq, DNA methylation, qRT-PCR, and immunohistochemistry. CD adenoma cells include a subpopulation of proliferating, terminally differentiated corticotrophs. In CD adenomas, we find recurrent promoter hypomethylation and transcriptional upregulation of PMAIP1 (encoding pro-apoptotic BH3-only bcl-2 protein noxa) but paradoxical noxa downregulation. Using primary CD adenoma cell cultures and a corticotroph-enriched mouse cell line, we find that selective proteasomal inhibition with bortezomib stabilizes noxa and induces apoptosis, indicating its utility as an anti-tumor agent.

Selective progesterone receptor modulators and reproductive health.

PURPOSE OF REVIEW: This review is intended to provide perspective on the history of selective progesterone receptor modulators (SPRMs) and progesterone antagonists, their current availability, therapeutic promise and safety concerns. RECENT FINDINGS: Despite keen interest in synthesis of these compounds, only a handful have had clinical test results allowing for commercialization. Mifepristone is well tolerated and effective for single dose first trimester at-home pregnancy termination and is available in much of the world. Ulipristal acetate, at single doses, is well tolerated and effective for emergency contraception, with less availability. Chronic use of these agents has been associated with abnormal liver enzymes, and rarely, with hepatic failure; causality is not understood. SUMMARY: SPRMs and progesterone antagonists have great therapeutic promise for use in other reproductive disorders, including breast cancer, endometriosis, adenomyosis, estrogen-free contraception and cervical ripening but require additional study. Alternative formulations, whether local (topical breast or intrauterine) or extended-release may reduce the incidence of liver function abnormalities and should be explored.

Hypercoagulability in Cushing's syndrome: incidence, pathogenesis and need for thromboprophylaxis protocols.

Cushing's syndrome (CS) is associated with a hypercoagulable state resulting in an increased risk on venous thromboembolism (VTE). In patients with untreated active CS VTE incidence is up to 18-fold higher compared to the general population, whereas after pituitary and adrenal surgery a postoperative VTE risk between 2.6 and 5.6% has been reported. Interestingly, after surgery the VTE risk is not only increased in the first week but also during several months postoperatively. The hypercoagulable state in CS is thought to be caused, at least in part, by an imbalance between activity of pro- and anticoagulant pathways. However, changes in activated partial thromboplastin time and plasma concentrations of pro-and anticoagulant factors are not observed in every CS patient. Only retrospective studies have shown that thromboprophylaxis lowers VTE risk in CS. Future prospective studies should asses the optimal timing, duration and type of thromboprophylaxis in CS to improve VTE-related morbidity and mortality.

Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing's Syndrome.

Endogenous Cushing's syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are often delayed. Thus, there are many opportunities for basic and clinical research leading to better tests, faster diagnosis, and optimized medical treatments. This review focuses on CS caused by excessive adrenocorticotropin (ACTH) production. It describes current concepts of the regulation of ACTH synthesis and secretion by normal corticotropes and mechanisms by which dysregulation occurs in corticotrope (termed "Cushing's disease") and noncorticotrope (so-called ectopic) ACTH-producing tumors. ACTH causes adrenal gland synthesis and pulsatile release of cortisol; the excess ACTH in these forms of CS leads to the hypercortisolism of endogenous CS. Again, the differences between healthy individuals and those with CS are highlighted. The clinical presentations and their use in the interpretation of CS screening tests are described. The tests used for screening and differential diagnosis of CS are presented, along with their relationship to cortisol dynamics, pathophysiology, and negative glucocorticoid feedback regulation in the two forms of ACTH-dependent CS. Finally, several gaps in current understanding are highlighted in the hope of stimulating additional research into this challenging disorder.

Characterization of Outcomes by Surgical Management of Lung Neuroendocrine Tumors Associated With Cushing Syndrome.

Importance: Ectopic adrenocorticotropic hormone secretion from lung tumors causing Cushing syndrome are associated with high rates of morbidity. Optimal management remains obscure because knowledge is based on rare reports with few patients. Objective: To characterize the outcomes of lung neuroendocrine tumors associated with Cushing syndrome. Design, Setting, and Participants: An observational case series review from 1982 to 2020 was conducted in a single institution referral center. Kaplan-Meier analysis estimated disease-free survival (DFS). Participants underwent curative-intent surgery for a lung neuroendocrine tumor causing Cushing syndrome. Exposures: Lobectomy or pneumonectomy vs sublobar resection. Main Outcomes and Measures: Disease-free survival, disease persistence/recurrence. Results: Of the 68 patients, the median age was 41 years (range, 17-80 years), 42.6% (29 of 68) were male, 81.8% (54 of 66) were White, with a mean follow-up after surgery was 16 months (range, 0.1-341 months). Lobectomy was the most common procedure (48 of 68 [70.6%]), followed by wedge resection (16 of 68 [23.5%]) and segmentectomy (3 of 68 [4.4%]). Video-assisted thoracoscopic surgery was performed in 19 of 68 (27.9%) of patients. Surgical morbidity was 19.1% (13 of 68), and perioperative mortality was 1.5% (1 of 68). Lymph node positivity was 37% (22 of 59) when evaluable. The overall incidence of persistence/recurrence was 16.2% (11 of 68) with a median time to recurrence of 55 months (range, 18-152 months). The median DFS was reached in 12.7 years (0.1-334 months). There were no statistical differences in DFS based on tumor size, stage (8th edition TNM), whether full systematic lymphadenectomy was performed or not, nodal status, or surgical approach. Conclusions and Relevance: In this case series study, neuroendocrine pulmonary tumors associated with Cushing syndrome had increased nodal metastasis, higher recurrence, and lower DFS than quiescent bronchopulmonary carcinoid tumors, but many patients experienced favorable outcomes. This observation is underscored by the discordance of TNM-stage classifications vs prognosis. Observing no difference in surgical techniques, the implication may be that a lung-sparing approach could suffice. These results may reflect the intrinsic importance of the hormone physiology instead of the carcinoid biologic factors.

Patient and Provider Perspectives on Postsurgical Recovery of Cushing Syndrome.

CONTEXT: Cushing syndrome (CS) is associated with impaired health-related quality of life (HRQOL) even after surgical cure. OBJECTIVE: To characterize patient and provider perspectives on recovery from CS, drivers of decreased HRQOL during recovery, and ways to improve HRQOL. DESIGN: Cross-sectional observational survey. PARTICIPANTS: Patients (n = 341) had undergone surgery for CS and were members of the Cushing's Support and Research Foundation. Physicians (n = 54) were Pituitary Society physician members and academicians who treated patients with CS. RESULTS: Compared with patients, physicians underestimated the time to complete recovery after surgery (12 months vs 18 months, P = 0.0104). Time to recovery did not differ by CS etiology, but patients with adrenal etiologies of CS reported a longer duration of cortisol replacement medication compared with patients with Cushing disease (12 months vs 6 months, P = 0.0025). Physicians overestimated the benefits of work (26.9% vs 65.3%, P < 0.0001), exercise (40.9% vs 77.6%, P = 0.0001), and activities (44.8% vs 75.5%, P = 0.0016) as useful coping mechanisms in the postsurgical period. Most patients considered family/friends (83.4%) and rest (74.7%) to be helpful. All physicians endorsed educating patients on recovery, but 32.4% (95% CI, 27.3-38.0) of patients denied receiving sufficient information. Some patients did not feel prepared for the postsurgical experience (32.9%; 95% CI, 27.6-38.6) and considered physicians not familiar enough with CS (16.1%; 95% CI, 12.2-20.8). CONCLUSION: Poor communication between physicians and CS patients may contribute to dissatisfaction with the postsurgical experience. Increased information on recovery, including helpful coping mechanisms, and improved provider-physician communication may improve HRQOL during recovery.

Approach to the Patient Treated with Steroidogenesis Inhibitors.

Steroidogenesis inhibitors can be given to control the hypercortisolism of Cushing's syndrome in various situations: when surgery has been unsuccessful or not possible; in metastatic adrenocorticotropin hormone (ACTH) or cortisol-secreting tumors; when waiting for the maximal efficacy of radiation techniques; for rapid treatment of severe hypercortisolism in patients with occult ACTH-producing tumors; or as a presurgical treatment in patients with severe comorbidities. Whilst biochemical "control" can be achieved in more than 50% of cases, daily management of such drugs can be challenging. Indeed, with a "dose-titration" or a "block and replace" approach, defining eucortisolism is usually difficult, requiring the measurement of several biological markers. Moreover, each drug has its own side effects, which must be monitored closely. The aim of this "approach to the patient" is to shed light on the management of hypercortisolism with 4 steroidogenesis inhibitors (ketoconazole, levoketoconazole, metyrapone, osilodrostat) to help endocrinologists dealing with patients with Cushing's syndrome. Various points will be discussed, such as initial dose of treatment, dose schedule, monitoring of efficacy, and side effects of monotherapy. The combination of steroidogenesis inhibitors will also be discussed.

The NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty: Protocol and rationale for methods and measures.

Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8-10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children.

Mifepristone Improves Adipose Tissue Insulin Sensitivity in Insulin Resistant Individuals.

BACKGROUND: Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. METHODS: We conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. RESULTS: Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ±â€…32.9 vs 42.8 ±â€…23.9; P = 0.002) and reduced adipo-IR (49.9 ±â€…45.9 vs 65.5 ±â€…43.8; P = 0.004), and HIRI (50.2 ±â€…38.7 vs 70.0 ±â€…44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or ß-cell glucose sensitivity. CONCLUSION: Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.

The short-term effects of estradiol, raloxifene, and a phytoestrogen in women with perimenopausal depression.

OBJECTIVE: We examined the short-term efficacies of three estrogen-like compounds under placebo-controlled conditions in women with perimenopause-related depression (PMD). METHODS: Women with PMD were randomized in a double-blind parallel design to one of four treatments: transdermal 17-beta estradiol (TE) (100 mcg/d); oral raloxifene (60 mg/d); a proprietary phytoestrogen compound, Rimostil (1,000 mg twice/d); or placebo for 8 weeks. The main outcome measures were the Center for Epidemiology Studies Depression Scale, 17-item Hamilton Rating Scale for Depression (HRSD), and the Beck Depression Inventory completed at each clinic visit. Secondary outcomes included a visual analogue self-rating completed at each clinic visit, and daily self-ratings of hot flush severity. Cognitive tests were performed at pretreatment baseline and at the end of the trial. In the primary analysis, we obtained four repeated measures in each woman in the four treatment arms. Analyses were done with SAS Version 9.4 software (SAS Institute, Inc, Cary, NC), using PROC MIXED (for mixed models). All models included the following four explanatory variables, regardless of whether they were statistically significant: 1) treatment group (TE, raloxifene, Rimostil, placebo); 2) week (W2, W4, W6, W8); 3) treatment group-by-week interaction; and 4) baseline value of the measure being analyzed. The inclusion of additional variables was evaluated individually for each outcome measure. RESULTS: Sixty-six women were randomized into the trial, four women dropped out of the trial, and 62 women were included in the final data analysis. No effect of treatment group was observed in either the Center for Epidemiology Studies Depression Scale (P = 0.34) or Beck Depression Inventory (P = 0.27) scores; however, there was a difference in HRSD scores between treatment groups (P = 0.0037) that pair-wise comparisons of the combined weekly scores in each treatment demonstrated TE's beneficial effects on HRSD scores compared with Rimostil (P = 0.0005), and less consistently with placebo (P = 0.099). The average (SD) of the baseline scores for each treatment group on the HRSD was as follows: TE-15.3 (4.5), raloxifene-16.0 (3.7), Rimostil-14.0 (2.7), and placebo-15.2 (3.0). Whereas the HRSD scores after 8 weeks of treatment (least-square means) were TE-5.2(1.1), raloxifene-5.8(1.2), Rimostil-11.2(1.4), and placebo-7.8(1.1). No differences were observed between raloxifene and either TE or placebo in any scale score. HRSD scores in women assigned to TE were improved compared with those on Rimostil during weeks 6 and 8 (P values = 0.0008, 0.0011, respectively). Cognitive testing at week 8 showed that none of the three active treatment groups performed better than placebo. CONCLUSIONS: This study did not identify significant therapeutic benefits of TE, Rimostil, or raloxifene compared with placebo in PMD. However, improvements in depression ratings were observed between TE compared with Rimostil. Thus, our findings do not support the role of ERbeta compounds in the treatment of PMD (and indeed could suggest a more important role of ERalpha).

The Hypothalamic-Pituitary-Thyroid Axis in Cushing Syndrome Before and After Curative Surgery.

BACKGROUND: We do not fully understand how hypercortisolism causes central hypothyroidism or what factors influence recovery of the hypothalamic-pituitary-thyroid axis. We evaluated thyroid function during and after cure of Cushing syndrome (CS). METHODS: We performed a retrospective cohort study of adult patients with CS seen from 2005 to 2018 (cohort 1, c1, n = 68) or 1985 to 1994 (cohort 2, c2, n = 55) at a clinical research center. Urine (UFC) and diurnal serum cortisol (F: ~8 am and ~midnight [pm]), morning 3,5,3'-triiodothyronine (T3), free thyroxine (FT4), and thyrotropin (TSH) (c1) or hourly TSH from 1500 to 1900 h (day) and 2400 to 04000 h (night) (c2), were measured before and after curative surgery. RESULTS: While hypercortisolemic, 53% of c1 had central hypothyroidism (low/low normal FT4 + unelevated TSH). Of those followed long term, 31% and 44% had initially subnormal FT4 and T3, respectively, which normalized 6 to 12 months after cure. Hypogonadism was more frequent in hypothyroid (69%) compared to euthyroid (13%) patients. Duration of symptoms, morning and midnight F, adrenocorticotropin, and UFC were inversely related to TSH, FT4, and/or T3 levels (r = -0.24 to -0.52, P < .001 to 0.02). In c2, the nocturnal surge of TSH (mIU/L) was subnormal before (day 1.00 ± 0.04 vs night 1.08 ± 0.05, P = .3) and normal at a mean of 8 months after cure (day 1.30 ± 0.14 vs night 2.17 ± 0.27, P = .01). UFC greater than or equal to 1000 µg/day was an independent adverse prognostic marker of time to thyroid hormone recovery. CONCLUSIONS: Abnormal thyroid function, likely mediated by subnormal nocturnal TSH, is prevalent in Cushing syndrome and is reversible after cure.

ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of Cushing's syndrome.

Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing's syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2-3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic.

Endocrine-Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management.

Immune checkpoint inhibitors have proven to be effective for various advanced neoplasia. Immune-related adverse events (irAEs) as a result of increased T cell activation are unique and potentially life-threating toxicities associated with the use of immune checkpoint inhibitors. Multiple endocrine irAEs, including primary hyperthyroidism and hypothyroidism, thyroiditis, primary adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis, have been reported with the use of various immune checkpoint inhibitors. In some cases, these irAEs can lead to discontinuation of treatment. Here we propose for the general oncologist algorithms for managing endocrine irAEs to aid in the clinical care of patients receiving immunotherapy. KEY POINTS: There is a relative high risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors, particularly when combination therapy is implemented. Patients treated with anti-CTLA-4 antibodies have an increased risk of hypophysitis, whereas patients treated with anti-PD-1/PD-L1 antibodies have a higher risk of primary thyroid dysfunction. Rarely, patients develop T1DM and central diabetes insipidus, and hypoparathyroidism is a rare occurrence. A growing clinical understanding of endocrine irAEs has led to effective treatment strategies with hormone replacement.

Transdermal estradiol for postpartum depression: results from a pilot randomized, double-blind, placebo-controlled study.

Postpartum depression (PPD) is a common complication following delivery, though evidence-based treatment options are limited. This study explores the feasibility and efficacy of outpatient PPD treatment with transdermal estradiol (TE). In a pilot, double-blind, placebo-controlled trial, women with PPD were randomized to receive transdermal 17ß-estradiol (100 mcg/day) or placebo patch. Over 6 weeks, women completed weekly ratings on the Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS), and Hamilton Depression Scale (HAM-D). Primary outcome measures were treatment response (> 50% decrease from baseline BDI) and remission (BDI < 10) at 6 weeks, and secondary outcome measures included severity on all scales at weeks 3 and 6. Of 12 recruited women, 6 received TE and 6 received placebo. By week 6, 5 women receiving TE responded to treatment and 4 showed symptom remission, compared to 2 responders and 1 remitter in the placebo group. This difference was not significant (p = 0.24). In a mixed-model of BDI ratings, TE was associated with a 9.2 point decrease at 3 weeks (95%CI - 19.5 to + 1.0, p = 0.074) and a 10.5 point decrease at 6 weeks (95%CI - 21.0-0.0, p = 0.049) compared to placebo, though these differences did not survive multiple comparisons correction. Analogous effects were found for HAM-D but not EPDS scores. Interestingly, no significant difference in plasma estradiol levels existed between groups. We were unable to demonstrate a significant therapeutic benefit of TE compared with placebo in PPD. Although limited by under-recruitment and loss to follow-up, our results suggest TE is a feasible option for outpatient PPD management, with preliminary evidence (based on secondary outcomes) for efficacy. Therapeutic effects may be seen as early as 3 weeks and may not directly depend on peripheral measures of estradiol.

Remission of hypertension after surgical cure of Cushing's syndrome.

CONTEXT: Hypertension associated with Cushing's syndrome (CS) increases cardiovascular risk. The time-course of improvement after cure is unclear. OBJECTIVE: To describe the time-course and predictors of blood pressure (BP) normalization during one year after surgical cure of CS. DESIGN: Retrospective chart review of 75 hypertensive adults cured of CS (72 with ACTH-dependent CS; 3 with adrenal adenoma). Hypertension was defined as current use of antihypertensives, a systolic BP >130 mm Hg, or diastolic BP >80 mm Hg. MAIN OUTCOME MEASURE(S): Remission of hypertension: BP ≤130/80 mm Hg and no antihypertensive medications. Improvement in hypertension: BP >130/80 mm Hg and decreased number or dose of medications, or blood pressure ≤130/80 with continued use of medications at constant dose. RESULTS: At postoperative discharge, 17 (23%, P < .001), 51 (68%, P < .001) and 7 (9%) patients had remission, improvement in hypertension or no change. Twenty-nine had no follow-up. Others achieved remission at 3 (n = 5), 6 (n = 6), or 12-months (n = 5). At the last evaluation, 33/75 (44%) had remission, 36/75 (48%) had improved hypertension and 6 were unchanged. Patients with improvement discontinued a median of one medication (P < .001). At 12-months, 27/42 (64%) patients had normal BP (P < .002). Longer estimated duration of CS (P = .0106), younger age (P = .0022), and lower baseline body mass index (P = .0413) predicted hypertension remission. CONCLUSIONS: About 80% of CS patients experienced BP normalization or improvement within 10 days of cure, but about half failed to normalize BP by one year. BP should be monitored after cure, and antihypertensive medications adjusted to avoid unwanted cardiovascular effects.