Possible Good News! Effects of Tubastatin A on Adrenocorticotropic Hormone Synthesis and Proliferation of Att-20 Corticotroph Tumor Cells

Posted on March 31, 2022 by MaryO
  • Rie HagiwaraDepartment of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
  • Kazunori KageyamaDepartment of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
  • Yasumasa IwasakiSuzuka University of Medical Science, Suzuka 510-0293, Japan
  • Kanako NiiokaDepartment of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
  • Makoto DaimonDepartment of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
Abstract

Cushing’s disease is an endocrine disorder characterized by hypercortisolism, mainly caused by autonomous production of ACTH from pituitary adenomas. Autonomous ACTH secretion results in excess cortisol production from the adrenal glands, and corticotroph adenoma cells disrupt the normal cortisol feedback mechanism. Pan-histone deacetylase (HDAC) inhibitors inhibit cell proliferation and ACTH production in AtT-20 corticotroph tumor cells. A selective HDAC6 inhibitor has been known to exert antitumor effects and reduce adverse effects related to the inhibition of other HDACs. The current study demonstrated that the potent and selective HDAC6 inhibitor tubastatin A has inhibitory effects on proopiomelanocortin (Pomc) and pituitary tumor-transforming gene 1 (Pttg1) mRNA expression, involved in cell proliferation. The phosphorylated Akt/Akt protein levels were increased after treatment with tubastatin A. Therefore, the proliferation of corticotroph cells may be regulated through the Akt-Pttg1 pathway. Dexamethasone treatment also decreased the Pomc mRNA level. Combined tubastatin A and dexamethasone treatment showed additive effects on the Pomc mRNA level. Thus, tubastatin A may have applications in the treatment of Cushing’s disease.

Access the PDF at https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ21-0778/_pdf/-char/en

 

Filed under: Cushing's, pituitary, Rare Diseases, Treatments | Tagged: , , , , | Leave a comment »

Association of Chronic Central Serous Chorioretinopathy with Subclinical Cushing’s Syndrome

Posted on March 30, 2022 by MaryO

https://doi.org/10.1016/j.ajoc.2022.101455

Abstract

Purpose

To report the clinical course of a patient with central serous chorioretinopathy (CSCR) secondary to subclinical hypercortisolism before and after adrenalectomy.

Observations

A 50-year-old female patient with multifocal, chronic CSCR was found to have an adrenal incidentaloma and was diagnosed with subclinical hypercortisolism. Patient elected to undergo minimally-invasive adrenalectomy and presented at 3 months after surgery without subretinal fluid.

Conclusions and Importance

Subclinical Cushing’s Syndrome (SCS) may present an underrecognized risk factor for developing chronic CSCR. Further investigation is needed to determine the threshold of visual comorbidity that may influence surgical management.

Keywords

Central serous chorioretinopathy
Subclinical Cushing’s syndrome
Hypercortisolism
Adrenalectomy
Retina
Surgical intervention

1. Introduction

Central serous chorioretinopathy (CSCR) is characterized by accumulation of fluid in the subretinal or sub-RPE space, often with consequential visual impairment. Chronic CSCR has been reported as a manifestation of hypercortisolism due to Cushing’s syndrome and subclinical hypercortisolism.1,2 However, the latter is often underrecognized owing to its inherently subtle nature and the optimal threshold for intervention based on associated comorbidities remains unclear. Herein we report the clinical course of a patient with CSCR secondary to subclinical hypercortisolism before and after adrenalectomy.

2. Case report

A 50-year-old female presented with blurred, discolored spots in the right eye for several months. Her past medical history included mild hypertension treated with amlodipine. Past ocular and family history were noncontributory.

On exam, Snellen visual acuity was 20/50 OD, 20/25 OS. Her pupils, intraocular pressure, and anterior segment exam were within normal limits. Dilated fundus exam revealed bilateral, multifocal areas of subretinal fluid and mottled pigmentary changes (Fig. 1A). Optical coherence tomography confirmed areas of subretinal fluid and other areas of outer retinal atrophy (Fig. 1B). Fundus autofluorescence revealed areas of hyperautofluorescence that highlighted the fundoscopic findings (Fig. 1C). Fluorescein angiography showed multifocal areas of expansile dot leakage (Fig. 1D). Altogether these findings were consistent with multifocal, chronic CSCR.

Fig. 1

  1. Download : Download high-res image (1MB)
  2. Download : Download full-size image

Fig. 1. Multimodal imaging of bilateral multifocal central serous chorioretinopathy. Fundus photographs reveal multifocal subretinal fluid and pigmentary changes (Fig. 1A). Optical coherence tomography demonstrates subretinal fluid and outer retinal atrophy (Fig. 1B). Areas of hyperautofluorescence highlight the fundoscopic findings of subretinal fluid (Fig. 1C). Fluorescein angiography showing multiple areas of expansile dot leakage (Fig. 1D).

On further clinical follow-up, an adrenal incidentaloma (AI) was detected when the patient underwent imaging for back pain. Subsequently she saw an endocrinologist; she had a normal serum cortisol, but low ACTH and an abnormal dexamethasone suppression test. This led to a diagnosis of subclinical hypercortisolism and provided a reason for her hypertension and chronic CSCR.

Since the blur and relative scotomata interfered with her daily activities, she elected to try eplerenone, which yielded a moderate but suboptimal therapeutic response at 50 mg daily. While contemplating photodynamic therapy, in discussion with her endocrinologist, the patient opted to undergo minimally-invasive adrenalectomy. At last follow-up 3 months after surgery and 6 years after her initial presentation, she has been off eplerenone and without subretinal fluid (Fig. 2).

Fig. 2

  1. Download : Download high-res image (1MB)
  2. Download : Download full-size image

Fig. 2. Optical coherence tomography imaging at presentation and at last follow-up 3 months after adrenalectomy. There is a significant improvement in subretinal fluid in both eyes, though outer retinal irregularity remains.

3. Discussion

CSCR has previously been associated with many risk factors including exposure to excess steroid. A recent study analyzing a nationally representative dataset of 35,000 patients found that patients with CSCR had a higher odds of Cushing’s syndrome (OR 2.19, 95% CI 1.33 to 3.59, p = 0.002) than exposure to exogenous steroids (OR 1.14, 95% CI 1.09 to 1.19, p < 0.001)1 Our case highlights the importance of thorough medication reconciliation and careful consideration of comorbid conditions in patients with chronic CSCR.

In recent years, subtle endogenous hypercortisolism, termed subclinical Cushing’s syndrome (SCS), has been of particular interest in the endocrinology literature because it can be a challenging diagnosis and the most appropriate management remains controversial.3 In general, SCS is comprised of: 1) the presence of an adrenal incidentaloma or mass, 2) biochemical confirmation of cortisol excess, and 3) no classic phenotypic manifestations of Cushing’s syndrome.4 Since adrenal incidentaloma has an estimated prevalence of 1–8% of the population,5 it is quite possible that SCS is an underrecognized risk factor for CSCR.

SCS may potentiate metabolic syndrome and osteoporosis; studies have found that surgical resection of adrenal incidentalomas improve weight, blood pressure, and glucose control. Consequently, some authors recommend those with SCS-associated comorbidities be considered for resection.6 An important consideration in these patients is how visual comorbidity factors into intervention. In our patient’s case, the recurrent CSCR, hypertension, and increased risk of metabolic syndrome were sufficient reasons to elect to have surgery.

4. Conclusion

In summary, SCS is a condition of subtle cortisol dysregulation that may represent an underrecognized risk factor for chronic CSCR. Further investigation is needed to determine the threshold of visual comorbidity that may influence surgical management.

Patient consent

Consent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.

Acknowledgments and Disclosures

Grant support was from the J. Arch McNamara Retina Research Fund. The following authors have no financial disclosures: RRS, AS, AC All authors attest that they meet the current ICMJE criteria for Authorship. No other contributions to acknowledge.

References

© 2022 The Authors. Published by Elsevier Inc.

Filed under: Cushing's, symptoms, Treatments | Tagged: , , | Leave a comment »

Increased Risk of Death in Cushing’s Disease Persists After Remission

Posted on March 28, 2022 by MaryO

An analysis of nationwide data from Sweden provides an overview of the increased risk of death associated with Cushing’s disease was present even after biochemical remission.

New data from an analysis of patient data over nearly 30 years suggests the increased risk of mortality associated with Cushing’s disease persists even after treatment.

A 4:1 matched analysis comparing data from 371 patients with Cushing’s disease with 1484 matched controls, indicated risk of mortality was 5-fold greater among those not in remission compared to matched controls, but even those in remission at the last follow-up were at a 50% greater risk of mortality compared to controls.

“To our knowledge, this is the first study that investigated mortality in an unselected cohort of patients treated for Cushing’s disease and followed up in comparison to mortality in matched controls. The mortality rate was more than doubled in patients with Cushing’s disease, and not being in remission was a strong predictor of premature death,” wrote investigators.

With a lack of consensus surrounding the impact of biochemical remission on life expectancy in patients with Cushing’s disease, a team of investigators from multiple institutions in Sweden designed their study with the intent of assessing this association with mortality in a time-to-event analysis of an unselected nationwide Cushing’s disease cohort. Using the Swedish Pituitary Registry, investigators identified 371 patients with Cushing’s disease for inclusion in their analysis.

The Swedish Pituitary Register is a nationwide registry that collected data on the majority of Swedish patients with Cushing’s disease. For the current study, investigators included all patients with Cushing’s disease from the register diagnosed between May 1991-September 2018 and followed these patients until the date of death, date of emigration, or December 26, 2018. From the register, investigators obtained data related to date of diagnosis, age, sex, treatment, and biochemical remission status evaluations.

The median age at diagnosis was 44 (IQR, 32-56) years and the median follow-up was 10.6 (IQR, 5.7-18) years. The remissions rates for the study cohort were 80%, 92%, 96%, 91%, and 97% at the 1-, 5-, 10-, 15- and 20-year follow-ups, respectively. These patients were matched in a 4:1 based on age, sex, and residential area at the diagnosis data, yielding a cohort of 1484 matched controls.

Upon analysis, the overall risk of mortality was greater among those with Cushing’s disease compared to the matched controls (HR, 2.1 [95% CI, 1.5-2.8]). Investigators pointed out increased risk was observed among patients in remission at the last follow-up (n=303; HR, 1.5 [95% CI, 1.02-2.2]), those in remission after a single pituitary surgery (n=177; HR, 1.7 [95% CI, 1.03-2.8]), and those not in remission (n=31; HR, 5.6 [95% CI, 2.7-11.6]). Additionally, results indicated cardiovascular disease and infections were the most overrepresented cases of death, accounting for 32 and 12 of the 66 total instances of mortality.

“The findings of the present study confirm and complement previous findings of increased overall mortality in Cushing’s disease patients, having a more than doubled HR for death compared to matched controls. Most importantly, an increased HR persisted among patients who had been successfully treated and reached a Cushing’s disease biochemical cure,” investigators added.

This study, “Increased mortality persists after treatment of Cushing’s disease: A matched nationwide cohort study,” was published in the Journal of the Endocrine Society.

 

Filed under: Cushing's, pituitary | Tagged: , , | Leave a comment »

Pregnancy Doesn’t Boost Cushing Disease Recurrences

Posted on March 25, 2022 by MaryO

Researchers published the study covered in this summary on Research Square as a preprint that has not yet been peer reviewed.

Key Takeaways

  • Among women who underwent pituitary surgery to treat Cushing disease subsequent pregnancy had no apparent effect on Cushing disease recurrence, in a single-center review of 113 women treated over a 30-year period.

Why This Matters

  • No single factor predicts the recurrence of Cushing disease during long-term follow-up of patients who have undergone pituitary surgery.
  • This is the first study to assess the effect of pregnancy on Cushing disease recurrence in a group of reproductive-age women who initially showed post-surgical remission.

Study Design

  • Retrospective study of 355 patients with confirmed Cushing disease who were admitted to a single tertiary hospital in Brazil between 1990 and 2020. All patients had transsphenoidal surgery, with a minimum follow-up of 6 months and median follow-up of 83 months. Remission occurred in 246 of these patients.
  • The current analysis focused on 113 of the patients who achieved remission, were women, were 45 years old or younger at time of surgery (median 32 years old), and had information available on their obstetric history.
  • Ninety-one of these women (81%) did not become pregnant after their surgery, and 22 (19%) became pregnant after surgery.

Key Results

  • Among the 113 women in the main analysis 43 (38%) had a Cushing disease recurrence, a median of 48 months after their pituitary surgery.
  • Following surgery, 11 women in each of the two subgroups (recurrence, no recurrence) became pregnant.
  • Although the subgroup with recurrence had a higher incidence of pregnancy (11/43; 26%) compared with those with no recurrence (11/70; 16%) Kaplan-Meier analysis showed that survival free of Cushing disease recurrence was similar and not significantly different in the women with a postsurgical pregnancy and those who did not become pregnant (P=.531).
  • The review also showed that, of the women who became pregnant, several obstetrical measures were similar between patients who had a recurrence and those who remained in remission, including number of pregnancies per patient, maternal weight gain, type of delivery (normal or cesarean), delivery time (term or premature), neonatal weight, and neonatal size. The review also showed roughly similar rates of maternal and fetal complications in these two subgroups of women who became pregnant.

Limitations

  • The study was retrospective and included a relatively small number of patients.
  • The authors collected information on obstetric history for some patients by telephone or email contacts.

Disclosures

  • The study received no commercial funding.
  • None of the authors had disclosures.

This is a summary of a preprint research study , ” Pregnancy After Pituitary Surgery Does Not Influence the Recurrence of Cushing‘ s Disease, “ written by researchers at the Sao Paulo (Brazil) University Faculty of Medicine on Research Square provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

Filed under: Cushing's, pituitary | Tagged: , , , | Leave a comment »

Copeptin Rules Out Diabetes Insipidus Post Pituitary Surgery

Posted on March 21, 2022 by MaryO

The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.

Key Takeaways

  • A study of 78 patients who underwent elective transsphenoidal adenomectomy to remove a pituitary tumor or other lesions within the pituitary fossa at a single center in the UK suggests that postoperative plasma levels of copeptin — a surrogate marker for levels of arginine vasopressin (antidiuretic hormone) — can rule out development of central (neurogenic) diabetes insipidus caused by a deficiency of arginine vasopressin following pituitary surgery.
  • The researchers suggest using as a cutoff a copeptin level of >3.4 pmol/L at postoperative day 1 to rule out diabetes insipidus. Such a cutoff yields the following:
    • A high sensitivity of 91% for ruling out diabetes insipidus.
    • A negative predictive value of 97%. Only 1 of 38 patients with a copeptin value >3.4 pmol/L at day 1 postoperatively developed diabetes insipidus.
    • A low specificity of 55%, meaning that copeptin level is not useful for diagnosing diabetes insipidus

Why This Matters

  • An estimated 1% to 67% of patients who undergo pituitary gland surgery develop diabetes insipidus, often soon after surgery, although it is often transient.
  • Diagnosing diabetes insipidus in such patients requires a combination of clinical assessment, the monitoring of fluid balance, and determining plasma and urine sodium and osmolality.
  • Currently, clinical laboratories in the UK do not have assays for arginine vasopressin, which has a short half-life in vivo and is unstable ex vivo, even when frozen, and is affected by delayed or incomplete separation from platelets.
  • Copeptin, an arginine vasopressin precursor, is much more stable and measurable by commercial immunoassays.
  • The findings suggest that patients who have just undergone pituitary gland surgery and are otherwise healthy and meet the copeptin cutoff for ruling out diabetes insipidus could be discharged 24 hours after surgery and that there is no need for additional clinical and biochemical monitoring. This change would ease demands on the healthcare system.

Study Design

  • The study reviewed 78 patients who underwent elective transsphenoidal adenomectomy to remove a pituitary tumor from November 2017 to June 2020 at the John Radcliffe Hospital in Oxford, United Kingdom.
  • Patients remained in hospital for a minimum of 48 hours after their surgery.
  • Clinicians collected blood and urine specimens preoperatively and at day 1, day 2, day 8, and week 6 post surgery.
  • The patients were restricted to 2 L of fluid a day postoperatively to prevent masking of biochemical abnormalities through compensatory drinking.
  • Diabetes insipidus was suspected when patients’ urine output was >200 mL/h for 3 consecutive hours or >3 L/d plus high plasma sodium (>145 mmol/L) and plasma osmolality (> 295 mosmol/kg) plus inappropriately low urine osmolality. Definitive diagnosis of diabetes insipidus was based on clinical assessment, urine and plasma biochemistry, and need for treatment with desmopressin (1-deamino-8-D-arginine vasopressin).

Key Results

  • The median age of the patients was 55, and 53% were men; 92% of the lesions were macroadenomas; the most common histologic type was gonadotroph tumor (47%).
  • Among the 78 patients, 11 (14%) were diagnosed with diabetes insipidus postoperatively and required treatment with desmopressin; of these, seven patients (9%) continued taking desmopressin after 6 weeks (permanent diabetes insipidus), but the other four did not need to take desmopressin for more than a week.
  • Patients who developed diabetes insipidus were younger than other patients (mean age, 46 vs 56), and 8 of the 11 patients who developed diabetes insipidus (73%) were women.
  • Preoperative copeptin levels were similar in the two groups. At day 1, day 8, and 6 weeks postoperatively, copeptin levels were significantly lower in the diabetes insipidus group; there were no significant differences at day 2, largely because of an outlier result.
  • An area under the receiver operating characteristic curve (AUC; C-statistic) analysis showed that on day 1 after surgery, copeptin levels could account for 74.22% of the incident cases of diabetes insipidus (AUC, 0.7422). On postop day 8, the AUC for copeptin was 0.8015, and after 6 weeks, the AUC associated with copeptin was 0.7321.

Limitations

  • Blood samples for copeptin tests from patients who underwent pituitary surgery were collected at specified times and were frozen for later analysis; performing the test in real time might alter patient management.
  • The study may have missed peak copeptin levels by not determining copeptin levels sooner after pituitary gland surgery, inasmuch as other researchers have reported better predictive values for diagnosing diabetes insipidus from samples taken 1 hour after extubation or <12 hours after surgery.

Disclosures

  • The study did not receive commercial funding.
  • The authors report no relevant financial relationships.

This is a summary of a preprint research study, “Post-Operative Copeptin Analysis Predicts Which Patients Do Not Develop Diabetes Insipidus After Pituitary Surgery,” by researchers from John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, in the United Kingdom. Preprints from Research Square are provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

Read the article here: https://www.medscape.com/viewarticle/970357#vp_1

Filed under: Cushing's, pituitary, Treatments | Tagged: , , , , | Leave a comment »

Next Page »
%d bloggers like this: