Sexual Dimorphism in Cellular and Molecular Features in Human ACTH-Secreting Pituitary Adenomas

(1) Background. Cushing’s disease presents gender disparities in prevalence and clinical course. Little is known, however, about sexual dimorphism at the level of the corticotrope adenoma itself. The aim of the present study was to evaluate molecular features of ACTH-secreting pituitary adenomas collected from female and male patients with Cushing’s disease. (2) Methods. We analyzed 153 ACTH-secreting adenomas collected from 31 men and 122 women. Adenomas were established in culture and ACTH synthesis and secretion assessed in basal conditions as well as during incubation with CRH or dexamethasone. Concurrently, microarray analysis was performed on formalin-fixed specimens and differences in the expression profiles between specimens from male and female patients identified. (3) Results. ACTH medium concentrations in adenomas obtained from male patients were significantly lower than those observed in adenomas from female patients. This could be observed for baseline as well as modulated secretion. Analysis of corticotrope transcriptomes revealed considerable similarities with few, selected differences in functional annotations. Differentially expressed genes comprised genes with known sexual dimorphism, genes involved in tumour development and genes relevant to pituitary pathophysiology. (4) Conclusions. Our study shows for the first time that human corticotrope adenomas present sexual dimorphism and underlines the need for a gender-dependent analysis of these tumours. Differentially expressed genes may represent the basis for gender-tailored target therapy.

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Mutation and Expression Analysis of Corticotropin-Releasing Factor 1 Receptor in Adrenocorticotropin-Secreting Pituitary Adenomas1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.9.5114 ◽

1998 ◽

Vol 83 (9) ◽

pp. 3327-3331

Author(s):

K. D. Dieterich ◽

E. D. Gundelfinger ◽

D. K. Lüdecke ◽

H. Lehnert

Keyword(s):

Expression Analysis ◽

Cushing’S Disease ◽

Pituitary Adenomas ◽

Messenger Rna ◽

Corticotropin Releasing Factor ◽

Cushing's Disease ◽

Receptor Regulation ◽

R Gene ◽

Acth Secreting

The present study was designed to investigate a possible role of CRF1 receptors (CRF1-R) in the pathogenesis of Cushing’s disease. ACTH-secreting pituitary adenomas and nonsecreting pituitary adenomas have been analyzed for mutations in the CRF1-R gene by PCR and sequencing and been compared with the sequences of normal anterior pituitaries. No mutations affecting the CRF1-R protein have been found in all tumors analyzed. However, we found a significant overexpression of the CRF1-R messenger RNA in ACTH-secreting pituitary adenomas vs. inactive adenomas and normal pituitaries. We conclude that mutations of the CRF1-R are unlikely to be involved in Cushing’s disease. We suggest that the overexpression of the CRF1-R messenger RNA may be related to a disturbed receptor regulation in ACTH-secreting pituitary adenomas.

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Corticotrophin-releasing activity of desmopressin in Cushing's disease: lack of correlation between in vivo and in vitro responsiveness

Journal of Endocrinology ◽

10.1677/joe.0.1770373 ◽

2003 ◽

Vol 177 (3) ◽

pp. 373-379 ◽

Cited By ~ 16

Author(s):

F Pecori Giraldi ◽

E Marini ◽

E Torchiana ◽

P Mortini ◽

A Dubini ◽

...

Keyword(s):

Cushing’S Disease ◽

Pituitary Adenomas ◽

Receptor Gene ◽

Normal Subjects ◽

Cushing's Disease ◽

Receptor Antagonists ◽

Releasing Effect ◽

Acth Secreting

Desmopressin (DDAVP), an arginine vasopressin analogue, markedly stimulates ACTH secretion in patients with Cushing's disease, in contrast to its minimal effect in normal subjects. However, little is known about the mechanisms underlying this action and it appeared to be of interest to evaluate the effect of DDAVP on ACTH-secreting pituitary adenomas in vitro, in comparison with its effect in the same patients in vivo. Pituitary adenomas from 14 patients with Cushing's disease were incubated with DDAVP, corticotrophin-releasing hormone (CRH) and DDAVP together with vasopressin receptor antagonists or CRH. Incubation with DDAVP induced a modest dose-dependent increase in ACTH concentrations which appeared maximal at 10 nM. CRH stimulated ACTH to a greater extent compared with DDAVP and potentiated the effect of DDAVP alone. The DDAVP-induced ACTH increase appeared blunted by vasopressin V(2) and V(3) receptor antagonists. V(3) receptor gene expression was detected by RT-PCR in all adenoma samples except for two which were not responsive to DDAVP in vitro but responsive to the peptide in vivo. Surprisingly, no difference in the in vitro ACTH secretory response was observed between in vivo DDAVP-responsive (ACTH peak>150% baseline) and -unresponsive (ACTH peak<120% baseline) patients, suggesting that the pituitary adenoma is not the sole mediator of the ACTH-releasing effect of DDAVP. In conclusion, the marked stimulatory effect of DDAVP observed in patients with Cushing's disease appears to be mainly dependent on an extrapituitary action, possibly the inhibition of a corticotrophin release-inhibitory factor.

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Pituitary Adenomas with Changing Phenotype: A Systematic Review

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1120-8277 ◽

2020 ◽

Vol 128 (12) ◽

pp. 835-844

Author(s):

Fernando Guerrero-Pérez ◽

Agustina Pia Marengo ◽

Noemi Vidal ◽

Carles Villabona

Keyword(s):

Systematic Review ◽

Cushing’S Disease ◽

Pituitary Adenomas ◽

Tumor Resection ◽

Cushing's Disease ◽

Complete Tumor Resection ◽

Null Cell ◽

Acth Secreting ◽

Complete Tumor

Abstract Purpose and Methods Phenotype transformation in pituitary adenomas (PA) is a little known and unexpected clinical phenomenon. We describe two illustrative cases and performed a systematic review of cases reported in literature. Results Case 1: A 24-year-old woman underwent surgery because of Cushing’s disease. A complete tumor resection and hypercortisolism resolution was achieved. Two years later, tumor recurred but clinical and hormonal hypercortisolism were absent. Case 2: A 77-year-old woman underwent surgery due to acromegaly. A complete tumor resection and GH excess remission was achieved. Four years later, tumor recurred but clinical and hormonal acromegaly was ruled out. Search of literature: From 20 patients (including our cases), 75% were female with median age 45 (19) years. Ten patients (50%) had initially functioning PA: 8 switched to NFPA (5 ACTH-secreting PA, 2 prolactinomas and 1 acromegaly) and 2 exchanged to acromegaly from TSH-secreting PA and microprolactinoma. One patient developed a pituitary carcinoma from ACTH-secreting PA. Ten patients (50%) initially had NFPA; 9 developed Cushing’s disease (4 silent corticotroph adenomas, 4 null cell PA and 1 managed conservatively). One patient with silent somatotroph PA changed to acromegaly. Treatments before transformation were surgery (80%), radiotherapy (40%), pharmacological (40%) and in 2 patients switching happened without any treatment. Median follow-up until transformation was 72 months (range 12–276). Conclusion PA can change from functioning to (NF) non-functioning (vice versa) and even exchange their hormonal expression. Clinicians should be aware and a careful lifelong follow-up is mandatory to detect it.

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TMOD-49. ANTITUMOR EFFICACY OF ANTI-PDL1 IN ACTH-SECRETING PITUITARY ADENOMAS: AN IMMUNOTHERAPEUTIC APPROACH FOR CUSHING’S DISEASE

Neuro-Oncology ◽

10.1093/neuonc/nox168.1085 ◽

2017 ◽

Vol 19 (suppl_6) ◽

pp. vi264-vi265

Author(s):

Aladine A Elsamadicy ◽

S Harrison Farber ◽

Pakawat Chongsathidkiet ◽

Hanna Kemeny ◽

Karolina Woroniecka ◽

...

Keyword(s):

Cushing’S Disease ◽

Pituitary Adenomas ◽

Antitumor Efficacy ◽

Cushing's Disease ◽

Immunotherapeutic Approach ◽

Acth Secreting

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Diagnosis, Manifestations, Laboratory Investigations, and Prognosis in Pediatric and Adult Cushing’s Disease in a Large Center in China

Frontiers in Endocrinology ◽

10.3389/fendo.2021.749246 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xueqing Zheng ◽

He Wang ◽

Wentai Zhang ◽

Shanshan Feng ◽

Yifan Liu ◽

...

Keyword(s):

Hair Loss ◽

Cushing’S Disease ◽

Clinical Manifestations ◽

Adult Patients ◽

Cushing's Disease ◽

Systematic Comparison ◽

Female Patients ◽

Significant Difference ◽

Male Patients ◽

The Impact

PurposeCushing’s disease (CD) is a rare disease that contributes to 70–80% hypercortisolemia, which presents similarities and differences between pediatric and adult patients, and even between male and female patients. However, the comparative study of CD between different age groups and different genders is still insufficient. The aim of the study is to make a systematic comparison to reveal the gender differences in children and adult patients of CD, helping clinicians to provide optimal treatment for different groups of patients.MethodsWe conducted a retrospective research consisting of 30 pediatric and 392 adult CD patients in a single center in Peking Union Medical College Hospital. All 422 patients showed symptoms related to hypercortisolism and received adenoma excision surgery in the department of neurosurgery between 2014 and 2020.ResultsFor the accuracy of diagnosis, the sensitivity of BIPSS at baseline in pediatric patients was lower than in adults (75 vs. 91%, P = 0.054) but increased greatly after desmopressin stimulation (94 vs. 95%). However, the accuracy of lateralization for BIPSS was not preferred for prediction. As for clinical manifestations, growth retardation, weight gain, hirsutism, and acne were more prevalent for children, while for adults, hypertension, osteopenia, glucometabolic disorder, easy bruising, hair loss, and weight loss were more frequently seen. As previously reported, we observed a significant difference between the male prevalence of pediatric and adult patients (50 vs. 17%, P < 0.001), which was possibly caused by the more severe and earlier onset of a series of symptoms. Gender-related comparison showed greater morbidity of nephrolithiasis, hypokalemia, hypertension, easy bruising, osteopenia, and striae for male patients, while irregular menses, hirsutism, and hair loss were more common for female patients. Further analysis showed that the secretory activity of the PA axis was higher for males, presenting as the more remarkable alteration of laboratory parameters and contributing to the more severe clinical manifestations. For patients treated with transsphenoidal pituitary surgery (TSS), the immediate prognosis could be predicted by operation history, invasiveness, Ki-67, and information provided by MRI, including tumor size and Knosp grading. However, we still lack methods to predict long-term prognosis.ConclusionsOur study is the first detailed and systematic comparison between pediatric and adult CD patients. Further exploration of the impact of CD on different genders reveals a more severe and probably an earlier-onset pattern of CD for male patients.

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301 Antitumor Efficacy of Anti-PDL-1 In ACTH-Secreting Pituitary Adenomas: A Novel Immunotherapeutic Approach for Cushing's Disease

Neurosurgery ◽

10.1093/neuros/nyy303.301 ◽

2018 ◽

Vol 65 (CN_suppl_1) ◽

pp. 122-123

Author(s):

Hanna Kemeny ◽

Aladine A Elsamadicy ◽

S. Harrison Farber ◽

Pakawat Chongsathidkiet ◽

Cosette Dechant ◽

...

Keyword(s):

Cushing’S Disease ◽

Pituitary Adenomas ◽

Antitumor Efficacy ◽

Cushing's Disease ◽

Immunotherapeutic Approach ◽

Acth Secreting

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Sleep quality and daytime sleepiness in patients with Cushing's disease and patients with non-functioning pituitary adenomas

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0030-1267006 ◽

2010 ◽

Vol 118 (08) ◽

Author(s):

C Dimopoulou ◽

S Fulda ◽

H Pfister ◽

J Schopohl ◽

GK Stalla ◽

...

Keyword(s):

Sleep Quality ◽

Cushing’S Disease ◽

Daytime Sleepiness ◽

Pituitary Adenomas ◽

Cushing's Disease ◽

Non Functioning Pituitary Adenomas

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MANAGEMENT OF ENDOCRINE DISEASE: Paediatric Cushing's disease

Acta Endocrinologica ◽

10.1530/eje-15-0013 ◽

2015 ◽

Vol 173 (1) ◽

pp. R35-R45 ◽

Cited By ~ 24

Author(s):

Helen L Storr ◽

Martin O Savage

Keyword(s):

Early Diagnosis ◽

Clinical Diagnosis ◽

Cushing’S Disease ◽

Therapeutic Strategy ◽

Cushing's Disease ◽

Significant Morbidity ◽

Endocrine Disease ◽

Definition Of ◽

Acth Secreting ◽

Biochemical Features

Cushing's disease (CD) is the commonest form of ACTH-dependent Cushing's syndrome and is a rare clinical diagnosis in paediatric and adolescent patients. CD is caused by an ACTH-secreting pituitary corticotroph adenoma and is associated with significant morbidity in children; therefore, early diagnosis and treatment are critical for optimal therapeutic outcome. This review highlights the key clinical and biochemical features of paediatric CD and appraises current practices in diagnosis and management. A close liaison with adult endocrinology colleagues, particularly, for interpretation of investigations and definition of therapeutic strategy is strongly advised.

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Gamma Knife surgery for Cushing's disease

Journal of Neurosurgery ◽

10.3171/jns.2007.106.6.980 ◽

2007 ◽

Vol 106 (6) ◽

pp. 980-987 ◽

Cited By ~ 192

Author(s):

Jay Jagannathan ◽

Jason P. Sheehan ◽

Nader Pouratian ◽

Edward R. Laws ◽

Ladislau Steiner ◽

...

Keyword(s):

Gamma Knife ◽

Cushing’S Disease ◽

Pituitary Adenomas ◽

Cranial Nerve ◽

Gamma Knife Surgery ◽

Cushing's Disease ◽

Free Cortisol ◽

Radiation Induced ◽

The Mean

Object In this study the authors address the efficacy and safety of Gamma Knife surgery (GKS) in patients with adrenocorticotropic hormone–secreting pituitary adenomas. Methods A review of data collected from a prospective GKS database between January 1990 and March 2005 was performed in patients with Cushing's disease. All but one patient underwent resection for a pituitary tumor, without achieving remission. Successful endocrine outcome after GKS was defined as a normal 24-hour urinary free cortisol (UFC) concentration posttreatment after a minimum of 1 year of follow up. Patient records were also evaluated for changes in tumor volume, development of new hormone deficiencies, visual acuity, cranial nerve neuropathies, and radiation-induced imaging changes. Ninety evaluable patients had undergone GKS, with a mean endocrine follow-up duration of 45 months (range 12–132 months). The mean dose to the tumor margin was 23 Gy (median 25 Gy). Normal 24-hour UFC levels were achieved in 49 patients (54%), with an average time of 13 months after treatment (range 2–67 months). In the 49 patients in whom a tumor was visible on the planning magnetic resonance (MR) image, a decrease in tumor size occurred in 39 (80%), in seven patients there was no change in size, and tumor growth occurred in three patients. Ten patients (20%) experienced a relapse of Cushing's disease after initial remission; the mean time to recurrence was 27 months (range 6–60 months). Seven of these patients underwent repeated GKS, with three patients achieving a second remission. New hormone deficiencies developed in 20 patients (22%), with hypothyroidism being the most common endocrinopathy after GKS. Five patients experienced new visual deficits or third, fourth, or sixth cranial nerve deficits; two of these patients had undergone prior conventional fractionated radiation therapy, and four of them had received previous GKS. Radiation-induced changes were observed on MR images in three patients; one had symptoms attributable to these changes. Conclusions Gamma Knife surgery is an effective treatment for persistent Cushing's disease. Adenomas with cavernous sinus invasion that are not amenable to resection are treatable with the Gamma Knife. A second GKS treatment appears to increase the risk of cranial nerve damage. These results demonstrate the value of combining two neurosurgical treatment modalities—microsurgical resection and GKS—in the management of pituitary adenomas.

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