Cushing‚Äôs Syndrome Diagnostic and Treatment Market See Huge Growth for New Normal

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Cushing’s Syndrome Diagnostic and Treatment Market research report is the new statistical data source added by Research Cognizance.

‚ÄúCushing‚Äôs Syndrome Diagnostic and Treatment Market is growing at a High CAGR during the forecast period 2022-2029. The increasing interest of the individuals in this industry is that the major reason for the expansion of this market‚ÄĚ.

Cushing’s Syndrome Diagnostic and Treatment Market research is an intelligence report with meticulous efforts undertaken to study the right and valuable information. The data which has been looked upon is done considering both, the existing top players and the upcoming competitors. Business strategies of the key players and the new entering market industries are studied in detail. Well explained SWOT analysis, revenue share, and contact information are shared in this report analysis.

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Top Key Players Profiled in this report are:

Novartis, Orphagen Pharmaceuticals, Inc., Corcept Therapeutics

The key questions answered in this report:

  • What will be the Market Size and Growth Rate in the forecast year?
  • What are the Key Factors driving Cushing‚Äôs Syndrome Diagnostic and Treatment Market?
  • What are the Risks and Challenges in front of the market?
  • Who are the Key Vendors in Cushing‚Äôs Syndrome Diagnostic and Treatment Market?
  • What are the Trending Factors influencing the market shares?
  • What are the Key Outcomes of Porter‚Äôs five forces model?
  • Which are the Global Opportunities for Expanding the Cushing‚Äôs Syndrome Diagnostic and Treatment Market?

Various factors are responsible for the market’s growth trajectory, which are studied at length in the report. In addition, the report lists down the restraints that are posing threat to the global Cushing’s Syndrome Diagnostic and Treatment market. It also gauges the bargaining power of suppliers and buyers, threat from new entrants and product substitute, and the degree of competition prevailing in the market. The influence of the latest government guidelines is also analyzed in detail in the report. It studies the Cushing’s Syndrome Diagnostic and Treatment market’s trajectory between forecast periods.

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Regions Covered in the Global Cushing’s Syndrome Diagnostic and Treatment Market Report 2022:
‚Äʬ†The Middle East and Africa¬†(GCC Countries and Egypt)
‚Äʬ†North America¬†(the United States, Mexico, and Canada)
‚Äʬ†South America¬†(Brazil etc.)
‚Äʬ†Europe¬†(Turkey, Germany, Russia UK, Italy, France, etc.)
‚Äʬ†Asia-Pacific¬†(Vietnam, China, Malaysia, Japan, Philippines, Korea, Thailand, India, Indonesia, and Australia)

The cost analysis of the Global Cushing’s Syndrome Diagnostic and Treatment Market has been performed while keeping in view manufacturing expenses, labor cost, and raw materials and their market concentration rate, suppliers, and price trend. Other factors such as Supply chain, downstream buyers, and sourcing strategy have been assessed to provide a complete and in-depth view of the market. Buyers of the report will also be exposed to a study on market positioning with factors such as target client, brand strategy, and price strategy taken into consideration.

The report provides insights on the following pointers:

Market Penetration: Comprehensive information on the product portfolios of the top players in the Cushing’s Syndrome Diagnostic and Treatment market.

Product Development/Innovation: Detailed insights on the upcoming technologies, R&D activities, and product launches in the market.

Competitive Assessment: In-depth assessment of the market strategies, geographic and business segments of the leading players in the market.

Market Development: Comprehensive information about emerging markets. This report analyzes the market for various segments across geographies.

Market Diversification: Exhaustive information about new products, untapped geographies, recent developments, and investments in the Cushing’s Syndrome Diagnostic and Treatment market.

Table of Content
Global Cushing’s Syndrome Diagnostic and Treatment Market Research Report
Chapter 1: Global Cushing’s Syndrome Diagnostic and Treatment Industry Overview
Chapter 2: Global Economic Impact on Cushing’s Syndrome Diagnostic and Treatment Industry
Chapter 3: Global Market Competition by Industry Producers
Chapter 4: Global Productions, Revenue (Value), according to regions
Chapter 5: Global Supplies (Production), Consumption, Export, Import, geographically
Chapter 6: Global Productions, Revenue (Value), Price Trend, Product Type
Chapter 7: Global Market Analysis, on the basis of Application
Chapter 8: Cushing’s Syndrome Diagnostic and Treatment Market Pricing Analysis
Chapter 9: Market Chain, Sourcing Strategy, and Downstream Buyers
Chapter 10: Strategies and key policies by Distributors/Suppliers/Traders
Chapter 11: Key Marketing Strategy Analysis, by Market Vendors
Chapter 12: Market Effect Factors Analysis
Chapter 13: Global Cushing’s Syndrome Diagnostic and Treatment Market Forecast

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Sparsely Granulated Corticotroph Pituitary Macroadenoma Presenting with Pituitary Apoplexy Resulting in Remission of Hypercortisolism

https://doi.org/10.1016/j.aace.2022.04.003Get rights and content
Under a Creative Commons license
Open access

Highlights

‚ÄĘ We describe a rare case of a patient with a sparsely granulated corticotroph pituitary macroadenoma with pituitary apoplexy who underwent transsphenoidal resection resulting in remission of hypercortisolism.
‚ÄĘ Corticotroph adenomas are divided into densely granulated, sparsely granulated and Crooke‚Äôs cell tumors.
‚ÄĘ macroadenomas account for 7-23% of patients with pituitary corticotroph adenomas
‚ÄĘ Sparsely granulated corticotroph tumors are associated with longer duration of Cushing disease prior to diagnosis, larger tumor size at diagnosis, decreased immediate remission rate, increased proliferative marker Ki-67 and increased recovery time of hypothalamic-pituitary-adrenal axis after surgery.
‚ÄĘ Granulation pattern is an important clinicopathological distinction impacting the behavior and treatment outcomes of pituitary corticotroph adenomas

Abstract

Background

/Objective: Pituitary corticotroph macroadenomas, which account for 7% to 23% of corticotroph adenomas, rarely present with apoplexy. The objective of this report is to describe a patient with a sparsely granulated corticotroph tumor (SGCT) presenting with apoplexy and remission of hypercortisolism.

Case Report

A 33-year-old male presented via ambulance with sudden onset of severe headache and nausea/vomiting. Physical exam revealed bitemporal hemianopsia, diplopia from right-sided third cranial nerve palsy, abdominal striae, facial plethora, dorsal and supraclavicular fat pad. Magnetic resonance imaging (MRI) demonstrated a 3.2 cm mass arising from the sella turcica with hemorrhage compressing the optic chiasm, extension into the sphenoid sinus and cavernous sinus. Initial investigations revealed plasma cortisol of 64.08 mcg/dL (Reference Range (RR), 2.36 ‚Äď 17.05). He underwent emergent transsphenoidal surgery. Pathology was diagnostic of SGCT. Post-operatively, cortisol was <1.8ug/dL (RR, 2.4 ‚Äď 17), adrenocorticotropic hormone (ACTH) 36 pg/mL (RR, 0 ‚Äď 81), thyroid stimulating hormone (TSH) 0.07 uIU/mL (RR, 0.36 – 3.74), free thyroxine 1 ng/dL (RR, 0.8 ‚Äď 1.5), luteinizing hormone (LH) <1 mIU/mL (RR, 1 ‚Äď 12), follicle stimulating hormone (FSH) 1 mIU/mL (RR, 1 ‚Äď 12) and testosterone 28.8 ng/dL (RR, 219.2 ‚Äď 905.6) with ongoing requirement for hydrocortisone, levothyroxine, testosterone replacement and continued follow-up.

Discussion

Corticotroph adenomas are divided into densely granulated, sparsely granulated and Crooke’s cell tumors. Sparsely granulated pattern is associated with larger tumor size and decreased remission rate after surgery.

Conclusion

This report illustrates a rare case of hypercortisolism remission due to apoplexy of a SGCT with subsequent central adrenal insufficiency, hypothyroidism and hypogonadism.

Keywords

pituitary apoplexy
pituitary macroadenoma
pituitary tumor
sparsely granulated corticotroph tumor
Cushing disease

Introduction

The incidence of Cushing Disease (CD) is estimated to be between 0.12 to 0.24 cases per 100,00 persons per year1,2. Of these, 7-23% are macroadenomas (>1 cm)3, 4, 5. Pituitary apoplexy is a potentially life-threatening endocrine and neurosurgical emergency which occurs due to infarction or hemorrhage in the pituitary gland. Apoplexy occurs most commonly in non-functioning macroadenomas with an estimated prevalence of 6.2 cases per 100,000 persons and incidence of 0.17 cases per 100,00 persons per year6. Corticotroph macroadenoma presenting with apoplexy is uncommon with only a handful of reports in the literature7. We present a case of a sparsely granulated corticotroph (SGCT) which presented with apoplexy leading to remission of hypercortisolism and subsequent central adrenal insufficiency.

Case Presentation

A 33-year-old male who was otherwise healthy and not on any medications presented to a community hospital with sudden and severe headache accompanied by hypotension, nausea, vomiting, bitemporal hemianopsia and diplopia. Computed Tomography (CT) scan of the brain demonstrated a hyperattenuating 2.0 cm x 2.8 cm x 1.5 cm mass at the sella turcica with extension into the right cavernous sinus and encasement of the right internal carotid arteries (Figure 1A). He was transferred to a tertiary care center for neurosurgical management with endocrinology consultation post-operatively.

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Figure 1. hyperattenuating 2.0 cm x 2.8 cm x 1.5 cm mass at the sella turcica on unenhanced CT (A); MRI demonstrated a 1.9 cm x 3.2 cm x 2.4 cm heterogeneous mass on T1 (B) and T2-weighted imaging (C) showing small hyperintense areas in solid part of the sella mass with flattening of the optic chiasm, remodeling/dehiscence of the floor of the sella and extending into the right cavernous sinus with at least partial encasement of the ICA

In retrospect, he reported a 3-year history of ongoing symptoms of hypercortisolism including increased central obesity, dorsal and supraclavicular fat pad, facial plethora, abdominal purple striae, easy bruising, fatigue, decreased libido and erectile dysfunction. Notably, at the time of presentation he did not have a history of diabetes, hypertension, osteoporosis, fragility fractures or proximal muscle weakness. He fathered 2 children previously. His physical examination was significant for Cushingoid facies, facial plethora, dorsal and supraclavicular fat pads and central obesity with significant axillary and abdominal wide purple striae (Figure 2). Neurological examination revealed bitemporal hemianopsia, right third cranial nerve palsy with ptosis and impaired extraocular movement. The fourth and sixth cranial nerves were intact as was the rest of his neurological exam. These findings were corroborated by Ophthalmology.

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Figure 2. Representative images illustrating facial plethora (A); abdominal striae (B, C); supraclavicular fat pad (D); dorsal fat pad (E)

Initial laboratory data at time of presentation to the hospital included elevated plasma cortisol of 64.08ug/dL (RR, 2.36 ‚Äď 17.05), ACTH was not drawn at the time of presentation, normal TSH 0.89 mIU/L (RR, 0.36 ‚Äď 3.74), free thyroxine 0.91ng/dL (RR, 0.76 ‚Äď 1.46), evidence of central hypogonadism with low total testosterone 28.8 ng/dL (RR, 219.2 ‚Äď 905.6) and inappropriately normal luteinizing hormone (LH) 1mIU/mL (RR, 1 ‚Äď 12) and follicle stimulating hormone (FSH) 3mIU/mL (RR, 1 ‚Äď 12), low prolactin <1 ng/mL (RR, 3 ‚Äď 20), and normal insulin growth factor ‚Äď 1 (IGF‚Äď1) 179ng/mL (RR, 82 ‚Äď 242).

A pituitary gland dedicated MRI was performed to further characterize the mass, which re-demonstrated a 1.9 cm x 3.2 cm x 2.4 cm heterogenous mass at the sella turcica extending superiorly and flattening the optic chiasm, remodeling of the floor of the sella and bulging into the sphenoid sinus and extending laterally into the cavernous sinus with encasement of the right internal carotid artery (ICA). As per the radiologist‚Äôs diagnostic impression, this appearance was most in keeping with a pituitary macroadenoma with apoplexy (Figure 1B ‚Äď C).

The patient underwent urgent TSS and decompression with no acute complications. Pathological examination of the pituitary adenoma showed features characteristic of sparsely granulated corticotroph pituitary neuroendocrine tumor (adenoma)8, with regional hemorrhage and tumor necrosis (apoplexy). The viable tumor exhibited a solid growth pattern (Figure 3A), t-box transcription factor (T-pit) nuclear immunolabeling (Figure 3B), diffuse cytoplasmic CAM5.2 (low molecular weight cytokeratin) immunolabeling (Figure 3C), and regional weak to moderate intense granular cytoplasmic ACTH immuno-staining (Figure 3D). The tumor was immuno-negative for: pituitary-specific positive transcription factor 1 (Pit-1) and steroidogenic factor 1 (SF-1) transcription factors, growth hormone, prolactin, TSH, FSH, LH, estrogen receptor-alpha, and alpha-subunit. Crooke hyalinization was not identified in an adjacent compressed fragment of non-adenomatous anterior pituitary tissue. Ki-67 immunolabeling showed a 1.5% proliferative index (11 of 726 nuclei).

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Figure 3.¬†Hematoxylin phloxine saffron staining showing adenoma with solid growth pattern (A); immunohistochemical staining showing T-pit reactivity of tumor nuclei (B); diffuse cytoplasmic staining for cytokeratin CAM5.2 (C); and regional moderately intense granular cytoplasmic staining for ACTH (D). Scale bar = 20 őľm

Post-operatively, he developed transient central diabetes insipidus requiring desmopressin but resolved on discharge. His postoperative cortisol was undetectable, ACTH 36 pg/mL (RR, 0 Р81), TSH 0.07 mIU/mL (RR, 0.36 Р3.74), free thyroxine 1 ng/dL (RR, 0.8 Р1.5), LH <1mIU/mL (RR, 1 Р12), FSH 1 mIU/mL (RR, 1 Р12) and testosterone 28.8 ng/dL (RR, 219.2 Р905.6) (Table 1 and Figure 4). One month later, he reported 15 pounds of weight loss and a 5-inch decrease in waist circumference. He also noted a reduction in the dorsal and supraclavicular fat pads, facial plethora, and Cushingoid facies as well as fading of the abdominal stretch marks. His visual field defects and right third cranial nerve palsy resolved on follow up with ophthalmology post-operatively. Repeat MRI six months post-operatively showed minor residual soft tissue along the floor of the sella. He is being followed by Neurosurgery, Ophthalmology, and Endocrinology for monitoring of disease recurrence, visual defects, and management of hypopituitarism.

Table 1. Pre- and post-operative hormonal panel

POD -1 POD 0 POD1 POD2 POD3 POD16 6 -9 months Comments
Cortisol(2.4 ‚Äď 17 ug/dL) 64‚Üď 32‚Üď 11‚Üď <1.8‚Üď <1.8‚Üď 1.8‚Üď HC started POD3 post bloodwork
ACTH(0 ‚Äď 81 pg/mL) 41‚Üď 36‚Üď 28‚Üď 13‚Üď
TSH(0.36 – 3.74 uIU/mL) 0.89 0.43 0.12‚Üď 0.07‚Üď 0.05‚Üď 0.73
Thyroxine, free(0.8 ‚Äď 1.5 ng/dL) 0.9 0.9 1.1 1 2.1‚ÜĎ 1 Levothyroxine started POD4
LH(1 ‚Äď 12 miU/mL) 1‚Üď <1‚Üď 1‚Üď 3
FSH(1 ‚Äď 12 mIU/mL) 3‚Üď 1‚Üď 1‚Üď 3
Testosterone(219.2 ‚Äď 905.6 ng/dL) 28.8‚Üď <20‚Üď 175.9‚Üď Testosterone replacement started as outpatient
Testosterone, free(160 – 699 pmol/L) <5.8‚Üď 137‚Üď
IGF-1(82 ‚Äď 242 ng/mL) 179 79
GH(fasting < 6 mIU/L) 4.5 <0.3
Prolactin(3 ‚Äď 20 ng/mL) <1‚Üď <1‚Üď

POD, postoperative day; HC, hydrocortisone; ACTH, adrenocorticotropic hormone; TSH, thyroid stimulating hormone; LH, luteinizing Hormone; FSH, follicle stimulating hormone; IGF-1, insulin like growth factor – 1; GH, growth hormone

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Figure 4. Trend of select pituitary hormonal panel with key clinical events denoted by black arrows.

Discussion

Microadenomas account for the majority of corticotroph tumors, but 7% ‚Äď 23% of patients are diagnosed with a macroadenoma3,¬†4,¬†5. It is even rarer for a corticotroph macroadenoma to present with apoplexy with only a handful of case reports or series in the literature7. Due to its rarity, appropriate biochemical workup on presentation, such as including an ACTH with the blood work, may be omitted especially if the patient is going for emergent surgery. In this case, the undetectable prolactin can reflect loss of anterior pituitary function and also suggest a functioning corticotroph adenoma due to the inhibitory effect of long term serum glucocorticoids on prolactin secretion9. After undergoing TSS, the patient developed central adrenal insufficiency, hypothyroidism and hypogonadism requiring hormone replacement. Presumably, the development of adrenal insufficiency demonstrated the remission of hypercortisolism as a result of apoplexy and/or TSS. The ACTH remains detectable likely representing residual tumor that was not obliterated by apoplexy nor excised by TSS given it location near the carotid artery and cavernous sinus. The presence of adrenal insufficiency in the setting of detectable ACTH is not contradictory as the physiological hypothalamic-pituitary-adrenal axis has been suppressed by the long-term pathological production of ACTH. IGF-1 and prolactin also failed to recover post-operatively. In CD where the production of IGF-1 and prolactin are attenuated by elevated cortisol, it would then be expected that IGF-1 and prolactin recover after hypercortisolism remission. However, the absence of this observation in our case is likely a sequalae of the apoplexy and extensive surgery leading to pituitary hypofunction.

We also want to highlight features of the pre-operative radiographical findings which can provide valuable insight into the subsequent histology. Previous literature has shown that, on T2-weight MRI, silent corticotroph adenomas are strongly correlated with characteristic a multimicrocystic appearance while nonfunctional gonadotroph macroadenomas are not correlated with this MRI finding10. The multimicrocystic appearance is described as small hyperintense areas with hyperintense striae in the solid part of the tumor (Figure 1C)10. This is an useful predictive tool for silent corticotroph adenomas with a sensitivity of 76%, specificity of 95% and a likelihood ratio of 15.310.

The ability to distinguish between silent corticotroph macroadenoma and other macroadenomas is important for assessing rate of remission and recurrence risk. In 2017, the WHO published updated classification for pituitary tumors. In this new classification, corticotroph adenomas are further divided into densely granulated, sparsely granulated and Crooke’s cell tumors11. DGCT are intensely Periodic Acid Schiff (PAS) stain positive and exhibit strong diffuse pattern of ACTH immunoreactivity, whereas SGCT exhibit faintly positive PAS alongside weak focal ACTH immunoreactivity4,12. Crooke’s cell tumors are characterized by Crooke’s hyaline changes in more than 50% of the tumor cells4. In the literature, SGCT account for an estimated 19-29% of corticotroph adenomas13, 14, 15. The clinicopathological relevance of granulation pattern in corticotroph tumors was unclear until recently.

In multiple studies examining granulation pattern and tumor size, SGCT were statistically larger13,15,16. Hence, we suspect that many of the previously labelled silent corticotroph macroadenomas in the literature were SGCT. The traditional teaching of CD has been ‚Äúsmall tumor, big Cushing and big tumor, small Cushing‚ÄĚ which reflects the inverse relationship between tumor size and symptomatology17. This observation appears to hold true as DońüanŇüen et al. found a trend towards longer duration of CD in SGCT of 34 months compared to 26 months in DGCT based on patient history13,17. It has been postulated that the underlying mechanism of the inverse relationship between tumor size and symptomatology is impaired processing of proopiomelanocortin resulting in less effective secretion of ACTH in corticotroph macroadenomas3. DońüanŇüen et al. also found that the recurrence rate was doubled for SGCT, while Witek et al. showed that SGCT were less likely to achieve remission postoperatively13,16.

Similar to other cases of SGCT, the diagnosis was only arrived retrospective after pathological confirmation10. Interestingly, the characteristic Crooke’s hyaline change of surrounding non-adenomatous pituitary tissue was not observed as one would expect in a state of prolonged glucocorticoid excess in this case. Although classically described, the absence of this finding does not rule out CD. As evident in a recent retrospective study where 10 out of 144 patients with CD did not have Crooke’s hyaline change18. In patients without Crooke’s hyaline change, the authors found a lower remission rate of 44.4% compared to 73.5% in patients with Crooke’s hyaline change. Together with the detectable post-operative ACTH, sparsely granulated pattern and absence of Crooke’s hyaline change in surrounding pituitary tissue, the risk of recurrence is increased. These risk factors emphasize the importance of close monitoring to ensure early detection of recurrence.

Declaration of Interests

‚ėí The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

‚ėźThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Conclusion

We present a case of a sparsely granulated corticotroph macroadenoma presenting with apoplexy leading to remission of hypercortisolism and development of central adrenal insufficiency, hypothyroidism and hypogonadism requiring hormone replacement.

References

Novel Application of Amniotic Membrane Saves Adrenal Tissue in Patients Undergoing Adrenal Surgery

The Carling Adrenal Center, a worldwide destination for the surgical treatment of adrenal tumors, becomes the first center to offer the use of amniotic membrane during adrenal surgery which saves functional adrenal tissue in patients undergoing adrenal surgery. This novel technique enables more patients to have a partial adrenalectomy thereby preserving some normal adrenal physiology, potentially eliminating life-long adrenal hormone replacement.

Preliminary clinical data from the Carling Adrenal Center suggest that the use of a human amniotic membrane allograph on the adrenal gland remnant following partial adrenal surgery leads to faster recovery of normal adrenal gland function. Rather than removing the entire adrenal gland‚ÄĒwhich has been standard of care for decades‚ÄĒa portion of the adrenal gland is able to be salvaged with amniotic membrane placed upon the remnant as a biologic covering.

Preliminary clinical data from the Carling Adrenal Center suggest that the use of a human amniotic membrane allograph on the adrenal gland remnant following partial adrenal surgery leads to faster recovery of normal adrenal gland function. Rather than removing the entire adrenal gland‚ÄĒwhich has been standard of care for decades‚ÄĒa portion of the adrenal gland is able to be salvaged with amniotic membrane placed upon the remnant as a biologic covering. The preliminary data from an ongoing clinical trial shows this technique translates into fewer patients needing steroid hormone replacement following adrenal surgery, and if they do, it is for a significantly shorter period of time.

“Sometimes it is possible, and preferable, to remove the adrenal tumor without removing the entire adrenal gland. This is called partial adrenal surgery and our study shows this technique is more successful when amniotic membrane is used,” said Dr. Carling. He further stresses that “removing only part of the adrenal gland is a more advanced operation and is typically only performed by¬†expert adrenal surgeons.¬†The goal is to leave some normal adrenal tissue so that the patient can¬†avoid¬†adrenal insufficiency¬†which requires a daily dose of several adrenal hormones and steroids. Partial adrenal surgery is especially beneficial for patients with pheochromocytoma, as well as Conn’s and Cushing’s syndrome. Avoiding daily steroids is life-changing for these patients so this is a major breakthrough.”

So how does it work? The increased viability of the adrenal gland remnant is presumed to be related to the release of growth factors known to be present in amniotic tissue which is in direct contact with the adrenal gland remnant as a covering. The results are improved rates of viable adrenal cortical tissues with faster regeneration and recovery to normal endocrine physiology by the adrenal cortical cells.

These findings come during Adrenal Disease Awareness Month. Adrenal gland diseases cause many debilitating symptoms like chronic headaches, anxiety, depression, fatigue, brain fog, memory loss, dangerously high blood pressure, heart arrythmia, weight gain, tremors, and more, yet they are often misdiagnosed or improperly treated. Since many doctors are inexperienced in the workup of adrenal hormone problems and only see a handful of adrenal tumors during their careers, it is important for patients to know about the symptoms of adrenal tumor disease and request their doctor measure adrenal hormones.

Adrenal.com¬†is the leading resource for adrenal gland function, tumors and cancers, and an award-winning resource for adrenal gland surgery. The diagnosis and surgical treatment of all types of adrenal tumor types are discussed.¬†Adrenal.com¬†is edited by¬†Dr. Tobias Carling¬†who has performed more adrenal surgery than any other surgeon and has published some of the most important scientific studies of adrenal disease and adrenal surgery including the understanding of the pathogenesis of pheochromocytoma and adrenal tumors causing Conn’s and Cushing’s syndrome.

Established by Dr. Tobias Carling in 2020, the Carling Adrenal Center located at the Hospital for Endocrine Surgery in Tampa FL, is the highest volume adrenal surgical center in the world. The Center now averages nearly 20 adrenal tumor patients every week. Dr Carling was the Director of Endocrine Surgery at Yale University prior to opening the Center in Tampa. At the new Hospital for Endocrine Surgery, Dr Carling joins the Norman Parathyroid Center, the Clayman Thyroid Center and the Scarless Thyroid Surgery Center as the highest volume endocrine surgery center in the world.

About the Carling Adrenal Center:¬†Founded by Dr.¬†Tobias Carling, one of the world’s leading experts in adrenal gland surgery, the Carling Adrenal Center is a worldwide destination for the surgical treatment of adrenal tumors. Dr. Carling spent nearly 20 years at¬†Yale University, including 7 as the Chief of Endocrine Surgery before leaving in 2020 to open to Carling Adrenal Center, which performs more adrenal operations than any other hospital in the world. (813) 972-0000. More about¬†partial adrenalectomy¬†for adrenal tumors can be found at the Center’s website¬†www.adrenal.com.

From https://www.streetinsider.com/PRNewswire/Novel+application+of+amniotic+membrane+saves+adrenal+tissue+in+patients+undergoing+adrenal+surgery/19915274.html

Osilodrostat Normalizes Urinary Free Cortisol in Most Adults with Cushing‚Äôs Disease

More than three-quarters of adults with Cushing’s disease assigned osilodrostat had a normalized mean urinary free cortisol level at 12 weeks and maintained a normal level at 36 weeks, according to data from the LINC 4 phase 3 trial.

In findings published in The Journal of Clinical Endocrinology & Metabolism, 77% of adults with Cushing’s disease randomly assigned to osilodrostat (Isturisa, Recordati) had mean urinary free cortisol (UFC) levels reduced to below the upper limit of normal at 12 weeks compared with 8% of adults assigned to placebo.

Osilodrostat normalizes UFC in most people with Cushing's disease at 12 weeks
Most adults with Cushing’s disease taking 2 mg twice daily osilodrostat had normalized mean UFC levels at 12 weeks compared with placebo. Data were derived from Gadelha M, et al.¬†J Clin Endocrinol Metab.¬†2022;doi:10.1210/clinem/dgac178.

‚ÄúOsilodrostat¬†is a highly effective treatment for Cushing‚Äôs disease, normalizing urinary free cortisol excretion in 77% of patients after 12 weeks‚Äô treatment,‚Ä̬†M√īnica Gadelha, MD, professor of endocrinology at The Federal University of Rio de Janeiro, and colleagues wrote. ‚ÄúCortisol reductions were maintained throughout 48 weeks of treatment and were accompanied by improvements in clinical signs of hypercortisolism and quality of life.‚ÄĚ

Gadelha and colleagues enrolled 73 adults aged 18 to 75 years with Cushing’s disease from 40 centers in 14 countries into the LINC 4 phase 3 trial. Participants were randomly assigned to 2 mg osilodrostat twice daily (n = 48) or placebo (n = 25) for 12 weeks. Urinary samples were collected at weeks 2, 5 and 8 to measure mean UFC, and dosage was adjusted based on efficacy and tolerability. After 12 weeks, participants from both groups received osilodrostat in a 36-week open-label treatment period. All participants restarted the open-label portion of the trial at 2 mg osilodrostat unless they were on a lower dose at week 12. Dose adjustments in the open-label phase were made using the same guidelines in the randomized, double-blind, placebo-controlled trial. The primary endpoint was the efficacy of osilodrostat at achieving a mean UFC below the upper limit of normal of 138 nmol per 24 hours at 12 weeks vs. placebo; the key secondary endpoint was the percentage of participants achieving a normal mean UFC at 36 weeks.

At 12 weeks, the percentage of adults with a normalized mean UFC level was higher in the osilodrostat group compared with placebo (77.1% vs. 8%; P < .0001).

At 36 weeks, 80.8% of all participants had a normal mean UFC level. The overall response rate was 79.5% at 48 weeks.

Median time to first controlled mean UFC response was 35 days for those randomly assigned to osilodrostat as well as those randomly assigned to placebo who crossed over to osilodrostat for the open-label phase. At 48 weeks, 84% of participants were receiving 10 mg or less of osilodrostat per day, including 56% receiving 4 mg or less daily.

At 12 weeks, the osilodrostat group had several cardiovascular and metabolic-related improvements, including systolic and diastolic blood pressure, HbA1c, HDL cholesterol, body weight and waist circumference. No changes were observed in the placebo group.

‚ÄúThe improvements in cardiovascular and metabolic parameters were sustained throughout osilodrostat treatment and have the potential to alleviate the burden of comorbidities in many patients with Cushing‚Äôs disease,‚ÄĚ the researchers wrote.

At 12 weeks, 52.5% of those receiving osilodrostat had a reduction in supraclavicular fat pad and 50% had a reduction in dorsal fat pad. At least 25% of participants also had improvements in facial redness, striae, proximal muscle atrophy and central obesity. Improvements were sustained through week 48.

During the placebo-controlled trial, grade 3 and 4 adverse events occurred for about 20% of participants in both groups. For the entire study, 38.4% of adults reported grade 3 and 4 adverse events, with the most common being hypertension. Eight participants discontinued the study due to adverse events.

From https://www.healio.com/news/endocrinology/20220408/osilodrostat-normalizes-urinary-free-cortisol-in-most-adults-with-cushings-disease

Simultaneous Pituitary and Adrenal Adenomas in a Patient with Non ACTH Dependent Cushing Syndrome

Highlights

‚ÄĘ

Cushing syndrome (CS) is a rare disorder with a variety of underlying etiologies.

‚ÄĘ

CS is expected to affect 0.2 to 5 people per million per year.

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Adrenal-dependent CS is an uncommon variant of CS.

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This study reports a rare occurrence of pituitary and adrenal adenoma with CS.

Abstract

Introduction

Cushing syndrome is a rare disorder with a variety of underlying etiologies, that can be exogenous or endogenous (adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent). The current study aims to report a case of ACTH-independent Cushing syndrome with adrenal adenoma and nonfunctioning pituitary adenoma.

Case report

A 37‚Äďyear‚Äďold female presented with amenorrhea for the last year, associated with weight gain. She had a moon face, buffalo hump, and central obesity. A 24-hour urine collection for cortisol was performed, revealing elevated cortisol. Cortisol level was non-suppressed after administering dexamethasone. MRI of the pituitary revealed a pituitary microadenoma, and the CT scan of the abdomen with adrenal protocol revealed a left adrenal adenoma.

Discussion

Early diagnosis may be postponed due to the variety of clinical presentations and the referral of patients to different subspecialists based on their dominant symptoms (gynecological, dermatological, cardiovascular, psychiatric); it is, therefore, critical to consider the entire clinical presentation for correct diagnosis.

Conclusion

Due to the diversity in the presentation of CS, an accurate clinical, physical and endocrine examination is always recommended.

Keywords

Cushing syndrome
Cushing’s disease
Adrenal adenoma
Pituitary adenoma
Urine free cortisol

1. Introduction

Cushing syndrome (CS) is a collection of clinical manifestations caused by an excess of glucocorticoids¬†[1]. CS is a rare disorder with a variety of underlying etiologies that can be exogenous due to continuous corticosteroid therapy for any underlying inflammatory illness or endogenous due to either adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent¬†[2],¬†[3]. Cushing syndrome is expected to affect 0.2 to 5 people per million per year. Around 10% of such cases involve children¬†[4],¬†[5]. ACTH-dependent glucocorticoid excess owing to pituitary adenoma accounts for the majority (60‚Äď70%) of endogenous CS, with primary adrenal causes accounting for only 20‚Äď30% and ectopic ACTH-secreting tumors accounting for the remaining 5‚Äď10%¬†[6]. Adrenal-dependent CS is an uncommon variant of CS caused mostly by benign (90%) or malignant (8%) adrenal tumors or, less frequently, bilateral micronodular (1%) or macronodular (1%) adrenal hyperplasia¬†[7].

The current study aims to report a case of ACTH-independent Cushing syndrome with adrenal adenoma and nonfunctioning pituitary adenoma. The report has been arranged in line with SCARE guidelines and includes a brief literature review [8].

2. Case report

2.1.¬†Patient’s information

A 37‚Äďyear‚Äďold female presented with amenorrhea for the last year, associated with weight gain. She denied having polyuria, polydipsia, headaches, visual changes, dizziness, dryness of the skin, cold intolerance, or constipation. She had no history of chronic disease and denied using steroids. She visited an internist, a general surgeon, and a gynecologist and was treated for hypothyroidism. She was put on Thyroxin 100 őľg daily, and oral contraceptive pills were given for her menstrual problems. Last time, the patient was referred to an endocrinology clinic, and they reviewed the clinical and physical examinations.

2.2. Clinical examination

She had a moon face, buffalo hump, central obesity, pink striae over her abdomen, and proximal weakness of the upper limbs. After reviewing the history and clinical examination, CS was suspected.

2.3. Diagnostic assessment

Because the thyroid function test revealed low thyroid-stimulating hormone (TSH), free T3, and freeT4, the patient was sent for a magnetic resonance imaging (MRI) of the pituitary, which revealed a pituitary microadenoma (7‚ÄĮ‚ąó‚ÄĮ6‚ÄĮ‚ąó‚ÄĮ5) mm (Fig. 1). Since the patient was taking thyroxin and oral contraceptive pills, the investigations were postponed for another six weeks due to the contraceptive pills’ influence on the results of the hormonal assessment for CS. After six weeks of no medication, a 24-hour urinary free cortisol (UFC) was performed three times, revealing elevated cortisol levels (1238, 1100, and 1248) nmol (normal range, 100‚Äď400) nmol. A dexamethasone suppression test was done (after administering dexamethasone tab 1‚ÄĮmg at 11‚ÄĮp.m., serum cortisol was measured at 9‚ÄĮa.m.). The morning serum cortisol level was 620‚ÄĮnmol (non-suppressed), which normally should be less than 50‚ÄĮnmol. The ACTH level was below 1‚ÄĮpg/mL.

Fig. 1

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Fig. 1.¬†Contrast enhanced T1W weighted MRI (coronal section) showing small 7‚ÄĮmm hypo-enhanced microadenoma (yellow arrow) in right side of pituitary gland with mild superior bulge.

Based on these findings, ACTH independent CS was suspected. The computerized tomography (CT) scan of the abdomen with adrenal protocol revealed a left adrenal adenoma (33‚ÄĮmm‚ÄĮ√ó‚ÄĮ25‚ÄĮmm) without features of malignancy (Fig. 2).

Fig. 2

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Fig. 2.¬†Computed tomography scan of the abdomen with IV contrast, coronal section, showing 33‚ÄĮmm‚ÄĮ√ó‚ÄĮ25‚ÄĮmm lobulated enhanced left adrenal tumor (yellow arrow), showing absolute washout on dynamic adrenal CT protocol, consistent with adrenal adenoma.

2.4. Therapeutic intervention

The patient was referred to the urologist clinic for left adrenalectomy after preparation for surgery and perioperative hormonal management. She underwent laparoscopic adrenalectomy and remained in the hospital for two days. The histopathology results supported the diagnosis of adrenal adenoma.

2.5. Follow-up

She was released home after two days on oral hydrocortisone 20‚ÄĮmg in the morning and 10‚ÄĮmg in the afternoon. After one month of follow-up, serum cortisol was 36‚ÄĮnmol, with the resolution of some features such as weight reduction (3‚ÄĮkg) and skin color (pink striae became white).

3. Discussion

Cushing’s syndrome is a serious and well-known medical condition that results from persistent exposure of the body to excessive glucocorticoids, either from endogenous or, most frequently, exogenous sources¬†[9]. The average age of diagnosis is 41.4‚ÄĮyears, with a female-to-male ratio of 3:1¬†[10]. ACTH-dependent CS accounts for almost 80% of endogenous CS, while ACTH-independent CS accounts for nearly 20%¬†[10]. This potentially fatal condition is accompanied by several comorbidities, including hypertension, diabetes, coagulopathy, cardiovascular disease, infections, and fractures¬†[11]. Exogenous CS, also known as iatrogenic CS, is more prevalent than endogenous CS and is caused by the injection of supraphysiologic glucocorticoid dosages¬†[12]. ACTH-independent CS is induced by uncontrolled cortisol release from an adrenal gland lesion, most often an adenoma, adrenocortical cancer, or, in rare cases, ACTH-independent macronodular adrenal hyperplasia or primary pigmented nodular adrenal disease¬†[13].

The majority of data suggests that early diagnosis is critical for reducing morbidity and mortality. Detection is based on clinical suspicion initially, followed by biochemical confirmation [14]. The clinical manifestation of CS varies depending on the severity and duration of glucocorticoid excess [14]. Some individuals may manifest varying symptoms and signs because of a rhythmic change in cortisol secretion, resulting in cyclical CS [15]. The classical symptoms of CS include weight gain, hirsutism, striae, plethora, hypertension, ecchymosis, lethargy, monthly irregularities, diminished libido, and proximal myopathy [16]. Neurobehavioral presentations include anxiety, sadness, mood swings, and memory loss [17]. Less commonly presented features include headaches, acne, edema, abdominal pain, backache, recurrent infection, female baldness, dorsal fat pad, frank diabetes, electrocardiographic abnormalities suggestive of cardiac hypertrophy, osteoporotic fractures, and cardiovascular disease from accelerated atherosclerosis [10]. The current case presented with amenorrhea, weight gain, moon face, buffalo hump, and skin discoloration of the abdomen.

Similar to the current case, early diagnosis may be postponed due to the variety of clinical presentations and the referral of patients to different subspecialists based on their dominant symptoms (gynecological, dermatological, cardiovascular, psychiatric); it is, therefore, critical to consider the entire clinical presentation for correct diagnosis [18]. Weight gain may be less apparent in children, but there is frequently an arrest in growth with a fall in height percentile and a delay in puberty [19].

The diagnosis and confirmation of the etiology can be difficult and time-consuming, requiring a variety of laboratory testing and imaging studies¬†[20]. According to endocrine society guidelines, the initial assessment of CS must include one or more of the three following tests: 24-hour UFC measurement; evaluation of the diurnal variation of cortisol secretion by assessing the midnight serum or salivary cortisol level; and a low-dose dexamethasone suppression test, typically the 1‚ÄĮmg overnight test¬†[21]. Although UFC has sufficient sensitivity and specificity, it does not function well in milder cases of Cushing’s syndrome¬†[22]. In CS patients, the typical circadian rhythm of cortisol secretion is disrupted, and a high late-night cortisol serum level is the earliest and most sensitive diagnostic indicator of the condition¬†[23]. In the current case, the UFC was elevated, and cortisol was unsuppressed after administration of dexamethasone.

All patients with CS should have a high-resolution pituitary MRI with a gadolinium-based contrast agent to prove the existence or absence of a pituitary lesion and to identify the source of ACTH between pituitary adenomas and ectopic lesions¬†[24]. Adrenal CT scan is the imaging modality of choice for preoperatively localizing and subtyping adrenocortical lesions in ACTH-independent Cushing’s syndrome¬†[9]. MRI of the pituitary gland of the current case showed a microadenoma and a CT scan of the adrenals showed left adrenal adenoma.

Surgical resection of the origin of the ACTH or glucocorticoid excess (pituitary adenoma, nonpituitary tumor-secreting ACTH, or adrenal tumor) is still the first-line treatment of all forms of CS because it leaves normal adjacent structures and results in prompt remission and inevitable recovery of regular adrenal function [12], [25]. Laparoscopic (retroperitoneal or transperitoneal) adrenalectomy has become the gold standard technique for adrenal adenomas since it is associated with fewer postoperative morbidity, hospitalization, and expense when compared to open adrenalectomy [17]. In refractory cases, or when a patient is not a good candidate for surgery, cortisol-lowering medication may be employed [26]. The current case underwent left adrenalectomy.

Symptoms of CS, such as central obesity, muscular wasting or weakness, acne, hirsutism, and purple striae generally improve first and may subside gradually over a few months or even a year; nevertheless, these symptoms may remain in 10‚Äď30% of patients¬†[27]. Glucocorticoid replacement is essential after adrenal-sparing curative surgery until the pituitary-adrenal function returns, which might take up to two years, especially if adrenal adenomas have been resected¬†[25]. Chronic glucocorticoid excess causes lots of new co-morbidities, lowering the quality of life and increasing mortality. The most common causes of mortality in CS are cardiovascular disease and infections¬†[28]. After one month of follow-up, serum cortisol was 36‚ÄĮnmol, and several features, such as weight loss (3‚ÄĮkg) and skin color, were resolved (pink striae became white).

In conclusion, the coexistence of adrenal adenoma and pituitary adenoma with CS is a rare possibility. Due to the diversity in the presentation of CS, an accurate clinical, physical and endocrine examination is always recommended. Laparoscopic adrenalectomy is the gold standard for treating adrenal adenoma.

Consent

Written informed consent was obtained from the patient’s family for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Ethical approval

Approval is not necessary for case report (till 3 cases in single report) in our locality.

The family gave consent for the publication of the report.

Funding

None.

Guarantor

Fahmi Hussein Kakamad, Fahmi.hussein@univsul.edu.iq.

Research registration number

Not applicable.

CRediT authorship contribution statement

Abdulwahid M. Salh: major contribution of the idea, literature review, final approval of the manuscript.

Rawa Bapir: Surgeon performing the operation, final approval of the manuscript.

Fahmi H. Kakamad: Writing the manuscript, literature review, final approval of the manuscript.

Soran H. Tahir, Fattah H. Fattah, Aras Gh. Mahmood, Rawezh Q. Salih, Shaho F. Ahmed: literature review, final approval of the manuscript.

Declaration of competing interest

None to be declared.

References

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