Scientists Discover Biological Reason Why Women Are More Likely to Develop Adrenal Disorders

Scientists have discovered a potential biological reason why women are more likely to develop adrenal disorders, including cancer. According to the researchers, the answer could lie in the increased turnover of hormone-producing cells found in the adrenal glands of females.

The adrenal gland is a hormone producing organ that sits on top of the kidneys. The outer part, or cortex, is responsible for the production of several hormones, including the stress-related hormone cortisol and the blood pressure controlling aldosterone. Adrenal cancer is relatively rare but occurs approximately three times more in women than in men. The cellular basis for this difference has not been investigated in detail but uncovering it might lead to sex-specific treatments and has huge implications for many areas of research.

Dr Andreas Schedl, from INSERM, France, who led the study said:

To our surprise we found that adrenal cells in female mice show a much more rapid turnover compared to males, which we could trace back to a different behaviour of adrenal stem cells between the two sexes. Furthermore, we could show that the observed differences are due to hormones that are produced by testes that suppress cell division, thus slowing down renewal in the male adrenal.”

The scientists studied the adrenal cortex of male and female adult mice and found that female mice replace their entire set of hormone-producing cells within 3 months, while it takes male mice an entire 9 months. Using different techniques to label cells within the adrenal cortex, they established that females not only have a higher proliferation rate of cells, but also recruit stem cells from a different part of the adrenal gland.

The research has wide reaching implications, as it demonstrates the basic mechanism underlying the increased turnover of cells within the adrenal gland, providing a possible explanation for the increased incidence of adrenal disorders in women.

Dr Schedl explained: “It is early days and many more experiments will need to be performed before our research can directly benefit patients. However, we believe that our study teaches a number of important lessons that are of immediate relevance to scientists, pharmacologists and clinicians.”

This research might lead to sex-specific treatment options for diseases like adrenal cancer and, according to Dr Schedl, could have implications on a far wider field of disorders: “Importantly, while our study concentrated on the adrenals, we are convinced that similar differences may also be found in other organ systems.”

Dr Helen Rippon, Chief Executive of the charity Worldwide Cancer Research, whose supporters helped fund the study, said: “Sex differences are not necessarily the first thing that comes to mind when thinking about cancer research or treatments. But this study has shown that it is crucial to consider potential differences between male and female when trying to understand the basis of cancer biology. Most importantly, these findings could have implications for treatment options further down the line and highlight the importance of early-stage, discovery research. We are delighted to fund this kind of research, as we believe that these innovative approaches are ultimately going to lead to a world where no life is cut short by cancer.”

Worldwide Cancer Research, La Ligue Contre le Cancer and the ANR supported this research. The research was published in Cell Stem Cell.

Source:

Worldwide Cancer Research

Journal reference:

Grabek, A. et al. (2019) The Adult Adrenal Cortex Undergoes Rapid Tissue Renewal in a Sex-Specific MannerCell Stem Celldoi.org/10.1016/j.stem.2019.04.012.

From https://www.news-medical.net/news/20190522/Scientists-discover-biological-reason-why-women-are-more-likely-to-develop-adrenal-disorders.aspx

Metastatic Pituitary Carcinoma Successfully Treated with Radiation, Chemo.

A man with Cushing’s disease — caused by an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma — who later developed metastases in the central nervous system without Cushing’s recurrence, was successfully treated over eight years with radiation and chemotherapy, according to a case report.

The report, “Long-term survival following transformation of an adrenocorticotropic hormone secreting pituitary macroadenoma to a silent corticotroph pituitary carcinoma: Case report,” was published in the journal World Neurosurgery.

Pituitary carcinomas make up only 0.1-0.2% of all pituitary tumors and are characterized by a primary pituitary tumor that metastasizes into cranial, spinal, or systemic locations. Fewer than 200 cases have been reported in the literature.

Most of these carcinomas secrete hormones, with ACTH being the most common. Though the majority of ACTH-secreting carcinomas present with Cushing’s disease, about one-third do not show symptoms of the condition and have normal serum cortisol and ACTH levels. These are called silent corticotroph adenomas and are considered more aggressive.

A research team at the University of Alabama at Birmingham presented the case of a 51-year-old Caucasian man with ACTH-dependent Cushing’s disease. He had undergone an incomplete transsphenoidal (through the nose) resection of an ACTH-secreting pituitary macroadenoma – larger than 10 mm in size – and radiation therapy the year before.

At referral in August 1997, the patient had persistent high cortisol levels and partial hypopituitarism, or pituitary insufficiency. He exhibited Cushing’s symptoms, including facial reddening, moon facies, weight gain above the collarbone, “buffalo hump,” and abdominal stretch marks.

About two years later, the man was weaned off ketoconazole — a medication used to lower cortisol levels — and his cortisol levels had been effectively reduced. He also had no physical manifestations of Cushing’s apart from facial reddening.

In May 2010, the patient reported two episodes of partial seizures, describing two spells of right arm tingling, followed by impaired peripheral vision. Imaging showed a 2.1-by-1-cm mass with an associated cyst within the brain’s right posterior temporal lobe, as well as a 1.8-by-1.2-cm mass at the cervicomedullary junction, which is the region where the brainstem continues as the spinal cord. His right temporal cystic mass was then removed by craniotomy.

A histopathologic analysis was consistent with pituitary carcinoma. Cell morphology was generally similar to the primary pituitary tumor, but cell proliferation was higher. Physical exams showed no recurrence of Cushing’s disease and 24-hour free urinary cortisol was within the normal range.

His cervicomedullary metastasis was treated with radiation therapy in July 2010. He took the oral chemotherapy temozolomide until August 2011, and Avastin (bevacizumab, by Genentech) was administered from September 2010 to November 2012.

At present, the patient continues to undergo annual imaging and laboratory draws. He receives treatment with hydrocortisone, levothyroxine — synthetic thyroid hormone — and testosterone replacement with androgel.

His most recent exam showed no progression over eight years of a small residual right temporal cyst, a residual mass along the pituitary stalk — the connection between the hypothalamus and the pituitary gland — and a small residual mass at the cervicomedullary junction. Lab results continue to show no Cushing’s recurrence.

“Our case is the first to document a patient who initially presented with an endocrinologically active ACTH secreting pituitary adenoma and Cushing’s disease who later developed cranial and spinal metastases without recurrence of Cushing’s disease and transformation to a silent corticotroph pituitary carcinoma,” the scientists wrote.

They added that the report is also the first documenting “8 years of progression-free survival in a patient with pituitary carcinoma treated with radiotherapy, [temozolomide] and bevacizumab.”

Adapted from https://cushingsdiseasenews.com/2019/01/03/successful-treatment-pituitary-carcinoma-radiation-chemo-case-report/

Rare Malignant Tumor of Adrenal Gland Led to Cushing’s, Girl’s Death

While adrenocortical carcinoma — a malignant tumor of the adrenal gland — appears only rarely in children, the tumor may cause secondary Cushing’s syndrome in these patients, a new case report shows.

Early diagnosis of the causes of Cushing’s syndrome could improve the prognosis of these children, researchers say.

The study, “Cushing Syndrome Revealing an Adrenocortical Carcinoma,” was published in the Open Journal of Pediatrics.

Adrenocortical carcinoma is a malignant tumor that develops in the cortex of the adrenal gland. It usually is identified by increased amounts of hormones that are produced by the adrenal glands, like cortisol.

This tumor type is very rare in children, representing fewer than two in every 1,000 pediatric tumors.

Researchers at the University Hospital Center Souro Sanou, in Burquina Faso (West Africa), described the case of a 10-year-old girl who developed this rare cancer.

The patient’s first symptoms were loss of consciousness and recurrent seizures without fever. The patient also had experienced excessive weight gain in the preceding months. At admission she was in a light state of coma and showed obesity in the face and trunk.

An initial analysis of blood, urine, and cerebrospinal fluid failed to detect any alterations, with no diabetes, kidney damage, or infection identified. And, even though no lesions or alteration were seen in the pituitary gland region, brain swelling was detected.

While in the hospital, the patient’s condition continued to deteriorate. She developed fever and difficulty speaking, while showing persistent seizures.

In the absence of a diagnosis, physicians focused on the safeguard of major vital function, control of seizures, and administration of large-spectrum antibiotics. Her condition improved slightly, regaining consciousness and control of seizures.

One month later, however, the patient developed symptoms that are commonly associated with increased levels of cortisol and male sex hormones, including obesity and early development of pubic hair.

After confirming high cortisol levels, physicians examined the patient’s abdominal region,  which revealed a tumor in the left adrenal gland.

The patient received a ketoconazole treatment and a surgery to remove the tumor was planned. But her condition worsened, with development of malignant hypertension and convulsive illness, which led to her death before the tumor was removed.

“The delay in the diagnosis and the insufficiency of the therapeutic means darken the prognosis in our context,” the researchers wrote.

“[Adrenocortical carcinoma] diagnosis should be considered in presence of virilization and early signs of puberty,” the researchers suggested. “Early diagnosis and multidisciplinary management of adrenocortical carcinoma could improve the prognosis in children.”

From https://cushingsdiseasenews.com/2018/05/04/rare-malignant-tumor-adrenal-gland-caused-cushings-case-report/

Rare Nasal Cancer May Have Caused Cushing’s Syndrome

A very rare case of Cushing’s syndrome developing as a result of a large and also rare cancer of the nasal sinuses gives insights into how to screen and treat such an anomaly, of which fewer than 25 cases have been reported in literature.

Paraneoplastic esthesioneuroblastoma (ENB), a very rare type of nasal tumor, may sometimes produce excess adrenocorticotrophic hormone (ACTH), leading to symptoms of Cushing’s syndrome, according to a recent case report that describes a case of ACTH-secreting ENB. The report aims to demonstrate the importance of recognizing its pathophysiology and treatment.

The case report, “A Case of Cushing’s Syndrome due to Ectopic Adrenocorticotropic Hormone Secretion from Esthesioneuroblastoma with Long Term Follow-Up after Resection,” was published in the journal Case Reports in Endocrinology.

It describes a 52-year-old Caucasian male who had a history of high blood pressure, severe weakness, abnormal production of urine, extreme thirstiness, and confusion.

He was scheduled to undergo surgery for a 7-centimeter skull base mass; the surgery was postponed due to severe high serum potassium concentrations and abnormally high pH levels. His plasma ACTH levels also were elevated and Cushing’s syndrome was suspected. Since imaging of the chest, abdomen, and pelvis did not show any ectopic (abnormal) sources of ACTH, the ENB was suspected to be the source.

Surgery was performed to remove the tumor, which was later found to be secreting ACTH. Consequently, following the procedure, his ACTH levels dropped to normal (below detection limit) and he did not need medication to normalize serum potassium levels. He then underwent subsequent chemoradiation and has shown no sign of recurrence 30 months after the operation, which is considered to be one of the longest follow-up periods for such a case.

Researchers declared it “a case of olfactory neuroblastoma with ectopic ACTH secretion that was treated with resection and adjuvant chemoradiation.”

“Given the paucity of this diagnosis, little is known about how best to treat these patients and how best to screen for complications such as adrenal insufficiency and follow-up,” they wrote. “Our case adds more data for better understanding of this disease.”

From https://cushingsdiseasenews.com/2018/04/03/rare-nasal-cancer-caused-cushings-syndrome-case-report-says/

Glowing cancer tool illuminates benign, but dangerous, brain tumors during pituitary surgery

University of Pennsylvania School of Medicine

PHILADELPHIA – An experimental imaging tool that uses a targeted fluorescent dye successfully lit up the benign brain tumors of patients during removal surgery, allowing surgeons to identify tumor tissue, a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania shows. The tumors, known as pituitary adenomas, are the third most common brain tumor, and very rarely turn cancerous, but can cause blindness, hormonal disorders, and in some cases, gigantism.

Findings from the pilot study of 15 patients, published this week in the Journal of Neurosurgery, build upon previous clinical studies showing intraoperative molecular imaging developed by researchers at Penn’s Center for Precision Surgery can improve tumor surgeries. According to first author John Y.K. Lee, MD, MSCE, an associate professor of Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania and co-director of the Center for Precision Surgery, this study describes the first targeted, near infrared dye to be employed in brain tumor surgery. Other dyes are limited either by their fluorescent range being in the busy visible spectrum or by lack of specificity.

“This study heralds a new era in personalized tumor surgery. Surgeons are now able to see molecular characteristics of patient’s tumors; not just light absorption or reflectance,” Lee said. “In real time in the operating room, we are seeing the unique cell surface properties of the tumor and not just color. This is the start of a revolution.”

Non-specific dyes have been used to visualize and precisely cut out brain tumors during resection surgery, but this dye is believed to be the first targeted, near infrared dye to be used in neurosurgery. The fluorescent dye, known as OTL38, consists of two parts: vitamin B9 (a necessary ingredient for cell growth), and a near infrared glowing dye. As tumors try to grow and proliferate, they overexpress folate receptors. Pituitary tumors can overexpress folate receptors more than 20 times above the level of the normal pituitary gland in some cases. This dye binds to these receptors and thus allows us to identify tumors.

“Pituitary adenomas are rarely cancerous, but they can cause other serious problems for patients by pushing up against parts of their brain, which can lead to Cushing’s disease, gigantism, blindness and death,” Lee explained. “The study shows that this novel, targeted, near infrared fluorescent dye technique is safe, and we believe this technique will improve surgery.”

Lee says larger studies are warranted to further demonstrate its clinical effectiveness, especially in nonfunctioning pituitary adenomas.

A big challenge with this type of brain surgery is ensuring the entire tumor is removed. Parts of the tumor issue are often missed by conventional endoscopy approaches during removal, leading to a recurrence in 20 percent of patients. The researchers showed that the technique was safe and effective at illuminating the molecular features of the tumors in the subset of patients with nonfunctioning pituitary adenomas.

The technique uses near-infrared, or NIR, imaging and OTL38 fluoresces brightly when excited by NIR light. The VisionSense IridiumTM 4mm endoscope is a unique camera system which can be employed in the narrow confines of the nasal cavity to illuminate the pituitary adenoma. Both the dye and the camera system are needed in order to perform the surgery successfully.

The rate of gross-total resection (GTR) for the 15 patients, based on postoperative MRI, was 73 percent. The GTR with conventional approaches ranges from 50 to 70 percent. Residual tumor was identified on MRI only in patients with more severe tumors, including cavernous sinus invasion or a significant extrasellar tumor.

In addition, for the three patients with the highest overexpression of folate, the technique predicted post-operative MRI results with perfect concordance.

Some centers have resorted to implementing MRI in the operating room to maximize the extent of resection. However, bringing a massive MRI into the operating room theater remains expensive and has been shown to produce a high number of false-positives in pituitary adenoma surgery. The fluorescent dye imaging tool, Lee said, may serve as a replacement for MRIs in the operating room.

Co-authors on the study include M. Sean Grady, MD, chair of Neurosurgery at Penn, and Sunil Singhal, MD, an associate professor of Surgery, and co-director the Center for Precision Surgery.

Over the past four years, Singhal, Lee, and their colleagues have performed more than 400 surgeries using both nonspecific and targeted near infrared dyes. The breadth of tumor types include lung, brain, bladder and breast.

Most recently, in July, Penn researchers reported results from a lung cancer trial using the OTL38 dye. Surgeons were able to identify and remove a greater number of cancerous nodules from lung cancer patients with the dye using preoperative positron emission tomography, or PET, scans. Penn’s imaging tool identified 60 of the 66 previously known lung nodules, or 91 percent. In addition, doctors used the tool to identify nine additional nodules that were undetected by the PET scan or by traditional intraoperative monitoring.

Researchers at Penn are also exploring the effectiveness of additional contrast agents, some of which they expect to be available in the clinic within a few months.

“This is the beginning of a whole wave of new dyes coming out that may improve surgeries using the fluorescent dye technique,” Lee said. “And we’re leading the charge here at Penn.”

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This study was supported in part by the National Institutes of Health (R01 CA193556), the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, and the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR000003).

Editor’s Note: Dr. Singhal holds patent rights over the technologies presented in this article.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.

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From https://eurekalert.org/pub_releases/2017-09/uops-gct090517.php

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