Ectopic CRH/ACTH-Co-Secreting Neuroendocrine Tumors Leading to Cushing’s Disease

Posted on March 17, 2025 by MaryO

Abstract

Adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) are essential regulators of cortisol production within the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol levels, resulting from excessive ACTH, can lead to Cushing’s syndrome, a condition with significant morbidity. Neuroendocrine tumors (NETs) can ectopically produce both ACTH and CRH, contributing to this syndrome. This review discusses the pathophysiology, types, clinical presentation, diagnosis, and management of these tumors. Emphasis is placed on the importance of identifying dual CRH/ACTH secretion, which complicates diagnosis and necessitates tailored therapeutic strategies. Furthermore, the review highlights the prognosis, common complications, and future directions for research in this area.

We report the case of a 53-year-old female patient who presented with severe Cushing’s syndrome and was diagnosed with ectopic ACTH syndrome. Despite initial indications pointing towards pituitary-dependent hypercortisolism, further investigations revealed the presence of a highly differentiated atypically located tumor in the upper lobe of the left lung, adjacent to the mediastinum. Immunohistochemistry of the tumor tissue demonstrated not only ACTH but also CRH and CRH-R1 expression. The simultaneous expression of these molecules supports the hypothesis of the presence of a positive endocrine feedback loop within the NET, in which the release of CRH stimulates the expression of ACTH via binding to CRH-R1. This case report highlights the challenges in diagnosing and managing ectopic ACTH syndrome, emphasizing the importance of a comprehensive diagnostic approach to identify secondary factors impacting cortisol production, such as CRH production and other contributing neuroendocrine mechanisms.

Journal Section:

Review Article

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The Author(s). Published by S. Karger AG, Basel
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From Weight Gain To Diabetes

Posted on March 10, 2025 by MaryO
Cushing’s syndrome happens when the body has too much cortisol, the stress hormone. It can cause weight gain, high blood pressure, and diabetes. So how to keep your health in check and what are the treatment options available? In an exclusive interview with Times Now, an Endocrinologist explains its symptoms, causes, and treatments.
We often blame stress for everything—from sleepless nights to stubborn weight gain. But did you know your body’s stress hormone, cortisol, could be at the root of more serious health issues like high blood pressure and diabetes? Yes, you read that right! But how? We got in touch with Dr Pranav A Ghody, Endocrinologist at Wockhardt Hospital, Mumbai Central, who explains how excessive cortisol levels can lead to a condition known as Cushing’s Syndrome.
What Exactly is Cortisol, and Why is it Important?
Hormones are the body’s chemical messengers, travelling through the bloodstream to regulate essential functions. Among them, cortisol, produced by the adrenal glands (tiny glands sitting above the kidneys), plays a crucial role in controlling blood pressure, blood sugar, energy metabolism, and inflammation. The pituitary gland, located at the base of the brain, regulates cortisol through another hormone called Adrenocorticotropic Hormone (ACTH).
Often referred to as the “stress hormone,” cortisol spikes when we’re under stress. However, when levels remain high for too long, it can lead to Cushing’s Syndrome, a disorder first identified in 1912 by Dr Harvey Cushing.

What Causes Cushing’s Syndrome?

Dr Ghody explains that Cushing’s Syndrome occurs when the body is exposed to excessive cortisol, which can happen in two ways:

1. Exogenous (External) Cushing’s Syndrome
This is the most common form and results from prolonged use of steroid medications (such as prednisone) to treat conditions like asthma, rheumatoid arthritis, and lupus, or to prevent transplant rejection. Since steroids mimic cortisol, long-term use can disrupt the body’s hormone balance.
2. Endogenous (Internal) Cushing’s Syndrome
This occurs when the body produces too much cortisol due to a tumour in the pituitary gland, adrenal glands, or other organs (lungs, pancreas, thymus). While rare—affecting about 10 to 15 people per million annually—it’s more common in women between 20 and 50 years old. When caused by a pituitary tumour, it’s specifically called Cushing’s Disease.

Symptoms: How To Recognize Signs Of Cushing’s Syndrome

Excess cortisol affects multiple organs, leading to a variety of symptoms. This includes:

– Weight gain around the belly (central obesity)
– Rounded, puffy face (moon face)
– Excess facial and body hair (hirsutism)
– Fat accumulation on the upper back (buffalo hump)
– Thin arms and legs
– Dark red-purple stretch marks on the chest and abdomen
– Extreme fatigue and muscle weakness
– Depression or anxiety
– Easily bruising with minimal trauma
– Irregular menstrual cycles in women
– Reduced fertility or low sex drive
– Difficulty sleeping
High blood pressure and newly diagnosed or worsening diabetes are also common red flags.

Why is Cushing’s Syndrome Often Misdiagnosed?

Dr Ghody explains that while severe cases of Cushing’s Syndrome are easier to identify, milder forms can often be missed or mistaken for conditions like obesity, diabetes, or polycystic ovary syndrome (PCOS).

Diagnosing Cushing’s Syndrome involves:
1. Measuring cortisol levels in the blood, urine, or saliva.
2. Identifying the source through ACTH hormone testing, MRI/CT scans, and advanced techniques like Inferior Petrosal Sinus Sampling (IPSS) or nuclear medicine scans
Treatment Options: How is Cushing’s Syndrome Managed?
Once diagnosed, the treatment depends on the cause:
– If due to steroid medication, the dosage is gradually reduced under medical supervision.
– If caused by a tumour, surgery is the primary treatment. Some patients, especially those with pituitary tumours, may require repeat surgery, gamma knife radiosurgery, or medications to control cortisol levels.

Can You Prevent Cushing’s Syndrome?

While complete prevention isn’t always possible, Dr Ghody shares some key strategies to reduce risk:

– Use steroids cautiously – If prescribed, take the lowest effective dose for the shortest time. Never stop abruptly without consulting a doctor.
– Genetic screening for people at risk – If you have a family history of pituitary or adrenal tumours, regular monitoring can help with early detection.
– Maintain a healthy lifestyle – A diet rich in fresh vegetables, and fruits, low sodium intake, adequate calcium, and vitamin D can help manage the metabolic effects of excess cortisol.
– Avoid alcohol and tobacco – These can further disrupt hormone balance and overall health.
“Cushing’s Syndrome can be life-threatening if left untreated, but early diagnosis and proper management can significantly improve quality of life. So if you experience unexplained weight gain, blood pressure spikes, or other symptoms, consult an endocrinologist to manage hormonal imbalances,” he said.

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Sterotherapeutics begins Phase II trial for ST-002 targeting Cushing’s Syndrome

Posted on March 2, 2025 by MaryO

US-based clinical-stage company Sterotherapeutics has announced the commencement of a Phase II clinical trial for its drug candidate, ST-002, for treating Cushing’s Syndrome, a rare endocrine disorder.

The trial will assess the drug’s efficacy, tolerability, and safety in individuals with this condition. It is set to be conducted in several European clinical sites.

Sterotherapeutics CEO Manohar Katakam said: “After extensive preparations and based on a large body of scientific data, we are excited to convene this important Investigator Meeting as we progress to the next stage of our clinical development programme.

“This trial represents a significant step forward in our mission to develop transformative therapies for unmet medical needs. Collaboration with our expert investigators is essential to ensuring the highest standards of scientific rigour and patient safety.”

An orphan drug designation was granted by the US Food and Drug Administration (FDA) to the drug underscoring the requirement for new treatments alternatives for this rare condition.

Through this designation, Sterotherapeutics is eligible for various development incentives. These include assistance in the drug development process, certain FDA fee exemptions, post-approval marketing exclusivity of seven years, and tax credits for clinical expenses.

Characterised by longer exposure to high cortisol levels, Cushing’s Syndrome is stated to result in serious health complications like diabetes, osteoporosis, and hypertension.

Sterotherapeutics concentrates on the orphan diseases therapy development. The company stated that its leading programmes, ST-002 for Cushing’s Syndrome and ST-003 for primary sclerosing cholangitis, have shown promise in prior animal and human studies. ST-003 has also been granted an orphan drug designation by the US regulator.

From https://www.clinicaltrialsarena.com/news/sterotherapeutics-trial-st-002/?cf-view&cf-closed

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Adrenal Insufficiency May Be Misdiagnosed as Anxiety

Posted on November 23, 2024 by MaryO

The hormone cortisol is produced by the adrenal glands, so adrenal insufficiency (also called Addison’s disease) is caused when the adrenal glands do not produce cortisol normally. Low cortisol can actually cause anxiety and depression, so some patients may really have anxiety — though doctors need to do further testing and/or evaluation to see that it is caused by their hormone levels, not a mental illness.

“I have adrenal insufficiency, which can cause depression and anxiety as a sign and symptom of low cortisol. After attempting hospitalization for depression, we found that I’d been living on almost undetectable cortisol for at least a year,” Sarah Reilley said. “Now that I’m on hydrocortisone replacement, my depression and anxiety are nearly gone and serve to warn me when my cortisol is dangerously low! I’m really lucky to be alive.”

Read about other conditions that may be misdiagnosed as anxiety here: https://themighty.com/topic/chronic-illness/misdiagnosed-anxiety-symptoms/

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‘Cortisol Face’ Is Real, But It’s Not As Common As You Might Think

Posted on September 6, 2024 by MaryO

Across social media platforms, the hashtag “#cortisolface” has gained traction, with many users claiming that facial swelling and puffiness are due to elevated cortisol levels. Influencers often start their videos with statements like, “You’re not ugly, you just have cortisol face,” and promote various remedies and lifestyle changes as solutions. However, experts warn that although high cortisol can contribute to these symptoms, it is not the sole cause of facial puffiness.

Before blindly believing social media trends, it’s crucial to explore the underlying causes, which might include medications, health conditions or lifestyle factors. Addressing high cortisol levels requires a different approach than what many of these social media influencers suggest.

Dr. Maria Olenick, associate professor at Texas A&M University School of Nursing, offers valuable insights into the concept of “cortisol face,” its effects on the body, and methods for lowering cortisol levels.

What Is ‘Cortisol Face’?

Although high cortisol levels are a factor in some cases of facial swelling and puffiness, the symptom is not as common as social media is making it out to be. In some cases, it’s not cortisol but the foods you eat. For example, eating a meal or snack that’s high in sodium can make you feel bloated because the salt can cause you to retain fluid and look a little puffier than normal.

“Some of the more severe things like moon face and other symptoms are what you might consider a serious issue when a person should really go and see their health care provider, because that would require some medical diagnosis,” Olenick said.

Moon face—or moon facies, in medical terminology—describes an increase of facial swelling due to high cortisol levels. This is a more serious condition that doesn’t just appear or disappear from one day to the next.

How Does Cortisol Affect The Body?

Cortisol is referred to as the body’s “built-in alarm system” because it plays a crucial role in the body’s response to stress, metabolism, immune activity and maintaining homeostasis. The amount of cortisol produced will differ from day to day due to different mental and physical stressors.

“Among healthy individuals, cortisol follows a diurnal pattern in which levels are higher upon waking, increase significantly over about 30 minutes, and steadily decrease from the peak throughout the rest of the day, reaching the nadir in the middle of the night,” said Olenick, whose research focuses on effective stress management techniques and therapies for veterans dealing with post-traumatic stress disorder (PTSD).

Hormones act as chemical messengers working through your bloodstream to regulate various bodily functions. Cortisol, often called the stress hormone, utilizes receptors that receive and use the hormone in different ways by communicating with your brain to control your mood, motivation and fear.

Different ways cortisol reacts and adapts to cope in a stress state include:

  • Regulating blood pressure
  • Regulating metabolism
  • Regulating blood sugar
  • Managing how your body uses carbohydrates, fats and proteins
  • Suppressing inflammation
  • Helping control your sleep/wake cycle
  • Aiding in forming memories

Cortisol secretion is regulated by a hormonal axis through a feedback loop that involves your hypothalamus, pituitary gland, adrenal glands and certain hormones known as the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus and pituitary gland in your brain monitor your blood’s cortisol levels before signaling the adrenal glands, which sit on top of each kidney. When a change in cortisol levels is detected, your adrenal glands react to these signals by adjusting the amount of cortisol needed to be released.

The feedback system starts when the hypothalamus detects stress and releases corticotrophin-releasing hormone (CRH) accordingly. This hormone travels into the pituitary gland, signaling it to secrete adrenocorticotropic hormone (ACTH). ACTH will then make its way to the adrenal glands, stimulating them to produce cortisol. Once produced, cortisol is released into the bloodstream, where it helps regulate various functions including stress response, metabolism and immune activity. The HPA axis feedback loop is completed when cortisol levels rise and signal the hypothalamus to reduce CRH production, which maintains an effective secretion loop.

What Causes High Cortisol Levels?

Cortisol is increased at times of stress for your body, but our bodies aren’t designed to handle long-term stress. When there’s too much cortisol or an excess amount of cortisol produced, it can cause major changes in your body’s everyday functions.

Chronic emotional or physical distress can lead to sustained high levels of cortisol as part of the body’s stress response system. Stress activates signals that prompt the adrenal glands to release hormones like adrenaline and cortisol, leading to an increased heart rate and heightened energy for the fight-or-flight response.

Cortisol temporarily suppresses non-essential functions such as digestion, reproduction and inflammation in the short term to prepare for danger. However, if stress is constant, this response can remain active, which can negatively impact many bodily functions such as sleep, weight management, memory, focus and mental health. Chronic stress can also increase the risk of anxiety, depression, digestive issues, headaches, muscle tension, pain and high blood pressure.

However, stress is not the only culprit for excess cortisol levels. It could indicate serious underlying health issues.

“You need to make sure that if you are having issues with cortisol levels that you don’t really have a tumor or something more serious. If you feel like you are having symptoms and they’re not resolved by implementing lifestyle changes, make sure you see a health care provider, because that could be something very different and it might need significant medical care,” Olenick said.

Cushing Syndrome

Cushing syndrome, also known as hypercortisolism, is characterized by excessive levels of cortisol in the body. Prolonged use of corticosteroid medications can result in exogenous Cushing syndrome, where the excess cortisol originates from external sources rather than the body’s own production. One common cause of high cortisol levels is the use of glucocorticoid medications, such as prednisone, which are prescribed for inflammatory conditions like asthma, rheumatoid arthritis and lupus.

“Sometimes people are on steroids such as prednisone for a different condition. When you’re taking steroids, if you start to show signs of serious cortisol issues, talk to your provider,” Olenick said.

Another significant cause of Cushing syndrome is pituitary tumors that secrete excessive amounts of ACTH, which overstimulates the adrenal glands to produce more cortisol. This form of Cushing syndrome, known as Cushing disease, is attributed to benign pituitary adenomas and accounts for a large proportion of cases in both adults and children. Effective management of Cushing syndrome involves addressing the underlying cause, which may include surgical removal of tumors or adjusting medication regimens to reduce cortisol levels and mitigate associated health challenges.

Adrenal gland tumors can also contribute to high cortisol levels. These tumors may be benign or malignant, leading to similar symptoms as those caused by pituitary tumors. Tumors affecting either the pituitary gland or adrenal glands can lead to elevated cortisol levels, but most of these tumors are noncancerous and may be manageable with proper medical care.

Understanding the underlying causes of high cortisol levels is crucial for appropriate diagnosis and treatment, as the medical implications of these conditions extend beyond the portrayals seen in popular media.

What Are Common Symptoms Of High Cortisol Levels?

Having the right cortisol balance is essential for your health, and producing too much or too little can cause health problems, including:

  • Puffiness or weight gain in the face
  • Weight gain in the midsection or abdomen
  • Excess fat behind the neck, above the back
  • Memory and concentration problems, or brain fog
  • Trouble sleeping, or insomnia
  • Severe fatigue
  • High blood pressure
  • Psychiatric disturbances

Symptoms may vary, so the only real way to validate if your cortisol levels are higher than normal is to get them checked, either with blood, urine or saliva tests. When Olenick evaluates cortisol levels in veterans for PTSD research, her preferred method is to collect samples of saliva. A saliva test can be conducted at home, but it’s most effective when collected at different times throughout the day.

How Can Someone Lower Their Cortisol Levels?

Maintaining a healthy diet, sticking to a regular sleep schedule and incorporating regular, moderate exercise can all help lower cortisol. It’s also important to manage stress effectively; this can involve finding healthy ways to cope with stress, such as talking to someone you trust or allowing yourself time to relax and unwind. Self-care is crucial—taking breaks and engaging in activities that rejuvenate you is not a waste of time but a necessary part of maintaining balance.

Avoid extreme measures like severe caloric restriction or high-intensity workouts, which can increase cortisol levels due to the stress they place on the body. Instead, go for low-intensity exercises like walking. Additionally, Olenick says natural remedies and supplements, such as apple cider vinegar and vitamins, may support cortisol management, but it’s wise to monitor their effects and consult with a health care provider if needed. Ultimately, finding a balance between self-care, stress management and maintaining a healthy lifestyle is key to controlling cortisol levels effectively.

“There are a lot of things you can do to regulate your cortisol, like eating well, sleeping well and lowering our stress. Basically, things to take care of ourselves,” Olenick said.

Olenick says social media platforms are great attention grabbers, but it’s important to take health trends with a grain of salt and pay attention to your body’s needs. If you relate to any of the symptoms and feel concerned about your cortisol levels, notify your health care provider and seek medical attention.

This article by Teresa Saenz originally appeared on Vital Record.

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