Increased Circulating Acth Level

1. Disease Summary:

Cushing's disease (CD) is a rare endocrine disorder characterized by chronic hypercortisolism due to excessive secretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. This condition leads to a range of serious health complications, including obesity, hypertension, diabetes, osteoporosis, and increased risk of cardiovascular diseases. Patients often experience significant impairments in their quality of life (QoL) due to both physical and psychological symptoms. The disease can be life-threatening if left untreated, and even after treatment, many patients continue to suffer from persistent comorbidities.

2. Global Prevalence and Disease Burden:

Cushing's disease has an estimated prevalence of 1 to 2 cases per million people per year, making it a rare condition. However, the burden of the disease is substantial. A study indicated that patients with Cushing's disease have a standardized mortality ratio (SMR) of 2.5, meaning they are 2.5 times more likely to die than the general population, even after achieving biochemical remission (PMID: 25722097). The economic impact is significant, with costs associated with long-term management of comorbidities, loss of productivity, and healthcare utilization. The burden of disease includes not only direct medical costs but also indirect costs related to lost workdays and reduced quality of life.

3. Unmet Medical Need:

Despite the availability of treatment options, there are several unmet medical needs for patients with increased circulating ACTH levels due to Cushing's disease:

Persistent Symptoms: A significant proportion of patients (88.4%) report ongoing symptoms such as fatigue, muscle weakness, and obesity even after treatment (PMID: 35904235). This indicates a need for more effective therapies that can address these persistent symptoms.
Delayed Diagnosis: Many patients experience delays in diagnosis, with 49% reporting a time to diagnosis of over two years (PMID: 35904235). This delay can lead to worsening of the disease and increased morbidity, highlighting the need for improved awareness and diagnostic protocols.
Limited Treatment Options: Current treatments, including surgery and pharmacotherapy, do not provide a cure for all patients. Approximately one-third of patients do not achieve remission after surgery, necessitating additional treatments (PMID: 33363514). There is a clear need for more effective medical therapies that can provide better control of hypercortisolism.
Quality of Life Concerns: Patients express a desire for improved quality of life and mental health support, which are often overlooked in treatment plans (PMID: 38315244). There is a need for a more holistic approach to treatment that includes psychological support and management of comorbidities.
Education and Awareness: Patients report a lack of education and awareness regarding their condition and treatment options, which can lead to feelings of isolation and helplessness (PMID: 38315244). There is a need for better educational resources for both patients and healthcare providers.

4. Current Treatment Options:

Current treatment options for Cushing's disease include:

Surgery: Transsphenoidal pituitary surgery is the first-line treatment for Cushing's disease. While it can be effective, it is not curative for all patients, with recurrence rates as high as 30% (PMID: 33363514).
Medical Therapy: Several medications are used to manage Cushing's disease, including:
- Pasireotide: A somatostatin analogue that has shown efficacy in controlling cortisol levels but is associated with side effects such as hyperglycemia (PMID: 33363514).
- Osilodrostat: An oral medication that inhibits cortisol production and has been shown to be effective in clinical trials (PMID: 32730798).
- Metyrapone and Ketoconazole: These drugs inhibit cortisol synthesis but have limitations in terms of efficacy and side effects (PMID: 33363514).
Radiation Therapy: This is typically reserved for patients who are not surgical candidates or have persistent disease after surgery. However, it has a slower onset of action and potential complications.

Despite these options, many patients do not achieve adequate control of their disease, and there is a significant need for new therapies that can provide better outcomes.

5. Current Clinical Trials:

Numerous clinical trials are currently investigating new therapies for Cushing's disease, including:

Pasireotide Long-Acting Release (LAR): A new formulation that may improve compliance and efficacy.
Osilodrostat: Ongoing studies are assessing its long-term safety and efficacy in diverse patient populations.
Novel Molecular Targets: Research is focusing on new molecular pathways involved in ACTH secretion, with potential new drugs targeting these pathways (PMID: 29754637).

6. Additional Context:

The management of Cushing's disease requires a multidisciplinary approach, including endocrinologists, surgeons, and mental health professionals. The complexity of the disease and its treatment necessitates ongoing research and collaboration to address the unmet needs of patients effectively. Improved education and awareness among healthcare providers and patients are crucial for timely diagnosis and management of this debilitating condition.