Advances in Cushing’s Syndrome Treatment - An Overview

Introduction

A condition where there is a chronic overproduction of cortisol, causing severe morbidity, is called Cushing syndrome. If left untreated, it increases the risk of mortality. Although a rare condition, it is linked to substantial morbidity and mortality, which indicates the importance of early diagnosis and effective treatment. It is essential to identify patients who may not respond to treatment on time because of the severe effects of prolonged overproduction of cortisol.

What Is Cushing Syndrome?

Long-term exposure to high amounts of circulating glucocorticoids causes Cushing's syndrome. It is due to a pituitary tumor, which causes an overabundance of adrenocorticotropic hormone (ACTH). As a result, high levels of cortisol are released persistently. Endocrinologists, neurosurgeons, radiation oncologists, and general surgeons must work closely together to provide tailored, multidisciplinary care for patients to manage and eliminate the devastating symptoms of hypercortisolemia successfully.

What Are the Symptoms of Cushing Syndrome?

Cushing syndrome presents with several unique signs as well as some that may be indicative of other diseases. The symptoms might not be common in every Cushing syndrome patient, it may vary from person to person. The common symptoms seen are:

• Quick weight gain in the chest, back of the neck, abdomen, and face. It can cause the appearance of a ‘moon face’ or a buffalo hump’.

• Poor healing of wounds.

• The affected individual’s face is usually round and reddish.

• Hypertension (elevated blood pressure).

• Diabetes (elevated blood sugar).

• Baldness or excessive hair growth on the face, neck, chest, belly, breasts, and thighs.

• The hands and legs get easily bruised.

• Purple-colored stretch marks are usually seen on the abdomen, hips, breasts, and thighs.

• Fatigue.

• Blurred vision.

• Dizziness.

• Thin hands and legs.

• Muscle weakness.

• Low sex drive (low libido).

• Erectile dysfunction (Inability to get or maintain erection).

• Infertility.

• Stunted growth in children.

• Obesity.

How Is Cushing Syndrome Treated?

Pituitary surgery is the main, ultimate treatment for people with Cushing's disease, and it is often carried out using a transsphenoidal technique. Cure rates for microadenomas can vary from 65 to 90 percent in the hands of the most qualified neurosurgeon, while rates for macroadenomas are significantly lower. Patients with recurrent Cushing's illness (where there is a twenty percent chance of a recurrence over time) may be eligible for a second pituitary surgery, particularly if the first operation was carried out at a less experienced facility. A second surgical procedure, however, results in decreased remission rates. Radiation therapy may also be taken into consideration for patients with recurrent Cushing's illness. There is a higher risk of hypopituitarism, though, and it will take years to correct hypercortisolemia (a condition where cortisol levels are high). In the interim, medical therapy is necessary. For individuals with Cushing's disease, bilateral adrenalectomy is typically regarded as a third-line treatment option.

Ketoconazole has been the first-line medical treatment for the majority of Cushing's syndrome cases with residual hypercortisolemia. The US Food and Drug Administration (FDA) has not, however, approved Ketoconazole for the treatment of Cushing's disease. In addition, the FDA has recently issued warnings about the drug's risk for severe liver damage and potentially hazardous drug interactions, which may further restrict its usage.

What Are the Advances in the Treatment of Cushing’s Syndrome?

• Pasireotide: The FDA and the European Commission (EC) have approved Pasireotide, a Somatostatin Receptor Ligand (SRL) having a high binding affinity for a protein called somatostatin receptor 5 (sstr5), as a therapy for adult Cushing's disease. A portion of the patients had tumor shrinkage and Urine-free cortisol (UFC) normalization, but their hyperglycemia was severe and to a high degree. Additional side effects resembled those reported with other SRLs. Research on healthy individuals revealed that while insulin sensitivity remains unchanged, hyperglycemia linked to Pasireotide is associated with reduced insulin production. The treatment of Pasireotide-induced hyperglycemia in Cushing's illness requires more research.

• Mifepristone: The FDA has approved Mifepristone, a glucocorticoid receptor blocker, to treat hyperglycemia in Cushing's disease patients. A phase III open-label study of the effectiveness and safety of Mifepristone showed significant improvements in glycemic control and Cushing's signs and symptoms in most individuals. The drug dose should only be changed per clinical improvements and tolerance, as there is no biochemical metric to determine efficacy. Adverse events, especially those related to adrenal insufficiency, hypokalemia, and vaginal bleeding in women, should be continuously watched in these patients.

• Cabergoline and Retinoic Acid: There have been a few encouraging studies on the effects of retinoic acid and Cabergoline in Cushing's disease patients. In addition, the identification of new therapeutic targets and pathways has been made possible by the in vitro data on the epidermal growth factor receptor.

• Etomidate: Etomidate is an injectable drug that induces analgesia, inhibiting 11-B hydroxylase and cholesterol side chain breakage. Patients with Cushing's syndrome who are too sick to take oral medication have responded well to Etomidate as a short-term treatment. Etomidate is the only intravenous preparation that is accessible, which makes it a great choice for quick hypercortisolemia management in emergencies.

• Mitotane: Mitotane lowers cortisol synthesis by inhibiting the enzymes responsible for the side chain cleavage of cholesterol. Additionally, Mitotane has been researched for the treatment of ACTH-dependent and ACTH-independent Cushing's syndrome.

• LCI699: LCI699 is a promising new therapeutic option for all types of Cushing's syndrome, as it catalyzes the last stage of cortisol synthesis. A modest proof-of-concept research on Cushing's disease patients revealed the medication's efficacy and excellent safety profile.

• Combination Therapy: The theory behind combination therapy is that treating people with Cushing's disease with a DA and a somatostatin receptor ligand may work in harmony to reduce the amount of ACTH secreted by corticotroph adenomas in an additive or synergistic way. It is vital to remember that case reports and limited open-label trial data primarily drive combination drug therapy information. However, the use of combination therapy is growing and offers the potential benefit of increasing drug treatment efficacy while minimizing side effects.

Conclusion

Cushing's disease has remained a significant clinical concern for healthcare professionals and patients ever since Harvey Cushing first described it in 1912. Hypercortisolism can be controlled following unsuccessful pituitary surgery with different response rates and considerable hazards involved. Other options include bilateral adrenalectomy and radiation or further pituitary surgery. Furthermore, as medication helps lower or normalize hypercortisolemia, it is crucial for patients whose surgery has failed to control their Cushing's illness. It also plays a critical role in caring for patients waiting for the full effects of pituitary radiation.