Cushing’s Syndrome

Overview

Basically, Pituitary corticotrope adenomas account for 70% of patients with endogenous causes of Cushing’s syndrome.

However, it should be emphasized that iatrogenic hypercortisolism is the most common cause of cushingoid features.[1]

Causes of Cushing’s Syndrome

1.Firstly,  ACTH excess i.e.: –

• Cushing’s disease Ectopic ACTH secretion
• Carcinoma of lung (especially small cell)
• Carcinoid tumors of either thymus or lung
• Medullary carcinoma of thyroid
• Carcinoma of colon
• Pheochromocytoma

2.Secondly, Non-ACT dependent i.e.: –

• Primary unilateral adrenocortical tumors (either adenoma or carcinoma)
• McCune-Albright syndrome: Bilateral tumor (e.g. Gsα mutation)
• Primary pigmented nodular dysplasia

3. Thirdly, ACTH – independent i.e.: –

• Macronodular adrenal hyperplasia Spontaneous Cushing’s syndrome

Types

There are two types of Cushing’s syndrome.

Exogenous Cushing’s syndrome

Exogenous Cushing’s syndrome is when the cause comes from something outside the body’s function.

It often results from long-term, high-dose usage of corticosteroid drugs, also known as glucocorticoids. These are similar to cortisol.

Examples include:

• prednisone
• dexamethasone
• methylprednisolone

People with rheumatoid arthritis, lupus, asthma, and recipients of an organ transplant may need high doses of these drugs.

Injectable corticosteroids, a treatment for joint pain, back pain and bursitis, can also lead to Cushing’s syndrome.

Steroid medications that do not appear to increase the risk of Cushing’s syndrome are:

• steroid creams, a treatment option for eczema
• inhaled steroids, a treatment for asthma

The National Institute of Diabetes and Digestive and Kidney Diseases Trusted Source (NIDDK) note that over 10 million people in the United States use glucocorticoid medications each year, but it remains unclear how many develop the symptoms of Cushing’s syndrome.

Endogenous Cushing’s syndrome

Endogenous Cushing’s syndrome is when the cause comes from inside the body, for example, when the adrenal glands produce too much cortisol.

Cushing’s disease is an example of this.

Similar symptoms can also result from adrenal gland tumors or from a benign or malignant tumor in the pancreas, thyroid, thymus gland, or lung. (6)

Risk factors of Cushing’s Syndrome

• Obesity, type 2 diabetes and poorly regulated blood glucose levels (blood sugar and hypertension)
• The taking of corticosteroid medications (long-term use)
• Pituitary gland tumours
• A primary adrenal gland disease or benign nodular enlargements of the adrenal glands
• An ectopic ACTH-secreting tumour. (4)

Pathophysiology

The pathophysiology of Cushing’s syndrome is linked to hypercortisolism which can develop by excess ACTH secretion or excess cortisol secretion by adrenal glands. The underlying mechanisms are usually genetic mutations or overexpression of proteins.

1. Excess ACTH secretion
   • The excess ACTH secretion can be due to the pituitary adenoma or ectopic (non-pituitary) ACTH secretion. ACTH stimulates the adrenal cortex to release cortisol and is not regulated by the feedback mechanism.
     1. Pituitary adenoma: Various gene mutations are involved in the development of pituitary adenoma commonly USP8, MEN1, CDKIs, and CDKN1B/p27Kip1. Many proteins are also overexpressed like Brg1, HDAC2, TR4, PTTG, and EGFR. It is the most important cause of ACTH-dependent cushing’s syndrome and is also called cushing’s disease. It is considered that the corticotroph tumors are resistant to glucocorticoid negative feedback inhibition which results in the pathological adrenal cortisol secretion.
     2. Ectopic ACTH secretion: The molecular defects in the neuroendocrine tumors leading to ectopic ACTH secretion from gastroenteropancreatic tumors are largely unknown. Germline menin mutations or RET oncogene mutations in multiple endocrine neoplasias (MEN) may be responsible. Ectopic secretion of ACTH can be seen as a manifestation of the paraneoplastic syndrome in small cell lung carcinoma and carcinoid tumors(bronchial and thymus).
2. Excess secretion of cortisol by adrenal gland
   • Excess secretion of the cortisol by the adrenal gland is due to the adrenal causes independent of ACTH secretion.
     1. Benign Adrenocortical adenoma: Common defects leading to adrenocortical adenoma are mutations or activation of the cAMP-dependent or β-catenin signaling pathways and aberrant expression and function of various G-protein-coupled receptors (GPCR).
     2. Adrenal cortical carcinoma It is associated with germline TP53 mutations and MEN syndrome.
     3. Bilateral adrenal hyperplasia: It is associated with MEN1, familial adenomatous polyposis, and fumarate hydratase gene mutations. Several inactivating mutations of armadillo repeat containing 5 genes (ARMC5, chromosome 16p11.2) are also identified.(5)

Sign & Symptoms of Cushing’s Syndrome

[1]

Clinical examination

Physical examination of patients with Cushing’s syndrome is as follows:

Appearance of the patient

• Patients with Cushing’s syndrome are usually higher weighter.

Vital signs

• Hypertension, due to cortisol’s enhancement of epinephrine’s vasoconstrictive effect.

Head

• Moon-face is a medical sign where the face swells up into a rounded shape. It is often associated with Cushing’s syndrome, which has led to it being known as Cushingoid facies ("Cushings-like face"), or steroid treatment, which has led to the name steroid facies.

Skin

• Hyperpigmentation – this is due to melanocyte stimulating hormone (MSH) production, as a byproduct of ACTH synthesis from Proopiomelanocortin (POMC)
• Telangiectasia (dilation of capillaries)
• Thinning of the skin (which causes easy bruising)
• Purple or red striae (the weight gain in Cushing’s stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness (hips, shoulders)
• Hirsutism (facial male-pattern hair growth)

Eye

• Bitemporal hemianopsia – pituitary lesion may cause compression of the optic chiasm.

Neck

• Growth of fat pads along the collar bone and on the back of the neck (known as lipodystrophy). (5)

Diagnosis of Cushing’s Syndrome

• In general, These tests may include increased 24-h urinary free cortisol excretion in three separate collections, failure to appropriately suppress morning cortisol after overnight exposure to dexamethasone, also evidence of loss of diurnal cortisol secretion with high levels at midnight, the time of the physiologically lowest secretion.
• Tests indicating cortisol overproduction i.e.-
  • 24-hour urinary cortisol excretion
  • Overnight dexamethasone suppression test
  • Low-dose dexamethasone suppression test
  • High-dose dexamethasone suppression test
  • Corticotrophin-releasing hormone test [1]

Investigations

• Full blood count
• Urea and electrolytes – Hypokalaemia occurs with severe cortisol excess.
• Liver function test
• Bone profile
• Fasting glucose, lipids and glycosylated haemoglobin – Cardiovascular risk is greatly increased in Cushing’s syndrome. Annual risk assessment is therefore mandatory.
• Thyroid stimulating hormone
• Urinary free cortisol
• Low dose dexamethasone suppression test
• Hydroxyprogesterone
• Testosterone, androstenedione, dehydroepiandrosterone, sex hormone binding globulin
• Luteinising hormone, follicle stimulating hormone
• High dose dexamethasone suppression test (7)

Treatment of Cushing’s Syndrome

• Basically, Antiglucocorticoid drug.
• Moreover, In ACTH-independent disease, treatment consists of surgical removal of the adrenal tumor.
• The treatment of choice is selective removal of the pituitary corticotrope tumor, usually via an endoscopic transsphenoidal approach.
• Besides this, If pituitary disease recurs, there are several options, including second surgery, radiotherapy, stereotactic radiosurgery, also bilateral adrenalectomy.
• Lastly, In some patients with very severe, overt Cushing’s (e.g., difficult to control hypokalemic either hypertension or acute psychosis), it may be necessary to introduce medical therapy to rapidly control the cortisol excess during the period leading up to surgery. [1]

Homeopathic Treatment of Cushing’s Syndrome 

Homeopathy treats the person as a whole. It means that homeopathic treatment focuses on the patient as a person, as well as his pathological condition. The homeopathic medicines selected after a full individualizing examination and case-analysis. 

Which includes 

• The medical history of the patient, 
• Physical and mental constitution, 
• Family history, 
• Presenting symptoms, 
• Underlying pathology, 

• Possible causative factors etc. 

A miasmatic tendency (predisposition/susceptibility) also often taken into account for the treatment of chronic conditions. 

What Homoeopathic doctors do? 

A homeopathy doctor tries to treat more than just the presenting symptoms. The focus is usually on what caused the disease condition? Why ‘this patient’ is sick ‘this way’? 

The disease diagnosis is important but in homeopathy, the cause of disease not just probed to the level of bacteria and viruses. Other factors like mental, emotional and physical stress that could predispose a person to illness also looked for. Now a days, even modern medicine also considers a large number of diseases as psychosomatic. The correct homeopathy remedy tries to correct this disease predisposition. 

The focus is not on curing the disease but to cure the person who is sick, to restore the health. If a disease pathology not very advanced, homeopathy remedies do give a hope for cure but even in incurable cases, the quality of life can greatly improve with homeopathic medicines. 

Homeopathic Medicines for Cushing’s Syndrome

The homeopathic remedies (medicines) given below indicate the therapeutic affinity but this is not a complete and definite guide to the homeopathy treatment of this condition. The symptoms listed against each homeopathic remedy may not be directly related to this disease because in homeopathy general symptoms and constitutional indications also taken into account for selecting a remedy, potency and repetition of dose by Homeopathic doctor. 

So, here we describe homeopathic medicine only for reference and education purpose. Do not take medicines without consulting registered homeopathic doctor (BHMS or M.D. Homeopath).  

Medicine for Cushing’s Syndrome:

Calcarea carbonica:

• Fair, fat, flabby and perspiring also cold, damp and sour. Additionally, Apprehensive.
• Craving for indigestible things – chalk, coal, peanuts.; also, for eggs, salt also sweets. Milk disagrees.
• Ravenous hunger. Besides this, Repugnance to hot food. Wants cold drinks.
• All in all, Loss of appetite when overworked. Palpitation. Weakness. Worse – especially; at night, after eating.

Fucous vesiculosus:

• Especially indicated medicine "For obesity and non – toxic goiter."
• Furthermore, Digestion is furthered and flatulence is diminished, Obstinate constipation.
• Forehead feels as if compressed by iron ring.
• Lastly, Thyroid enlargement in higher weighter subjects.

Graphites:

• Generally, Stout, fair complexion with tendency to skin affections also constipation, fat, chilly and costive.
• Moreover, Tendency to obesity. Aversion to meat. Besides this, Sweets nauseate.
• Hot drinks disagree. Additionally, Burning in stomach causing hunger.
• Worse – warmth, night, during also after menstruation. On the other hand, Better – dark, from wrapping up.

Mercurious:

• Good medicine for Cushing’s Syndrome.
• Bruised pain in small of back, especially when sitting. Tearing pain in coccyx, better pressing on abdomen.
• Extremities – Weakness of limbs, bone-pain alsonin limbs, worse night.
• Patient very sensitive to cold. Additionally, Oily perspiration.
• Trembling extremities, especially hands, paralysis agitans. Specifically, Lacerating pains in joints.
• Cold, clammy sweat on legs at night. Lastly, Dropsical swelling of feet also legs.

Phosphorus:

• Back- Burning in back; especially, pain as if broken, heat between the shoulder blades, Weak spine.
• Extremities- Weakness and trembling from every exertion.
• Can scarcely hold anything with hands. Tibia inflamed also becomes necrosed.
• Arms, hands become numb. All in all, Can lie only right side, joints suddenly give way.

Thyroidinum:

• Specifically indicated medicine for Cushing’s Syndrome.
• Most importantly, Thyroid exercises a general regulating influence over the mechanism of the organs of nutrition, growth and development.
• Another key point is that, Thyroid weakness causes decided craving for large amounts of sweets.
• At last, Excessive obesity. Best with pale patients. Weak; tachycardia; Palpitation from least exertion.

Silicea:

• Back Weak spine, very susceptible to draughts on back. Additionally, Pain in coccyx, diseases of bones of spine.

Capsicum:

• Lax fiber, weak; diminished vital heat. Generally, Fat, indolent, opposed to physical exertion.
• General uncleanliness of body. Especially in Homesickness.
• Worse – while eating, from heat. Whereas; Better – open air, uncovering, draughts.[2]

Diet & Regimen of Cushing’s Syndrome

• Reducing sodium intake
• Increasing calcium and vitamin D intake
• Reducing cholesterol
• Controlling blood sugar
• Reducing or eliminating alcohol and tobacco [3]

The Do’s & Don’ts 

Do’s:

• Seek medical attention: If you experience symptoms suggestive of Cushing’s syndrome, consult a healthcare provider promptly for evaluation and diagnosis.
• Follow treatment plan: Adhere to the prescribed treatment plan, which may include medication, surgery, or radiation therapy.
• Monitor blood pressure and glucose: Regularly check blood pressure and blood glucose levels as directed by your doctor.
• Maintain a healthy lifestyle: Eat a balanced diet rich in fruits, vegetables, and whole grains. Engage in regular physical activity as tolerated.
• Manage stress: Practice stress reduction techniques such as yoga, meditation, or deep breathing exercises.
• Communicate with your doctor: Discuss any concerns or side effects of treatment with your healthcare provider.
• Attend regular checkups: Schedule regular follow-up appointments with your endocrinologist to monitor your condition and adjust treatment as needed.

Don’ts:

• Ignore symptoms: Don’t dismiss symptoms as minor or unrelated. Seek medical attention if you experience any changes in your health.
• Self-medicate: Don’t take any medications or supplements without consulting your doctor.
• Stop treatment abruptly: Don’t stop taking prescribed medications or skip appointments without discussing it with your healthcare provider.
• Overexert yourself: Avoid strenuous exercise or activities that may cause injury or strain.
• Consume excessive salt: Limit your intake of salty foods to help manage blood pressure.
• Smoke or drink alcohol: These habits can worsen the complications of Cushing’s syndrome.[16]

Terminology

1. Cushing’s Syndrome: A disorder caused by chronic exposure to excess corticosteroids, leading to various clinical manifestations.

2. Hypercortisolism: Another term for Cushing’s syndrome, referring specifically to the high levels of cortisol in the body.

3. Epidemiology: The study of the distribution and determinants of health-related states or events in specific populations, and the application of this study to control health problems.

4. Pathogenesis: The origin and development of a disease.

5. Pathophysiology: The study of the disordered physiological processes associated with disease or injury.

6. Clinical Features: The signs and symptoms observed in patients with a particular condition.

7. Diagnosis: The process of identifying a disease or condition from its signs and symptoms.

8. Differential Diagnosis: The distinguishing of a particular disease or condition from others that present similar clinical features.

9. Complications: Secondary conditions or diseases that develop in the course of a primary disease.

10. Investigations: The diagnostic tests and procedures used to identify the nature and cause of a medical condition.

11. Treatment: The medical care given to a patient for an illness or injury.

12. Prevention: Measures taken to prevent disease or injury.

13. Homeopathic Treatment: A system of alternative medicine that uses small, highly diluted doses of natural substances that in larger amounts would produce symptoms of the ailment in healthy people.

14. Diet & Regimen: The recommended diet and lifestyle modifications for managing a health condition.

15. Do’s and Don’ts: Recommendations and precautions for managing a health condition.

16. Terminology: Specific terms and definitions used in the context of the article.

Reference

1.  Medicine Golwala
2.  ABC Manual Of Materia Medica And Therapeutics (Therap Part) By Clarke G. H.
3.  https://www.healthline.com/health/cushings-syndrome#:~:text=Cushing%20syndrome%20can%20lead%20to,high%20blood%20pressure%20(hypertension).
4. What risk factors are associated with Cushing’s syndrome? (mymed.com)
5. Cushing’s syndrome pathophysiology – wikidoc
6. Cushing’s syndrome: Causes, symptoms, types, and diagnosis (medicalnewstoday.com)
7. Cushing’s syndrome diagnosis – investigation (endobible.com)
8. Prevention of cushing’s disease | Healthy Living articles | Well Being center | SteadyHealth.com
9. Psychosocial morbidity in Cushing disease: a study from India 2015.
10. Pattern of Lipid Abnormalities Among South Asian Indians With Cushing’s Syndrome and the Short Term Impact of Surgical Correction of hypercortisolism 2019.
11. Cushing Syndrome Caused by Pituitary and Adrenal Hybrid Tumor: A Rare Case Report (2023).
12. Williams Textbook of Endocrinology.
13. Harrison’s Principles of Internal Medicine.
14. Greenspan’s Basic & Clinical Endocrinology 11th Edition.
15. Endocrinology: Adult and Pediatric 7th Edition.
16. The Complete Guide to Cushing’s Syndrome 1st Edition.