Cushing’s disease is a neuroendocrine disorder that develops as a result of damage to the hypothalamic-pituitary system, hypersecretion of ACTH and secondary hyperfunction of the adrenal cortex. The symptom complex characterizing Cushing’s disease includes obesity, hypertension, diabetes mellitus, osteoporosis, decreased function of the genital glands, dry skin, striae on the body, hirsutism, etc. For diagnostic purposes, a number of biochemical parameters of blood, hormones (ACTH, cortisol, 17-ACS, etc.), craniogram, CT of the pituitary gland and adrenal glands, adrenal scintigraphy, Liddle test are determined. Medical therapy, X-ray therapy, surgical methods (adrenalectomy, removal of pituitary tumor) are used in the treatment.
Meaning
In endocrinology, there is a distinction between the disease and Cushing’s syndrome (primary hypercorticism). Both diseases are manifested by a common symptom complex, but they have different etiology. The basis of Cushing’s syndrome is hyperproduction of glucocorticoids by hyperplastic tumors of the adrenal cortex (corticosteroma, glucosteroma, adenocarcinoma) or hypercorticism caused by prolonged administration of exogenous glucocorticoid hormones. In some cases, with ectopic corticotropinomas originating from the cells of the APUD system (ovarian cancer, lung cancer, pancreatic cancer, intestines, thymus, thyroid gland, etc.), the so-called ectopic ACTH syndrome develops with similar clinical manifestations.
In Cushing’s disease, the primary lesion is localized at the level of the hypothalamic-pituitary system, and the peripheral endocrine glands are involved in the pathogenesis of the disease a second time. The disease develops in women 3-8 times more often than in men; mainly women of childbearing age (25-40 years) are ill. The course of pathology is characterized by severe neuroendocrine disorders: disorders of carbohydrate and mineral metabolism, a symptom complex of neurological, cardiovascular, digestive, and renal disorders.
Causes
The development of Cushing’s disease in most cases is associated with the presence of basophilic or chromophobic pituitary adenoma secreting adrenocorticotropic hormone. With a tumor lesion of the pituitary gland, microadenoma, macroadenoma, adenocarcinoma are detected in patients. In some cases, there is a connection between the onset of the disease and previous infectious lesions of the central nervous system (encephalitis, arachnoiditis, meningitis), traumatic brain injuries, intoxication. In women, Cushing’s disease can develop against the background of hormonal restructuring caused by pregnancy, childbirth, menopause.
The basis of the pathogenesis of the disease is a violation of the hypothalamic-pituitary-adrenal relationship. A decrease in the inhibitory effect of dopamine mediators on the secretion of CRH (corticotropic releasing hormone) leads to hyperproduction of ACTH (adrenocorticotropic hormone).
Increased ACTH synthesis causes a cascade of adrenal and extrarenal effects. In the adrenal glands, the synthesis of glucocorticoids, androgens increases, to a lesser extent – mineralocorticoids. An increase in the level of glucocorticoids has a catabolic effect on protein-carbohydrate metabolism, which is accompanied by atrophy of muscle and connective tissue, hyperglycemia, relative insufficiency of insulin and insulin resistance, followed by the development of steroid diabetes mellitus. Violation of fat metabolism causes the development of obesity.
Increased mineralocorticoid activity activates the renin-angiotensin-aldosterone system, thereby contributing to the development of hypokalemia and hypertension. The catabolic effect on bone tissue is accompanied by leaching and a decrease in calcium reabsorption in the gastrointestinal tract and the development of osteoporosis. The androgenic properties of steroids cause ovarian dysfunction.
The severity of the current can be mild, moderate or severe. A mild degree of the disease is accompanied by moderate symptoms: menstrual function can be preserved, osteoporosis is sometimes absent. With moderate severity, the symptoms are pronounced, but complications do not develop. The severe form of the disease is characterized by the development of complications: muscle atrophy, hypokalemia, hypertensive kidney, severe mental disorders, etc.
According to the rate of development of pathological changes, there is a progressive and torpid course of Cushing’s disease. The progressive course is characterized by a rapid (within 6-12 months) increase in symptoms and complications of the disease; with a torpid course, pathological changes form gradually, over 3-10 years.
Cushing’s disease symptoms
In Cushing’s disease, disorders of fat metabolism, changes in the bone, neuromuscular, cardiovascular, respiratory, sexual, digestive system, and psyche develop.
Patients differ in their kushingoid appearance due to the deposition of adipose tissue in typical places: on the face, neck, shoulders, mammary glands, back, abdomen. The face has a moon-shaped shape, a fatty “climacteric hump” is formed in the area of the VII cervical vertebra, the volume of the chest and abdomen increases; at the same time, the limbs remain relatively thin. The skin becomes dry, flaky, with a pronounced purple-marble pattern, striae in the area of the mammary glands, shoulders, abdomen, intradermal hemorrhages. The appearance of acne or furunculosis is often noted.
Endocrine disorders in women with Cushing’s disease are expressed by a violation of the menstrual cycle, sometimes by amenorrhea. There is excessive body hair (hirsutism), facial hair growth and hair loss on the head. In men, there is a decrease and loss of hair on the face and body; a decrease in sexual desire, impotence. The onset of the disease in childhood can lead to a delay in sexual development due to a decrease in the secretion of gonadotropins.
Changes on the part of the bone system, which are a consequence of osteoporosis, are manifested by pain, deformation and fractures of bones, in children – a delay in growth and differentiation of the skeleton. Cardiovascular disorders may include hypertension, tachycardia, electrolyte-steroid cardiopathy, and the development of chronic heart failure. Patients are subject to frequent incidence of bronchitis, pneumonia, tuberculosis.
The defeat of the digestive system is accompanied by the appearance of heartburn, epigastric pain, the development of chronic hyperacid gastritis, steroid diabetes mellitus, “steroid” ulcers of the stomach and duodenum, gastrointestinal bleeding. Due to damage to the kidneys and urinary tract, chronic pyelonephritis, urolithiasis, nephrosclerosis, renal failure up to uremia may occur.
Neurological disorders can be expressed in the development of pain, amyotrophic, stem-cerebellar and pyramidal syndromes. If pain and amyotrophic syndromes are potentially reversible under the influence of adequate therapy of the disease, then stem-cerebellar and pyramidal syndromes are irreversible. With stem-cerebellar syndrome, ataxia, nystagmus, and pathological reflexes develop. Pyramidal syndrome is characterized by tendon hyperreflexia, a central lesion of the facial and sublingual nerves with corresponding symptoms.
In Cushing’s disease, mental disorders of the type of neurasthenic, asthenoadynamic, epileptiform, depressive, hypochondriac syndromes may occur. It is characterized by a decrease in memory and intelligence, lethargy, a decrease in the magnitude of emotional fluctuations; patients may be visited by obsessive suicidal thoughts.
Diagnostics
The development of diagnostic and therapeutic tactics requires close cooperation of an endocrinologist, neurologist, cardiologist, gastroenterologist, urologist, gynecologist.
In Cushing’s disease, typical changes in blood biochemical parameters are noted: hypercholesterolemia, hyperglobulinemia, hyperchloremia, hypernatremia, hypokalemia, hypophosphatemia, hypoalbuminemia, decreased activity of alkaline phosphatase. With the development of steroid diabetes mellitus, glucosuria and hyperglycemia are registered. The study of blood hormones reveals an increase in the level of cortisol, ACTH, renin; erythrocytes, protein, granular and hyaline cylinders are detected in the urine, the release of 17-CS, 17-ACS, cortisol increases.
For the purpose of differential diagnosis of the disease and Cushing’s syndrome, diagnostic tests with dexamethasone and metopyron (Liddle test) are performed. An increase in the excretion of 17-OXA in urine after taking metopyron or a decrease in the excretion of 17-OXA by more than 50% after administration of dexamethasone indicates Cushing’s disease, while the absence of changes in the excretion of 17-OXA indicates in favor of Cushing’s syndrome.
With the help of skull x–ray, pituitary macroadenomas are detected; with CT and MRI of the brain with the introduction of contrast, microadenomas (in 50-75% of cases). Spine x-ray reveals pronounced signs of osteoporosis.
Examination of the adrenal glands (ultrasound of the adrenal glands, MRI of the adrenal glands, CT, scintigraphy) reveals bilateral adrenal hyperplasia. At the same time, an asymmetric unilateral enlargement of the adrenal gland indicates a glucosteroma. Differential diagnosis of Cushing’s syndrome is carried out with a similar syndrome, hypothalamic syndrome of puberty, obesity.
Cushing’s disease treatment
In Cushing’s disease, it is necessary to eliminate hypothalamic shifts, normalize the secretion of ACTH and corticosteroids, and restore impaired metabolism. For the treatment of the disease, drug therapy, gamma, X-ray therapy, protonotherapy of the hypothalamic-pituitary region, surgical treatment, as well as a combination of various methods can be used.
Drug therapy is used in the initial stages of the disease. In order to block the pituitary function, reserpine, bromocriptine is prescribed. In addition to drugs of central action that suppress the secretion of ACTH, blockers of the synthesis of steroid hormones in the adrenal glands can be used in therapy. Symptomatic therapy is carried out aimed at correcting protein, mineral, carbohydrate, and electrolyte metabolism.
Gamma, X-ray and proton therapy are usually performed in patients who do not have X-ray data for a pituitary tumor. One of the methods of radiation therapy is stereotactic implantation of radioactive isotopes into the pituitary gland. Usually, a few months after radiation therapy, clinical remission occurs, which is accompanied by a decrease in body weight, blood pressure, normalization of the menstrual cycle, and a decrease in damage to the bone and muscle systems. Irradiation of the pituitary gland area can be combined with unilateral adrenalectomy or directed destruction of the hyperplastic substance of the adrenal gland.
In severe cases, bilateral removal of the adrenal glands (bilateral adrenalectomy) may be indicated, requiring further lifelong CT with glucocorticoids and mineralocorticoids. In case of detection of pituitary adenoma, endoscopic transnasal or transcranial removal of the tumor, transsphenoidal cryodestruction is performed. After adenomectomy, remission occurs in 70-80% of cases, about 20% may have a recurrence of the pituitary tumor.
Prognosis and prevention
The prognosis of Cushing’s disease is determined by the duration, severity of the disease, and age of the patient. With early treatment and mild form of the disease, a full recovery is possible in young patients. The long course of the disease, even with the elimination of the root cause, leads to persistent changes in the bone, cardiovascular, urinary systems, which disrupts the ability to work and aggravates the prognosis. Neglected forms end in death due to the addition of septic complications, kidney failure.
Patients should be monitored by an endocrinologist, cardiologist, neurologist, gynecologist-endocrinologist; avoid excessive physical and psycho-emotional stress, night shift work. Prevention of the development of Cushing’s disease is reduced to general preventive measures – prevention of TBI, intoxication, neuroinfections, etc.