CS is characterized by a broad spectrum of symptoms, where milder forms may remain subclinical and more severe cases present as complex multisystem diseases. Symptoms may develop in an insidious manner, or they may be cyclic [1] [2]. What's more, the triggers of CS, namely tumors of the pituitary or adrenal glands, may release distinct hormones or destroy adjacent tissues, thereby affecting several branches of the hypothalamic-pituitary-axis or more than one layer of the adrenal cortex. The resulting clinical presentation is even more heterogeneous.

With regards to pure CS, this endocrinopathy may manifest in decreasing growth velocity in children, truncal weight gain, rounded face with acne, plethora, striae, hirsutism, hypertension, glucose intolerance or diabetes mellitus, proximal muscle wasting and weakness, osteoporosis, nephrolithiasis, as well as amenorrhea and impotence [1] [2]. Patients are prone to mood swings and sleep disorders and are more likely to develop depression [3] [4]. Laboratory analyses of blood samples may reveal lymphopenia, neutrophilia, thrombophilia, hyperglycemia, and hyperlipidemia.

The clinical presentation of CS patients does not allow for a distinction between endogenous and exogenous CS. Accordingly, the patient should be queried for possible causes of exogenous CS. Glucocorticoid therapy is commonly applied to treat autoimmune diseases, allergies, asthma, and a large variety of poorly diagnosed conditions. Patients may not be aware of the side effects of such therapy, and thus may decide to increase doses or prolong the treatment to pursue greater effects.

The diagnosis of CS, both the endogenous and exogenous variants, is based on biochemical studies. First-line screenings comprise the assessment of late-night salivary cortisol, 24-hour urinary free cortisol, and the realization of an overnight dexamethasone suppression test. These tests serve to confirm excess cortisol secretion in a 24-hour period and demonstrate the loss of feedback inhibition along the hypothalamic-pituitary-adrenal axis. At least two of these tests should be abnormal to diagnose CS, and repeated measurements may be required to confirm the diagnosis of cyclic CS [5]. It should be noted that random cortisol measurements yield unreliable results, since presumably high levels may be linked to the normal diurnal variation of cortisol excretion [2] [6].

If the results of the aforementioned tests confirm the tentative diagnosis of CS, the condition should be related to exogenous causes as described above, or such causes should be ruled out. In a next step, and to narrow down the long list of potential causes of endogenous CS, it should be clarified whether the disease is dependent or independent of stimulation by the adrenocorticotropic hormone (ACTH) [6]. Thus, ACTH levels need to be measured. Normal to high levels of ACTH are consistent with ACTH-dependent CS, while ACTH-independent CS is associated with values below the reference range. This is due to the physiological inhibition of ACTH secretion by glucocorticoids. Accordingly, either one of the following causes may be assumed:

• ACTH-dependent CS may be triggered by a pituitary tumor releasing ACTH, or by tumors located elsewhere that serve as an ectopic source of ACTH.
• ACTH-independent CS is most commonly provoked by adrenal masses.

Diagnostic imaging is generally employed to identify and characterize the source of excess hormones, and the results will guide subsequent steps in the workup of the index case. For instance, if magnetic resonance imaging does not reveal any signs of a pituitary tumor in a patient diagnosed with ACTH-dependent CS, inferior petrosal sinus sampling may be carried out to clarify whether the tropic hormone originates from the pituitary gland [6].

Furthermore, the diagnosis of endogenous CS in pediatric patients should entail a thorough familial workup and possibly genetic studies to identify mutations conferring an increased risk for the development of endocrine neoplasias.

Treatment decisions should be made according to the etiology of the disease. The more common exogenous CS requires the reduction or cessation of glucocorticoid therapy. The side effects of the latter should be balanced against the consequences of an exacerbation of the primary disorder in order to obtain the best possible life quality.

In the setting of hormone-secreting tumors, the surgical removal of the degenerated tissue is usually the procedure of choice:

• Transsphenoidal surgery is carried out to resect tumors of the pituitary gland; radiotherapy is considered a second-line approach to persistent or recurrent disease after surgery [5]. In any case, pituitary interventions may occasionally lead to partial or complete panhypopituitarism. Affected patients require lifelong hormone replacement therapy [4].
• While unilateral adrenal tumors warrant unilateral adrenalectomy, bilateral adrenalectomy should be considered in case of bilateral lesions. Such are most frequently identified in patients with cancer predisposition syndromes and other hereditary disorders inducing CS. Bilateral adrenalectomy necessarily causes adrenal insufficiency, which requires lifetime replacement with both glucocorticoids and mineralocorticoids [1].

Patients who are not eligible for surgery may benefit from the administration of drugs that reduce the endogenous production of glucocorticoids. Similar approaches may be taken in case of acute, potentially life-threatening complications of CS. The respective compounds may target the pituitary or adrenal glands: Dopamine and somatostatin analogs, glucocorticoid and progesterone antagonists act on the pituitary gland, while ketoconazole, metyrapone, etomidate, and mitotane inhibit the synthesis of glucocorticoids in the adrenal glands [4].

A better understanding of the genetic conditions predisposing to CS and their molecular pathophysiology would pave the way towards the development of targeted therapies. To date, no such therapies are available to treat those hereditary disorders associated with CS.

Pediatric patients treated for CS may not be able to compensate for deficits in growth and body composition [4]. Furthermore, CS patients tend to stay overweight, and they are at an increased risk of cardiovascular events, regardless of their age at the time of symptom onset. Osteoporosis and further metabolic complications may also arise, and patients may suffer from psychiatric changes and cognitive impairment. These conditions are only partially reversible, and thus, associated morbidity and mortality are particularly high among those who have been diagnosed and treated late in the course of the disease [3] [4]. If left untreated, about half of the patients will succumb to the disease within five years [3].

CS may be triggered by endogenous factors resulting in an excess release of glucocorticoids from the adrenal glands or degenerated cells located elsewhere in the body [7] [8]. Most commonly though, CS is of iatrogenic nature, is induced as a side effect of prolonged, high-dose glucocorticoid therapy.

With regard to the endogenous variant of the disease, subtypes may be defined as follows:

• ACTH-dependent CS is generally caused by a pituitary adenoma but may be related to the ectopic production of ACTH or corticotropin-releasing hormone (CRH). The latter has been reported for a variety of malignancies, namely small cell lung carcinoma, medullary thyroid carcinoma, and functionally active neuroendocrine tumors [6]. Pituitary adenomas are the most common cause of endogenous CS [3] [4].
• ACTH-independent CS is related to adrenal abnormalities, and thus, is sometimes also referred to as primary CS or adrenal CS. Possible causes of this type of the disease comprise adrenal adenomas as well as bilateral micronodular or macronodular adrenocortical hyperplasia [1].

There are some hereditary conditions that either favor the development of tumors as described above or disturb the hypothalamic-pituitary-axis by interfering with the function of endocrine cells. Such conditions are Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia type 1, Carney complex, isolated micronodular adrenocortical disease, isolated primary pigmented nodular adrenocortical disease, macronodular adrenocortical hyperplasia, and primary bimorphic adrenal disease as seen in McCune–Albright syndrome [1] [4] [7].

Endogenous CS is a rare disorder whose annual incidence has been estimated at <3 per million inhabitants. The female-to-male ratio is 3:1, although particular subtypes may be more common in men [6]. The patients' mean age at symptom onset is 41 years [2], with about 10% of them being children [8]. About two-thirds of all cases are caused by pituitary adenomas, while adrenal tumors account for up to 30% of them. The ectopic production of ACTH or CRH is observed in a minority of cases only [5].

CRH is produced in the hypothalamus and transported to the anterior pituitary via the portal system. Here, the tropic hormone promotes the release of ACTH, which primarily binds to ACTH receptors in the zona fasciculata of the adrenal cortex. Cells located in the zona fasciculata secrete glucocorticoids like cortisol and corticosterone, and these hormones physiologically reduce ACTH and CRH secretion via negative feedback loops. In CS patients, these regulatory mechanisms are invalidated.

• CS may be related to increased levels of ACTH. ACTH-producing tumor cells don't usually respond to the negative feedback transmitted by glucocorticoids, thereby providing a permanent stimulus to the cells in the zona fasciculata. Glucocorticoid levels rise, but ACTH levels don't diminish.
• On the other hand, adrenal tumor cells may release excess glucocorticoids. Despite the proper reaction of the pituitary gland and hypothalamus, which consists in a reduction of ACTH and CRH secretion, respectively, there's no response of the adrenal gland. Glucocorticoid levels rise despite abnormally low levels of ACTH.

In both cases, glucocorticoids interfere with a myriad of metabolic processes: They promote hepatic gluconeogenesis and induce peripheral insulin resistance, so serum glucose levels increase. At the same time, glucocorticoids enhance protein and lipid catabolism. Of note, similar effects may be noted in patients with physiological hypercortisolism. In the absence of CS, this condition is referred to as pseudo-Cushing syndrome. It may be provoked by pregnancy, physical stress and strenuous exercise, malnutrition or anorexia nervosa, obesity, poorly controlled diabetes mellitus, alcohol dependence, and depression [2].

The vast majority of CS patients suffers from exogenous CS, a condition related to the long-term administration of glucocorticoids. Such treatments should be avoided; if required to treat chronic conditions, doses should be maintained as low as possible.

Few recommendations can be given to prevent endogenous CS. This type of the disease is generally induced by tumoral hormone release, and the causes of tumor growth are poorly understood. Nevertheless, some cases can be related to cancer predisposition syndromes such as multiple endocrine neoplasia type 1 and Carney complex. What's more, additional entities related to endogenous CS have recently been linked to germline mutations, e.g., macronodular adrenal hyperplasia has been associated with mutations in the ARMC5 gene [9]. Such diseases may thus be considered partially genetic diseases [1].

Families known to harbor the respective mutations should be offered genetic counseling, and patients at risk should be included in surveillance programs [5]. This way, neoplasms may be identified at earlier stages, and paraneoplastic syndromes such as CS may possibly be avoided.

CS is a rare entity whose clinical presentation is highly heterogeneous. Thus, a high index of suspicion is needed to recommend the patient for an assessment of the function of the hypothalamic-pituitary-adrenal axis. To date, years may pass until the right diagnosis is made. In the meantime, excess glucocorticoids interfere with a myriad of metabolic processes, leading to retarded growth, weight gain and the redistribution of body fat, degenerative disorders of the cardiovascular and other organ systems, among others. These are only partially reversible, so most CS patients have to face long-term sequelae that diminish their health-related quality of life and result in an increased need for care.

Cushing syndrome (CS) refers to the entirety of signs and symptoms arising in the wake of the prolonged exposure to excess glucocorticoids. In the majority of cases, such exposure is induced by glucocorticoid therapy. Treatment with glucocorticoids may be unavoidable to manage chronic conditions, such as autoimmune disorders, or to prevent the rejection of transplants. However, glucocorticoids are often employed where alternatives exist, and the treating physician or the patients themselves may provoke what's known as exogenous CS.

On the other hand, excess glucocorticoids or hormones stimulating the release of glucocorticoids may be produced by degenerated tissues within the human body. Benign tumors developing in the pituitary or adrenal glands are the most common causes of this variant of the disease, which is also referred to as endogenous CS. Rarely, tumors may develop elsewhere and secrete the aforementioned hormones. Furthermore, there are hereditary conditions that either predispose to the development of such tumors or that otherwise interfere with the regulation of glucocorticoid production.

The treatment of CS, which may manifest in many different symptoms, depends on the underlying cause. The cessation or reduction of glucocorticoid therapy is the approach of choice to exogenous CS, while tumors provoking CS are generally removed surgically. Possible presentations of CS include, but are not limited to, retarded growth, truncal and abdominal weight gain, rounded face with acne, stretch marks, hypertension, diabetes mellitus, muscle wasting and weakness, osteoporosis, kidney stones, as well as the cessation of menses, impotence, and reduced libido.

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